EA046387B1 - DESIGNS BASED ON DIFFERENTIATION AND GROWTH FACTOR 15 (GDF15) - Google Patents

Description

Field of technology

The present invention relates to monomers and multimers containing a polypeptide that contains the GDF15 region.

State of the art

Growth differentiation factor 15 (GDF15) is an atypical member of the TGFe superfamily. It is also called macrophage inhibitory cytokine 1 (MIC1) (Bootcov MR, 1997, Proc Natl Acad Sci 94:11514-9), placental bone morphogenetic factor (PLAB) (Hromas R 1997, Biochim Biophys Acta. 1354:40-4), placental transforming growth factor beta (PTGFB) (Lawton LN 1997, Gene. 203:17-26), prostate derived factor (PDF) ) (Paralkar VM 1998, J Biol Chem. 273:137 60-7) and the nonsteroidal anti-inflammatory drug-activated gene, NAG-1 (Baek SJ 2001, J Biol Chem. 276: 33384-92).

The human GDF15 gene is located on chromosome 19p13.2-13.1; the rat GDF15 gene is located on chromosome 16; and the mouse GDF15 gene is located on chromosome 8. The GDF15 open reading frames span two exons (Bottner M 1999, Gene. 237:105-11 and NCBI). The mature GDF15 peptide has low homology with other family members (Katoh M 2006, Int J Mol Med. 17:951-5.).

GDF15 is synthesized as a large precursor protein that is cleaved at a dibasic cleavage site to release a carboxy-terminal mature peptide. Mouse and rat GDF15 prepropeptides each contain 303 amino acids. The full-length human precursor protein contains 308 amino acids. Mature rodent peptides after processing at the RGRR cleavage site (SEQ ID NO: 1) contain 115 amino acids. The mature human peptide, after processing at the RGRRRAR cleavage site (SEQ ID NO: 2), contains 112 amino acids. The sequence similarity between the mature human GDF15 peptide and the mature rat and mouse GDF15 peptide sequences is 66.1% and 68.1% (Bottner M 1999, Gene. 237:105-11; Bauskin AR 2000, EMBO J. 19:2212-20; NCBI). The mature GDF15 peptide lacks a glycosylation site.

The mature GDF15 peptide contains seven conserved cysteine residues required to form the cysteine knot motif (which contains three intrachain disulfide bonds) and one interchain disulfide bond, which are typical of members of the TGFe superfamily. The mature GDF15 peptide also contains two additional cysteine residues forming a fourth intrachain disulfide bond. Biologically active GDF15 is a homodimer of a mature 25 kDa peptide covalently linked by a single interchain disulfide bond.

Circulating GDF15 levels have been reported to increase in many pathological and physiological conditions, particularly pregnancy (Moore AG 2000. J Clin Endocrinol Metab 85: 4781-4788), β-thalassemia (Tanno T 2007, Nat Med 13:1096-101; Zimmermann MB, 2008 Am J Clin Nutr 88:1026-31) and congenital dyserythropoietic anemia (Tamary H 2008, Blood. 112:5241-4). GDF15 has also been associated with a variety of biological activities in published reports. Studies of GDF15 knockout and transgenic mice suggest that GDF15 may protect against cardiac injury caused by ischemia/reperfusion or overload (Kempf T, 2006, Circ Res. 98:351-60; Xu J, 2006, Circ Res. 98:342-50 ), protect against age-related loss of motor and sensory neurons (Strelau J, 2009, J Neurosci. 29:13640-8), moderately protect against metabolic acidosis in the kidneys, and may also cause wasting in patients suffering from cancer ( Johnen H 2007 Nat Med 11:1333-40). Several groups have also investigated the role of GDF15 in cell apoptosis and proliferation, with conflicting results obtained using different cell cultures and xenograft models. Studies in transgenic mice have shown that GDF15 protects against intestinal and lung neoplasms caused by a carcinogen or Apc mutation (Baek SJ 2006, Gastroenterology. 131:1553-60; Cekanova M 2009, Cancer Prev Res 2:450-8).

Brief description of the invention

The present invention provides fusion proteins comprising a GDF15 polypeptide or a mutant GDF15 polypeptide and an Fc domain.

According to one embodiment of the present invention, the Fc domain contains a sequence that is selected from the group consisting of SEQ ID NO: 16, 22, 28, 29, 33, 35, 38, 48, 85, 91, 106, 132, 141, 148, 155, 162, 169, 176, 183, 192, 199, 206, 213, 220, 227, 233, 236, 268, 275, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290 , 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301 and 302. In another embodiment of the present invention, the GDF15 polypeptide or mutant GDF15 polypeptide contains

- 1046387 contains a sequence that is selected from the group consisting of SEQ ID NOs: 4, 8, 12, 25, 52 and 55. According to another embodiment of the present invention, the fusion protein also contains a polypeptide linker. According to one embodiment of the present invention, the polypeptide linker contains a sequence that is selected from the group consisting of SEQ ID NO: 18, 30, 34, 40, 58, 61, 64, 69, 72, 75, 78, 113, 116, 119, 122 , 125, 128. According to one embodiment of the present invention, the fusion protein contains two or more Fc domains. According to one embodiment of the present invention, the fusion protein contains two or more polypeptide linkers. According to one embodiment of the present invention, the fusion protein contains a sequence that is selected from the group consisting of SEQ ID NO: 46, 24, 27, 32, 37, 20, 42, 50, 54, 57, 60, 63, 66, 68, 71 , 74, 77, 82, 84, 88, 93, 96, 98, 100, 102, 104, 108, 134, 137, 139, 143, 146, 150, 153, 269, 272, 276, 279, 157, 160 , 164, 167, 171, 174, 178, 181, 185, 188, 194, 197, 201, 204, 208, 211, 215, 218, 222, 225, 229, 232, 233, 238 and 240.

Also provided by the present invention are dimers comprising (i) a first polypeptide chain that contains one of the above-mentioned fusion proteins, and (ii) a second polypeptide chain that contains an Fc domain. According to yet another embodiment of the present invention, the construct also contains a sequence that is selected from the group consisting of SEQ ID NO: 16, 22, 28, 29, 33, 35, 38, 48, 85, 91, 106, 132, 141, 148 , 155, 162, 169, 176, 183, 192, 199, 206, 213, 220, 227, 233, 236, 268, 275, 281, 282, 283, 284, 285, 286, 287, 288, 289, 2 90 , 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301 and 302.

According to one embodiment of the present invention, the first and second polypeptide chains are joined in a non-covalent manner. According to another embodiment of the present invention, the first and second polypeptide chains are joined in a covalent manner. According to one embodiment of the present invention, the first and second polypeptide chains are covalently linked through disulfide bonds between the respective Fc domains. According to another embodiment of the present invention, the first and second polypeptide chains are connected through both covalent and non-covalent interactions.

According to a specific embodiment of the present invention, there is provided a dimer that contains: (a) two fusion proteins containing the sequence SEQ ID NO: 46; (b) two fusion proteins containing the sequence SEQ ID NO: 24; or (c) two fusion proteins containing the sequence SEQ ID NO: 27.

According to a specific embodiment of the present invention, there is provided a dimer that contains (a) two fusion proteins containing the sequence SEQ ID NO: 32; or (b) two fusion proteins containing the sequence SEQ ID NO: 37.

According to a specific embodiment of the present invention, there is provided a dimer that comprises a first polypeptide chain comprising the sequence SEQ ID NO: 20 and a second polypeptide chain comprising the sequence SEQ ID NO: 17.

According to a specific embodiment of the present invention, there is provided a dimer that contains (a) a first polypeptide chain containing the sequence of SEQ ID NO: 42, and a second polypeptide chain containing the sequence of SEQ ID NO: 39; (b) a first polypeptide chain containing the sequence SEQ ID NO: 50, and a second polypeptide chain containing the sequence SEQ ID NO: 47; (c) a first polypeptide chain containing the sequence of SEQ ID NO: 54, and a second polypeptide chain containing the sequence of SEQ ID NO: 47; (d) a first polypeptide chain containing the sequence of SEQ ID NO: 57, and a second polypeptide chain containing the sequence of SEQ ID NO: 47; (e) a first polypeptide chain containing the sequence SEQ ID NO: 60, and a second polypeptide chain containing the sequence SEQ ID NO: 47; (f) a first polypeptide chain containing the sequence SEQ ID NO: 63, and a second polypeptide chain containing the sequence SEQ ID NO: 47; (g) a first polypeptide chain containing the sequence SEQ ID NO: 66, and a second polypeptide chain containing the sequence SEQ ID NO: 47; (h) a first polypeptide chain containing the sequence SEQ ID NO: 68, and a second polypeptide chain containing the sequence SEQ ID NO: 47; (i) a first polypeptide chain containing the sequence of SEQ ID NO: 71, and a second polypeptide chain containing the sequence of SEQ ID NO: 47; (j) a first polypeptide chain containing the sequence of SEQ ID NO: 74, and a second polypeptide chain containing the sequence of SEQ ID NO: 47; (k) a first polypeptide chain containing the sequence SEQ ID NO: 77, and a second polypeptide chain containing the sequence SEQ ID NO: 4 7; (l) a first polypeptide chain containing the sequence SEQ ID NO: 80, and a second polypeptide chain containing the sequence SEQ ID NO: 47; (m) a first polypeptide chain containing the sequence SEQ ID NO: 82, and a second polypeptide chain containing the sequence SEQ ID NO: 47; or (n) a first polypeptide chain containing the sequence of SEQ ID NO: 84, and a second polypeptide chain containing the sequence of SEQ ID NO: 47.

According to a specific embodiment of the present invention, there is provided a dimer that contains (a) a first polypeptide chain containing the sequence SEQ ID NO: 88, and a second

- 2 046387 polypeptide chain containing the sequence SEQ ID NO: 86; (b) a first polypeptide chain containing the sequence of SEQ ID NO: 93, and a second polypeptide chain containing the sequence of SEQ ID NO: 90; (c) a first polypeptide chain containing the sequence of SEQ ID NO: 96, and a second polypeptide chain containing the sequence of SEQ ID NO: 90; (d) a first polypeptide chain containing the sequence of SEQ ID NO: 98, and a second polypeptide chain containing the sequence of SEQ ID NO: 90; (e) a first polypeptide chain containing the sequence of SEQ ID NO: 100, and a second polypeptide chain containing the sequence of SEQ ID NO: 90; (f) a first polypeptide chain containing the sequence SEQ ID NO: 102, and a second polypeptide chain containing the sequence SEQ ID NO: 90; (g) a first polypeptide chain containing the sequence of SEQ ID NO: 104, and a second polypeptide chain containing the sequence of SEQ ID NO: 90; or (h) a first polypeptide chain comprising the sequence of SEQ ID NO: 108 and a second polypeptide chain containing the sequence of SEQ ID NO: 105.

According to a specific embodiment of the present invention, there is provided a dimer that contains (a) a first polypeptide chain containing the sequence of SEQ ID NO: 112, and a second polypeptide chain containing the sequence of SEQ ID NO: 12; (b) two polypeptide chains, each of which contains the sequence SEQ ID NO: 112; (c) two polypeptide chains, each containing the sequence SEQ ID NO: 115; (d) two polypeptide chains, each of which contains the sequence SEQ ID NO: 118; (e) two polypeptide chains, each of which contains the sequence SEQ ID NO: 121; (f) two polypeptide chains, each of which contains the sequence of SEQ ID NO: 124; (g) two polypeptide chains, each of which contains the sequence SEQ ID NO: 127; (h) two polypeptide chains, each of which contains the sequence SEQ ID NO: 130; or (i) two polypeptide chains, each of which contains the sequence of SEQ ID NO: 242.

According to a specific embodiment of the present invention, there is provided a dimer that contains: (a) a first polypeptide chain containing the sequence of SEQ ID NO: 134, and a second polypeptide chain containing the sequence of SEQ ID NO: 131; (b) a first polypeptide chain containing the sequence of SEQ ID NO: 137, and a second polypeptide chain containing the sequence of SEQ ID NO: 131; (c) a first polypeptide chain containing the sequence of SEQ ID NO: 139, and a second polypeptide chain containing the sequence of SEQ ID NO: 131; (d) a first polypeptide chain containing the sequence of SEQ ID NO: 143, and a second polypeptide chain containing the sequence of SEQ ID NO: 140; (e) a first polypeptide chain containing the sequence of SEQ ID NO: 146, and a second polypeptide chain containing the sequence of SEQ ID NO: 140; (f) a first polypeptide chain containing the sequence of SEQ ID NO: 150, and a second polypeptide chain containing the sequence of SEQ ID NO: 147; (g) a first polypeptide chain containing the sequence of SEQ ID NO: 153, and a second polypeptide chain containing the sequence of SEQ ID NO: 147; (h) a first polypeptide chain containing the sequence SEQ ID NO: 269, and a second polypeptide chain containing the sequence SEQ ID NO: 2 67; (i) a first polypeptide chain containing the sequence of SEQ ID NO: 272, and a second polypeptide chain containing the sequence of SEQ ID NO: 267; (j) a first polypeptide chain containing the sequence of SEQ ID NO: 276, and a second polypeptide chain containing the sequence of SEQ ID NO: 274; or (k) a first polypeptide chain containing the sequence of SEQ ID NO: 279, and a second polypeptide chain containing the sequence of SEQ ID NO: 274.

According to a specific embodiment of the present invention, there is provided a dimer that contains: (a) a first polypeptide chain containing the sequence of SEQ ID NO: 157, and a second polypeptide chain containing the sequence of SEQ ID NO: 154; (b) a first polypeptide chain containing the sequence of SEQ ID NO: 160, and a second polypeptide chain containing the sequence of SEQ ID NO: 154; (c) a first polypeptide chain containing the sequence of SEQ ID NO: 164, and a second polypeptide chain containing the sequence of SEQ ID NO: 161; (d) a first polypeptide chain containing the sequence of SEQ ID NO: 167, and a second polypeptide chain containing the sequence of SEQ ID NO: 161.

According to a specific embodiment of the present invention, there is provided a dimer that contains: (a) a first polypeptide chain containing the sequence of SEQ ID NO: 171, and a second polypeptide chain containing the sequence of SEQ ID NO: 168; or (b) a first polypeptide chain comprising the sequence of SEQ ID NO: 174 and a second polypeptide chain containing the sequence of SEQ ID NO: 168.

According to a specific embodiment of the present invention, there is provided a dimer that contains: (a) a first polypeptide chain containing the sequence of SEQ ID NO: 178, and a second polypeptide chain containing the sequence of SEQ ID NO: 175; (b) a first polypeptide chain containing the sequence of SEQ ID NO: 181, and a second polypeptide chain containing the sequence of SEQ ID NO: 175; (c) a first polypeptide chain containing the sequence of SEQ ID NO: 185, and a second polypeptide chain containing the sequence of SEQ ID NO: 182; (d)

- 3 046387 a first polypeptide chain containing the sequence SEQ ID NO: 188, and a second polypeptide chain containing the sequence SEQ ID NO: 182; (e) a first polypeptide chain containing the sequence SEQ ID NO: 194, and a second polypeptide chain containing the sequence SEQ ID NO: 191; (f) a first polypeptide chain containing the sequence of SEQ ID NO: 197, and a second polypeptide chain containing the sequence of SEQ ID NO: 191; (g) a first polypeptide chain containing the sequence SEQ ID NO: 201, and a second polypeptide chain containing the sequence SEQ ID NO: 198; or (h) a first polypeptide chain containing the sequence of SEQ ID NO: 204, and a second polypeptide chain containing the sequence of SEQ ID NO: 198.

According to a specific embodiment of the present invention, there is provided a dimer that contains: (a) a first polypeptide chain containing the sequence of SEQ ID NO: 208, and a second polypeptide chain containing the sequence of SEQ ID NO: 205; (b) a first polypeptide chain containing the sequence of SEQ ID NO: 211, and a second polypeptide chain containing the sequence of SEQ ID NO: 205; (c) a first polypeptide chain containing the sequence of SEQ ID NO: 215, and a second polypeptide chain containing the sequence of SEQ ID NO: 212; or (d) a first polypeptide chain containing the sequence of SEQ ID NO: 218, and a second polypeptide chain containing the sequence of SEQ ID NO: 212.

According to a specific embodiment of the present invention, there is provided a dimer that contains: (a) a first polypeptide chain containing the sequence of SEQ ID NO: 222, and a second polypeptide chain containing the sequence of SEQ ID NO: 219; (b) a first polypeptide chain containing the sequence of SEQ ID NO: 225, and a second polypeptide chain containing the sequence of SEQ ID NO: 219; (c) a first polypeptide chain containing the sequence of SEQ ID NO: 229, and a second polypeptide chain containing the sequence of SEQ ID NO: 226; or (d) a first polypeptide chain containing the sequence of SEQ ID NO: 232, and a second polypeptide chain containing the sequence of SEQ ID NO: 226.

According to a specific embodiment of the present invention, there is provided a dimer that contains: (a) two polypeptide chains, each of which contains the sequence of SEQ ID NO: 235; (b) two polypeptide chains, each of which contains the sequence SEQ ID NO: 238; or (c) two polypeptide chains, each of which contains the sequence of SEQ ID NO: 240.

According to certain embodiments of the present invention, there is provided a tetramer that contains (i) a first dimer containing one of the above dimers, and (ii) a second dimer containing one of the above dimers. In certain embodiments of the present invention, the first polypeptide chain of the first dimer is linked to the first polypeptide chain of the second dimer via an interchain disulfide bond between the respective GDF15 regions of these chains.

According to some embodiments of the present invention, the dimer is not a dimer selected from the group consisting of DhCpmFc(-)-(G ₄ S) ₄ -GDF15:DhCpmFc(+), DhCpmFc(+)-(G ₄ S) ₄ GDF15:DhCpmFc (-), DhCpmFc(-)-(G ₄ S) ₄ -GDF15(H6D):DhCpmFc(+), DhCpmFc(+)-(G ₄ S) ₄ GDF 15(H6D):DhCpmFc(-), DhCpmFc( +)-(G ₄ S) ₄ -GDF 15(N3Q):DhCpmFc(-), DhCpmFc(+)GDF15:DhCpmFc(-), DhCpmFc(+)-G ₄ -GDF15:DhCpmFc(-), DhCpmFc(+ )-(G ₄ S) ₂ -GDF15:DhCpmFc(-), DhCpmFc(+)-(G ₄ Q) ₄ -GDF15:DhCpmFc(-), DhCpmFc(+)(L351C)-G ₄ -GDF15:DhCpmFc( -)(L351C),

DhCpmFc(+)(S354C)-G4-GDF15:DhCpmFc(-)(Y349C), CpmFc(-)-(G ₄ S) ₄ -GDF15:CpmFc(+), Fc-(G ₄ S) ₈ -FcGS( G4S)4-GDF15, Fc-(G4S)3-Fc-GS(G4S)4-GDF15 and Fc-(G4S)5-Fc-GS(G4S)4-GDF15.

According to some embodiments of the present invention, the dimer is not a dimer selected from the group consisting of DhCpmFc(-)-(G ₄ S) ₄ -GDF15:DhCpmFc(+), DhCpmFc(+)-(G ₄ S) ₄ GDF15:DhCpmFc (-), DhCpmFc(-)-(G4S)4-GDF15(H6D):DhCpmFc(+), DhCpmFc(+)-(G4S)4GDF 15(H6D):DhCpmFc(-), DhCpmFc(+)-(G4S )4-GDF 15(N3Q):DhCpmFc(-), DhCpmFc(+)GDF15:DhCpmFc(-), DhCpmFc(+)-G4-GDF15:DhCpmFc(-), DhCpmFc(+)-(G4S)2-GDF15 :DhCpmFc(-), DhCpmFc(+)-(G ₄ Q) ₄ -GDF15:DhCpmFc(-), DhCpmFc(+)(L351C)-G ₄ -GDF15:DhCpmFc(-)(L351C) and

DhCpmFc(+)(S354C)-G4-GDF15:DhCpmFc(-)(Y349C).

According to some embodiments of the present invention, the fusion protein is a protein selected from the group consisting of Fc-(G ₄ S) ₈ -Fc-GS(G ₄ S) ₄ -GDF15, Fc-(G ₄ S) ₃ -Fc-GS (G ₄ S) ₄ GDF15 and Fc-(G ₄ S) ₅ -Fc-GS(G ₄ S) ₄ -GDF15.

In some embodiments of the present invention, the dimer is not a dimer selected from the group consisting of DhCpmFc(+)(L351C)-G ₄ -GDF15:DhCpmFc(-)(L351C) and DhCpmFc(+)(S354C)-G4-GDF15: DhCpmFc(-)(Y349C).

In some embodiments of the present invention, the dimer is not: DhCpmFc(-)-(G4S)4-GDF15:DhCpmFc(+), DhCpmFc(+)-(G4S)4-GDF15:DhCpmFc(-), DhCpmFc(-)( G4S)4-GDF 15(H6D):DhCpmFc(+), DhCpmFc(+)-(G4S)4-GDF 15(H6D):DhCpmFc(-), DhCpmFc(+)-(G4S)4GDF15(N3Q):DhCpmFc (-), DhCpmFc(+)-GDF15:DhCpmFc(-), DhCpmFc(+)-G ₄ -GDF15:DhCpmFc(-), DhCpmFc(+)-(G ₄ S) ₂ -GDF15:DhCpmFc(-), DhCpmFc(+)-(G ₄ Q) ₄ -GDF15:DhCpmFc(-), DhCpmFc(+)(L351C)G ₄ -GDF15:DhCpmFc(-)(L351C), DhCpmFc(+)(S354C)-G4-GDF15 :DhCpmFc(-)(Y349C), CpmFc(-)-(G ₄ S) ₄

- 4 046387

GDF15:CpmFc(+), Fc-(G4S)8-Fc-GS(G4S)4-GDF15, Fc-(G4S)3-Fc-GS(G4S)4—GDF15 or Fc-(G4S)s-FcGS( G4S)4-GDF15.

In some embodiments of the present invention, the dimer is not DhCpmFc(-)-(G ₄ S) ₄ -GDF15:DhCpmFc(+), DhCpmFc(+)-(G ₄ S) ₄ -GDF15:DhCpmFc(-), DhCpmFc( -)-(G ₄ S) ₄ GDF 15(H6D):DhCpmFc(+), DhCpmFc(+)-(G ₄ S) ₄ -GDF 15(H6D) :DhCpmFc(-), DhCpmFc(+)-(G ₄ S) ₄ GDF15(N3Q):DhCpmFc(-), DhCpmFc(+)-GDF15:DhCpmFc(-), DhCpmFc(+)-G ₄ -GDF15:DhCpmFc(-), DhCpmFc(+)-(G ₄ S ) ₂ -GDF15:DhCpmFc(-), DhCpmFc(+)-(G ₄ Q) ₄ -GDF15:DhCpmFc(-), DhCpmFc(+)(L351C)G ₄ -GDF15:DhCpmFc(-)(L351C) or DhCpmFc (+)(S354C)-G ₄ -GDF15:DhCpmFc(-)(Y349C).

In some embodiments of the present invention, the fusion protein is not a protein selected from the group consisting of Fc-(G ₄ S) ₈ -Fc-GS(G ₄ S) ₄ -GDF15, Fc-(G ₄ S) ₃ -FcGS( G4S)4-GDF15 and Fc-(G4S)5-Fc-GS(G4S)4-GDF15.

In some embodiments of the present invention, the fusion protein is not a protein selected from the group consisting of DhCpmFc(+)(L351C)-G ₄ -GDF15:DhCpmFc(-) (L351C) and DhCpmFc(+)(S354C)-G ₄ - GDF15:DhCpmFc(-)(Y349C).

In some embodiments of the present invention, the dimer is not DhCpmFc(-)-(G ₄ S) ₄ -GDF15:DhCpmFc(+). In some embodiments of the present invention, the dimer is not DhCpmFc(+)-(G ₄ S) ₄ -GDF15:DhCpmFc(-). In some embodiments of the present invention, the dimer is not DhCpmFc(-)-(G ₄ S) ₄ GDF15(H6D):DhCpmFc(+). In some embodiments of the present invention, the dimer is not DhCpmFc(+)-(G ₄ S) ₄ -GDF15(H6D):DhCpmFc(-). In some embodiments of the present invention, the dimer is not DhCpmFc(+)-(G4S)4GDF15(N3Q):DhCpmFc(-). In some embodiments of the present invention, the dimer is not DhCpmFc(+)-GDF15:DhCpmFc(-). In some embodiments of the present invention, the dimer is not DhCpmFc(+)-G ₄ -GDF15:DhCpmFc(-). In some embodiments of the present invention, the dimer is not DhCpmFc(+)-(G4S)2GDF15:DhCpmFc(-). In some embodiments of the present invention, the dimer is not DhCpmFc(+)-(G ₄ Q) ₄ -GDF15:DhCpmFc(-). In some embodiments of the present invention, the dimer is not DhCpmFc(+)(L351C)-G ₄ -GDF15:DhCpmFc(-)(L351C). In some embodiments of the present invention, the dimer is not DhCpmFc(+)(S354C)-G ₄ -GDF15:DhCpmFc(-)(Y349C). In some embodiments of the present invention, the dimer is not CpmFc(-)-(G ₄ S) ₄ -GDF15:CpmFc(+). In some embodiments of the present invention, the dimer is not Fc-(G4S)8-Fc-GS(G4S)4GDF15. In some embodiments of the present invention, the dimer is not Fc-(G ₄ S) ₃ -Fc-GS(G ₄ S) ₄ -GDF15. In some embodiments of the present invention, the dimer is not Fc-(G ₄ S) ₅ -Fc-GS(G ₄ S) ₄ -GDF15.

The present invention also provides fusion proteins containing a GDF15 polypeptide or a mutant GDF15 polypeptide and a human serum albumin (HSA) polypeptide. In another embodiment of the present invention, the sequence of the HSA polypeptide is the sequence of SEQ ID NO: 110. In another embodiment of the present invention, the GDF15 polypeptide or mutant GDF15 polypeptide contains a sequence that is selected from the group consisting of SEQ ID NO: 4, 8, 12, 25 , 52 and 55. According to another embodiment of the present invention, the fusion protein also contains a polypeptide linker that connects a GDF15 polypeptide or a mutant GDF15 polypeptide to an HSA polypeptide. According to one embodiment of the present invention, the polypeptide linker contains a sequence that is selected from the group consisting of SEQ ID NO: 18, 30, 34, 40, 58, 61, 64, 69, 72, 75, 78, 113, 116, 119, 122 125, 128. According to one embodiment of the present invention, the fusion protein comprises two or more HSA polypeptides. According to one embodiment of the present invention, the fusion protein contains a sequence that is selected from the group consisting of SEQ ID NO: 115, 118, 121, 124, 127 and 130.

Also provided by the present invention are dimers comprising (i) a first polypeptide chain that contains a fusion protein comprising a first GDF15 region and a first HSA polypeptide, and (ii) a second polypeptide chain that contains a second HSA polypeptide. In some embodiments of the present invention, the second polypeptide chain also comprises a second GDF15 region. According to some embodiments of the present invention, the dimer is a heterodimer (ie, the first and second polypeptide chains contain different sequences). According to some embodiments of the present invention, the dimer is a homodimer (ie, the first and second polypeptide chains contain the same sequence). In some embodiments of the present invention, the first polypeptide chain comprises a sequence that is selected from the group consisting of SEQ ID NOs: 115, 118, 121, 124, 127, and 130. In some embodiments of the present invention, the second polypeptide chain contains a sequence that is selected from the group comprising SEQ ID NOs: 115, 118, 121, 124, 127 and 130. In one embodiment of the present invention, the first and second polypeptide chains with

- 5 046387 united in a non-covalent manner. According to another embodiment of the present invention, the first and second polypeptide chains are joined in a covalent manner. In one embodiment of the present invention, the second polypeptide chain comprises a second GDF15 region, and the first and second polypeptide chains are covalently linked through disulfide bonds between the respective GDF15 regions of the chains. According to another embodiment of the present invention, the first and second polypeptide chains are connected through both covalent and non-covalent interactions.

Also provided by the present invention are dimers comprising (i) a first polypeptide chain that comprises a fusion protein comprising a first GDF15 region and an HSA polypeptide, and (ii) a second polypeptide chain comprising a second GDF15 region. In some embodiments of the present invention, the first polypeptide chain comprises a sequence that is selected from the group consisting of SEQ ID NOs: 115, 118, 121, 124, 127, and 130. In some embodiments of the present invention, the second polypeptide chain contains a sequence that is selected from the group comprising SEQ ID NOs: 4, 8, 12, 25, 52 and 55. In one embodiment of the present invention, the first and second polypeptide chains are joined in a non-covalent manner. According to another embodiment of the present invention, the first and second polypeptide chains are joined in a covalent manner. According to another embodiment of the present invention, the first and second polypeptide chains are connected through both covalent and non-covalent interactions.

Brief description of drawings

Fig. 1 is a graphical representation representing a knob-hole construct containing a dimer that consists of two DhknobFc-(G ₄ S) ₄ GDF15:DhholeFc heterodimers.

Fig. 2 is a graphical representation of a DhMonoFc construct containing a dimer that consists of two DhMonoFc-(G ₄ S) ₄ -GDF15 fusion proteins.

Fig. 3 is a graphical representation of a HemiFc construct containing a dimer that consists of two GGGFc-(G ₄ S) ₄ -Fc-S(G ₄ S) ₄ -GDF15 fusion proteins.

Fig. 4 is a graphical representation representing a charged pair construct (delHinge) containing a dimer consisting of two DhCpmFc(-)(G ₄ S) ₂ -GDF15:DhCpmFc(+) heterodimers.

Fig. 5 is a graphical representation representing a charged pair (delHinge) cysteine clamp construct containing a dimer consisting of two heterodimers DhCpmFc(-)(L351C)-(G ₄ S) ₂ -GDF15:DhCpmFc(- )(L351C).

Fig. 6 is a graphical representation of an HSA (human serum albumin) construct containing a dimer consisting of two HSA-(G4S)4GDF15 fusion proteins.

Fig. 7 is a graph showing the effect of administration of the DhknobFc-G ₄ -GDF15:DhholeFc heterodimer dimer on food intake (gram of food/gram of body weight (BW)) in ob/ob mice as a function of dose (log [gram of construct/kg BW]) .

Fig. 8 is a graph showing the effect of administration of Fc-(G ₄ S) ₄ -GDF15 fusion protein dimer on food intake (gram of food/gram of body weight) in ob/ob mice as a function of dose (log [gram of construct/kg BW]) .

Fig. 9 is a graph showing the effect of administration of the Fc-(G ₄ S) ₄ -GDF15(H6D) fusion protein dimer on food intake (gram of food/gram of body weight) in ob/ob mice as a function of dose (log [gram of construct/kg MT]).

Fig. 10 is a graph showing the effect of administration of Fc-(G ₄ S) ₄ -Fc-(G ₄ S) ₄ -GDF15 fusion protein dimer on food intake (gram of food/gram of body weight) in ob/ob mice as a function of dose ( log [gram construct/kg BW]).

Fig. 11 is a graph showing the effect of administration of the DhFc-(G ₄ S) ₅ -DhFc-(G ₄ S) ₄ -GDF15 fusion protein dimer on food intake (gram of food/gram of body weight) in ob/ob mice as a function of dose ( log [gram construct/kg BW]).

Fig. 12 is a graph showing the effect of administration of the DhCpmFc(+)-(1K)-GDF15:DhCpmFc(-) heterodimer dimer on food intake (gram of food/gram of body weight) in ob/ob mice as a function of dose (log [gram of construct/ kg MT]).

Fig. 13 is a graph showing the effect of administration of the DhCpmFc(-)-GDF15:DhCpmFc(+) heterodimer dimer on food intake (gram of food/gram of body weight) in ob/ob mice as a function of dose (log [gram of construct/kg BW]) .

Fig. 14 is a graph showing the effect of administration of the DhCpmFc(-)-GDF15(N3D):DhCpmFc(+) heterodimer dimer on food intake (gram of food/gram of body weight) in ob/ob mice as a function of dose (log [gram of construct/kg MT]).

Fig. 15 is a graph showing the effect of administration of the DhCpmFc(-)-GDF15(Ndel3):DhCpmFc(+) heterodimer dimer on food intake (gram of food/gram of body weight) in mice

- 6 046387 ob/ob depending on dose (log [gram of construct/kg BW]).

Fig. 16 is a graph showing the effect of administration of the DhCpmFc(-)-G ₄ -GDF15(N3D):DhCpmFc(+) heterodimer dimer on food intake (gram of food/gram of body weight) in ob/ob mice as a function of dose (log [gram structures/kg MT]).

Fig. 17 is a graph showing the effect of administration of the DhCpmFc(-)-G ₄ S-GDF15:DhCpmFc(+) heterodimer dimer on food intake (gram of food/gram of body weight) in ob/ob mice as a function of dose (log [gram of construct/ kg MT]).

Fig. 18 is a graph showing the effect of administration of the DhCpmFc(-)-(G ₄ S) ₂ -GDF15:DhCpmFc(+) heterodimer dimer on food intake (gram of food/gram of body weight) in ob/ob mice as a function of dose (log [ grams of structure/kg BW]).

Fig. 19 is a graph showing the effect of administration of DhCpmFc(-)-(G ₄ S) ₂ -GDF15(N3D):DhCpmFc(+) heterodimer dimer on food intake (grams of food/grams of body weight) in ob/ob mice as a function of dose (log [gram construct/kg BW]).

Fig. 20 is a graph showing the effect of administration of the heterodimer dimer DhCpmFc(-)-(G ₄ Q) ₂ -GDF15(N3D):DhCpmFc(+) on food intake (gram of food/gram of body weight) in ob/ob mice as a function of dose (log [gram construct/kg BW]).

Fig. 21 is a graph showing the effect of administration of the DhCpmFc(-)-G ₄ P-GDF15:DhCpmFc(+) heterodimer dimer on food intake (gram of food/gram of body weight) in ob/ob mice as a function of dose (log [gram of construct/ kg MT]).

Fig. 22 is a graph showing the effect of administration of the DhCpmFc(-)-(G ₄ P) ₂ -GDF15:DhCpmFc(+) heterodimer dimer on food intake (gram of food/gram of body weight) in ob/ob mice as a function of dose (log[ grams of structure/kg BW]).

Fig. 23 is a graph showing the effect of administration of the DhCpmFc(-)-G ₄ Q-GDF15:DhCpmFc(+) heterodimer dimer on food intake (gram of food/gram of body weight) in ob/ob mice as a function of dose (log [gram of construct/ kg MT]).

Fig. 24 is a graph showing the effect of administration of the heterodimer dimer DhCpmFc(-)-(G ₄ Q) ₂ -GDF15(N3D):DhCpmFc(+) on food intake (gram of food/gram of body weight) in ob/ob mice as a function of dose (log [gram construct/kg BW]).

Fig. 25 is a graph showing the effect of administration of the heterodimer dimer DhCpmFc(-)-(G ₄ Q) ₂ -GDF15(Ndel3):DhCpmFc(+) on food intake (gram of food/gram of body weight) in ob/ob mice as a function of dose (log [gram construct/kg BW]).

Fig. 26 is a graph showing the effect of administration of the DhCpmFc(+)(Y349C)-GDF15(N3D):DhCpmFc(-)(S354C) heterodimer dimer on food intake (gram of food/gram of body weight) in ob/ob mice as a function of dose ( log [gram construct/kg BW]).

Fig. 27 is a graph showing the effect of administration of the DhCpmFc(-)(Y349C)-GDF15:DhCpmFc(+)(S354C) heterodimer dimer on food intake (gram of food/gram of body weight) in ob/ob mice as a function of dose (log [gram structures/kg MT]).

Fig. 28 is a graph showing the effect of administration of the DhCpmFc(-)(Y349C)-GDF15(N3D):DhCpmFc(+)(S354C) heterodimer dimer on food intake (gram of food/gram of body weight) in ob/ob mice as a function of dose ( log [gram construct/kg BW]).

Fig. 29 is a graph showing the effect of administration of the DhCpmFc(-)(Y349C)-GDF15(Ndel3):DhCpmFc(+)(S354C) heterodimer dimer on food intake (gram of food/gram of body weight) in ob/ob mice as a function of dose ( log [gram construct/kg BW]).

Fig. 30 is a graph showing the effect of administration of the DhCpmFc(-)(Y349C)-G ₄ -GDF15(N3D):DhCpmFc(+)(S354C) heterodimer dimer on food intake (grams of food/grams of body weight) in ob/ob mice as a function of by dose (log [gram construct/kg BW]).

Fig. 31 is a graph showing the effect of administration of the DhCpmFc(-)(Y349C)-(G ₄ S) ₂ -GDF15(N3D):DhCpmFc(+)(S354C) heterodimer dimer on food intake (grams of food/grams of body weight) in ob mice /ob as a function of dose (log [gram construct/kg BW]).

Fig. 32 is a graph showing the effect of administration of the DhCpmFc(-)(Y349C)-(G ₄ Q) ₂ -GDF15(N3D):DhCpmFc(+)(S354C) heterodimer dimer on food intake (grams of food/grams of body weight) in ob mice /ob as a function of dose (log [gram construct/kg BW]).

Fig. 33 is a graph showing the effect of administration of the DhCpmFc(-)(L351C)-(G ₄ S) ₂ -GDF15:DhCpmFc(+)(L351C) heterodimer dimer on food intake (grams of food/grams of body weight) in ob/ob mice dose-dependent (log [gram construct/kg BW]).

Fig. 34 is a graph showing the effect of administration of the HSA-GSAAQAAQQGS-GDF15 fusion protein dimer on food intake (gram of food/gram of body weight) in ob/ob mice as a function of dose (log [gram of construct/kg BW]).

Fig. 35 is a graph showing the effect of administration of the HSA-GSPAPAPGS-GDF15 fusion protein dimer on food intake (gram of food/gram of body weight) in ob/ob mice as a function of dose (log [gram of construct/kg BW]).

Fig. 36 is a graph showing the effect of using a hybrid dimer

- 7,046,387 HSA-GS(AAQAAQQ)2GS-GDF15 protein per food intake (gram of food/gram of body weight) in ob/ob mice in a dose-dependent manner (log [gram of construct/kg BW]).

Fig. 37 is a graph showing the effect of administration of the HSA-GS(PAPAP)2GS-GDF15 fusion protein dimer on food intake (gram of food/gram of body weight) in ob/ob mice as a function of dose (log [gram of construct/kg BW]).

Fig. 38 is a graph showing the effect of HSA-GDF15 fusion protein dimer administration on food intake (gram of food/gram of body weight) in ob/ob mice as a function of dose (log [gram of construct/kg BW]).

Fig. 39 is a graph showing the effect of administration of the HSA-GGNAEAAAKEAAAKEAAAKAGG-GDF15 fusion protein dimer on food intake (gram of food/gram of body weight) in ob/ob mice as a function of dose (log [gram of construct/kg BW]).

Fig. 40 is a graph showing the effect of administration of the HSA-(G4S) ₆ -GDF15 fusion protein dimer on food intake (gram of food/gram of body weight) in ob/ob mice as a function of dose (log [gram of construct/kg BW]).

Fig. 41 is a graph showing the effect of administration of the DhCpmFc(-)(N297G)-GDF15(Ndel3):DhCpmFc(+)(N297G) heterodimer dimer on food intake (gram of food/gram of body weight) in ob/ob mice as a function of dose ( log [gram construct/kg BW]).

Fig. 42 is a graph showing the effect of administration of the DhCpmFc(-)(N297G)-GDF15(N3D):DhCpmFc(+)(N297G) heterodimer dimer on food intake (gram of food/gram of body weight) in ob/ob mice as a function of dose ( log [gram construct/kg BW]).

Fig. 43 is a graph showing the effect of administration of the DhCpmFc(-)(N297G)(Y349C)-GDF15(Ndel3):DhCpmFc(+)(N297G)(S354C) heterodimer dimer on food intake (grams of food/grams of body weight) in ob/ mice ob dose-dependent (log [gram construct/kg BW]).

Fig. 44 is a graph showing the effect of administration of the DhCpmFc(-)(N297G)(Y349C)-GDF15(N3D):DhCpmFc(+)(N297G)(S354C) heterodimer dimer on food intake (grams of food/grams of body weight) in ob/ mice ob dose-dependent (log [gram construct/kg BW]).

Fig. 45 is a graph showing the effect of administration of the DhCpmFc(-)(N297G)(L351C)-GDF15(Ndel3):DhCpmFc(+)(N297G)(L351C) heterodimer dimer on food intake (grams of food/grams of body weight) in ob/ mice ob dose-dependent (log [gram construct/kg BW]).

Fig. 46 is a graph showing the effect of administration of the DhCpmFc(-)(N297G)(L351C)-GDF15(N3D):DhCpmFc(+)(N297G)(L351C) heterodimer dimer on food intake (grams of food/grams of body weight) in ob/ mice ob dose-dependent (log [gram construct/kg BW]).

Fig. 47 is a graph showing the effect of administration of the DhCpmFc(-)(N297G)(A287C)-GDF15(Ndel3):DhCpmFc(+)(N297G)(L306C) heterodimer dimer on food intake (grams of food/grams of body weight) in ob/ mice ob dose-dependent (log [gram construct/kg BW]).

Fig. 48 is a graph showing the effect of CpmFc(-)(N297G)-GDF15(Ndel3):CpmFc(+)(N297G) heterodimer dimer administration on food intake (gram of food/gram of body weight) in ob/ob mice as a function of dose ( log [gram construct/kg BW]).

Fig. 49 is a graph showing the effect of administration of the Dh3CpmFc(-)-GDF15(Ndel3):Dh3CpmFc(N297G) heterodimer dimer on food intake (gram of food/gram of body weight) in ob/ob mice as a function of dose (log [gram of construct/kg MT]).

Fig. 50 is a graph showing the effect of administration of the Dh3CpmFc(-)-GDF15(N3D):Dh3CpmFc(+)(N297G) heterodimer dimer on food intake (gram of food/gram of body weight) in ob/ob mice as a function of dose (log [gram structures/kg MT]).

Fig. 51 is a graph showing the effect of administration of the Dh3CpmFc(-)(Y349C)-GDF15(Ndel3):Dh3CpmFc(+)(N297G)(S354C) heterodimer dimer on food intake (grams of food/grams of body weight) in ob/ob mice as a function of by dose (log [gram construct/kg BW]).

Fig. 52 is a graph showing the effect of administration of the Dh3CpmFc(-)(Y349C)-GDF15(N3D):Dh3CpmFc(-)(N297G)(S354C) heterodimer dimer on food intake (grams of food/grams of body weight) in ob/ob mice as a function of by dose (log [gram construct/kg BW]).

Fig. 53 is a graph showing the effect of administration of the DhMonoFc(N297G)-GDF15 fusion protein dimer on food intake (gram of food/gram of body weight) in ob/ob mice as a function of dose (log [gram of construct/kg BW]).

Fig. 54 is a graph of body weight (g) versus time (days after ^1st injection) upon administration of vehicle, 0.1 nmol, 1 nmol, and 10 nmol of Dh3CpmFc(-)GDF15(N3D):Dh3CpmFc(+) heterodimer dimer and 0.1 nmol, 1 nmol and 10 nmol of Dh3ComFc(-)GDF15(Ndel3) heterodimer dimer.

Fig. 55 is a bar graph of the area under the curve (AUC) for a glucose tolerance test at week 2 of administration of (a) vehicle (b) 10 mmol dimer of the heterodimer Dh3CpmFc(-)GDF15(N3D):Dh3CpmFc(+), (c) 1 mmol heterodimer dimer Dh3CpmFc(-)-GDF15(N3D):Dh3CpmFc(+), (d) 0.1 mmol heterodimer dimer Dh3CpmFc(-)-GDF15(N3D):Dh3CpmFc(+), (e) 10 mmol heterodimer dimer Dh3CpmFc( -)-GDF15(Ndel3):Dh3CpmFc(+)(g) 1 mmol heterodimer dimer Dh3CpmFc(-)- 8 046387

GDF15(Ndel3):Dh3CpmFc(+) or (g) 0.1 mmol of the heterodimer dimer Dh3CpmFc(-)GDF 15(Ndel):Dh3 CpmFc(+).

Fig. 56 is a bar graph of insulin levels (ng/ml) (postprandial) at week 3 of administration of (a) vehicle, (b) 10 mmol of Dh3CpmFc(-)GDF15(N3D):Dh3CpmFc(+) heterodimer dimer, (c) 1 mmol heterodimer dimer Dh3CpmFc(-)-GDF15(N3D):Dh3CpmFc(+), (d) 0.1 mmol heterodimer dimer Dh3CpmFc(-)-GDF15(N3D):Dh3CpmFc(+), (e) 10 mmol heterodimer dimer Dh3CpmFc(-)-GDF15(Ndel3):Dh3CpmFc(+), (g) 1 mmol heterodimer dimer Dh3CpmFc(-)GDF15(Ndel3):Dh3CpmFc(+) or (g) 0.1 mmol heterodimer dimer Dh3CpmFc(-)GDF 15(Ndel):Dh3 CpmFc(+).

Fig. 57 is a bar graph of triglyceride levels (mg/ml) (postprandial) at week 3 of administration of (a) vehicle, (b) 10 mmol of Dh3CpmFc(-)GDF15(N3D):Dh3CpmFc(+) heterodimer dimer, (c) 1 mmol heterodimer dimer Dh3CpmFc(-)-GDF15(N3D):Dh3CpmFc(+), (d) 0.1 mmol heterodimer dimer Dh3CpmFc(-)-GDF15(N3D):Dh3CpmFc(+), (e) 10 mmol heterodimer dimer Dh3CpmFc(-)-GDF15(Ndel3):Dh3CpmFc(+), (g) 1 mmol heterodimer dimer Dh3CpmFc(-)GDF15(Ndel3):Dh3CpmFc(+) or (g) 0.1 mmol heterodimer dimer Dh3CpmFc(-)GDF 15(Ndel):Dh3 CpmFc(+).

Fig. 58 is a bar graph of cholesterol levels (mg/ml) (postprandial) at week 3 of administration of (a) vehicle, (b) 10 mmol of Dh3CpmFc(-)GDF15(N3D):Dh3CpmFc(+) heterodimer dimer, (c) 1 mmol heterodimer dimer Dh3CpmFc(-)-GDF15(N3D):Dh3CpmFc(+), (d) 0.1 mmol heterodimer dimer Dh3CpmFc(-)-GDF15(N3D):Dh3CpmFc(+), (e) 10 mmol heterodimer dimer Dh3CpmFc(-)-GDF15(Ndel3):Dh3CpmFc(+), (g) 1 mmol heterodimer dimer Dh3CpmFc(-)GDF15(Ndel3):Dh3CpmFc(+) or (g) 0.1 mmol heterodimer dimer Dh3CpmFc(-)GDF 15(Ndel):Dh3 CpmFc(+).

Fig. 59 is a bar graph of the area under the curve (AUC) for a glucose tolerance test at week 5 of administration of (a) vehicle, (b) 10 mmol dimer of the heterodimer Dh3CpmFc(-)GDF15(N3D):Dh3CpmFc(+), (c) 1 mmol heterodimer dimer Dh3CpmFc(-)-GDF15(N3D):Dh3CpmFc(+), (d) 0.1 mmol heterodimer dimer Dh3CpmFc(-)-GDF15(N3D):Dh3CpmFc(+), (e) 10 mmol heterodimer dimer Dh3CpmFc (-)-GDF15(Ndel3):Dh3CpmFc(+), (g) 1 mmol heterodimer dimer Dh3CpmFc(-)GDF15(Ndel3):Dh3CpmFc(+) or (g) 0.1 mmol heterodimer dimer Dh3CpmFc(-)GDF 15 (Ndel):Dh3 CpmFc(+).

Fig. 60 is a bar graph showing the binding determined by SPR surface plasmon resonance (ES, response units) to FcyRI, FcyRIIIA and FcyRIIA for (a) dimer DhCpmFc(-)-GDF15(Ndel3):DhCpmFc(+), ( b) dimer DhCpmFc(-) (Y349C)-GDF15(Ndel3):DhCpmFc(+)(S354C); (c) dimer Dh3CpmFc(-)-GDF15(Ndel3); (d) dimer Dh3CpmFc(-)(Y349C)-GDF15(Ndel3)-Dh3CpmFc(+)(S354C); (e) dimer Dh3CpmFc(-)-GDF15(N3D); and (f) the dimer Dh3CpmFc(-)(Y349C)-GDF15(N3D):Dh3CpmFc(+)(S354C) (from left to right with respect to each receptor).

Fig. 61 is a bar graph showing the first Tm (°C) determined by DSC (differential scanning calorimetry) in relation to (a) (for a pair of bars labeled N3D) dimer DhCpmFc(-)-GDF15(N3D):DhCpmFc(+ ) and dimer Dh3CpmFc(-)GDF15(N3D):DhCpmFc(+); (b) (for a pair of columns labeled Ndel3) of the dimer DhCpmFc(-)GDF15(Ndel3):DhCpmFc(+) and the dimer Dh3CpmFc(-)-GDF15(Ndel3):DhCpmFc(+); (c) (for a pair of columns labeled N3D+CC) dimer DhCpmFc(-)(Y349C)-GDF15(N3D):DhCpmFc(+)(S354C) and dimer Dh3CpmFc(-)(Y349C)-GDF15(N3D):DhCpmFc (+)(S354C); and (U (for a pair of columns labeled Ndel3+CC) dimer DhCpmFc(-)(Y349C)-GDF15(Ndel3):DhCpmFc(+)(S354C) and dimer Dh3CpmFc(-)(Y349C)-GDF15(Ndel3):DhCpmFc (+)(S354C).

Detailed Description of the Invention

The present invention provides fusion proteins containing a GDF15 polypeptide or mutant GDF15 polypeptides, and constructs containing such fusion proteins. The preparation and use of the disclosed molecules are also provided, for example, in the treatment of a metabolic disorder such as type 2 diabetes, increased glucose levels, increased insulin levels, dyslipidemia, or obesity. GDF15 polypeptides, mutant GDF15 polypeptides, and certain polypeptide constructs containing GDF15 polypeptides and mutant GDF15 polypeptides are described in the same applicant's applications PCT/US2012/032415, filed April 5, 2012, and PCT/2013/023465, filed January 28, 2013, which clearly are hereby incorporated by reference into this application for any purpose.

The recombinant polypeptide and nucleic acid methods used in the present invention, including the examples, are generally set forth in Sambrook et al., Molecular Cloning: A Laboratory Manual (Cold Spring Harbor Laboratory Press, 1989) or Current Protocols in Molecular Biology (Ausubel et al., eds., Green Publishers Inc. and Wiley and Sons 1994).

- 9 046387

I. General definitions.

As used herein, the singular terms used herein mean one or more of the listed entities unless specifically stated to the contrary.

In the present invention, the terms amino acid and residue are used interchangeably and, when used in the context of a peptide or polypeptide, mean both naturally occurring and synthetic amino acids, as well as amino acid analogs, amino acid mimetics, and non-naturally occurring amino acids that are chemically similar to naturally occurring amino acids. nature of amino acids.

The terms naturally occurring amino acid and naturally encoded amino acid are used interchangeably to mean an amino acid that is genetically encoded as well as amino acids that are genetically encoded that are modified after synthesis, such as hydroxyproline, γ-carboxyglutamate, and O-phosphoserine.

An amino acid analog is a compound that has the same basic chemical structure as a naturally occurring amino acid, i.e. An α-carbon that is bonded to a hydrogen, a carboxyl group, an amino group, and an R group, e.g. homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium. Such analogues may contain modified R groups (eg, norleucine) or modified peptide backbones, but retain the same basic chemical structure as the naturally occurring amino acid.

An amino acid mimetic is a chemical compound whose structure differs from the general chemical structure of an amino acid, but which functions in a manner similar to that of a naturally occurring amino acid. Examples include methacryolyl or acryolyl amide derivatives, β-, γ-, δ-imino acids (such as piperidine-4carboxylic acid) and the like.

The terms non-naturally occurring amino acid and non-naturally occurring amino acid are used interchangeably and mean a compound that has the same basic chemical structure as a naturally occurring amino acid, but which is not incorporated into the growing polypeptide chain by the translation complex. The term non-naturally occurring amino acid also includes, but is not limited to, amino acids that are formed by modification (e.g., post-translational modifications) of a naturally occurring amino acid (including, but not limited to, the 20 common amino acids), but which are themselves naturally occurring. themselves are not integrated into the growing polypeptide chain by the translation complex. Non-limiting examples of non-naturally occurring amino acids that may be included in a polypeptide sequence or with which a wild-type residue in a polypeptide sequence may be substituted include β-amino acids, homoamino acids, cyclic amino acids, and amino acids with derivatized side chains. Examples include (in L-form or D-form; abbreviated name in parentheses): citrulline (Cit), homocitrulline (hCit), Na-methylcitrulline (NMeCit), Namethylhomocitrulline (Na-MeHoCit), ornithine (Orn), Na- Methylornithine (Na-MeOrn or NMeOrn), sarcosine (Sar), homolysine (hLys or hK), homoarginine (hArg or hR), homoglutamine (hQ), Na-methylarginine (NMeR), Na-methylleucine (Na-MeL or NMeL) , N-methylgomolysine (NMeHoK), Na-methylglutamine (NMeQ), norleucine (Nle), norvaline (Nva), 1,2,3,4-tetrahydroisoquinoline (Tic), octahydroindole-2carboxylic acid (Oic), 3-(1 -naphthyl)alanine (1-Nal), 3-(2-naphthyl)alanine (2-Nal), 1,2,3,4tetrahydroisoquinoline (Tic), 2-indanylglycine (IgI), para-iodophenylalanine (pI-Phe) , para-aminophenylalanine (4AmP or 4-Amino-Phe), 4-guanidinophenylalanine (Guf), glycylysine (abbreviated as K(N-glycyl) or K(glycyl) or K(gly)), nitrophenylalanine (nitrophe), aminophenylalanine (aminophe or Amino-Phe), benzylphenylalanine (benzylphe), γ-carboxyglutamic acid (γcarboxyglu), hydroxyproline (hydroxypro), p-carboxyl-phenylalanine (Cpa), α-aminoadipic acid (Aad), Na-methylvaline (NMeVal), N-a-methylleucine (NMeLeu), Na-methylnorleucine (NMeNle), cyclopentylglycine (Cpg), cyclohexylglycine (Chg), acetylarginine (acetylarg), α, β-diaminopropionic acid (Dpr), α,γ-diaminobutyric acid (Dab), diaminopropionic acid (Dap ), cyclohexylalanine (Cha), 4-methyl-phenylalanine (MePhe), β,β-diphenyl-alanine (BiPhA), aminobutyric acid (Abu), 4-phenyl-phenylalanine (or biphenylalanine; 4Bip), α-amino-isobutyric acid (Aib), betaalanine, beta-aminopropionic acid, piperidic acid, aminocaproic acid, aminoheptanoic acid, aminopimelic acid, desmosine, diaminopimelic acid, Nethylglycine, N-ethylasparagine, hydroxylysine, allohydroxylysine, isodesmosine, alloisoleucine , Nmethylglycine, N-methylisoleucine, N-methylvaline, 4-hydroxyproline (Hyp), γ-carboxyglutamate, e-N,N,Ntrimethyllysine, ε-N-acetyl-lysine, O-phosphoserine, N-acetylserine, N-formylmethionine, 3-methylhistidine, 5-hydroxylysine, ω-methylarginine, 4-amino-O-phthalic acid (4APA), N-acetylglucosaminyl-Gserine, N-acetylglucosylaminyl-G-threonine, O-phosphotyrosine and other similar amino acids and derivatized forms of any of the above amino acids.

Also included in the definition of a non-naturally occurring amino acid is any amino acid

- 10 046387 having a structure

R

[COOH] where the R group is any substituent other than those found in the twenty natural amino acids.

In some embodiments of the present invention, the non-naturally occurring amino acid contains a carbonyl group. In some embodiments of the present invention, the non-naturally occurring amino acid has the structure:

(CH^R^OR,

RjHN COR4 where n represents 0-10; R1 represents alkyl, aryl, substituted alkyl or substituted aryl; R2 represents H, alkyl, aryl, substituted alkyl and substituted aryl; R3 is H, an amino acid, polypeptide or amino-terminal modifying group, and R4 is H, an amino acid, polypeptide or carboxy-terminal modifying group.

In some embodiments of the present invention, the non-naturally occurring amino acid contains an aminooxy group. In some embodiments of the present invention, the non-naturally occurring amino acid contains a hydrazide group. In some embodiments of the present invention, the non-naturally occurring amino acid contains a hydrazine group. In some embodiments of the present invention, the non-naturally occurring amino acid residue contains a semicarbazide group.

In some embodiments of the present invention, the non-naturally occurring amino acid residue contains an azide group. In some embodiments of the present invention, the non-naturally occurring amino acid has the structure:

(CH ₂ )„R _L X(CH ₂ )„N ₃

R ₂ hn cor ₃ where n represents 0-10; R1 is alkyl, aryl, substituted alkyl, substituted aryl, or none; X is O, N, S or absent; m represents 0-10; R2 is H, an amino acid, polypeptide or amino-terminal modifying group, and R ₃ is H, an amino acid, polypeptide or carboxy-terminal modifying group.

In some embodiments of the present invention, the non-naturally occurring amino acid contains an alkyne group. In some embodiments of the present invention, the non-naturally occurring amino acid has the structure:

(ch^r^ch^cch r ₂ hn cor ₃ where n represents 0-10; R1 represents alkyl, aryl, substituted alkyl or substituted aryl; X represents O, N, S or none; m represents 0- 10, R ₂ represents H, an amino acid, polypeptide or amino-terminal modifying group, and R ₃ represents H, an amino acid, polypeptide or carboxy-terminal modifying group.

The term substituted means that a hydrogen atom in a molecule or group is replaced by a group or atom, which is called a substituent. Typical substituents include: halogen, C _1-8 alkyl, hydroxyl, C _1-8 alkoxy, -NR ^x R ^x , nitro, cyano, halogen or perhalo C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, SR ^x , -S (=O)2R ^x , -C(=O)OR ^x , -C(=O)R ^x , where each R ^x is independently hydrogen or C1-C ₈ alkyl. It should be noted that when the substituent is -NR ^x R ^x , the R ^x groups can be combined via a nitrogen atom to form a ring.

The term alkyl means a straight or branched chain hydrocarbon. Typical examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, sec-butyl, pentyl and hexyl. Typical alkyl groups are alkyl groups containing from 1 to 8 carbon atoms; such groups are widely represented by Schilk.

- 11 046387

The term alkoxy means an alkyl group attached to an oxygen atom. Typical examples of alkoxy groups include methoxy, ethoxy, t-butoxy, propoxy and isobutoxy. Common alkoxy groups are C^alkoxy.

The term halogen means chlorine, fluorine, bromine or iodine.

The term alkenyl means a straight or branched chain hydrocarbon containing one or more carbon-carbon double bonds. Typical examples of alkenyl groups include vinyl, propenyl, allyl, butenyl and 4-methylbutenyl. Common alkenyl groups are C.'2-halkenyl.

The term alkynyl means a straight or branched chain hydrocarbon containing one or more carbon-carbon triple bonds. Typical examples of alkynyl groups include ethynyl, propynyl (propargyl) and butynyl. Common alkynyl groups are C'2-chalkynyl.

The term cycloalkyl means a cyclic non-aromatic hydrocarbon. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. A cycloalkyl group may contain one or more double bonds. Examples of cycloalkyl groups containing double bonds include cyclopentenyl, cyclohexenyl, cyclohexadienyl and cyclobutadienyl. Common cycloalkyl groups are ^^cycloalkyl groups.

The term perfluoroalkyl means an alkyl group in which all hydrogen atoms have been replaced by fluorine atoms. Common perfluoroalkyl groups are C^perfluoroalkyl. An example of a common perfluoroalkyl group is CF3.

The term acyl means a group obtained from an organic acid by removing a hydroxyl group (-OH). For example, the acyl group CH ₃ C(=O) is formed by removing the hydroxyl group from CH3C(=O)OH.

The term aryl means a cyclic aromatic hydrocarbon. Examples of aryl groups include phenyl and naphthyl. Common aryl groups are six to thirteen membered rings.

The term heteroatom in the present invention means an oxygen, nitrogen or sulfur atom.

The term heteroaryl means a cyclic aromatic hydrocarbon in which one or more carbon atoms of the aryl group have been replaced by a heteroatom. If a heteroaryl group contains more than one heteroatom, the heteroatoms may be the same or different. Examples of heteroaryl groups include pyridyl, pyrimidinyl, imidazolyl, thienyl, furyl, pyrazinyl, pyrrolyl, indolyl, triazolyl, pyridazinyl, indazolyl, purinyl, quinolizinyl, isoquinolyl, quinolyl, naphthyridinyl, quinoxalinyl, isothiazolyl and benzo[b]thienyl. Common heteroaryl groups are five- to thirteen-membered rings containing 1-4 heteroatoms. Heteroaryl groups, which are five- or six-membered rings containing 1 to 3 heteroatoms, are especially common.

The term heterocycloalkyl means a cycloalkyl group in which one or more carbon atoms have been replaced by a heteroatom. If a heterocycloalkyl group contains more than one heteroatom, the heteroatoms may be the same or different. Examples of heterocycloalkyl groups include tetrahydrofuryl, morpholinyl, piperazinyl, piperidinyl and pyrrolidinyl. A heterocycloalkyl group may also contain one or more double bonds, but is not aromatic. Examples of heterocycloalkyl groups containing double bonds include dihydrofuran. Common heterocycloalkyl groups are three- to ten-membered rings containing 1-4 heteroatoms. Heterocycloalkyl groups, which are five- or six-membered rings containing 1-2 heteroatoms, are especially common.

It should also be noted that cyclic ring groups, i.e. aryl, heteroaryl, cycloalkyl and heterocycloalkyl may contain more than one ring. For example, the naphthyl group is a fused bicyclic ring system. It is also contemplated that the present invention includes ring groups containing bridging atoms or ring groups having a spiro orientation.

Typical examples of five- and six-membered aromatic rings, optionally containing one or two heteroatoms, are phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyridiazinyl, pyrimidinyl and pyrazinyl.

Typical examples of partially saturated, fully saturated or fully unsaturated five to eight membered rings, optionally containing one to three heteroatoms, are cyclopentyl, cyclohexyl, cycloheptyl, cycloactyl and phenyl. Additional examples of five-membered rings are furyl, thienyl, pyrrolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 1,3dioxolanyl, oxazolyl, thiazolyl, imidazolyl, 2H-imidazolyl, 2-imidazolinyl, imidazolidinyl, pyrazolyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2-dithiolyl, 1,3-dithiolyl, 3H-1,2oxathiolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2,3triazolyl, 1,2,4-triazolyl, 1,3,4-thiadiazolyl, 3H-1,2,3-dioxazolyl, 1,2,4-dioxazolyl, 1,3,2

- 12 046387 dioxazolyl, 1,3,4-dioxazolyl, 5H-1,2,5-oxathiazolyl and 1,3-oxathiolyl.

Additional examples of six-membered rings are 2H-pyranyl, 4H-pyranyl, pyridinyl, piperidinyl, 1,2-dioxynyl, 1,3-dioxynyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl, pindazinyl, pyrimidinyl, pyrazinyl, piperazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, 1,3,5-tritianyl, 4H-1,2-oxazinyl, 2H-1,3- oxazinyl, 6H-1,3-oxazinyl, 6H-1,2oxazinyl, 1,4-oxazinyl, 2H-1,2-oxazinyl, 4H-1,4-oxazinyl, 1,2,5-oxathiazinyl, 1,4- oxazinyl, oisoxazinyl, p-isoxazinyl, 1,2,5-oxathiazinyl, 1,2,6-(3-oxathiazinyl, 1,4,2-oxadiazinyl.

Additional examples of seven-membered rings are azepinyl, oxepinyl, thiepinyl and 1,2,4-triazepinyl.

Additional examples of eight-membered rings are cyclooctyl, cyclooctenyl and cyclooctadienyl.

Examples of bicyclic rings consisting of two fused partially saturated, fully saturated or fully unsaturated five- and/or six-membered rings, optionally containing from one to four heteroatoms, are indolizinyl, indolyl, isoindolyl, indolinyl, cyclopenta(b)pyridinyl, pyrano( 3,4P)pyrrolyl, benzofuryl, isobenzofuryl, benzo(b)thienyl, benzo^thienyl, N-indazolyl, indoxazinyl, benzoxazolyl, anthranilyl, benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1, 8-naphthyridinyl, pteridinyl, indenyl, isoindenyl, naphthyl, tetralinyl, decalinyl, 2H-1benzopyranyl, pyrido(3,4-b)pyridinyl, pyrido(3,2-b)pyridinyl, pyrido(4,3-b)-pyridinyl , 2H-1,3benzoxazinyl, 2H-1,4-benzoxazinyl, Ш-2,3-benzoxazinyl, 4H-3,1-benzoxazinyl, 2H-1,2benzoxazinyl and 4H-1,4-benzoxazinyl.

A cyclic ring group can be attached to another group in more than one way. If a specific location of links is not specified, all possible locations are included. For example, the term pyridyl includes 2-, 3- or 4-pyridyl, and the term thienyl includes 2- or 3-thienyl.

The term isolated nucleic acid molecule means a single- or double-stranded polymer of deoxyribonucleotide or ribonucleotide bases read from the 5' end to the 3' end (for example, the GDF15 nucleic acid sequence proposed in the present invention), or an analogue of the said polymer that has been separated from at least about 50 percent of the polypeptides, peptides, lipids, carbohydrates, polynucleotides or other substances with which the nucleic acid is found in nature when the total nucleic acid is isolated from source cells. Preferably, the isolated nucleic acid molecule is substantially free from any other contaminating nucleic acid molecules or other molecules that are found in the natural environment of the nucleic acid that would interfere with its use for polypeptide production or use in therapy, diagnosis, prophylaxis or research.

The term isolated polypeptide means a polypeptide (e.g., a GDF15 polypeptide or a mutant GDF15 polypeptide as provided herein) that has been isolated from at least about 50 percent of the polypeptides, peptides, lipids, carbohydrates, polynucleotides, or other substances with which the polypeptide is found in nature when it is isolated from source cells. Preferably, the isolated polypeptide is substantially free from any other contaminating polypeptides or other contaminants found in its natural environment that would interfere with its use in therapy, diagnosis, prophylaxis, or research.

The term coding means a polynucleotide sequence encoding one or more amino acids. This term does not require a start or stop codon. The amino acid sequence may be encoded in any of the various reading frames that the polynucleotide sequence contains.

The terms identical and percentage identity in the context of two or more nucleic acid sequences or polypeptide sequences refer to two or more sequences or subsequences that are similar. Percent identity refers to the percentage of identical residues among amino acids or nucleotides in the molecules being compared; the percent identity is calculated based on the size of the smallest molecule among the molecules being compared. For these calculations, taking into account gaps in alignments (if any), you can resort to a specific mathematical model or computer program (i.e., algorithm). Methods that can be used to calculate the identity of aligned nucleic acids or polypeptides include those described in the manuals of Computational Molecular Biology, (Lesk, A. M., ed.), (1988) New York: Oxford University Press; Biocomputing Informatics and Genome Projects, (Smith, D. W., ed.), 1993, New York: Academic Press; Computer Analysis of Sequence Data, Part I, (Griffin, A. M., and Griffin, H. G., eds.), 1994, New Jersey: Humana Press; von Heinje, G., (1987) Sequence Analysis in Molecular Biology, New York: Academic Press; Sequence Analysis Primer, (Gribskov, M. and Devereux, J., eds.), 1991, New York: M. Stockton Press; and Carillo et al., (1988) SIAM J. Applied Math. 48:1073.

When calculating percent identity, the sequences being compared are aligned in a manner that provides maximum sequence match. Computer

- 13 046387 the program used to determine percent identity is the GCG software package, which includes GAP (Devereux et al., (1984) Nucl. Acid Res. 12:387; Genetics Computer Group, University of Wisconsin, Madison, WI ). The GAP computer algorithm is used to align two polypeptides or polynucleotides for which percent sequence identity is determined. Sequences are aligned for maximum matching of the corresponding amino acids or nucleotides of these sequences (a similar region, which is determined by the algorithm). Together with the algorithm, a gap opening penalty is used, which is calculated as the average diagonal multiplied by 3, where the average diagonal is the average value of the diagonal of the comparison matrix used; the diagonal is a point or quantitative indicator assigned for each complete amino acid match according to with a specific comparison matrix) and a gap extension penalty, which is typically 1/10th of the gap penalty), as well as a comparison matrix such as PAM 250 or BLOSUM 62. In certain embodiments of the present invention, this The algorithm also uses a standard comparison matrix (see Dayhoff et al., (1978) Atlas of Protein Sequence and Structure 5:345-352 for the PAM 250 comparison matrix; Henikoff et al., (1992) Proc. Natl. Acad. Sci. U.S.A. 89:10915-10919 for the BLOSUM 62 comparison matrix).

The recommended parameters for determining the percentage identity of a polypeptide or nucleotide sequence using the GAP program are as follows:

Algorithm: Needleman et al., 1970, J. Mol. Biol. 48:443-13;

Comparison matrix: BLOSUM 62 from Henikoff et al., 1992, above;

Gap Penalty: 12 (no penalties for end gaps);

Gap Length Penalty: 4;

Threshold of Similarity: 0.

Certain alignment schemes for aligning two amino acid sequences may result in only a short region of the two sequences matching, and a given small aligned region may have very high sequence identity even in the absence of significant relationship between the two full-length sequences. Accordingly, the selected alignment method (eg, GAP program) can be adjusted as necessary to provide an alignment that covers at least 50 consecutive amino acids of the target polypeptide.

The term GDF15 polypeptide means naturally occurring GDF15 or wild-type GDF15 that is expressed in mammals, including, but not limited to, human, rabbit, monkey (eg, cynomolgus monkey), dog, rat, mouse or pig. In one aspect of the present invention, a GDF15 polypeptide means any full-length GDF15, for example, SEQ ID NO: 4, which consists of 308 amino acid residues and which is encoded by the nucleotide sequence SEQ ID NO: 3; any form containing the active domain and prodomains of a polypeptide, for example, SEQ ID NO: 8, which consists of 279 amino acid residues and is encoded by the nucleotide sequence of SEQ ID NO: 7 and in which 29 amino acid residues are at the amino terminal end of full-length GDF15 (i.e. .residues forming the signal peptide) have been removed; and any form of GDF15 containing the active domain from which the prodomain and signal sequence have been deleted, for example, SEQ ID NO: 12, which consists of 112 amino acid residues and is encoded by the nucleotide sequence SEQ ID NO: 11 from which the signal sequence and prodomain have been deleted . GDF15 polypeptides may, but do not necessarily contain, an amino-terminal methionine, which may be introduced by genetic engineering or by bacterial expression.

The term mutant GDF15 polypeptide means a GDF15 polypeptide (eg, SEQ ID NO: 4, 8 or 12) that has been modified. Such modifications include, but are not limited to, substitutions of one or more amino acids, including substitutions with non-naturally occurring amino acids, non-naturally occurring amino acid analogues and amino acid mimetics, deletions or additions. According to one aspect of the present invention, the term mutant GDF15 polypeptide means a GDF15 polypeptide in which at least one residue that is normally present at a given position of a naturally occurring GDF15 polypeptide has been deleted or replaced by a residue that is not normally present at a given position of a naturally occurring GDF15 polypeptide. the nature of the GDF15 polypeptide. In some cases, it is necessary to replace a single residue that is normally present at a given position in the sequence of a naturally occurring GDF15 polypeptide with more than one residue that is not normally present at that position; in other cases it may be necessary to retain the sequence of a naturally occurring GDF15 polypeptide and insert one or more residues at a given position in the protein; in other cases it may be necessary to remove the residue completely; all of these constructs are covered by the term GDF15 mutant polypeptide.

- 14 046387

In various embodiments of the present invention, the mutant GDF15 polypeptide contains an amino acid sequence that is at least about 85 percent identical to a naturally occurring GDF15 polypeptide (eg, SEQ ID NO: 4, 8, or 12). In other embodiments of the present invention, the mutant GDF15 polypeptide contains an amino acid sequence that is at least about 90 percent, or about 95, 96, 97, 98, or 99 percent identical to the amino acid sequence of a naturally occurring GDF15 polypeptide (e.g., SEQ ID NO: 4 , 8 or 12). Such mutant GDF15 polypeptides preferably, but not necessarily, have at least one activity of a naturally occurring GDF15 polypeptide, such as the ability to reduce blood glucose, insulin, triglyceride or cholesterol levels; the ability to reduce body weight; ability to improve glucose tolerance, lipid tolerance, or insulin sensitivity; or the ability to reduce urinary glucose and protein excretion.

The term GDF15 region covers GDF15 polypeptides and mutant GDF15 polypeptides and the sequences defined above.

The GDF15 polypeptide or mutant GDF15 polypeptide is preferably biologically active. In some cases, a GDF15 polypeptide or a mutant GDF15 polypeptide of a species or originating from a species other than the subject's is used to treat or alleviate a metabolic disorder in a subject. In some cases, a GDF15 polypeptide or a mutant GDF15 polypeptide of the same species or originating from the same species as the subject is used to treat or alleviate a metabolic disorder in a subject.

The term native Fc means a molecule or sequence containing a sequence other than the antigen binding fragment sequence obtained by cleavage of the whole antibody, which is present in monomeric or multimeric form. The native immunoglobulin source of native Fc is preferably human derived and can be any immunoglobulin, but IgG1 and IgG2 are preferred. Native Fcs are composed of monomeric polypeptides that can be assembled into dimeric or multimeric forms through covalent (ie, disulfide bonds) and non-covalent binding. The number of intramolecular disulfide bonds between monomeric subunits of native Fc molecules varies from 1 to 4 depending on the class (eg, IgG, IgA, IgE) or subclass (eg, IgG1, IgG2, IgG3, IgA1, IgGA2). An example of a native Fc is a disulfide-linked dimer resulting from papain digestion of IgG (Ellison et al. (1982), Nucleic Acids Res. 10: 4071-9). The term native Fc in the present invention is general for monomeric, dimeric and multimeric forms.

The term Fc variant means a molecule or sequence that is modified from a native Fc. Such modifications include, but are not limited to, substitutions of one or more amino acids, including substitutions with non-naturally occurring amino acids, non-naturally occurring amino acid analogues and amino acid mimetics, deletions or additions. Thus, the term Fc variant includes a molecule or sequence that is a humanized native Fc other than human Fc. Moreover, the native Fc contains sites that can be removed because these sites are responsible for structural properties or biological activities that are not required for the hybrid molecules of the present invention. Thus, the term Fc variant includes a molecule or sequence lacking one or more native Fc sites or residues affecting or involved in (1) disulfide bond formation, (2) incompatibility with a selected host cell, (3) N-terminal heterogeneity after expression in a selected host cell, (4) glycosylation, (5) interaction with complement, (6) binding to an Fc receptor other than the salvage receptor, or (7) antibody-dependent cellular cytotoxicity , ADCC). Fc variants are described in more detail below. In various embodiments of the present invention, the Fc variant comprises an amino acid sequence that is at least about 85 percent identical to the native Fc. In other embodiments of the present invention, the Fc variant comprises an amino acid sequence that is at least about 90 percent, or about 95, 96, 97, 98, or 99 percent identical to the native Fc.

The term Fc domain encompasses native Fc and variant Fc molecules and sequences as defined above. As with Fc variants and native Fcs, the term Fc domain includes molecules in monomeric or multimeric form.

The term multimer, when applied to Fc domains or Fc domain-containing molecules, means molecules containing two or more polypeptide chains linked in a covalent manner, a non-covalent manner, or through both covalent and non-covalent interactions. IgG molecules tend to form dimers; IgM - pentamers; IgD - dimers; and IgA monomers, dimers, trimers or tetramers. Multimers can be obtained by using the sequence and resulting activity of the native Ig source Fc or by obtaining derivatives

- 15 046387 such native Fc.

The term dimer, as applied to Fc domains or Fc domain-containing molecules, means molecules containing two polypeptide chains joined in a covalent manner, a non-covalent manner, or through both covalent and non-covalent interactions.

The term hinge or hinge region as used herein includes a mobile polypeptide comprising amino acids located between the first and second constant domains of an antibody. A hinge region in the present invention means a sequence region, 6-62 amino acids in length, present only in IgA, IgD and IgG, which spans the cysteine residues that bridge the two heavy chains.

Polypeptide linker means a short polypeptide, typically 1 to 30 amino acid residues in length, that covalently links two polypeptides together, typically through peptide bonds.

As used herein, the term HSA polypeptide covers naturally occurring wild-type human serum albumin. The term also includes various biologically active fragments and variants, fusion proteins and modified forms of wild-type HSA protein. Such biologically active fragments or variants, fusion proteins and modified forms of the wild-type HSA protein contain at least a portion of the amino acid sequence having significant sequence identity to the wild-type HSA protein. In certain embodiments of the present invention, such biologically active fragments or variants, fusion proteins, and modified forms of wild-type HSA protein contain an amino acid sequence that is at least about 85 percent identical to the sequence of wild-type HSA. In other embodiments of the present invention, such biologically active fragments or variants, fusion proteins, and modified forms of wild-type HSA protein contain an amino acid sequence that is at least about 90 percent or about 95, 96, 97, 98, or 99 percent identical to the sequence of wild-type HSA .

II. Fc fusions containing GDF15 polypeptides or mutant GDF15 polypeptides, as well as polynucleotides.

The present invention provides a series of Fc fusion proteins containing a GDF15 polypeptide or a mutant GDF15 polypeptide. In some embodiments of the present invention, the fusion proteins comprise native Fc. In some embodiments of the present invention, the fusion proteins comprise an Fc domain that has been engineered.

In some embodiments of the present invention, Fc fusion proteins comprising a GDF15 polypeptide (or a mutant GDF15 polypeptide) are linked to another polypeptide chain consisting of or containing an Fc domain to form a heterodimer. In some embodiments of the present invention, two such heterodimers combine to form a heterotetramer. Some of these polypeptide constructs (i.e., Fc-fusion proteins containing the GDF15 polypeptide (hth mutant GDF15 polypeptide), and multimers containing one or more such Fc-fusion proteins containing the GDF15 polypeptide (hth mutant GDF15 polypeptide)) were studied empirically in a manner as described in the examples presented in the present invention below.

Antibodies belong to the class of immunoglobulin proteins, which includes IgG, IgA, IgE, IgM and IgD. The most abundant class of immunoglobulins in human serum is IgG (Deisenhofer J 1981 Biochem 20:2361-2370; Huber R 1984 Behring Inst Mitt 76:1-14; Roux KH 1999 Int Arch Allergy Immunol 120:85-99). The structure of IgG includes four chains, two light and two heavy chains; each light chain contains two domains, and each heavy chain contains four domains. The antigen-binding site is located in the Fab domain (fragment antigen binding, antigen-binding fragment), which contains the variable domain of the light (VL) and variable domain of the heavy (VH) chain, as well as the constant domain of the light (LC) and constant domain of the heavy ( CH1) chains. The region of the CH2 and CH3 domains of the heavy chain is called Fc (fragment crystallizable, crystallizable fragment). The IgG molecule can be considered as a heterotetramer containing two heavy chains, which are held together by disulfide bonds (-S-S-) in the hinge region, and two light chains. The number of disulfide bonds in the hinge region varies among immunoglobulin subclasses (Papadea C 1989 Crit Rev Clin Lab Sci 27:27-58). The FcRn binding site is located in the Fc domain of the antibody (Martin WL 2001 Mol Cell 7:867-877), and thus the extended serum half-life property of the antibody is mediated by the Fc moiety. The Fc domain itself can be considered a homodimer that consists of heavy chains containing CH2 and CH3 domains.

In certain preferred embodiments, the fusion proteins described herein comprise an IgG Fc domain derived from a wild-type human IgG Fc domain. By wild-type human IgG Fc is meant a sequence of amino acids that is naturally present in the human population. Of course, since Fc sequences may vary slightly among individuals, one or more changes could be introduced into the wild-type sequence and the sequence would still be classified as

- 16 046387 to the scope of the present invention. For example, the Fc domain may contain additional changes not related to the present invention, such as a mutation in a glycosylation site or the insertion of an unnatural amino acid. In certain embodiments of the present invention, the polypeptide comprising a CH3 region is an IgG molecule and also contains a CH1 and a CH2 domain. Examples of human IgG sequences include the constant regions of IgG1, IgG2, IgG3 and IgG4. The Fc domain may also be contained in the heavy chain constant region of IgA, IgD, IgE and IgM.

Certain Fc fusion proteins containing a GDF15 polypeptide or a mutant GDF15 polypeptide, and multimers containing such Fc fusion proteins, include those described below.

II.A. DhMonoFc designs.

The definitions of Mono or MonoFc domain in the present invention mean an Fc domain that has been designed to reduce or prevent the formation of homodimers. In one embodiment of the present invention, a MonoFc domain is generated by introducing a tyrosine to threonine mutation (Y349T) and two lysine to aspartic acid mutations (K392D and K409D) into a native Fc or variant Fc.

The C-terminal lysine (K447) in MonoFc may optionally be removed. This modification may be advantageous, for example, when the peptide is C-terminally fused to reduce proteolysis of the fusion protein.

A hybrid protein containing the MonoFc domain and the GDF15 region has been proposed. Typically, the N-terminus of the GDF15 region is connected directly or via a polypeptide linker to the C-terminus of the MonoFc domain. However, in some embodiments of the present invention, the N-terminus of the MonoFc domain is connected directly or via a polypeptide linker to the C-terminus of the GDF15 region.

According to certain embodiments of the present invention, a dimer is provided that contains two such fusion proteins linked through an interchain disulfide bond between the corresponding GDF15 regions of the proteins. In some embodiments of the present invention, the dimer is a homodimer. In other embodiments of the present invention, the dimer is a heterodimer.

The term DhMono or DhMonoFc domain as used herein means an Fc domain from which all or part of the hinge region has been removed and which has been engineered to reduce or prevent the formation of homodimers. One embodiment of the present invention provides a DhMonoFc domain in which a tyrosine to threonine mutation (Y349T) and two lysine to aspartic acid mutations (K392D and K409D) have been introduced into a native Fc or a variant Fc from which all or any of the hinge region has been removed. Part.

The C-terminal lysine (K447) in DhMonoFc may optionally be removed. This modification may be advantageous, for example when the peptide is fused at the C-terminus, to reduce proteolysis of the fusion protein.

A hybrid protein containing the DhMonoFc domain and the GDF15 region has been proposed. Typically, the N terminus of the GDF15 region is connected directly or via a polypeptide linker to the C terminus of the DhMonoFc domain. However, in some embodiments of the present invention, the N-terminus of the DhMonoFc domain is connected directly or via a polypeptide linker to the C-terminus of the GDF15 region.

According to certain embodiments of the present invention, a dimer is provided that contains two such fusion proteins linked through an interchain disulfide bond between the corresponding GDF15 regions of the proteins. In some embodiments of the present invention, the dimer is a homodimer. In other embodiments of the present invention, the dimer is a heterodimer.

II .A.1 DhMonoFc-GDF15.

The definition of MonoFc-GDF15 in the present invention means a fusion protein containing a GDF15 polypeptide, the N-terminus of which is connected directly to the C-terminus of the MonoFc domain.

Certain embodiments of the present invention provide a homodimer comprising two such fusion proteins linked through an interchain disulfide bond between the respective GDF15 regions of the proteins.

More specifically, according to a particular embodiment of the present invention, the homodimer comprises:

(a) two MonoFc domains (in each monomer) containing the sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA

PIEKTISKAKGQPREPQVTTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE

WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHE

ALHNHYTQKSLSLSPG (SEQ ID NO:22), and (b) two GDF15 polypeptides (b each monomer) containing the sequence SEQ ID NO: 12.

- 17 046387

According to a preferred embodiment of the present invention, the fusion protein contains the amino acid sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVTTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPGARNGDHCPLGPGRCCRLHTVRASLEDLGWAD WVL S PREVQVTMCIGAC PS Q FRAANMHAQICT S LHRLKPDTVPAPCCVPASYN PMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:46), which is encoded by the nucleic acid sequence: gcacctgaactcctggggggaccgtcagtcttcctcttccccc caaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgc gtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggta cgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagc agtacaacagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccag gactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccct cccag cccccatcgagaaaaccatctccaaagccaaagggcagccccgag aaccacaggtgaccaccctgcccccatcccgggaggagatgaccaagaac caggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgc cgtggagtgggagagcaatgggcagccggagaacaactacgacaccacgc ctcccgtgctggactccgacggct ccttcttcctctatagcgacctcacc gtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgat gcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctc cgggtgcgcgcaacggagaccactgtccgctcgggcccgggcgttgctgc cgtctgcacacggtccgcgcg tcgctggaagacctgggctggggccgattg ggtgctgtcgccacgggaggtgcaagtgaccatgtgcatcggcgcgtgcc cgagccagttccgggcggcaaacatgcacgcgcagatcaagacgagcctg caccgcctgaagcccgacacggtgccagcgccctgctgcgtgcccgccag ctacaatcccat ggtgctcattcaaaagaccgacaccggggtgtcgctcc agacctatgatgacttgttagccaaagactgccactgcata (SEQ ID NO :45).

As discussed above, according to a specific embodiment of the present invention there is provided a homodimer that contains two monomers containing the sequence SEQ ID NO: 46.

II.A.2 DhMonoFc-(G ₄ S) ₄ -GDF15.

The definition of DhMonoFc-(G ₄ S) ₄ -GDF15 in the present invention means a fusion protein comprising a GDF15 polypeptide linked to a DhMonoFc domain by a polypeptide linker which contains the sequence SEQ ID NO: 18 and which connects the N-terminus of the GDF15 polypeptide to the C- the end of the DhMonoFc domain.

Certain embodiments of the present invention provide a homodimer comprising two such fusion proteins linked through an interchain disulfide bond between the respective GDF15 regions of the proteins.

More specifically, according to a particular embodiment of the present invention, the homodimer comprises:

(a) two DhMonoFc domains (in each monomer) containing the sequence SEQ ID NO: 22, (b) two GDF15 polypeptides (in each monomer) containing the sequence SEQ ID NO: 12, and (c) two polypeptide linkers (in each monomer) containing the sequence: GGGGSGGGGSGGGGSGGGGS (SEQ ID NO:18), with each linker connecting the N-terminus of the GDF15 polypeptide to the C-terminus of the DhMonoFc domain.

According to a preferred embodiment of the present invention, the fusion protein contains the amino acid sequence (the linker sequence is underlined by a double line):

- 18 046387

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVD GVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVTTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFS CSVMHE ALHNHYTQKSLSLSPGgGSX^SSXSSSXSSgSXXARNGDHCPLGPGRC CRLHTVRAS LE DLGWADWVL S PREVQVTMCIGAG P S Q FRAANMHAQIKT S LHRLKPDTVPAPCCVPASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:2 4) which is encoded by the nucleic acid sequence: c acctgaactcctggggggaccgtcagtcttcctcttccccccaaaaccc aaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggt ggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacg gcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaac agcacgtaccg tgtggtcagcgtcctcaccgtcctgcaccaggactggct gaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagccc ccatcgagaaaaccatctctccaaagccaaagggcagccccgagaaccacag gtgaccaccctgcccccatcccgggaggagatgaccaagaaccaggtcag cctgacctgcctggtcaaaggcttctat cccagcgacatcgccgtggagt gggagagcaatgggcagccggagaacaactacgacaccacgcctcccgtg ctggactccgacggctccttcttoctetatagcgacctcaccgtggacaa gagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgagg ctctgcacaaccactacacgcagaagagcctctctccctgt ctccgggtgga ggtggtggatccggaggcggtggaagcggaggtggtggatctggaggcgg tggaagcgcgcgcaacggagaccactgtccgctcgggcccgggcgttgct gccgtctgcacacggtccgcgcgtcgctggaagacctgggctgggccgat tgggtgctgtcgccacgggaggtgca agtgaccatgtgcatcggcgcgtg cccgagccagttccgggcggcaaacatgcacgcgcagatcaagacgagcc tgcaccgcctgaagcccgacacggtgccagcgccctgctgcgtgcccgcc agctacaatcccatggtgctcattcaaaagaccgacaccggggtgtcgct ccagacctatgatgacttgttagccaaagactgccactgcatatga (SEQ ID NO:23).

As discussed above, according to a specific embodiment of the present invention there is provided a homodimer that contains two monomers containing the sequence SEQ ID NO: 24.

II.A.3 DhMonoFc-(G ₄ S) ₄ -GDF 15(H6D).

DhMonoFc-(G ₄ S) ₄ -GDF15(H6D) as used herein means a fusion protein comprising a GDF15 polypeptide linked to a DhMonoFc domain by a polypeptide linker which contains the sequence SEQ ID NO: 18 and which connects the N-terminus of the GDF15 polypeptide with the C-terminus of the DhMonoFc domain. The GDF15(H6D) variant is a naturally occurring human variant of GDF15.

Certain embodiments of the present invention provide a homodimer comprising two such fusion proteins linked through an interchain disulfide bond between the respective GDF15 regions of the proteins.

More specifically, according to a particular embodiment of the present invention, the homodimer comprises:

(a) two DhMonoFc domains (in each monomer) containing the sequence SEQ ID NO: 22, (b) two GDF15(H6D) polypeptides (in each monomer) containing the sequence: ARNGDDCPLGPGRCCRLHTVRASLEDLGWADWVLSPREVQVTMCIGACPS QFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYNPMVLIQKTDTGVSLQT

YDDLLAKDCHCI (SEQ ID NO:25), and (c) two polypeptide linkers (in each monomer) containing the sequence SEQ ID NO: 18, each linking the N-terminus of the GDF15 polypeptide to the C-terminus of the DhMonoFc domain.

According to a preferred embodiment of the present invention, the fusion protein contains the amino acid sequence (the linker sequence is underlined by a double line):

- 19 046387

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVD GVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVTTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFS CSVMHE ALHNHYTOKSLSLSPGGGGGSGGGGSGGGGSGGGGSARNGDDCPLGPGRC CRLHTVRAS LE DLGWADWVL S PREVQVTMCIGAG P S Q FRAANMHAQIKT S LHRLKPDTVPAPCCVPASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO: 2 7) which is encoded by the nucleic acid sequence:

gcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacc caaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtgg tggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggac ggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaa cagcacgtacc gtgtggtcagcgtcctcaccgtcctgcaccaggactggc tgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcc cccatcgagaaaaccatctctccaaagccaaagggcagccccgagaaccaca ggtgaccaccctgcccccatcccgggaggagatgaccaagaaccaggtca gcctgacctgcctggtcaaaggctt ctatcccagcgacatcgccgtggag tgggagagcaatgggcagccggagaacaactacgacaccacgcctcccgt getggactccgacggctccttcttoctetatagcgacctcaccgtggaca agagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgag gctctgcacaaccactacacgcagaagagcctctccctgt ctccgggtgg aggtggtggatccggaggcggtggaagcggaggtggtggatctggaggcg gtggaagcgcgcgcaacggagacgactgtccgctcgggcccgggcgttgc tgccgtctgcacacggtccgcgcgtcgctggaagacctgggctgggccga ttgggtgctgtcgccacgggaggt gcaagtgaccatgtgcatcggcgcgt gcccgagccagttccgggcggcaaacatgcacgcgcagatcaagacgagc ctgcaccgcctgaagcccgacacggtgccagcgccctgctgcgtgcccgc cagetacaatcecatggtgctcattcaaaagaccgacaccggggtgtcgc tccagacctatgatgactt gttagccaaagactgccactgcatatga (SEQ ID

NO :2 6) .

As discussed above, according to a specific embodiment of the present invention there is provided a homodimer that contains two monomers containing the sequence SEQ ID NO: 27.

II.B. HemiFc.

The definitions of Hemi- or HemiFc-domain in the present invention mean a polypeptide chain containing a first Fc domain connected directly or via a polypeptide linker to a second Fc domain. According to one embodiment of the present invention, the first Fc domain and the second Fc domain contain the same sequence. According to another embodiment of the present invention, the first Fc domain and the second Fc domain contain different sequences. Typically, the first and second Fc domains are covalently linked via disulfide bonds between the respective hinge regions of the domains.

The C-terminal lysine (K447) may optionally be removed in the first Fc domain, in the second Fc domain, or in both domains. This modification may be advantageous, for example when the peptide is fused at the C-terminus, to reduce proteolysis of the fusion protein.

A hybrid protein containing the HemiFc domain and the GDF15 region has been proposed. Typically, the N-terminus of the GDF15 region is connected directly or via a polypeptide linker to the C-terminus of the HemiFc domain. However, in some embodiments of the present invention, the N-terminus of the HemiFc domain is connected directly or via a polypeptide linker to the C-terminus of the GDF15 region.

According to certain embodiments of the present invention, a dimer is provided that contains two such fusion proteins linked through an interchain disulfide bond between the corresponding GDF15 regions of the proteins. In some embodiments of the present invention, the dimer is a homodimer. In other embodiments of the present invention, the dimer is a heterodimer. For a graphical representation of an embodiment of a homodimer consisting of two hybrid proteins GGG-Fc-(G ₄ S) ₄ -Fc-S(G ₄ S) ₄ -GDF15, see FIG. 3.

GGGFc-(G4S)4-Fc-S(G4S)4-GDF15.

The definition of GGGFc-(G ₄ S) ₄ -Fc-S(G ₄ S) ₄ -GDF15 in the present invention means a hybrid

- 20 046387 lok containing a GDF15 polypeptide connected to the HemiFc domain by a first polypeptide linker that contains the sequence SEQ ID NO: 30 and which connects the N-terminus of the GDF15 polypeptide to the C-terminus of the HemiFc domain. The HemiFc domain contains a first Fc domain connected to a second Fc domain by a polypeptide linker that contains the sequence SEQ ID NO: 18 and which connects the N-terminus of the first Fc domain to the C-terminus of the second Fc domain (which contains three residues glycine attached to its N-terminus).

Certain embodiments of the present invention provide a homodimer comprising two such fusion proteins linked through an interchain disulfide bond between the corresponding GDF15 regions of the proteins.

More specifically, according to a particular embodiment of the present invention, the homodimer comprises:

(a) two second Fc domains (in each monomer) containing the sequence (part of the hinge region is included in parentheses):

GGG(ERKSSVECPPCP)APPVAGPSVFLFPPKPKDTLMISRTPEVTCVW DVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRWSVLTWHQDWL NGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVS LTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGS FFLYSKLTVDK SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO:28), (b) the first two Fc domains (in each monomer) containing the sequence (part of the hinge region is included in parentheses):

(ERKSSVECPPCP)APPVAGPSVFLFPPKPKDTLMISRTPEVTCVWDVS HEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRWSVLTWHQDWLNGK EYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTC LVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYS KLTVDKSRW QQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO :29).

(c) two second polypeptide linkers (in each monomer) containing the sequence SEQ ID NO: 18, which connect the N-terminus of the first Fc domain to the C-terminus of the second Fc domain, (d) two GDF15 polypeptides (in each monomer) containing the sequence SEQ ID NO: 12, and (e) two first polypeptide linkers (in each monomer) containing the sequence: SGGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 30), which connect the N-terminus of the GDF15 polypeptide to the C-terminus of the first Fc domain .

According to a preferred embodiment of the present invention, the fusion protein contains the amino acid sequence (part of the hinge region is included in parentheses; the linker sequence is underlined by a double dash):

GGG (ERKSSVECPPCP) APPVAGPSVFLFPPKPKDTLMISRTPEVTCVW DVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRWSVLTWHQDWL NGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVS LTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGS FFLYSKLTVDK S RWQQGNVFS WITH SVMHEALHNHYT QKS L S L SPGGGGGSGGGGSGGGGSGGG GS> (ERKSSVECPPCP) APPVAGPSVFLFPPKPKDTLMISRTPEVTCVWD VSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRWSVLTWHQDWLN GKEYKCKVSNKGLPAPIEKTISKT KGQPREPQVYTLPPSREEMTKNQVSL TCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKS RWQQGNVFSCSVMHEALHNHYTQKSLSLSPGSGGGGSGGGGSGGGGSGGG GQARNGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPREVQVTMCIGAC PSQFRAANMHAQIKTSLHRLKPDTV PAPCCVPASYNPMVLIQKTDTGVSL QTYDDLLAKDCHCI (SEQ ID NO:32), which is encoded by the nucleic acid sequence:

- 21 046387 ggaggtggagagcgcaaatcttctgtcgagtgcccaccgtgcccagcacc acctgtggcaggaccgtcagtcttcctcttccccccaaaacccaaggaca ccctcatgatctcccggacccctgaggtcacgtgcgtggtggtggacgtg agccacgaagaccccgaggtccagttcaact ggtacgtggacggcgtgga ggtgcataatgccaagacaaaaccacgggaggagcagttcaacagcacgt tccgtgtggtcagcgtcctcaccgttgtgcaccaggactggctgaacggc aaggagtacaagtgcaaggtctccaacaaaggcctcccagcccccatcga gaaaaccatctccaaaaccaaagggcagcccc gagaaccacaggtgtaca ccctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacc tgcctggtcaaaggcttctaccccagcgacatcgccgtggagtggggagag caatgggcagccggagaacaactacaagaccacacctcccatgctggact ccgacggctccttcttcctctacagcaagctcaccgtggacaagagcagg tgg cagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgca caaccactacacgcagaagagcctctccctgtctccgggtggaggtggcg gtagcggtggcggaggttcaggtggcggcggaagcggtggaggaggttca gagcggaaatccagcgttgaatgtcctccgtgccctgctccacccgtcgc t ttctgtgctgaccgtggtgcaccaagattggctcaacggcaaggagtac aagtgcaaggtaagcaataaggggctccctgcccccattgagaagactat ctccaagacaaagggacagccacgcgagccacaagtctatacactccccc cttcccgcgaagaaatgaccaagaatcaggttagcctgacatgcttggtacccctctgacat agccgtggagtgggagagcaatggaca accagagaacaactacaagaccaccccacccatgctggatagcgacggtt cattctttctgtatagtaagcttaccgtggacaagtcccggtggcaacaa ggaaatgtcttttcatgctctgtgatgcacgaggccttgcataatcacta tactcagaagagcttgagcctcagccccggatctgg aggtggcggatccg ggggcggtggaagcggaggtggtggatcgggaggcggtggaagcgcgcgc aacggcgaccactgtccgctcgggcccggacgttgctgccgtctgcacac ggtccgcgcgtcgctggaagacctgggctgggccgattgggtgctgtcgc cacgggaggtgcaagtgacca tgtgcatcggcgcgtgcccgagccagttc cgggcggcaaacatgcacgcgcagatcaagacgagcctgcaccgcctgaa gcccgacacggtgccagcgccctgctgcgtgcccgccagctacaatccca tggtgctcattcaaaagaccgacaccggggtgtcgctccagacctatgat gacttgttagcca aagactgccactgcatatga (SEQ ID NO:31).

As discussed above, according to a specific embodiment of the present invention there is provided a homodimer that contains two monomers containing the sequence SEQ ID NO: 32.

II.C. DhHemiFc.

The definitions of DhHemi- or DhHemiFc-domain in the present invention mean a polypeptide chain containing a first Fc domain from which all or part of the hinge region has been removed (DhFc domain), connected directly or via a polypeptide linker to a second DhFc domain. In particular embodiments of the present invention, the 12 N-terminal amino acids in the hinge region are removed, for example, ERKSSVECPPCP (SEQ ID NO: 15). According to one embodiment of the present invention, the first DhFc domain and the second DhFc domain contain the same sequence. According to another embodiment of the present invention, the first DhFc domain and the second DhFc domain contain different sequences.

A hybrid protein containing the DhHemiFc domain and the GDF15 region has been proposed. Typically, the N terminus of the GDF15 region is connected directly or via a polypeptide linker to the C terminus

- 22 046387

DhHemiFc domain. However, in some embodiments of the present invention, the N-terminus of the DhHemiFc domain is connected directly or via a polypeptide linker to the C-terminus of the GDF15 region.

According to certain embodiments of the present invention, a dimer is provided that contains two such fusion proteins linked through an interchain disulfide bond between the corresponding GDF15 regions of the proteins. In some embodiments of the present invention, the dimer is a homodimer. In other embodiments of the present invention, the dimer is a heterodimer.

GGGDhFc-(G4S)5-DhFc-S(G4S)4-GDF 15.

The definition of GGGDhFc-(G ₄ S) ₅ -DhFc-S(G ₄ S) ₄ -GDF15 in the present invention means a fusion protein containing a GDF15 polypeptide connected to a DhHemiFc domain through a first polypeptide linker that contains the sequence SEQ ID NO: 30 and which connects the N-terminus of the GDF15 polypeptide to the C-terminus of the HemiFc domain. The HemiFc domain contains a first DhFc domain connected to a second DhFc domain by a polypeptide linker that contains the sequence SEQ ID NO: 34 and which connects the N-terminus of the first DhFc domain to the C-terminus of the second DhFc domain (which contains three residues glycine attached to its N-terminus).

Certain embodiments of the present invention provide a homodimer comprising two such fusion proteins linked through an interchain disulfide bond between the respective GDF15 regions of the proteins.

More specifically, according to a particular embodiment of the present invention, the homodimer comprises:

(a) two second DhFc domains (in each monomer) containing the sequence:

GGGAPPVAGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVQFNWY

VDGVEVHNAKTKPREEQFNSTFRWSVLTWHQDWLNGKEYKCKVSNKGL

PAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIA

VEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM

HEALHNHYTQKSLSLSPG (SEQ ID NO:33), (b) the first two DhFc domains (in each monomer) containing the sequence:

APPVAGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVQFNWYVDG

VEVHNAKTKPREEQFNSTFRWSVLTWHQDWLNGKEYKCKVSNKGLPAP

IEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEW

ESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA

LHNHYTQKSLSLSPG (SEQ ID NO:35), (c) two second polypeptide linkers (in each monomer) containing the sequence: GGGGSGGGGSGGGGSGGGGSGGGGS (SEQ ID NO:34), which connect the N-terminus of the first DhFc domain to the C-terminus of the second DhFc domain domain, (d) two GDF15 polypeptides (in each monomer) containing the sequence SEQ ID NO: 12, and (e) two first polypeptide linkers (in each monomer) containing the sequence SEQ ID NO: 30 that connect the N-terminus of the polypeptide GDF15 with the C-terminus of the first DhFc domain.

According to a preferred embodiment of the present invention, the fusion protein contains the amino acid sequence (the linker sequence is underlined by a double line):

GGGAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVQFNWY

VDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGL

PAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIA

VEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM

HEALHNHY T QKSLSLSP GGGGGSGGGGSGGGGSGGGGSGGGGSAPVAGP

SVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAK

TKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISK

TKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPE

NNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQ

KSLSLSPGSGGGGSGGGGSGGGGSGGGGSARNGDHCPLGPGRCCRLHTVR

ASLEDLGWADWVLSPREVQVTMCIGACPSQFRAANMHAQIKTSLHRLKPD

TVPAPCCVPASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:37), which is encoded by the nucleic acid sequence:

- 23 046387 ggcggtggagctccgccggtggctggaccctcagtgttcctctttccacc gaagccgaaggacacccttatgattagccggaccccagaggtcacttgcg tcgtcgtggacgtgtcccatgaggatcccgaagtgcagtttaactggtat gtggacggagtggaggtccataacgccaagaccaagccaa gggaagaaca gttcaatagcaccttccgggtggtgtccgtgctcaccgtggtgcatcaag actggctgaatggcaaagagtacaaatgtaaggtgtcaaacaaggggctc ccagcccctattgaaaagaccatctcaaagactaagggacagccacgcga acctcaagtgtataccctcccgccttcacgcgaagaaatgactaaga atc aggtcagccttacttgtctggtcaagggcttctacccgagcgacattgca gtcgaatggggagagcaatggtcagccagagaataactacaagaccactcc tcccatgcttgatagcgatggaagctttttcctttacagcaagcttactg tggataagtctcgctggcaacagggaaatgtgttcagctgttcagtgatg cat gaagcactccacaatcattacacccgaagtcactcagcctctcacc cggaggaggaggcggttctggtggaggagggtctggaggtggagggagcg gcggaggcgggtctggcggtggtgggtctgagaggaagtcatcagtggaa tgcccaccatgccctgctcctcccgtggccggtccgagcgtgtttctctt cccacc taagcccaaggacactctgatgatctcacggactccggaagtga cttgtgtggtggtggacgtgtctcatgaggaccctgaagtgcagttcaac tggtacgtggacggcgtggaggtgcacaatgctaagaccaagcctagaga ggaacagttcaattccacctttcgcgtggtgagcgtcctgaccgtcgtgc accagg actggcttaacggaaaggaatacaagtgcaaggtgtccaacaaa ggccttccagctcccattgagaaaaccatctctaaaactaagggtcaacc aagggaaccccaagtctacaccctccctccgtctagagaagagatgacca aaaaccaggtgtccctgacctgtctggtgaagggattttacccctcagac atcgccgtggagtgggaaagca acggacagcccgaaaacaactataagac tacccctcctatgctggactcagacggatctttcttcctctatagcaagc tcactgtggacaaatccagatggcaacaagggaatgtgttctcatgcagc gtgatgcacgaggctcttcacaaccactatacccagaagagcctgtctct ttcacctggttccggaggtggtgggagcggag ggggtggatcaggtggtg gagggtccggaggcggaggatccgcacggaatggcgaccactgtccactg ggacccggaagatgttgtcgcctccacaccgtgagggcctctctggagga ccttggctgggccgactgggtcctgtcacctcgggaggtccaagtcaeca tgtgtatcggagcctgccccagccaattcagagca gcaaatatgcacgca gardenattaagaccagcctgcatcggcttaaacctgatactgtgccggctee ttgttgcgtgccagcatcttacaacccgatggtgctgatccagaaaaccg ataccggtgtctccctccagacttacgacgacctccttgcaaaggactgc cattgcatc (SEQ ID NO:36).

As discussed above, according to a specific embodiment of the present invention there is provided a homodimer that contains two monomers containing the sequence SEQ ID NO: 37.

II.D. Knob/Hole.

Definitions knob or knobFc domain in the present invention means an Fc domain containing a knob mutation (overhang). The definitions of hole or holeFc domain in the present invention mean a native Fc or an Fc variant containing a hole mutation.

Knob mutations can be produced by replacing small side chain amino acids with larger amino acids, and hole mutations can be produced by replacing large side chain amino acids with smaller amino acids. See, for example, Ridgway JBB 1996, Protein Eng. 9:617-621; Merchant AM 1998, Nature Biotech. 16:677-681.

In one embodiment of the present invention, a knobFc domain is generated by introducing a threonine to tryptophan mutation (T366W) into the Fc domain sequence. According to one embodiment of the present invention, the holeFc domain is obtained by introducing into

- 24 046387 sequence of the Fc domain of the threonine to serine mutation (T366S), the leucine to alanine mutation (L368A) and the tyrosine to valine mutation (Y407V).

The C-terminal lysine (K447) may optionally be removed in the knobFc domain, holeFc domain, or both domains. This modification may be advantageous, for example when the peptide is fused at the C-terminus, to reduce proteolysis of the fusion protein.

According to one embodiment of the present invention, the DhknobFc domain is obtained by introducing a threonine to tryptophan mutation (T366W) into the sequence of the Fc domain from which all or part of the hinge region has been removed. In one embodiment of the present invention, a DhholeFc domain is generated by introducing into a sequence an Fc domain from which all or part of the hinge region has been removed, a threonine to series mutation (T366S), a leucine to alanine mutation (L368A), and a tyrosine to valine mutation (Y407V ).

The C-terminal lysine (K447) may optionally be removed in DhknobFc, DhholeFc, or both domains. This modification may be advantageous, for example when the peptide is fused at the C-terminus, to reduce proteolysis of the fusion protein.

In some embodiments, the present invention provides a heterodimer that comprises (i) a first polypeptide chain comprising a GDF15 region linked to a holeFc domain directly or via a polypeptide linker, and (ii) a second polypeptide chain comprising a knobFc domain. In other embodiments, the present invention provides a heterodimer that comprises (i) a first polypeptide chain comprising a GDF15 region linked to a knobFc domain directly or via a polypeptide linker, and (ii) a second polypeptide chain comprising a holeFc domain.

In some embodiments, the present invention provides a heterodimer that comprises (i) a first polypeptide chain comprising a GDF15 region linked to a DhholeFc domain directly or via a polypeptide linker, and (ii) a second polypeptide chain comprising a DhknobFc domain. In other embodiments, the present invention provides a heterodimer that comprises (i) a first polypeptide chain comprising a GDF15 region linked to a DhknobFc domain directly or via a polypeptide linker, and (ii) a second polypeptide chain comprising a DhholeFc domain.

According to some embodiments of the present invention, there is provided a tetramer comprising two such heterodimers, in which the heterodimers are linked via an interchain disulfide bond between the GDF15 regions of the respective first polypeptide chains of the heterodimers. For a graphical representation of an embodiment of a heterotetramer containing two heterodimers, in which each heterodimer contains (i) a first polypeptide chain containing a GDF15 polypeptide that is connected to a DhknobFc domain via a polypeptide linker, and (ii) a second polypeptide chain containing a DhholeFc domain, see .in fig. 1.

DhknobFc-(G ₄ S) ₄ -GDF15:DhholeFc.

The definition of DhknobFc-(G ₄ S) ₄ -GDF15:DhholeFc in the present invention means a heterodimer that contains (i) a first polypeptide chain containing a GDF15 polypeptide connected to a DhknobFc domain via a linker that contains the sequence SEQ ID NO: 18 and which connects the N-terminus of the GDF15 polypeptide to the C-terminus of the DhknobFc domain, and (ii) a polypeptide chain containing the DhholeFc domain.

According to certain embodiments of the present invention, there is provided a tetramer comprising a dimer of two DhknobFc-(G ₄ S) ₄ -GDF15:DhholeFc heterodimers, in which the first polypeptide chains of each heterodimer are connected through an interchain disulfide bond between the corresponding GDF15 regions of these chains.

More specifically, according to a particular embodiment of the present invention, the tetramer comprises:

(a) two DhknobFc domains (in each heterodimer) containing the sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA

PIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLWCLVKGFYPSDIAVE

WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE

ALHNHYTQKSLSLSPG (SEQ ID NO:16), (b) two DhholeFc domains (in each heterodimer) containing the sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPA

PIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLSCAVKGFYPSDIAVE

WESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHE

ALHNHYTQKSLSLSPG (SEQ ID NO:281),

- 25 046387 (c) two GDF15 polypeptides (in each heterodimer) containing the sequence SEQ ID NO: 12, and (d) two polypeptide linkers (in each heterodimer) containing the sequence SEQ ID NO: 18, each of which binds N- end of the GDF15 polypeptide with the C-terminus of the DhknobFc domain via peptide bonds.

According to a preferred embodiment of the present invention, the first polypeptide chain contains the amino acid sequence (the linker sequence is underlined by a double line):

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVD GVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLWCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHE ALHNHY T QKSLSLSP GGGGGSGGGGSGGGGSGGGGSARNGDHCPLGРGRC CRLHTVRASLEDLGWADWVLSPREVQVTMCIGACPSQFRAANMHAQIKTS LHRLKPDTVPAPCCVPASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:2 0) which is encoded by the nucleic acid sequence: gcacctga actcctggggggaccgtcagtcttcctcttccccccaaaacc caaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtgg tggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggac ggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaa cagcacgtaccgtgtggt cagcgtcctcaccgtcctgcaccaggactggc tgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcc cccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccaca ggtgtacaccctgcccccatcccgggatgagctgaccaagaaccaggtca gcctgtggtgcctggtcaaaggcttctatc ccagcgacatcgccgtggag tgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgt gctggactccgacggctccttcttcctctacagcaagctcaccgtggaca agagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgag gctctgcacaaccactacacgcagaagagcctctccctgtctcc gggtgg aggtggtggatccggaggcggtggaagcggaggtggtggatctggaggcg gtggaagcgcgcgcaacggagaccactgtccgctcgggcccgggcgttgc tgccgtctgcacacggtccgcgcgtcgctggaagacctgggctgggccga ttgggtgctgtcgccacgggaggtgcaag tgaccatgtgcatcggcgcgt gcccgagccagttccgggcggcaaacatgcacgcgcagatcaagacgagc ctgcaccgcctgaagcccgacacggtgccagcgccctgctgcgtgcccgc cagctacaatcccatggtgctcattcaaaagaccgacaccggggtgtcgc tccagacctatgatgacttg ttagccaaagactgccactgcatatga (SEQ ID NO :19) .

According to a preferred embodiment of the present invention, the second polypeptide chain contains the amino acid sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVD GVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLSCAVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQ GNVFSCSVMHE ALHNHYTQKSLSLSPGK (SEQ ID NO:17), which is encoded by the nucleic acid sequence:

- 26 046387 gcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacc caaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtgg tggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggac ggcgtggaggtgcataatgccaagacaaagccgcgggaggagca gtacaa cagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggc tgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcc cccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccaca ggtgtacaccctgcccccatcccgggatgagctgaccaagaaccaggtca gcctga gctgcgcggtcaaaggcttctatcccagcgacatcgccgtggag tggggagagcaatgggcagccggagaacaactacaagaccacgcctcccgt gctggactccgacggctccttcttcctcgtcagcaagctcaccgtggaca agagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgag gctctgca caaccactacacgcagaagagcctctccctgtctccggggtaa atga (SEQ ID NO:21)

As discussed above, according to a specific embodiment of the present invention, there is provided a tetramer that contains two monomers containing the sequence SEQ ID NO: 20 and two monomers containing the sequence SEQ ID NO: 17.

II.E. Charged pair (charged pair, delHinge).

The definition of CpmFc(+) domain in the present invention means an Fc domain containing a positively charged pair of mutations. The definition of CpmFc(-) domain in the present invention means an Fc domain containing a negatively charged pair of mutations. It should be noted that the use of the terms positive and negative is intended for convenience of description (ie, to describe the nature of the charged pair of mutations in the Fc domains) and does not imply that the sequence or construct as a whole is necessarily positively or negatively charged.

In one embodiment of the present invention, a positively charged mutation pair is generated by introducing a glutamic acid to lysine mutation (E356K) and an aspartic acid to lysine mutation (D399K) into the Fc domain sequence. According to one embodiment of the present invention, a negatively charged pair of mutations is obtained by introducing mutations of two lysines to aspartic acid (K392D, K409D) into the Fc domain sequence.

When incubated together, aspartate residues bind to lysine residues through electrostatic interactions, which facilitates the formation of heterodimers between CpmFc(+) domains and CpmFc(−) domains and reduces or prevents the formation of heterodimers between CpmFc(+) sequences or between CpmFc(−) sequences.

The C-terminal lysine (K447) may optionally be removed in the CpmFc(+) domain, the CpmFc(-) domain, or both domains. This modification may be advantageous, for example when the peptide is fused at the C-terminus, to reduce proteolysis of the fusion protein.

In one embodiment of the present invention, a DhCpmFc(+) domain is generated by introducing into a sequence an Fc domain from which all or part of the hinge region has been removed, a glutamic acid to lysine mutation (E356K) and an aspartic acid to lysine mutation (D399K). According to one embodiment of the present invention, the DhCpmFc() domain is obtained by introducing mutations of two lysines to aspartic acid (K392D, K409D) into the sequence of the Fc domain from which all or part of the hinge region has been removed.

When incubated together, aspartate residues bind to lysine residues through electrostatic interactions, which facilitates the formation of heterodimers between DhCpmFc(+) domains and DhCpmFc(−) domains and reduces or prevents the formation of homodimers between DhCpmFc(+) sequences or between DhCpmFc(−) sequences.

The C-terminal lysine (K447) may optionally be removed in DhCpmFc(+), DhCpmFc(-) or both domains. This modification may be advantageous, for example when the peptide is fused at the C-terminus, to reduce proteolysis of the fusion protein.

In some embodiments, the present invention provides a heterodimer that comprises (i) a first polypeptide chain comprising a GDF15 region coupled to a CpmFc(+) domain, and (ii) a second polypeptide chain comprising a CpmFc(-) domain. In some embodiments of the present invention, the N-terminus of the GDF15 region is connected to the C-terminus of the CpmFc(+) domain directly or through a polypeptide linker. In other embodiments of the present invention, the N-terminus of the CpmFc(+) domain is connected to the C-terminus of the GDF15 region directly or through a polypeptide linker.

According to other embodiments of the present invention, there is provided a heterodimer that

- 27 046387 contains (i) a first polypeptide chain containing a GDF15 region connected to a CpmFc(-) domain, and (ii) a second polypeptide chain containing a CpmFc(+) domain. In some embodiments of the present invention, the N-terminus of the GDF15 region is connected to the C-terminus of the CpmFc(-) domain directly or through a polypeptide linker. In other embodiments of the present invention, the N-terminus of the CpmFc(-) domain is connected to the C-terminus of the GDF15 region directly or through a polypeptide linker.

In some embodiments, the present invention provides a heterodimer that comprises (i) a first polypeptide chain comprising a GDF15 region coupled to a DhCpmFc(+) domain, and (ii) a second polypeptide chain comprising a DhCpmFc(-) domain. In some embodiments of the present invention, the N-terminus of the GDF15 region is connected to the C-terminus of the DhCpmFc(+) domain directly or through a polypeptide linker. In other embodiments of the present invention, the N-terminus of the DhCpmFc(+) domain is connected to the C-terminus of the GDF15 region directly or through a polypeptide linker.

In other embodiments, the present invention provides a heterodimer that comprises (i) a first polypeptide chain comprising a GDF15 region coupled to a DhCpmFc(-) domain, and (ii) a second polypeptide chain comprising a DhCpmFc(+) domain. In some embodiments of the present invention, the N-terminus of the GDF15 region is connected to the C-terminus of the DhCpmFc(-) domain directly or through a polypeptide linker. In other embodiments of the present invention, the N-terminus of the DhCpmFc(-) domain is connected to the C-terminus of the GDF15 region directly or through a polypeptide linker.

According to some embodiments of the present invention, there is provided a tetramer containing a dimer consisting of two such heterodimers, in which the first two polypeptide chains of the heterodimers are connected through an interchain disulfide bond between the corresponding GDF15 regions of these chains. Graphical representation of an embodiment of a tetramer containing two heterodimers, in which each heterodimer contains (i) a first polypeptide chain containing a GDF15 polypeptide connected via a polypeptide linker to a DhCpmFc(-) domain, and (ii) a second polypeptide chain containing a DhCpmFc(+) domain ), see in Fig. 4.

II.E.1 DhCpmFc(+)-(1K)-GDF15:DhCpmFc(-).

The definition of DhCpmFc(+)-(1K)-GDF15:DhCpmFc(-) in the present invention means a heterodimer that contains (i) a first polypeptide chain containing a GDF15 polypeptide that is connected to a DhCpmFc(+) domain by a linker that contains the sequence SEQ ID NO: 40 and which connects the N-terminus of the GDF15 polypeptide to the C-terminus of the DhCpmFc(+) domain, and (ii) a second polypeptide chain containing the DhCpmFc(-) domain.

According to certain embodiments of the present invention, there is provided a tetramer containing a dimer consisting of two heterodimers DhCpmFc(+)-(1K)-GDF15:DhCpmFc(-), in which the first two polypeptide chains of each heterodimer are connected through an interchain disulfide bond between the corresponding GDF15 data regions chains.

More specifically, according to a particular embodiment of the present invention, the tetramer comprises:

(a) two DhCpmFc(+) domains (in each heterodimer) containing the sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA

PIEKTISKAKGQPREPQVYTLPPSRKEMTKNQVSLTCLVKGFYPSDIAVE

WESNGQPENNYKTTPPVLKSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE

ALHNHYTQKSLSLSPG (SEQ ID NO:38), (b) two DhCpmFc(-) domains (in each heterodimer) containing the sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA

PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE

WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHE

ALHNHYTQKSLSLSPG (SEQ ID NO:282), (c) two GDF15 polypeptides (in each heterodimer) containing the sequence SEQ ID NO: 12, and (d) two polypeptide linkers (in each heterodimer) containing the sequence: GSGSATGGSGSVASSGSGSATHL (SEQ ID NO :40), each of which connects the N-terminus of the GDF15 polypeptide to the C-terminus of the DhCpmFc(+) domain via a peptide bond.

According to a preferred embodiment of the present invention, the first polypeptide chain contains an amino acid sequence (the linker sequence is double underlined

- 28 046387 with a dash):

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVD GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPSRKEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLKSDGSFFLYSKLTVDKSR WQQGNVFSCSVMHE ALHNHYTQKSLSLSPGGSGSATGGSGSVASSGSGSATHLARNGDHCPLGP GRCCRLHTVRAS LE DLGWADWVL S PREVQVTMCIGAG P S Q FRAANMHAQI KTSLHRLKPDTVPAPCCVPASYNPMVLIQKTDTGVSLQTYDDLLAKDCHC I (SEQ ID NO:42), which is encoded by the nucleic acid sequence: gcc ccagagctgcttggtggaccatccgtgttcctgtttcctccaaagcc gaaggacaccctgatgatctcaagaactccggaagtgacttgcgtcgtcg tggacgtgtcacatgaggatccagaggtcaagttcaattggtatgtggac ggagtggaagtgcataacgccaagaccaaaccccgcgaagaacagtacaa tagcacctaccg cgtggtgagcgtccttactgtgctccaccaggactggc ttaatgggaaggaatacaagtgtaaggtgtccaacaaggccctccccgct cccatcgaaaagaccatctcaaaggcaaaggggcaaccaagggaacctca agtgtacaccctgcctccgagcaggaaggagatgaccaagaaccaggtca gcctgacttgtctcgtgaag ggcttctatcccagcgatattgctgtggaa tgggagtcaaatggccagcccgagaataactacaaaactaccccacccgt gctgaaatctgatgggtccttcttcctttactccaagctgaccgtggaca agagccgctggcaacaaggcaatgtctttagctgctcagtgatgcatgag gctctccataatcactacactcagaagtcact gtccctgtcacctggcgg atccggttctgctactggtggttccggctccgtcgcaagctctggttcag gcagtgcgactcatctggcacggaacggggaccattgtcccctgggacct ggtcggtgctgccggcttcacaccgtcagagcctctctggaggaccttgg atgggctgattgggtgctgagccctcgggaggtg caagtcaccatgtgca tcggggcctgccctagccagttccgcgcagccaacatgcacgctcagatc aaaacctctcttcacagactgaagcccgacaccgtgccagcaccttgctg tgtgccggcctcttataaccccatggtcctcattcagaaaaccgacaccg gagtgtcacttcagacttacgatgacctcctggccaa ggactgccactgc ata (SEQ ID NO:41).

In a preferred embodiment of the present invention, the second polypeptide chain comprises the amino acid sequence

APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD GVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQG NVFSCSVMHE ALHNHYTQKSLSLSPGK (SEQ ID NO:39), which is encoded by the nucleic acid sequence: gcgccggaactgctgggcggcccgagcgtgtttctgtttccgccgaaacc gaaagataccctgatgattagccgcaccccggaagtgacctgcgtggtgg tggatgtgagccatgaagatccggaagtgaaatttaact ggtatgtggat ggcgtggaagtgcataacgcgaaaaccaaaccgcgcgaagaacagtataa cagcacctatcgcgtggtgagcgtgctgaccgtgctgcatcaggattggc tgaacggcaaagaatataaatgcaaagtgagcaacaaagcgctgccggcg ccgattgaaaaaaccattagcaaagcgaaaggcca gccgcgcgaaccgca

- 29 046387 ggtgtataccctgccgccgagccgcgaagaaatgaccaaaaaccaggtga gcctgacctgcctggtgaaaggcttttatccgagcgatattgcggtggaa tgggaaagcaacggccagccggaaaacaactatgataccaccccgccggt gctggatagcgatggcagcttttttctgta tagcgatctgaccgtggata aaagccgctggcagcagggcaacgtgtttagctgcagcgtgatgcatgaa gcgctgcataaccattatacccagaaaagcctgagcctgagcccgggcaa a (SEQ ID NO:43).

As discussed above, a tetramer is provided containing two polypeptide chains that contain the sequence SEQ ID NO: 42, and two polypeptide chains that contain the sequence SEQ ID NO: 39.

II.E.2 DhCpmFc(-)-GDF15:DhCpmFc(+).

The definition of DhCpmFc(-)-GDF15:DhCpmFc(+) in the present invention means a heterodimer that contains (i) a first polypeptide chain containing a GDF15 polypeptide, the N-terminus of which is connected directly to the C-terminus of the DhCpmFc(-) domain, and (ii ) second polypeptide chain containing the DhCpmFc(+) domain.

According to certain embodiments of the present invention, there is provided a tetramer comprising a dimer consisting of two DhCpmFc(-)-GDF15:DhCpmFc(+) heterodimers, in which the first two polypeptide chains of each heterodimer are connected through an interchain disulfide bond between the corresponding GDF15 regions of these chains.

More specifically, according to a particular embodiment of the present invention, the tetramer comprises:

(a) two DhCpmFc(+) domains (in each heterodimer) containing the amino acid sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPSRKEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLKSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPG(SEQ ID NO:283), (b ) two DhCpmFc(-) domains (in each heterodimer) containing the amino acid sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPG(SEQ ID NO :48), and (c) two poly GDF15 peptide (in each heterodimer) containing the sequence SEQ ID NO: 12.

According to a preferred embodiment of the present invention, the first polypeptide chain contains the amino acid sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPGARNGDHCPLGPGRCCRLHTVRASLEDLGW ADWVL S PREVQVTMCIGAG P S Q FRAANMHAQIKT S LHRLKPDTVPAPCCVPAS YN PMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:50), which is encoded by the nucleic acid sequence:

- 30 046387 gcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacc caaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtgg tggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggac ggcgtggaggtgcataatgccaagacaaagccgcgggaggagca gtacaa cagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggc tgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcc cccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccaca ggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtca gcctgacc tgcctggtcaaaggcttctatcccagcgacatcgccgtggag tggggagagcaatgggcagccggagaacaactacgacaccacgcctcccgt gctggactccgacggctccttcttcctctatagcgacctcaccgtggaca agagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgag gctctgcacaaccact acacgcagaagagcctctccctgtctccgggtgc gcgcaacggagaccactgtccgctcgggcccgggcgttgctgccgtctgc acacggtccgcgcgtcgctggaagacctgggctgggccgattgggtgctg tcgccacgggaggtgcaagtgaccatgtgcatcggcgcgtgcccgagcca gttcc gggcggcaaacatgcacgcgcagatcaagacgagcctgcaccgcc tgaagcccgacacggtgccagcgccctgctgcgtgcccgccagctacaat cccatggtgctcattcaaaagaccgacaccggggtgtcgctccagaccta tgatgacttgttagccaaagactgccactgcata (SEQ ID NO:49).

According to a preferred embodiment of the present invention, the second polypeptide chain contains the amino acid sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVD GVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPSRKEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLKSDGSFFLYSKLTVDKSRW QQGNVFSCSVMHE ALHNHYTQKSLSLSPGK(SEQ ID NO:47), which is encoded by the nucleic acid sequence:

gcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacc caaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtgg tggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggac ggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaa cagcacgtacc gtgtggtcagcgtcctcaccgtcctgcaccaggactggc tgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcc cccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccaca ggtgtacaccctgcccccatcccggaaggagatgaccaagaaccaggtca gcctgacctgcctggtcaaagg cttctatcccagcgacatcgccgtggag tgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgt getgaagtccgacggctccttcttoctetatagcaagctcaccgtggaca agagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgag gctctgcacaaccactacacgcagaagagcctctccct gtctccgggtaa atga (SEQ ID NO:51).

As discussed above, a tetramer is provided containing two polypeptide chains that contain the sequence SEQ ID NO: 50, and two polypeptide chains that contain the sequence SEQ ID NO: 47.

II.E.3 DhCpmFc(-)-GDF15(N3D):DhCpmFc(+).

The definition of DhCpmFc(-)-GDF15(N3D):DhCpmFc(+) in the present invention means a heterodimer that contains (i) a first polypeptide chain containing a naturally occurring variant of GDF15 that contains a mutation of asparagine to aspartic acid (N3D) (GDF15( N3D)) and

- 31 046387

The N-terminus of which is connected directly to the C-terminus of the DhCpmFc(-) domain, and (ii) a second polypeptide chain containing the DhCpmFc(+) domain. The N3D mutation may reduce the heterogeneity caused by deamidation.

According to certain embodiments of the present invention, there is provided a tetramer containing a dimer consisting of two heterodimers DhCpmFc(-)-GDF15(N3D):DhCpmFc(+), in which the first two polypeptide chains of each heterodimer are connected through an interchain disulfide bond between the corresponding GDF15 regions of these chains .

More specifically, according to a particular embodiment of the present invention, the tetramer comprises:

(a) two DhCpmFc(+) domains (in each heterodimer) containing the sequence SEQ ID NO: 283, (b) two DhCpmFc(-) domains (in each heterodimer) containing the sequence SEQ ID NO: 48, and (c) two GDF15(N3D) polypeptides (in each heterodimer) containing the sequence: ARDGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPREVQVTMCIGACPS QFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYNPMVLIQKTDTGVSLQT

YDDLLAKDCHCI (SEQ ID NO:52).

According to a preferred embodiment of the present invention, the first polypeptide chain contains the amino acid sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVD GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQG NVFSCSVMHE ALHNHYTQKSLSLSPGARDGDHCPLGPGRCCRLHTVRASLEDLGWADWVL S PREVQVTMCIGAC R S Q FRAANMHAQIKT S LHRLKPDTVPAPCCVPAS YN PMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:54), which is encoded by the nucleic acid sequence: gcacctgaactcctggggggaccgtcagt cttcctcttccccccaaaacc caaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtgg tggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggac ggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaa cagcacgtaccgtgtggtcagcgtcctcaccgtcc tag ggagagcaatgggcagccggagaacaactacgacaccacgcctcccgt gctggactccgacggctccttcttcctctatagcgacctcaccgtggaca agagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgag gctctgcacaaccactacacgcagaagagcctctccctgtctccgggtgc gcgcgacggag accactgtccgctcgggcccggggcgttgctgccgtctgc acacggtccgcgcgtcgctggaagacctgggctgggccgattgggtgctg tcgccacgggaggtgcaagtgaccatgtgcatcggcgcgtgcccgagcca gttccgggcggcaaacatgcacgcgcagatcaagacgagcctgcaccg cc tgaagcccgacacggtgccagcgccctgctgcgtgcccgccagctacaat cccatggtgctcattcaaaagaccgacaccggggtgtcgctccagaccta tgatgacttgttagccaaagactgccactgcata (SEQ ID NO:53).

In a preferred embodiment of the present invention, the second polypeptide chain comprises the amino acid sequence SEQ ID NO: 47, which is encoded by the nucleic acid sequence SEQ ID NO: 51.

As discussed above, a tetramer is proposed containing two polypeptide chains that

- 32 046387 contain the sequence SEQ ID NO: 54, and two polypeptide chains that contain the sequence SEQ ID NO: 47.

II.E.4 DhCpmFc(-)-GDF15(Ndel3):DhCpmFc(+).

The definition of DhCpmFc(-)-GDF15(Ndel3):DhCpmFc(+) in the present invention means a heterodimer that contains (i) a first polypeptide chain containing a variant of GDF15 in which the first three amino acids are deleted (GDF15(Ndel3) and the N-terminus of which connected directly to the C-terminus of the DhCpmFc(-) domain, and (ii) a second polypeptide chain containing the DhCpmFc(+) domain.The Ndel3 variant may reduce N3 deamidation and heterogeneity caused by D3 isomerization.

According to certain embodiments of the present invention, there is provided a tetramer that contains a dimer consisting of two heterodimers DhCpmFc(-)-GDF15(Ndel3):DhCpmFc(+), in which the first two polypeptide chains of each heterodimer are connected through an interchain disulfide bond between the corresponding GDF15 data regions chains.

More specifically, according to a particular embodiment of the present invention, the tetramer comprises:

(a) two DhCpmFc(+) domains (in each heterodimer) containing the sequence SEQ ID NO: 283, (b) two DhCpmFc(-) domains (in each heterodimer) containing the sequence SEQ ID NO: 48, and (c) two GDF15(Ndel3) polypeptides (in each heterodimer) containing the sequence: GDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPREVQVTMCIGACPSQFR AANMHAQIKTSLHRLKPDTVPAPCCVPASYNPMVLIQKTDTGVSLQTYDD

LLAKDCHCI (SEQ ID NO:55).

According to a preferred embodiment of the present invention, the first polypeptide chain contains the amino acid sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD GVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQG NVFSCSVMHE ALHNHYTQKSLSLSPGGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPR EVQVTMCIGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYNPMV LIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:57), which is encoded by the nucleic acid sequence: gcacctgaactcctggggggaccgtcagtcttcctcttcc ccccaaaacc caaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtgg tggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggac ggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaa cagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactgg c tgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcc cccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccaca ggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtca gcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggag tgggagagcaatggg cagccggagaacaactacgacaccacgcctcccgt gctggactccgacggctccttcttcctctatagcgacctcaccgtggaca agagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgag gctctgcacaaccactacacgcagaagagcctctccctgtctccgggtgg agaccactgtccgctcgggcccggg cgttgctgccgtctgcacacggtcc gcgcgtcgctggaagacctgggctgggccgattgggtgctgtcgccacgg gaggtgcaagtgaccatgtgcatcggcgcgtgcccgagccagttccgggc ggcaaacatgcacgcgcagatcaagacgagcctgcaccgcctgaagcccg acacggtg ccagcgccctgctgcgtgcccgccagctacaatcccatggtg ctcattcaaaagaccgacaccggggtgtcgctccagacctatgatgactt gttagccaaagactgccactgcata (SEQ ID NO:56).

According to a preferred embodiment of the present invention, the second polypeptide

- 33 046387 chain contains the amino acid sequence SEQ ID NO: 47, which is encoded by the nucleic acid sequence SEQ ID NO: 51.

As discussed above, a tetramer is provided containing two polypeptide chains that contain the sequence SEQ ID NO: 57, and two polypeptide chains that contain the sequence SEQ ID NO: 47.

II.E.5 DhCpmFc(-)-G ₄ -GDF15(N3D):DhCpmFc(+).

The definition of DhCpmFc(-)-G ₄ -GDF15(N3D):DhCpmFc(+) in the present invention means a heterodimer that contains (i) a first polypeptide chain containing a GDF15(N3D) polypeptide connected to a DhCpmFc(-) domain via a linker, which contains the sequence SEQ ID NO: 58 and which connects the N-terminus of the GDF15(N3D) polypeptide to the C-terminus of the DhCpmFc(-) domain, and (ii) a second polypeptide chain containing the DhCpmFc(+) domain.

According to certain embodiments of the present invention, there is provided a tetramer that contains a dimer consisting of two heterodimers DhCpmFc(-)-G ₄ -GDF15(N3D):DhCpmFc(+), in which the first two polypeptide chains of each heterodimer are connected through an interchain disulfide bond between the corresponding GDF15 areas of these circuits.

More specifically, according to a particular embodiment of the present invention, the tetramer comprises:

(a) two DhCpmFc(+) domains (in each heterodimer) containing the sequence SEQ ID NO: 283, (b) two DhCpmFc(+) domains (in each heterodimer) containing the sequence SEQ ID NO: 48, (c) two a GDF15(N3D) polypeptide (in each heterodimer) containing the sequence SEQ ID NO: 52, and (d) two polypeptide linkers (in each heterodimer) containing the sequence:

each of which connects the N-terminus of the GDF15(N3D) polypeptide to the C-terminus of the DhCpmFc(-) domain via peptide bonds.

According to a preferred embodiment of the present invention, the first polypeptide contains the amino acid sequence (the linker sequence is underlined by a double line):

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPG^^ARDGDHCPLGPGRCCRLHTVRASLEDL GWA DWVL S PREVQVTMCIGAC P S Q FRAANMHAQIKT S LHRLKP DTVPAP WITH CVP ASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:60), which is encoded by the nucleic acid sequence: gcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacc caaggacaccctcatgatctcccggacccctga ggtcacatgcgtggtgg tggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggac ggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaa cagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggc tgaatggcaaggagtacaagtgcaaggtctccaaca aagccctcccagcc cccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccaca ggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtca gcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggag tggggagagcaatgggcagccggagaacaactacgacaccacgcctcccgt gct ggactccgacggctccttcttcctctatagcgacctcaccgtggaca

- 34 046387 agagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgag gctctgcacaaccactacacgcagaagagcctctccctgtctccgggtgg aggtggtggagcgcgcgacggagaccactgtccgctcgggcccgggcgtt gctgccgtctgcacacggtccgcgcgt cgctggaagacctgggctgggcc gattgggtgctgtcgccacgggaggtgcaagtgaccatgtgcatcggcgc gtgcccgagccagttccgggcggcaaacatgcacgcgcagatcaagacga gcctgcaccgcctgaagcccgacacggtgccagcgccctgctgcgtgccc gccagctacaatcccatggt gctcattcaaaagaccgacaccggggtgtc gctccagacctatgatgacttgttagccaaagactgccactgcata (SEQ ID NO:59).

In a preferred embodiment of the present invention, the second polypeptide chain comprises the amino acid sequence SEQ ID NO: 47, which is encoded by the nucleic acid sequence SEQ ID NO: 51.

As discussed above, a tetramer is provided containing two polypeptide chains that contain the sequence SEQ ID NO: 60, and two polypeptide chains that contain the sequence SEQ ID NO: 47.

II.E.6 DhCpmFc(-)-G ₄ S-GDF15:DhCpmFc(+).

The definition of DhCpmFc(-)-G ₄ S-GDF15:DhCpmFc(+) in the present invention means a heterodimer that contains (i) a first polypeptide chain containing a GDF15 polypeptide that is connected to a DhCpmFc(-) domain via a polypeptide linker that contains the sequence SEQ ID NO: 61 and which connects the N-terminus of the GDF15 polypeptide to the C-terminus of the DhCpmFc(-) domain, and (ii) a second polypeptide chain containing the DhCpmFc(+) domain.

According to certain embodiments of the present invention, there is provided a tetramer that contains a dimer consisting of two heterodimers DhCpmFc(-)-G ₄ S-GDF15:DhCpmFc(+), in which the first two polypeptide chains of each heterodimer are connected through an interchain disulfide bond between the corresponding regions of GDF15 circuit data.

More specifically, according to a particular embodiment of the present invention, the tetramer comprises:

(a) two DhCpmFc(+) domains (in each heterodimer) containing the sequence SEQ ID NO: 283, (b) two DhCpmFc(-) domains (in each heterodimer) containing the sequence SEQ ID NO: 48, (c) two a GDF15 polypeptide (in each heterodimer) containing the sequence SEQ ID NO: 12, and (d) two polypeptide linkers (in each heterodimer) containing the sequence:

GGGGS (SEQ ID NO:61), each of which connects the N-terminus of the GDF15 polypeptide to the C-terminus of the DhCpmFc(-) domain via peptide bonds.

According to a preferred embodiment of the present invention, the first polypeptide contains the amino acid sequence (the linker is underlined by a double line): APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD GVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPS DIAVE WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPG^^^ARNGDHCPLGPGRCCRLHTVRASLEDLGW ADWVLSPREVQVTMCIGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCV PASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:63), which is encoded sequentially nucleic acid strength:

- 35 046387 gcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacc caaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtgg tggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggac ggcgtggaggtgcataatgccaagacaaagccgcgggaggagca gtacaa cagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggc tgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcc cccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccaca ggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtca gcctgacc tgcctggtcaaaggcttctatcccagcgacatcgccgtggag tggggagagcaatgggcagccggagaacaactacgacaccacgcctcccgt gctggactccgacggctccttcttcctctatagcgacctcaccgtggaca agagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgag gctctgcacaaccact acacgcagaagagcctctccctgtctccgggtgg aggtggtggatccgcgcgcaacggagaccactgtccgctcgggcccgggc gttgctgccgtctgcacacggtccgcgcgtcgctggaagacctgggctgg gccgattgggtgctgtcgccacgggaggtgcaagtgaccatgtgcatcgg cgcgtg cccgagccagttccgggcggcaaacatgcacgcgcagatcaaga cgagcctgcaccgcctgaagcccgacacggtgccagcgccctgctgcgtg cccgccagctacaatcccatggtgctcattcaaaagaccgacaccggggt gtcgctccagacctatgatgacttgttagccaaagactgccactgcatat ga (SEQ ID NO :62).

In a preferred embodiment of the present invention, the second polypeptide comprises the amino acid sequence SEQ ID NO: 47, which is encoded by the nucleic acid sequence SEQ ID NO: 51.

As discussed above, a tetramer is provided containing two polypeptide chains that contain the sequence SEQ ID NO: 63, and two polypeptide chains that contain the sequence SEQ ID NO: 47.

II.E.7 DhCpmFc(-)-(G ₄ S) ₂ -GDF15:DhCpmFc(+).

The definition of DhCpmFc(-)-(G ₄ S) ₂ -GDF15:DhCpmFc(+) in the present invention means a heterodimer that contains (i) a first polypeptide chain containing a GDF15 polypeptide, which is connected to a DhCpmFc(-) domain via a polypeptide linker, which contains the sequence SEQ ID NO: 64 and which connects the N-terminus of the GDF15 polypeptide to the C-terminus of the DhCpmFc(-) domain, and (ii) a second polypeptide chain containing the DhCpmFc(+) domain.

According to certain embodiments of the present invention, there is provided a tetramer that contains a dimer consisting of two heterodimers DhCpmFc(-)-(G ₄ S) ₂ -GDF15:DhCpmFc(+), in which the first two polypeptide chains of each heterodimer are connected through an interchain disulfide bond between corresponding GDF15 areas of these circuits.

More specifically, according to a particular embodiment of the present invention, the tetramer comprises:

(a) two DhCpmFc(+) domains (in each heterodimer) containing the sequence SEQ ID NO: 283, (b) two DhCpmFc(-) domains (in each heterodimer) containing the sequence SEQ ID NO: 48, (c) two a GDF15 polypeptide (in each heterodimer) containing the sequence SEQ ID NO: 12, and (d) two polypeptide linkers (in each heterodimer) containing the sequence: GGGGSGGGGS (SEQ ID NO: 64), each connecting the N-terminus of the GDF15 polypeptide with the C-terminus of the sequence DhCpmFc(-) via a peptide bond.

According to a preferred embodiment of the present invention, the first polypeptide chain contains the amino acid sequence (the linker is underlined by a double line):

- 36 046387

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVD GVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNV FSCSVMHE ALHNHYTQKSLSLSPGGGGGSGGGGSARNGDHCPLGPGRCCRLHTVRASL EDLGWADWVLSPREVQVTMCIGACPSQFRAANMHAQIKTSLHRLKPDTVP APCCVPASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:66), which is encoded by the nucleic acid sequence: gcacctgaactcctggggggaccgtcagt cttcctcttccccccaaaacc caaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtgg tggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggac ggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaa cagcacgtaccgtgtggtcagcgtcctcaccgtcc tag ggagagcaatgggcagccggagaacaactacgacaccacgcctcccgt gctggactccgacggctccttcttcctctatagcgacctcaccgtggaca agagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgag gctctgcacaaccactacacgcagaagagcctctccctgtctccgggtgg aggtggtggatccgg aggcggtggaagcgcgcgcaacggagaccactgtc cgctcgggcccgggcgttgctgccgtctgcacacggtccgcgcgtcgctg gaagacctgggctgggccgattgggtgctgtcgccacgggaggtgcaagt gaccatgtgcatcggcgcgtgcccgagccagttccgggcggcaaacat gc acgcgcagatcaagacgagcctgcaccgcctgaagcccgacacggtgcca gcgccctgctgcgtgcccgccagctacaatcccatggtgctcattcaaaa gaccgacaccggggtgtcgctccagacctatgatgacttgttagccaaag actgccactgcata (SEQ ID NO:65).

In a preferred embodiment of the present invention, the second polypeptide chain comprises the amino acid sequence SEQ ID NO: 47, which is encoded by the nucleic acid sequence SEQ ID NO: 51.

As discussed above, a tetramer is provided containing two polypeptide chains that contain the sequence SEQ ID NO: 66, and two polypeptide chains that contain the sequence SEQ ID NO: 47.

II.E.8 DhCpmFc(-)-(G4S)2-GDF15(N3D):DhCpmFc(+).

The definition of DhCpmFc(-)-(G ₄ S) ₂ -GDF15(N3D):DhCpmFc(+) in the present invention means a heterodimer that contains (i) a first polypeptide chain containing a GDF15(N3D) polypeptide connected to a DhCpmFc(-) domain ) by means of a linker which contains the sequence SEQ ID NO: 64 and which connects the N-terminus of the GDF15(N3D) polypeptide to the C-terminus of the DhCpmFc(-) domain, and (ii) a second polypeptide chain containing the DhCpmFc(+) domain.

According to certain embodiments of the present invention, there is provided a tetramer that contains a dimer consisting of two heterodimers DhCpmFc(-)-(G ₄ S) ₂ -GDF15(N3D):DhCpmFc(+), in which the first two polypeptide chains of each heterodimer are connected through an interchain disulfide bond between the corresponding GDF15 regions of these chains.

More specifically, according to a particular embodiment of the present invention, the tetramer comprises:

(a) two DhCpmFc(+) domains (in each heterodimer) containing the sequence SEQ ID NO: 283, (b) two DhCpmFc(-) domains (in each heterodimer) containing the sequence SEQ ID NO: 48, (c) two a GDF15(N3D) polypeptide (in each heterodimer) containing the sequence SEQ ID NO: 52, and (d) two polypeptide linkers (in each heterodimer) containing the sequence SEQ ID NO: 64, each of which connects the N-terminus of the GDF15 polypeptide ( N3D) with the C-terminal domain DhCpmFc(

- 37 046387 ) via a peptide bond.

According to a preferred embodiment of the present invention, the first polypeptide chain contains the amino acid sequence (the linker sequence is underlined by a double line):

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVD GVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQG NVFSCSVMHE ALHNHYTOKSLSLSPGGGGGSGGGGSARDGDHCPLGPGRCCRLHTVRASL EDLGWADWVLSPREVQVTMCIGACPSQFRAANMHAQIKTSLHRLKPDTVP APCCVPASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:68), which is encoded by the nucleic acid sequence: gcacctgaactcctggggggaccgtcagt cttcctcttccccccaaaacc caaggacacccteatgatctcccggacccctgaggtcacatgcgtggtgg tggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggac ggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaa cagcacgtaccgtgtggtcagcgtcctcaccgt cctgcaccaggactggc tgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcc cccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccaca ggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtca gcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggag t ggggagagcaatgggcagccggagaacaactacgacaccacgcctcccgt getggactccgacggctcottettoctetatagcgacctcaccgtggaca agagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgag gctctgcacaaccactacacgcagaagagcctctccctgtctccgggtgg aggtggtggatccggaggcgg tggaagcgcgcgcgacggagaccactgtc cgctcgggcccgggcgttgctgccgtctgcacacggtccgcgcgtcgctg gaagacctgggctgggccgattgggtgctgtcgccacgggaggtgcaagt gaccatgtgcatcggcgcgtgcccgagccagttccgggcggcaaacatgc gcgcagatcaagacgagcctgcaccgcctgaagcccgacacggtgcca gcgccctgctgcgtgcccgccagctacaatcccatggtgctcattcaaaa gaccgacaccggggtgtcgctccagacctatgatgacttgttagccaaag actgccactgcata (SEQ ID NO:67).

In a preferred embodiment of the present invention, the second polypeptide chain comprises the amino acid sequence SEQ ID NO: 47, which is encoded by the nucleic acid sequence SEQ ID NO: 51.

As discussed above, a tetramer is provided containing two polypeptide chains that contain the sequence SEQ ID NO: 68, and two polypeptide chains that contain the sequence SEQ ID NO: 47.

II.E.9 DhCpmFc(-)-G ₄ P-GDF15:DhCpmFc(+).

The definition of DhCpmFc(-)-(G ₄ P)-GDF15:DhCpmFc(+) in the present invention means a heterodimer that contains (i) a first polypeptide chain containing a GDF15 polypeptide, which is connected to a DhCpmFc(-) domain via a linker that contains sequence SEQ ID NO: 69 and which connects the N-terminus of the GDF15 polypeptide to the C-terminus of the DhCpmFc(-) domain, and (ii) a second polypeptide chain containing the DhCpmFc(+) domain.

According to certain embodiments of the present invention, there is provided a tetramer that contains a dimer consisting of two heterodimers DhCpmFc(-)-(G ₄ P)-GDF15:DhCpmFc(+), in which the first two polypeptide chains of each heterodimer are connected through an interchain disulfide bond between the corresponding GDF15 areas of these circuits.

More specifically, according to a particular embodiment of the present invention, the tetramer comprises:

(a) two DhCpmFc(+) domains (in each heterodimer) containing the sequence SEQ ID NO: 283, (b) two DhCpmFc(-) domains (in each heterodimer) containing the sequence SEQ ID NO:

- 38 046387

48, (c) two GDF15 polypeptides (in each heterodimer) containing the sequence SEQ ID NO: 12, and (d) two polypeptide linkers (in each heterodimer) containing the sequence: GGGGP (SEQ ID NO: 69), each of which connects the N-terminus of the GDF15 polypeptide to the C-terminus of the DhCpmFc(-) domain via a peptide bond.

According to a preferred embodiment of the present invention, the first polypeptide chain contains the amino acid sequence (the linker sequence is underlined by a double line):

APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD GVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQG NVFSCSVMHE ALHNHYTQKSLSLSPG^QGQPARNGDHCPLGPGRCCRLHTVRASLEDLGW ADWVL S P REVQVTMCIGAG P S Q FRAANMHAQIKTSLHRLKPD TVPAPSCV PASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:71) which is encoded by the nucleic acid sequence: gcacctgaactcctgggggg accgtcagtcttcctcttccccccaaaacc caaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtgg tggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggac ggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaa cagcacgtaccgtgtggtcagcgtcc tcaccgtcctgcaccaggactggc tgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcc cccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccaca ggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtca gcctgacctgcctggtcaaaggcttctatcccagcgacatcgcc gtggag tgggagagcaatgggcagccggagaacaactacgacaccacgcctcccgt gctggactccgacggctccttcttcctctatagcgacctcaccgtggaca agagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgag gctctgcacaaccactacacgcagaagagcctctccctgtctccgggtgg aggt ggtggacccgcgcgcaacggagaccactgtccgctcgggcccgggc gttgctgccgtctgcacacggtccgcgcgtcgctggaagacctgggctgg gccgattgggtgctgtcgccacgggaggtgcaagtgaccatgtgcatcgg cgcgtgcccgagccagttccgggcggcaaacatgcacgcg cagatcaaga cgagcctgcaccgcctgaagcccgacacggtgccagcgccctgctgcgtg cccgccagctacaatcccatggtgctcattcaaaagaccgacaccggggt gtcgctccagacctatgatgacttgttagccaaagactgccactgcata (SEQ ID NO:7 0) .

In a preferred embodiment of the present invention, the second polypeptide chain comprises the amino acid sequence SEQ ID NO: 47, which is encoded by the nucleic acid sequence SEQ ID NO: 51.

As discussed above, a tetramer is provided containing two polypeptide chains that contain the sequence SEQ ID NO: 71, and two polypeptide chains that contain the sequence SEQ ID NO: 47.

II.E.10 DhCpmFc(-)-(G4P)2-GDF 15:DhCpmFc(+).

The definition of DhCpmFc(-)-(G ₄ P) ₂ -GDF15:DhCpmFc(+) in the present invention means a heterodimer that contains (i) a first polypeptide chain containing a GDF15 polypeptide, which is connected to a DhCpmFc(-) domain by a linker that contains the sequence SEQ ID NO: 72 and which connects the N-terminus of the GDF15 polypeptide to the C-terminus of the DhCpmFc(-) domain, and (ii) a second v containing the DhCpmFc(+) sequence.

According to certain embodiments of the present invention, there is provided a tetramer that contains a dimer consisting of two heterodimers DhCpmFc(-)-(G ₄ P) ₂ -GDF15:DhCpmFc(+), in which the first two polypeptide chains of each heterodimer are connected through an interchain disulfide bond between corresponding GDF15 areas of these circuits.

- 39 046387

More specifically, according to a particular embodiment of the present invention, the tetramer comprises:

(a) two DhCpmFc(+) domains (in each heterodimer) containing the sequence SEQ ID NO: 283, (b) two DhCpmFc(-) domains (in each heterodimer) containing the sequence SEQ ID NO: 48, (c) two a GDF15 polypeptide (in each heterodimer) containing the sequence SEQ ID NO: 12, and (d) two polypeptide linkers (in each heterodimer) containing the sequence: GGGGPGGGGP(SEQ ID NO: 72), each connecting the N-terminus of the GDF15 polypeptide with the C-terminus of the DhCpmFc(-) domain via a peptide bond.

According to a preferred embodiment of the present invention, the first polypeptide chain contains the amino acid sequence (the linker sequence is underlined by a double line):

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVD GVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNV FSCSVMHE ALHNHYTQKSLSLSPGGGGGPGGGGPARNGDHCPLGPGRCCRLHTVRASL EDLGWADWVLSPREVQVTMCIGACPSQFRAANMHAQIKTSLHRLKPDTVP APCCVPASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:74), which is encoded by the nucleic acid sequence: gcacctgaactcctggggggaccgtcagt cttcctcttccccccaaaacc caaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtgg tggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggac ggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaa cagcacgtaccgtgtggtcagcgtcctcaccgtcc tag ggagagcaatgggcagccggagaacaactacgacaccacgcctcccgt gctggactccgacggctccttcttcctctatagcgacctcaccgtggaca agagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgag gctctgcacaaccactacacgcagaagagcctctccctgtctccgggtgg aggtggtggacctgg aggcggtggaccagcgcgcaacggagaccactgtc cgctcgggcccgggcgttgctgccgtctgcacacggtccgcgcgtcgctg gaagacctgggctgggccgattgggtgctgtcgccacgggaggtgcaagt gaccatgtgcatcggcgcgtgcccgagccagttccgggcggcaaacatgc acgcgcagatcaagacgagcctgcaccgcctgaagcccgacacggtgcca gcgccctgctgcgtgcccgccagctacaatcccatggtgctcattcaaaa gaccgacaccggggtgtcgctccagacctatgatgacttgttagccaaag actgccactgcatatga (SEQ ID NO:73).

In a preferred embodiment of the present invention, the second polypeptide chain comprises the amino acid sequence SEQ ID NO: 47, which is encoded by the nucleic acid sequence SEQ ID NO: 51.

As discussed above, a tetramer is provided containing two polypeptide chains that contain the sequence SEQ ID NO: 74, and two polypeptide chains that contain the sequence SEQ ID NO: 47.

II.E.11 DhCpmFc(-)-G ₄ Q-GDF 15:DhCpmFc(+).

The definition of DhCpmFc(-)-G ₄ Q-GDF15:DhCpmFc(+) in the present invention means heterodyne

- 40 046387 mer, which contains (i) a first polypeptide chain containing a GDF15 polypeptide that is connected to the DhCpmFc(-) domain by a linker that contains the sequence SEQ ID NO: 75 and that connects the N-terminus of the GDF15 polypeptide to the C-terminus of the domain DhCpmFc(-), and (ii) a second polypeptide chain containing the DhCpmFc(+) domain.

According to certain embodiments of the present invention, there is provided a tetramer that contains a dimer consisting of two heterodimers DhCpmFc(-)-G4Q-GDF15:DhCpmFc(+), in which the first two polypeptide chains of each heterodimer are connected through an interchain disulfide bond between the corresponding GDF15 regions of these chains .

More specifically, according to a particular embodiment of the present invention, the tetramer comprises:

(a) two DhCpmFc(+) chains (in each heterodimer) containing the sequence SEQ ID NO: 283, (b) two DhCpmFc(-) chains (in each heterodimer) containing the sequence SEQ ID NO: 48, (c) two a GDF15 polypeptide (in each heterodimer) containing the sequence SEQ ID NO: 12, and (d) two polypeptide linkers (in each heterodimer) containing the sequence: GGGGQ (SEQ ID NO: 75), each connecting the N-terminus of the GDF15 polypeptide with the C-terminus of the DhCpmFc(-) domain via a peptide bond.

According to a preferred embodiment of the present invention, the first polypeptide chain contains the amino acid sequence (the linker sequence is underlined by a double line):

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVD GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQG NVFSCSVMHE ALHNHYTQKSLSLSPGGGGGQARNGDHCPLGPGRCCRLHTVRASLEDLGW ADWVL S PREVQVTMCIGAO R S Q FRAANMHAQIKT S LHRLKP DTVPAPCCV PASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:77), which is encoded by the nucleic acid sequence: gcacctgaactcctggggggaccgtca gtcttcctcttccccccaaaacc caaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtgg tggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggac ggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaa cagcacgtaccgtgtggtcagcgtcctcaccg tcctgcaccaggactggc tgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcc cccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccaca ggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtca gcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggag tggggagagcaatgggcagccggagaacaactacgacaccacgcctcccgt gctggactccgacggctccttcttcctctatagcgacctcactgtggaca agagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgag gctctgcacaaccactacacgcagaagagcctctccctgtctccggggtgg aggtggtgga caggcgcgcaacggagaccactgtccgctcgggcccggggc gttgctgccgtctgcacacggtccgcgcgtcgctggaagacctgggctgg gccgattgggtgctgtcgccacgggaggtgcaagtgaccatgtgcatcgg cgcgtgcccgagccagttccgggcggcaaacatgcacgcgcagatca aga cgagcctgcaccgcctgaagcccgacacggtgccagcgccctgctgcgtg cccgccagctacaatcccatggtgctcattcaaaagaccgacaccggggt gtcgctccagacctatgatgacttgttagccaaagactgccactgcatat ga (SEQ ID NO:76).

According to a preferred embodiment of the present invention, the second polypeptide

- 41 046387 chain contains the amino acid sequence SEQ ID NO: 47, which is encoded by the nucleic acid sequence SEQ ID NO: 51.

As discussed above, a tetramer is provided containing two polypeptide chains that contain the sequence SEQ ID NO: 77, and two polypeptide chains that contain the sequence SEQ ID NO: 47.

II.E. 12 DhCpmFc(-)-(G ₄ Q) ₂ -GDF15:DhCpmFc(+).

The definition of DhCpmFc(-)-(G ₄ Q) ₂ -GDF15:DhCpmFc(+) in the present invention means a heterodimer that contains (i) a first polypeptide chain containing a GDF15 polypeptide that is connected to a DhCpmFc(-) domain via a linker that contains the sequence SEQ ID NO: 78 and which connects the N-terminus of the GDF15 polypeptide to the C-terminus of the DhCpmFc(-) domain, and (ii) a second polypeptide chain containing the DhCpmFc(+) domain.

According to certain embodiments of the present invention, there is provided a tetramer that contains a dimer consisting of two heterodimers DhCpmFc(-)-(G ₄ Q) ₂ -GDF15:DhCpmFc(+), in which the first two polypeptide chains of each heterodimer are connected through an interchain disulfide bond between corresponding GDF15 areas of these circuits.

More specifically, according to a particular embodiment of the present invention, the tetramer comprises:

(a) two DhCpmFc(+) domains (in each heterodimer) containing the sequence SEQ ID NO: 283, (b) two DhCpmFc(-) domains (in each heterodimer) containing the sequence SEQ ID NO: 48, (c) two a GDF15 polypeptide (in each heterodimer) containing the sequence SEQ ID NO: 12, and (d) two polypeptide linkers (in each heterodimer) containing the sequence: GGGGQGGGGQ (SEQ ID NO: 78), each connecting the N-terminus of the GDF15 polypeptide with the C-terminus of the DhCpmFc(-) domain via a peptide bond.

According to a preferred embodiment of the present invention, the first polypeptide chain contains the amino acid sequence (the linker sequence is underlined by a double line):

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA

PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE

WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHE

ALHNHYTOKSLSLSPGGGGGQGGGGQARNGDHCPLGPGRCCRLHTVRASL

EDLGWADWVLSPREVQVTMCIGACPSQFRAANMHAQIKTSLHRLKPDTVP

APCCVPASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:80), which is encoded by the nucleic acid sequence:

- 42 046387 gcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacc caaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtgg tggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggac ggcgtggaggtgcataatgccaagacaaagccgcgggaggagca gtacaa cagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggc tgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcc cccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccaca ggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtca gcctgacc tgcctggtcaaaggcttctatcccagcgacatcgccgtggag tggggagagcaatgggcagccggagaacaactacgacaccacgcctcccgt gctggactccgacggctccttcttcctctatagcgacctcaccgtggaca agagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgag gctctgcacaaccact acacgcagaagagcctctccctgtctccgggtgg aggtggtggacagggaggcggtggacaggcgcgcaacggagaccactgtc cgctcgggcccgggcgttgctgccgtctgcacacggtccgcgcgtcgctg gaagacctgggctgggccgattgggtgctgtcgccacgggaggtgcaagt gaccatg tgcatcggcgcgtgcccgagccagttccggggcggcaaacatgc acgcgcagatcaagacgagcctgcaccgcctgaagcccgacacggtgcca gcgccctgctgcgtgcccgccagctacaatcccatggtgctcattcaaaa gaccgacaccggggtgtcgctccagacctatgatgacttgttagccaaag actg ccactgcatatga (SEQ ID NO:79).

In a preferred embodiment of the present invention, the second polypeptide chain comprises the amino acid sequence SEQ ID NO: 47, which is encoded by the nucleic acid sequence SEQ ID NO: 51.

As discussed above, a tetramer is provided containing two polypeptide chains that contain the sequence SEQ ID NO: 80, and two polypeptide chains that contain the sequence SEQ ID NO: 47.

II.E. 13 DhCpmFc(-)-(G ₄ Q) ₂ -GDF15(N3D):DhCpmFc(+).

The definition of DhCpmFc(-)-(G ₄ Q)2-GDF15(N3D):DhCpmFc(+) in the present invention means a heterodimer that contains (i) a first polypeptide chain containing a GDF15(N3D) polypeptide linked to a DhCpmFc(-) domain ) by means of a linker which contains the sequence SEQ ID NO: 78 and which connects the N-terminus of the GDF15(N3D) polypeptide to the C-terminus of the DhCpmFc(-) domain, and (ii) a second polypeptide chain containing the DhCpmFc(+) domain.

According to certain embodiments of the present invention, there is provided a tetramer that contains a dimer consisting of two heterodimers DhCpmFc(-)-(G ₄ Q)2-GDF15(N3D):DhCpmFc(+), in which the first two polypeptide chains of each heterodimer are connected through an interchain disulfide bond between the corresponding GDF15 regions of these chains.

More specifically, according to a particular embodiment of the present invention, the tetramer comprises:

(a) two DhCpmFc(+) domains (in each heterodimer) containing the sequence SEQ ID NO: 283, (b) two DhCpmFc(-) domains (in each heterodimer) containing the sequence SEQ ID NO: 48, (c) two a GDF15(N3D) polypeptide (in each heterodimer) containing the sequence SEQ ID NO: 52, and (d) two polypeptide linkers (in each heterodimer) containing the sequence SEQ ID NO: 78, each of which connects the N-terminus of the GDF15 polypeptide ( N3D) with the C-terminus of the DhCpmFc(-) domain via a peptide bond.

According to a preferred embodiment of the present invention, the first polypeptide chain contains the amino acid sequence (the linker sequence is underlined by a double line):

- 43 046387

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVD GVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNV FSCSVMHE ALHNHYTQKSLSLSPGGGGGQGGGGQARDGDHCPLGPGRCCRLHTVRASL E DLGWADWVL S PREVQVTMCIGAG P S Q FRAANMHAQIKT S LHRLKPD TVP APCCVPASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:82), which is encoded by the nucleic acid sequence: gcacctgaactcctgggggg accgtcagtcttcctcttccccccaaaacc caaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtgg tggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggac ggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaa cagcacgtaccgtgtggtcagcgtcc tcaccgtcctgcaccaggactggc tgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcc cccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccaca ggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtca gcctgacctgcctggtcaaaggcttctatcccagcgacatcgcc gtggag tgggagagcaatgggcagccggagaacaactacgacaccacgcctcccgt getggactccgacggctccttcttoctetatagcgacctcaccgtggaca agagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgag gctctgcacaaccactacacgcagaagagcctctccctgtctccggggtgg aggtggt ggacaggaggcggtggacaggcgcgcgacggagaccactgtc cgctcgggcccgggcgttgctgccgtctgcacacggtccgcgcgtcgctg gaagacctgggctgggccgattgggtgctgtcgccacgggaggtgcaagt gaccatgtgcatcggcgcgtgcccgagccagttccggggcgg caaacatgc acgcgcagatcaagacgagcctgcaccgcctgaagcccgacacggtgcca gcgccctgctgcgtgcccgccagctacaatcccatggtgctcattcaaaa gaccgacaccggggtgtcgctccagacctatgatgacttgttagccaaag actgccactgcata (SEQ ID NO:81).

In a preferred embodiment of the present invention, the second polypeptide chain comprises the amino acid sequence SEQ ID NO: 47, which is encoded by the nucleic acid sequence SEQ ID NO: 51.

As discussed above, a tetramer is provided containing two polypeptide chains that contain the sequence SEQ ID NO: 82, and two polypeptide chains that contain the sequence SEQ ID NO: 47.

II.E. 14 DhCpmFc(-)-(G ₄ Q) ₂ -GDF15(Ndel3):DhCpmFc(+).

The definition of DhCpmFc(-)-(G ₄ Q) ₂ -GDF15(Ndel3):DhCpmFc(+) in the present invention means a heterodimer that contains (i) a first polypeptide chain containing a GDF15(Ndel3) polypeptide linked to a DhCpmFc(- ) by means of a linker which contains the sequence SEQ ID NO: 78 and which connects the N-terminus of the GDF15(Ndel3) polypeptide to the C-terminus of the DhCpmFc(-) domain, and (ii) a second polypeptide chain containing the DhCpmFc(+) domain.

According to certain embodiments of the present invention, there is provided a tetramer that contains a dimer consisting of two heterodimers DhCpmFc(-)-(G ₄ Q) ₂ -GDF15(Ndel3):DhCpmFc(+), in which the first two polypeptide chains of each heterodimer are connected through an interchain disulfide bond between the corresponding GDF15 regions of these chains.

More specifically, according to a particular embodiment of the present invention, the tetramer comprises:

(a) two DhCpmFc(+) domains (in each heterodimer) containing the sequence SEQ ID NO: 283, (b) two DhCpmFc(-) domains (in each heterodimer) containing the sequence SEQ ID NO: 48, (c) two a GDF15(Ndel3) polypeptide (in each heterodimer) containing the sequence SEQ ID NO: 55, and (d) two polypeptide linkers (in each heterodimer) containing the sequence SEQ ID

- 44 046387

NO: 78, each of which connects the N-terminus of the GDF15(Ndel3) polypeptide to the C-terminus of the DhCpmFc(-) domain via a peptide bond.

According to a preferred embodiment of the present invention, the first polypeptide chain contains the amino acid sequence (the linker sequence is underlined by a double line):

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVD GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQG NVFSCSVMHE ALHNHYTOKSLSLSPGGGGGQGGGGQGDHCPLGPGRCCRLHTVRASLEDL GWADWVL S PREVQVTMCIGAC R S Q FRAANMHAQIKT S LHRLKPDTVPAPC CVPASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:84), which is encoded by the nucleic acid sequence: gcacctgaactcctggggggaccgtca gtcttcctcttccccccaaaacc caaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtgg tggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggac ggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaa cagcacgtaccgtgtggtcagcgtcctcaccg tcctgcaccaggactggc tgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcc cccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccaca ggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtca gcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggag tggggagagcaatgggcagccggagaacaactacgacaccacgcctcccgt getggactccgacggctccttcttoctetatagcgacctcaccgtggaca agagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgag gctctgcacaaccactacacgcagaagagcctctccctgtctccgggtgg aggtggtggacagg gaggcggtggacagggagaccactgtccgctcgggc ccggggcgttgctgccgtctgcacacggtccgcgcgtcgctggaagacctg ggctgggccgattgggtgctgtcgccacgggaggtgcaagtgaccatgtg catcggcgcgtgcccgagccagttccgggcggcaaacatgcacgcgcaga tcaagacgagcctgcaccgcctgaagcccgacacggtgccagcgccctgc tgcgtgcccgccagctacaatcccatggtgctcattcaaaagaccgacac cggggtgtcgctccagacctatgatgacttgttagccaaagactgccact gcata ( SEQ ID NO:83).

In a preferred embodiment of the present invention, the second polypeptide chain comprises the amino acid sequence SEQ ID NO: 47, which is encoded by the nucleic acid sequence SEQ ID NO: 51.

As discussed above, a tetramer is provided containing two polypeptide chains that contain the sequence SEQ ID NO: 84, and two polypeptide chains that contain the sequence SEQ ID NO: 47.

II.F. Charged pair (charged pair, delHinge) cysteine clamp (cysteine clamp).

A cysteine clamp mutation can be introduced into an Fc domain such as a CpmFc(+) domain, a CpmFc(-) domain, a DhCpmFc(+) domain, or a DhCpmFc(-) domain. A cysteine clamp mutation typically involves introducing a cysteine into the CH3 domain of an Fc domain at a specific position by mutation so that, when incubated with another Fc domain also containing a cysteine introduced into the CH3 domain at a specific position by mutation, between two Fc- domains (for example, between a CpmFc(+) domain containing a cysteine clamp mutation and a CpmFc(-) domain containing a cysteine clamp mutation, or between a DhCpmFc(+) domain containing a cysteine clamp mutation and a DhCpmFc(-) domain containing a mutation cysteine clamp) a disulfide bond may be formed (cysteine clamp). The Fc domain may contain one or more of these cysteine clamp mutations.

In one embodiment of the present invention, a cysteine clamp is produced by introducing a serine to cysteine mutation (S354C) in the first Fc domain and a tyrosine to cysteine mutation

- 45 046387 (Y349C) in the second Fc domain.

The definition of DhCpmFc(-)(S354C) domain in the present invention means a DhCpmFc(-) domain containing a mutation of serine to cysteine (S354C). The definition of DhCpmFc(+)(S354C) domain in the present invention means a DhCpmFc(+) domain containing a mutation of serine to cysteine (S354C). The definition of DhCpmFc(-)(Y349C) domain in the present invention means a DhCpmFc(-) domain containing a mutation of serine to cysteine (Y349C). The definition of DhCpmFc(+)(Y349C) domain in the present invention means a DhCpmFc(+) domain containing a mutation of serine to cysteine (Y349C).

The definition of CpmFc(-)(S354C) domain in the present invention means a CpmFc(-) domain containing a mutation of serine to cysteine (S354C). The definition of a CpmFc(+)(S354C) domain in the present invention means a CpmFc(+) domain containing a mutation of serine to cysteine (S354C). The definition of CpmFc(-)(Y349C) domain in the present invention means a CpmFc(-) domain containing a mutation of serine to cysteine (Y349C). The definition of CpmFc(+)(Y349C) domain in the present invention means a CpmFc(+) domain containing a mutation of serine to cysteine (Y349C).

According to another embodiment of the present invention, a cysteine clamp is obtained by introducing a leucine to cysteine mutation (L351C) in the first and Fc domains.

The definition of DhCpmFc(-)(L351C) domain in the present invention means a DhCpmFc(-) domain containing a serine to cysteine mutation (L351C). The definition of DhCpmFc(+)(L351C) domain in the present invention means a DhCpmFc(+) domain containing a serine to cysteine mutation (L351C).

The definition of CpmFc(-)(L351C) domain in the present invention means a CpmFc(-) domain containing a mutation of serine to cysteine (L351C). The definition of CpmFc(+)(L351C) domain in the present invention means a CpmFc(+) domain containing a serine to cysteine mutation (L351C).

The C-terminal lysine (K447) may optionally be removed in the CpmFc(+) domain, the CpmFc(-) domain, or both domains. This modification may be advantageous, for example when the peptide is fused at the C-terminus, to reduce proteolysis of the fusion protein.

According to some embodiments of the present invention, there is provided a heterodimer that contains (i) a first polypeptide chain comprising a GDF15 region coupled to a CpmFc(+) domain containing a cysteine clamp mutation, and (ii) a second polypeptide chain that contains a CpmFc(-) domain. , containing a cysteine clamp mutation. In some embodiments of the present invention, the N-terminus of the GDF15 region is connected to the C-terminus of the CpmFc(+) domain containing the cysteine clamp mutation, directly or through a polypeptide linker. In other embodiments of the present invention, the N-terminus of the CpmFc(+) domain containing the cysteine clamp mutation is connected to the C-terminus of the GDF15 region directly or via a polypeptide linker.

According to some embodiments of the present invention, there is provided a heterodimer that contains (i) a first polypeptide chain comprising a GDF15 region coupled to a CpmFc(-) domain containing a cysteine clamp mutation, and (ii) a second polypeptide chain that contains a CpmFc(+) domain. , containing a cysteine clamp mutation. In some embodiments, the N-terminus of the GDF15 region is connected to the C-terminus of the cysteine clamp mutation-containing CpmFc(-) domain, directly or via a polypeptide linker. In other embodiments of the present invention, the N-terminus of the CpmFc(-) domain containing the cysteine clamp mutation is connected to the C-terminus of the GDF15 region directly or through a polypeptide linker.

According to some embodiments of the present invention, there is provided a heterodimer that contains (i) a first polypeptide chain comprising a GDF15 region coupled to a DhCpmFc(+) domain containing a cysteine clamp mutation, and (ii) a second polypeptide chain that contains a DhCpmFc(-) domain. , containing a cysteine clamp mutation. In some embodiments, the N-terminus of the GDF15 region is connected to the C-terminus of the DhCpmFc(+) domain containing the cysteine clamp mutation, directly or through a polypeptide linker. In other embodiments of the present invention, the N-terminus of the DhCpmFc(+) domain containing the cysteine clamp mutation is connected to the C-terminus of the GDF15 region directly or through a polypeptide linker.

According to some embodiments of the present invention, there is provided a heterodimer that contains (i) a first polypeptide chain comprising a GDF15 region coupled to a DhCpmFc(-) domain containing a cysteine clamp mutation, and (ii) a second polypeptide chain that contains a DhCpmFc(+) domain. , containing a cysteine clamp mutation. In some embodiments, the N-terminus of the GDF15 region is connected to the C-terminus of the DhCpmFc(-) domain containing the cysteine clamp mutation, directly or through a polypeptide linker. In other embodiments of the present invention, the N-terminus of the DhCpmFc(-) domain containing the cysteine clamp mutation is connected to the C-terminus of the GDF15 region directly or through a polypeptide linker.

According to some embodiments of the present invention, there is provided a tetramer containing a dimer consisting of two such heterodimers, in which the first two polypeptide chains of the heterodimers are connected through an interchain disulfide bond between the corresponding GDF15 regions of these chains. Graphical representation of an embodiment of a tetramer containing

- 46 046387 two heterodimers, in which each heterodimer contains (i) a first polypeptide chain containing a GDF15 polypeptide connected via a polypeptide linker to a DhCpmFc(+)(L351C) domain, and (ii) a second polypeptide chain containing a DhCpmFc(-) domain (L351C), see Fig. 5.

II.F. 1 DhCpmFc(+)(S354C)-GDF15(N3D):DhCpmFc(-)(Y349C).

The definition of DhCpmFc(+)(S354C)-GDF15(N3D):DhCpmFc(-)(Y349C) in the present invention means a heterodimer that contains (i) a first polypeptide chain containing a GDF15(N3D) polypeptide, the N-terminus of which is connected directly to The C-terminus of the DhCpmFc(+)(S354C) domain, and (ii) a second polypeptide chain containing the DhCpmFc(-)(Y349C) domain. Cysteine clamp mutations allow the first and second polypeptide chains to be joined via an interchain disulfide bond between C354 of the first polypeptide chain and C349 of the second polypeptide chain.

According to certain embodiments of the present invention, there is provided a tetramer that contains a dimer consisting of two heterodimers DhCpmFc(+)(S354C)-GDF15(N3D):DhCpmFc())(Y349C), in which the first two polypeptide chains of each heterodimer are connected through an interchain disulfide bond between the corresponding GDF15 regions of these circuits.

More specifically, according to a particular embodiment of the present invention, the tetramer comprises:

(a) two DhCpmFc(+)(S354C) domains (in each heterodimer) containing the sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPA

PIEKTISKAKGQPREPQVYTLPPCRKEMTKNQVSLTCLVKGFYPSDIAVE

WESNGQPENNYKTTPPVLKSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE

ALHNHYTQKSLSLSPG (SEQ ID NO:85), (b) two DhCpmFc(-)(Y349C) domains (in each heterodimer) containing the sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVCTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPG (SEQ ID NO:284), and (c) two polypeptide and GDF15(N3D) (in each heterodimer) containing the sequence SEQ ID NO: 52.

According to a preferred embodiment of the present invention, the first polypeptide chain contains the amino acid sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVD GVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPCRKEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLKSDGSFFLYSKLTVDKSRW QQGNVFSCSVMHE ALHNHYTQKSLSLSPGARDGDHCPLGPGRCCRLHTVRASLEDLGWADWVL S PREVQVTMCIGAO R S Q FRAANMHAQIKT S LHRLKPDTVPAPCCVPAS YN PMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:88), which is encoded by the nucleic acid sequence: gccccagagctgcttggtggaccatcc gtgttcctgtttcctccaaagcc gaaggacaccctgatgatctcaagaactccggaagtgacttgcgtcgtcg tggacgtgtcacatgaggatccagaggtcaagttcaattggtatgtggac ggagtggaagtgcataacgccaagaccaaaccccgcgaagaacagtacaa tagcacctaccgcgtggtgagcgtcctt actgtgctccaccaggactggc ttaatgggaaggaatacaagtgtaaggtgtccaacaaggccctccccgct cccatcgaaaagaccatctcaaaggcaaaggggcaaccaagggaacctca

- 47 046387 agtgtacaccctgcctccgtgcaggaaggagatgaccaagaaccaggtca gcctgacttgtctcgtgaagggcttctatcccagcgatattgctgtggaa tgggagtcaaatggccagcccgagaataactacaaaactaccccacccgt gctgaaatctgatgggtccttcttccttttactcca agctgaccgtggaca agagccgctggcaacaaggcaatgtctttagctgctcagtgatgcatgag gctctccataatcactacactcagaagtcactgtccctgtcacctggcgc gcgcgacggagaccactgtccgctcgggcccgggcgttgctgccgtctgc acacggtccgcgcgtcgctggaagacctggg ctgggccgattgggtgctg tcgccacgggaggtgcaagtgaccatgtgcatcggcgcgtgcccgagcca gttccgggcggcaaacatgcacgcgcagatcaagacgagcctgcaccgcc tgaagcccgacacggtgccagcgccctgctgcgtgcccgccagctacaat cccatggtgctcattcaaaagacc gacaccggggtgtcgctccagaccta tgatgacttgttagccaaagactgccactgcata (SEQ ID NO:87).

According to a preferred embodiment of the present invention, the second polypeptide chain contains the amino acid sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVD GVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVCTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNV FSCSVMHE ALHNHYTQKSLSLSPGK (SEQ ID NO:86), which is encoded by the nucleic acid sequence: gcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacc caaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtgg tggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggac ggc gtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaa cagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggc tgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcc cccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccaca ggtgtgcacc ctgcccccatcccgggaggagatgaccaagaaccaggtca gcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggag tggggagagcaatgggcagccggagaacaactacgacaccacgcctcccgt gctggactccgacggctccttcttcctctatagcgacctcaccgtggaca agagcaggtggcagcaggggaac gtcttctcatgctccgtgatgcatgag gctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaa a (SEQ ID NO:89) .

As discussed above, a tetramer is provided containing two polypeptide chains that contain the sequence SEQ ID NO: 88, and two polypeptide chains that contain the sequence SEQ ID NO: 86.

II.F.2 DhCpmFc(-)(Y349C)-GDF15:DhCpmFc(+)(S354C).

The definition of DhCpmFc(-)(Y349C)-GDF15:DhCpmFc(+)(S354C) in the present invention means a heterodimer that contains (i) a first polypeptide chain containing a GDF15 polypeptide, the N-terminus of which is connected directly to the C-terminus of the DhCpmFc(-) domain (Y349C), and (ii) a second polypeptide chain containing the DhCpmFc(+)(S345C) domain. Cysteine clamp mutations allow the first and second polypeptide chains to be joined via an interchain disulfide bond between C349 of the first polypeptide chain and C354 of the second polypeptide chain.

According to certain embodiments of the present invention, there is provided a tetramer that contains a dimer consisting of two heterodimers DhCpmFc(-)(Y349C)GDF15:DhCpmFc(+)(S354C), in which the first two polypeptide chains of each heterodimer are connected through an interchain disulfide bond between the respective regions GDF15 data circuits.

More specifically, according to a particular embodiment of the present invention, the tetramer comprises:

- 48 046387 (a) two DhCpmFc(+)(S354C) domains (in each heterodimer) containing the sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPCRKEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLKSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPG (SEQ ID NO:285), (b ) two DhCpmFc(-)(Y349C) domains (in each heterodimer) containing the sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA

PIEKTISKAKGQPREPQVCTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPG (SEQ ID NO:91), and (c) two GDF15 polypeptides (in each heterodimer) containing the sequence SEQ ID NO: 12.

According to a preferred embodiment of the present invention, the first polypeptide chain contains the amino acid sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVD GVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVCTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFS CSVMHE ALHNHYTQKSLSLSPGARNGDHCPLGPGRCCRLHTVRASLEDLGWADWVL S PREVQVTMCIGAG P S Q FRAANMHAQIKT S LHRLKPDTVPAPCCVPAS YN PMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:93), which is encoded by the nucleic acid sequence: gcacctgaactcctggggggaccgtcagtctt cctcttccccccaaaacc caaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtgg tggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggac ggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaa cagcacgtaccgtgtggtcagcgtcctcaccgtcctg caccaggactggc tgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcc cccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccaca ggtgtgcaccctgcccccatcccgggaggagatgaccaagaaccaggtca gcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggag tggg agagcaatgggcagccggagaacaactacgacaccacgcctcccgt gctggactccgacggctccttcttcctctatagcgacctcaccgtggaca agagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgag gctctgcacaaccactacacgcagaagagcctctccctgtctccgggtgc gcgcaacggagaccact t gaagcccgacacggtgccagcgccctgctgcgtgcccgccagctacaat cccatggtgctcattcaaaagaccgacaccggggtgtcgctccagaccta tgatgacttgttagccaaagactgccactgcata (SEQ ID NO:92).

According to a preferred embodiment of the present invention, the second polypeptide chain contains the sequence:

- 49 046387

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVD GVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPCRKEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLKSDGSFFLYSKLTVDKSRW QQGNVFSCSVMHE ALHNHYTQKSLSLSPGK (SEQ ID NO:90), which is encoded by the nucleic acid sequence:

gccccagagctgcttggtggaccatccgtgttcctgtttcctccaaagcc gaaggacaccctgatgatctcaagaactccggaagtgacttgcgtcgtcg tggacgtgtcacatgaggatccagaggtcaagttcaattggtatgtggac ggagtggaagtgcataacgccaagaccaaaccccgcgaagaacagtacaa tagcacc taccgcgtggtgagcgtccttactgtgctccaccaggactggc ttaatgggaaggaatacaagtgtaaggtgtccaacaaggccctccccgct cccatcgaaaagaccatctcaaaggcaaaggggcaaccaagggaacctca agtgtacaccctgcctccgtgcaggaaggagatgaccaagaaccaggtca gcctgacttgtctc gtgaagggcttctatcccagcgatattgctgtggaa tgggagtcaaatggccagcccgagaataactacaaaactaccccacccgt gctgaaatctgatgggtccttcttcctttactccaagctgaccgtggaca agagccgctggcaacaaggcaatgtctttagctgctcagtgatgcatgag gctctccataatcactacactcaga agtcactgtccctgtctccggggtaa (SEQ ID NO:94).

As discussed above, a tetramer is provided containing two polypeptide chains that contain the sequence SEQ ID NO: 93, and two polypeptide chains that contain the sequence SEQ ID NO: 90.

II.F.3 DhCpmFc(-)(Y349C)-GDF15(N3D):DhCpmFc(+)(S354C).

The definition of DhCpmFc(-)(Y349C)-GDF15(N3D):DhCpmFc(+)(S354C) in the present invention means a heterodimer that contains (i) a first polypeptide chain containing a GDF15(N3D) polypeptide, the N-terminus of which is connected directly to The C-terminus of the DhCpmFc(-)(Y349C) domain, and (ii) a second polypeptide chain containing the DhCpmFc(+)(S345C) domain. Cysteine clamp mutations allow the first and second polypeptide chains to be joined via an interchain disulfide bond between C349 of the first polypeptide and C354 of the second polypeptide.

According to certain embodiments of the present invention, there is provided a tetramer that contains a dimer consisting of two heterodimers DhCpmFc(-)(Y349C)GDF15(N3D):DhCpmFc(+)(S354C), in which the first two polypeptide chains of each heterodimer are connected through an interchain disulfide bond between the corresponding GDF15 regions of these circuits. The N3D mutation can be introduced into the GDF15 sequence, for example, to eliminate heterogeneity caused by N-deamidation.

More specifically, according to a particular embodiment of the present invention, the tetramer comprises:

(a) two DhCpmFc(+)(S354C) domains (in each heterodimer) containing the sequence SEQ ID NO: 285, (b) two DhCpmFc(-)(Y349C) domains (in each heterodimer) containing the sequence SEQ ID NO: 91, and (c) two GDF15(N3D) polypeptides (in each heterodimer) containing the sequence SEQ ID NO: 52.

According to a preferred embodiment of the present invention, the first polypeptide chain contains the amino acid sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD GVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVCTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNV FSCSVMHE ALHNHYTQKSLSLSPGARDGDHCPLGPGRCCRLHTVRASLEDLGWADWVL SPREVQVTMCIGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYN PMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:96), which is encoded by the nucleic acid sequence:

- 50 046387 gcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacc caaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtgg tggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggac ggcgtggaggtgcataatgccaagacaaagccgcgggaggagca gtacaa cagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggc tgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcc cccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccaca ggtgtgcaccctgcccccatcccgggaggagatgaccaagaaccaggtca gcctg acctgcctggtcaaaggcttctatcccagcgacatcgccgtggag tggggagagcaatgggcagccggagaacaactacgacaccacgcctcccgt gctggactccgacggctccttcttcctctatagcgacctcaccgtggaca agagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgag gctctgcacaacc actacacgcagaagagcctctccctgtctccgggtgc gcgcgacggagaccactgtccgctcgggcccgggcgttgctgccgtctgc acacggtccgcgcgtcgctggaagacctgggctgggccgattgggtgctg tcgccacgggaggtgcaagtgaccatgtgcatcggcgcgtgcccgagcca gt tccgggcggcaaacatgcacgcgcagatcaagacgagcctgcaccgcc tgaagcccgacacggtgccagcgccctgctgcgtgcccgccagctacaat cccatggtgctcattcaaaagaccgacaccggggtgtcgctccagaccta tgatgacttgttagccaaagactgccactgcata (SEQ ID NO:95).

In a preferred embodiment of the present invention, the second polypeptide chain comprises the amino acid sequence SEQ ID NO: 90, which is encoded by the nucleic acid sequence SEQ ID NO: 94.

As discussed above, a tetramer is provided containing two polypeptide chains that contain the sequence SEQ ID NO: 96, and two polypeptide chains that contain the sequence SEQ ID NO: 90.

II.F.4 DhCpmFc(-)(Y349C)-GDF15(Ndel3):DhCpmFc(+)(S354C).

The definition of DhCpmFc(-)(Y349C)-GDF15(Ndel3):DhCpmFc(+)(S354C) in the present invention means a heterodimer that contains (i) a first polypeptide chain containing a GDF15(Ndel3) polypeptide, the N-terminus of which is connected directly to The C-terminus of the DhCpmFc(-)(Y349C) domain, and (ii) a second polypeptide chain containing the DhCpmFc(+)(S345C) domain. Cysteine clamp mutations allow the first and second polypeptide chains to be joined via an interchain disulfide bond between C349 of the first polypeptide chain and C354 of the second polypeptide chain.

According to certain embodiments of the present invention, there is provided a tetramer that contains a dimer consisting of two heterodimers DhCpmFc(-)(Y349C)GDF15(Ndel3):DhCpmFc(+)(S354C), in which the first two polypeptide chains of each heterodimer are connected through an interchain disulfide bond between the corresponding GDF15 regions of these circuits. Removal of the N-terminal 3 amino acids (Ndel3) in the GDF15 sequence can be used, for example, to eliminate heterogeneity caused by deamidation of asparagines or isomerization of aspartic acid.

More specifically, according to a particular embodiment of the present invention, the tetramer comprises:

(a) two DhCpmFc(+)(S354C) domains (in each heterodimer) containing the sequence SEQ ID NO: 285, (b) two DhCpmFc(-)(Y349C) domains (in each heterodimer) containing the sequence SEQ ID NO: 91, and (c) two GDF15(Ndel3) polypeptides (in each heterodimer) containing the sequence SEQ ID NO: 55.

According to a preferred embodiment of the present invention, the first polypeptide chain contains the amino acid sequence:

- 51 046387

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVD GVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVCTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFS CSVMHE ALHNHYTQKSLSLSPGGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPR EVQVTMCIGAG P S Q FRAANMHAQIKT S LHRLKPDTVPAPC CVPAS YNPMV LIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:98), which is encoded by the nucleic acid sequence: gcacctgaactcctggggggaccgtcagtcttcctct tccccccaaaacc caaggacacccteatgatctcccggacccctgaggtcacatgcgtggtgg tggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggac ggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaa cagcacgtaccgtgtggtcagcgtcctcaccgtcctgcacca ggactggc tgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcc cccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccaca ggtgtgcaccctgcccccatcccgggaggagatgaccaagaaccaggtca gcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggag tgggagag caatgggcagccggagaacaactacgacaccacgcctcccgt getggactccgacggctccttcttoctetatagcgacctcaccgtggaca agagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgag gctctgcacaaccactacacgcagaagagcctctccctgtctccgggtgg agaccactgtccgctcgggccc gggcgttgctgccgtctgcacacggtcc gegegtegetggaagacctgggctgggccgattgggtgetgtcgccacgg gaggtgcaagtgaccatgtgcatcggcgcgtgcccgagccagttccgggc ggcaaacatgcacgcgcagatcaagacgagcctgcaccgcctgaagcccg acacggtgccagc gccctgctgcgtgcccgccagctacaatcccatggtg ctcattcaaaagaccgacaccggggtgtcgctccagacctatgatgactt gttagccaaagactgccactgcata (SEQ ID NO:97).

In a preferred embodiment of the present invention, the second polypeptide chain comprises the amino acid sequence SEQ ID NO: 90, which is encoded by the nucleic acid sequence SEQ ID NO: 94.

As discussed above, a tetramer is provided containing two polypeptide chains that contain the sequence SEQ ID NO: 98, and two polypeptide chains that contain the sequence SEQ ID NO: 90.

II.F.5 DhCpmFc(-)(Y349C)-G4-GDF15(N3D):DhCpmFc(+)(S354C).

The definition of DhCpmFc(-)(Y349C)-G4-GDF15(N3D):DhCpmFc(+)(S354C) in the present invention means a heterodimer that contains (i) a first polypeptide chain containing a GDF15(N3D) polypeptide linked to a DhCpmFc( -)(Y349C) by means of a linker which contains the sequence SEQ ID NO: 58 and which connects the N-terminus of the GDF15(N3D) polypeptide to the C-terminus of the DhCpmFc(-)(Y349C) domain, and (ii) a second polypeptide chain containing the domain DhCpmFc(+)(S345C). Cysteine clamp mutations allow the first and second polypeptide chains to be joined via an interchain disulfide bond between C349 of the first polypeptide chain and C354 of the second polypeptide chain.

According to certain embodiments of the present invention, there is provided a tetramer that contains a dimer consisting of two heterodimers DhCpmFc(-)(Y349C)-G4GDF15(N3D):DhCpmFc(+)(S354C), in which the first two polypeptide chains of each heterodimer are connected through an interchain disulfide connections between the corresponding GDF15 regions of these circuits.

More specifically, according to a particular embodiment of the present invention, the tetramer comprises:

(a) two DhCpmFc(+)(S354C) domains (in each heterodimer) containing the sequence SEQ ID NO: 285,

- 52 046387 (b) two DhCpmFc(-)(Y349C) domains (in each heterodimer) containing the sequence SEQ ID NO: 91, (c) two GDF15(N3D) polypeptides (in each heterodimer) containing the sequence SEQ ID NO: 52, and (d) two polypeptide linkers (in each heterodimer) containing the sequence SEQ ID NO: 58, each of which connects the N-terminus of the GDF15(N3D) polypeptide to the C-terminus of the DhCpmFc() (Y349C) domain via a peptide bond.

According to a preferred embodiment of the present invention, the first polypeptide chain contains the amino acid sequence (the linker sequence is underlined by a double line):

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVCTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPGXGXXARDGDHCPLGPGRCCRLHTVRASLEDL GWA DWVL S PREVQVTMCIGAG P S Q FRAANMHAQIKT S LHRLKPD TVPAP CCVP ASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:100), which is encoded by the nucleic acid sequence: gcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacc caaggacaccctcatgatctcccggacccctgagg tcacatgcgtggtgg tggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggac ggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaa cagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggc tgaatggcaaggagtacaagtgcaaggtctccaacaa agccctcccagcc cccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccaca ggtgtgcaccctgcccccatcccgggaggagatgaccaagaaccaggtca gcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggag tggggagagcaatgggcagccggagaacaactacgacaccacgcctcccgt gct ggactccgacggctccttcttcctctatagcgacctcaccgtggaca agagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgag gctctgcacaaccactacacgcagaagagcctctccctgtctccgggtgg tggaggtggtgcgcgcgacggagaccactgtccgctcgggcccgggcgtt gctg ccgtctgcacacggtccgcgcgtcgctggaagacctgggctgggcc gattgggtgctgtcgccacgggaggtgcaagtgaccatgtgcatcggcgc gtgcccgagccagttccgggcggcaaacatgcacgcgcagatcaagacga gcctgcaccgcctgaagcccgacacggtgccagcgccctgctg cgtgccc gccagctacaatcccatggtgctcattcaaaagaccgacaccggggtgtc gctccagacctatgatgacttgttagccaaagactgccactgcata (SEQ ID NO:99).

In a preferred embodiment of the present invention, the second polypeptide chain comprises the amino acid sequence SEQ ID NO: 90, which is encoded by the nucleic acid sequence SEQ ID NO: 94.

As discussed above, according to a specific embodiment of the present invention, there is provided a heterotetramer that contains two monomers containing the sequence SEQ ID NO: 100 and two monomers containing the sequence SEQ ID NO: 90.

II.F.6 DhCpmFc(-)(Y349C)-(G4S)2-GDF15(N3D):DhCpmFc(+)(S354C).

The definition of DhCpmFc(-)(Y349C)-(G ₄ S) ₂ -GDF15(N3D):DhCpmFc(+)(S354C) in the present invention means a heterodimer that contains (i) a first polypeptide chain containing a GDF15(N3D) polypeptide, connected to the DhCpmFc(-)(Y349C) domain by a linker which contains the sequence SEQ ID NO: 64 and which connects the N-terminus of the GDF15(N3D) polypeptide to the C-terminus of the DhCpmFc(-)(Y349C) domain, and (ii) a second polypeptide chain containing a domain

- 53 046387

DhCpmFc(+)(S345C). Cysteine clamp mutations allow the first and second polypeptide chains to be joined via an interchain disulfide bond between C349 of the first polypeptide chain and C354 of the second polypeptide chain.

According to certain embodiments of the present invention, there is provided a tetramer that contains a dimer consisting of two heterodimers DhCpmFc(-)(Y349C)-(G ₄ S) ₂ GDF15(N3D):DhCpmFc(+)(S354C), in which the first two polypeptide chains of each heterodimer are connected via an interchain disulfide bond between the corresponding GDF15 regions of these chains.

More specifically, according to a particular embodiment of the present invention, the tetramer:

(a) two DhCpmFc(+)(S354C) domains (in each heterodimer) containing the sequence SEQ ID NO: 285, (b) two DhCpmFc(-)(Y349C) domains (in each heterodimer) containing the sequence SEQ ID NO: 91, (c) two GDF15(N3D) polypeptides (in each heterodimer) containing the sequence SEQ ID NO: 52, and (d) two polypeptide linkers (in each heterodimer) containing the sequence SEQ ID NO: 64, each of which connects The N-terminus of the GDF15(N3D) polypeptide with the C-terminus of the DhCpmFc() (Y349C) domain via a peptide bond.

According to a preferred embodiment of the present invention, the first polypeptide contains the amino acid sequence (the linker sequence is underlined by a double line):

APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVCTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQG NVFSCSVMHE ALHNHYTOKSLSL5PGGGGGSGGGGSARDGDHCPLGPGRCCRLHTVRASL E DLGWADWVL S PREVQVTMCIGAC R S Q FRAANMHAQICT S LHRLKPDTVP APCCVPASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:102), which is encoded by the nucleic acid sequence: gcacctgaactcctgggggg accgtcagtcttcctcttccccccaaaacc caaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtgg tggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggac ggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaa cagcacgtaccgtgtggtcagcgtcc tcaccgtcctgcaccaggactggc tgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcc cccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccaca ggtgtgcaccctgcccccatcccgggaggagatgaccaagaaccaggtca gcctgacctgcctggtcaaaggcttctatcccagcgacatcg ccgtggag tgggagagcaatgggcagccggagaacaactacgacaccacgcctcccgt gctggactccgacggctccttcttcctctatagcgacctcaccgtggaca agagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgag gctctgcacaaccactacacgcagaagagcctctccctgtctccggggtgg agg tggtggatccggaggcggtggaagcgcgcgcgacggagaccactgtc cgctcgggcccgggcgttgctgccgtctgcacacggtccgcgcgtcgctg gaagacctgggctgggccgattgggtgctgtcgccacgggaggtgcaagt gaccatgtgcatcggcgcgtgcccgagccagttcc gggcggcaaacatgc acgcgcagatcaagacgagcctgcaccgcctgaagcccgacacggtgcca gcgccctgctgcgtgcccgccagctacaatcccatggtgctcattcaaaa gaccgacaccggggtgtcgctccagacctatgatgacttgttagccaaag actgccactgcata (SEQ ID NO:101).

In a preferred embodiment of the present invention, the second polypeptide chain comprises the amino acid sequence SEQ ID NO: 90, which is encoded by the sequence

- 54 046387 nucleic acid content SEQ ID NO: 94.

As discussed above, according to a specific embodiment of the present invention, there is provided a heterotetramer that contains two monomers containing the sequence SEQ ID NO: 102 and two monomers containing the sequence SEQ ID NO: 90.

II.F.7 DhCpmFc(-)(Y349C)-(G ₄ Q) ₂ -GDF15(N3D):DhCpmFc(+)(S354C).

The definition of DhCpmFc(-)(Y349C)-(G ₄ Q) ₂ -GDF15(N3D):DhCpmFc(+)(S354C) in the present invention means a heterodimer that contains (i) a first polypeptide chain containing a GDF15(N3D) polypeptide, connected to the DhCpmFc(-)(Y349C) domain by a linker which contains the sequence SEQ ID NO: 78 and which connects the N-terminus of the GDF15(N3D) polypeptide to the C-terminus of the DhCpmFc(-)(Y349C) domain, and (ii) a second polypeptide chain containing the DhCpmFc(+)(S345C) domain. Cysteine clamp mutations allow the first and second polypeptide chains to be joined via an interchain disulfide bond between C349 of the first polypeptide chain and C354 of the second polypeptide chain.

According to certain embodiments of the present invention, there is provided a tetramer that contains a dimer consisting of two heterodimers DhCpmFc(-)(Y349C)-(G ₄ Q) ₂ GDF15(N3D):DhCpmFc(+)(S354C), in which the first two polypeptide chains of each heterodimer are connected via an interchain disulfide bond between the corresponding GDF15 regions of these chains.

More specifically, according to a particular embodiment of the present invention, the tetramer comprises:

(a) two DhCpmFc(+)(S354C) domains (in each heterodimer) containing the sequence SEQ ID NO: 285, (b) two DhCpmFc(-)(Y349C) domains (in each heterodimer) containing the sequence SEQ ID NO: 91, (c) two GDF15(N3D) polypeptides (in each heterodimer) containing the sequence SEQ ID NO: 52, and (d) two polypeptide linkers (in each heterodimer) containing the sequence SEQ ID NO: 78, each of which connects The N-terminus of the GDF15(N3D) polypeptide with the C-terminus of the DhCpmFc(-) domain (Y349C) via a peptide bond.

According to a preferred embodiment of the present invention, the first polypeptide contains the amino acid sequence (the linker sequence is underlined by a double line):

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA

PIEKTISKAKGQPREPQVCTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE

WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHE

ALHNHYTOKSLSLSPGGGGGQGGGGQARDGDHCPLGPGRCCRLHTVRASL

EDLGWADWVLSPREVQVTMCIGACPSQFRAANMHAQIKTSLHRLKPDTVP APCCVPASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:104), which is encoded by the nucleic acid sequence:

- 55 046387 gcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacc caaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtgg tggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggac ggcgtggaggtgcataatgccaagacaaagccgcgggaggagca gtacaa cagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggc tgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcc cccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccaca ggtgtgcaccctgcccccatcccgggaggagatgaccaagaaccaggtca gcctg acctgcctggtcaaaggcttctatcccagcgacatcgccgtggag tggggagagcaatgggcagccggagaacaactacgacaccacgcctcccgt gctggactccgacggctccttcttcctctatagcgacctcaccgtggaca agagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgag gctctgcacaacc actacacgcagaagagcctctccctgtctccgggtgg aggtggtggacagggaggcggtggacaggcgcgcgacggagaccactgtc cgctcgggcccgggcgttgctgccgtctgcacacggtccgcgcgtcgctg gaagacctgggctgggccgattgggtgctgtcgccacgggaggtgcaagt gacc atgtgcatcggcgcgtgcccgagccagttccggggcggcaaacatgc acgcgcagatcaagacgagcctgcaccgcctgaagcccgacacggtgcca gcgccctgctgcgtgcccgccagctacaatcccatggtgctcattcaaaa gaccgacaccggggtgtcgctccagacctatgatgacttgttagccaaag actngccactgcata (SEQ ID NO:103).

In a preferred embodiment of the present invention, the second polypeptide chain comprises the amino acid sequence SEQ ID NO: 90, which is encoded by the nucleic acid sequence SEQ ID NO: 94.

As discussed above, according to a specific embodiment of the present invention, there is provided a heterotetramer that contains two monomers containing the sequence SEQ ID NO: 104 and two monomers containing the sequence SEQ ID NO: 90.

II.F.8. DhCpmFc(-)(L3 51 C)-(G ₄ S)2-GDF 15: DhCpmFc(+)(L3 51C).

The definition of DhCpmFc(-)(L351C)-(G ₄ S)2-GDF15:DhCpmFc(+)(L351C) in the present invention means a heterodimer that contains (i) a first polypeptide chain containing a GDF15 polypeptide that is connected to a DhCpmFc( -)(L351C) through a linker that contains the sequence SEQ ID NO: 64 and which connects the N-terminus of the GDF15 polypeptide to the C-terminus of the DhCpmFc(-)(L351C) domain, and (ii) a second polypeptide chain containing the DhCpmFc(+) domain )(L351C). Cysteine clamp mutations allow the first and second polypeptide chains to be joined via an interchain disulfide bond between C351 of the first polypeptide chain and C351 of the second polypeptide chain.

According to certain embodiments of the present invention, there is provided a tetramer that contains a dimer consisting of two heterodimers DhCpmFc(-)(L351C)-(G ₄ S)2GDF15:DhCpmFc(+)(L351C), in which the first two polypeptide chains of each heterodimer are connected by interchain disulfide bond between the corresponding GDF15 regions of these chains.

More specifically, according to a particular embodiment of the present invention, the tetramer comprises:

(a) two DhCpmFc(+)(L351C) domains (in each heterodimer) containing the sequence: APELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTCPPSRKEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLKSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPG (SEQ ID NO:286), (b ) two DhCpmFc(-)(L351C) domains (in each heterodimer) containing the sequence:

- 56 046387

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVD GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTCPPSREEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQG NVFSCSVMHE ALHNHYTQKSLSLSPG (SEQ ID NO:106), (c) two chains of GDF15 polypeptide (in each heterodimer) containing the sequence SEQ

ID NO: 12, and (d) two polypeptide linkers (in each heterodimer) containing the sequence SEQ ID NO: 64, each of which connects the N-terminus of the GDF15 polypeptide to the C-terminus of the DhCpmFc(-)(L351C) domain via a peptide bond .

According to a preferred embodiment of the present invention, the first polypeptide chain contains the amino acid sequence (the linker sequence is underlined by a double line):

APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD GVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTCPPSREEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQG NVFSCSVMHE ALHNHYTOKSLSLSPGGGGGSGGGGSARNGDHCPLGPGRCCRLHTVRASL EDLGWADWVLSPREVQVTMCIGACPSQFRAANMHAQIKTSLHRLKPDTVP

APCCVPASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:108) which is encoded by the nucleic acid sequence:

gcgccggaactgctgggcggcccgagcgtgtttctgtttccgccgaaacc gaaagataccctgatgattagccgcaccccggaagtgacctgcgtggtgg tggatgtgagccatgaagatccggaagtgaaatttaactggtatgtggat ggcgtggaagtgcataacgcgaaaaccaaaccgcgcgaagaac agtataa cagcacctatcgcgtggtgagcgtgctgaccgtgctgcatcaggattggc tgaacggcaaagaatataaatgcaaagtgagcaacaaagcgctgccggcg ccgattgaaaaaaccattagcaaagcgaaaggccagccgcgcgaaccgca ggtgtatacctgcccgccgagccgcgaagaaatgaccaaa aaccaggtga gcctgacctgcctggtgaaaggcttttatccgagcgatattgcggtggaa tgggaaagcaacggccagccggaaaacaactatgataccaccccgccggt gctggatagcgatggcagcttttttctgtatagcgatctgaccgtggata aaagccgctggcagcagggcaacgtgtttagctgcagcg tgatgcatgaa gcgctgcataaccattatacccagaaaagcctgagcctgagcccgggcgg cggcggcggcagcggcggcggcggcagcgcgcgcaacggcgatcattgcc cgctgggcccgggccgctgctgccgcctgcataccgtgcgcgcgagcctg gaagatctgggctgggcggattgggtgctga gcccgcgcgaagtgcaggt gaccatgtgcattggcgcgtgcccgagccagtttcgcgcggcgaacatgc atgcgcagattaaaaccagcctgcatcgcctgaaaccggataccgtgccg gcgccgtgctgcgtgccggcgagctataacccgatggtgctgattcagaa aaccgataccggcgtgag cctgcagacctatgatgatctgctggcgaaag attgccattgcatt (SEQ ID NO:107).

According to a preferred embodiment of the present invention, the second polypeptide chain contains the amino acid sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVD GVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTCPPSRKEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLKSDGSFFLYSKLTVDKSRW QQGNVFSCSVMHE ALHNHYTQKSLSLSPGK (SEQ ID NO:105), which is encoded by the nucleic acid sequence:

- 57 046387 gcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacc caaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtgg tggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggac ggcgtggaggtgcataatgccaagacaaagccgcgggaggagca gtacaa cagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggc tgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcc cccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccaca ggtgtacacctgtcccccatcccgggaggagatgaccaagaaccaggtca gcctg acctgcctggtcaaaggcttctatcccagcgacatcgccgtggag tggggagagcaatgggcagccggagaacaactacgacaccacgcctcccgt gctggactccgacggctccttcttcctctatagcgacctcaccgtggaca agagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgag gctctgcacaacc actacacgcagaagagcctctccctgtctccgggtaa a (SEQ ID NO:109).

As discussed above, according to a specific embodiment of the present invention there is provided a heterotetramer that contains two monomers containing the sequence SEQ ID NO: 108 and two monomers containing the sequence SEQ ID NO: 105.

IIG. HSA.

As used herein, HSA or human serum albumin means a fusion protein comprising a GDF15 region linked directly or via a polypeptide linker to a human serum albumin (HSA) polypeptide. In some embodiments of the present invention, the fusion protein comprises two or more HSA polypeptides.

Typically, the N-terminus of the GDF15 region is connected directly or via a polypeptide linker to the C-terminus of the HSA polypeptide. However, in some embodiments of the present invention, the N-terminus of the HSA polypeptide is connected directly or via a polypeptide linker to the C-terminus of the GDF15 region.

Certain embodiments of the present invention provide a homodimer comprising two such fusion proteins linked through an interchain disulfide bond between the respective GDF15 regions of the proteins. For a graphical representation of an embodiment of such a homodimer, see FIG. 6. Alternatively, a heterodimer is provided that contains one such fusion protein and a GDF15 polypeptide or mutant GDF polypeptide linked through an interchain disulfide bond between the GDF15 region of the fusion protein and the GDF15 polypeptide or mutant polypeptide.

II.G.1 Heterodimer HSA-(G4S)4-GDF15:GDF15.

The definition of HSA-(G4S)4-GDF15:GDF15 in the present invention means a heterodimer that contains (i) a first polypeptide chain containing a GDF15 polypeptide connected to an HSA polypeptide through a linker that contains the sequence SEQ ID NO: 18 and that connects N- the end of the GDF15 polypeptide with the C-terminus of the HSA polypeptide, and (ii) a second polypeptide chain containing the GDF15 polypeptide.

Typically, the first and second polypeptide chains are connected via an interchain disulfide bond between the respective GDF15 regions of the given chains.

More specifically, according to a particular embodiment of the present invention, the heterodimer comprises:

(a) one HSA polypeptide (in the first monomer) containing the sequence:

DAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQCPFEDHVKLVNEVTEFA KTCVADESAENCDKSLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNE CFLQHKDDNPNLPRLVRPEVDVMCTAFHDNEETFLKKYLYEIARRHPYFY

- 58 046387

APELLFFAKRYKAAFTECCQAADKAACLLPKLDELRDEGKASSAKQRLKC

ASLQKFGERAFKAWAVARLSQRFPKAEFAEVSKLVTDLTKVHTECCHGDL

LECADDRADLAKYICENQDSISSKLKECCEKPLLEKSHCIAEVENDEMPA

DLPSLAADFVESKDVCKNYAEAKDVFLGMFLYEYARRHPDYSWLLLRLA

KTYETTLEKCCAAADPHECYAKVFDEFKPLVEEPQNLIKQNCELFEQLGE YKFQNALLVRYTKKVPQVSTPTLVEVSRNLGKVGSKCCKHPEAKRMPCAE DYLSWLNQLCVLHEKTPVSDRVTKCCTESLVNRRPCFSALEVDETYVPK E FNAE TFT FHADICTLSEKERQIKKQTALVE LVKH KPKATKE QLKAVMDD FAAFVEKCCKADDKETCFAEEGKKLVAASQAALGL(SEQ ID NO:110), and (b) two GDF15 polypeptides (in each monomer) containing the sequence SEQ ID NO: 12, and (c) one polypeptide linker (in the first monomer ), containing the sequence SEQ ID NO: 18, which connects the N-terminus of the GDF15 polypeptide to the C-terminus of the HSA polypeptide via a peptide bond.

According to a preferred embodiment of the present invention, the first polypeptide contains the amino acid sequence (the linker is underlined by a double line):

DAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQCPFEDHVKLVNEVTEFA KTCVADESAENCDKSLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNE CFLQHKDDNPNLPRLVRPEVDVMCTAFHDNEETFLKKYLYEIARRHPYFY APELLFFAKRYKAAFTECCQAADKAACLLPKLDELRDEGKASSAKQRLKC ASLQ KFGERAFKAWAVARLSQRFPKAEFAEVSKLVTDLTKVHTECCHGDL LECADDRADLAKYICENQDSISSKLKECCEKPLLEKSHCIAEVENDEMPA DLPSLAADFVESKDVCKNYAEAKDVFLGMFLYEYARRHPDYSWLLLRLA KTYETTLEKCCAAADPHECYAKVFDEFKPLVEEPQNLIKQNCELFEQLGE YKFQNALLVR YTKKVPQVSTPTLVEVSRNLGKVGSKCCKHPEAKRMPCAE DYLSWLNQLCVLHEKTPVSDRVTKCCTESLVNRRPCFSALEVDETYVPK E FNAE TFT FHADICTLSEKERQIKKQTALVE LVKHKPKATKE QLKAVMDD FAAFVEKCCKADDKE TC FAEEGKKLVAAS QAALGLGGGGSGGGGSG GGGS GGGGSARNGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPREVQVTMCI GACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYNPMVLIQKTDTG VSLQTYDDLLAKDCHCI (SEQ ID NO:112), which is encoded by the nucleic acid sequence:

- 59 046387 gatgcacacaagagtgaggttgctcatcgatttaaagatttgggagaaga aaatttcaaagccttggtgttgattgcctttgctcagtatcttcagcagt gtccatttgaagatcatgtaaaattagtgaatgaagtaactgaatttgca aaaacatgtgttgctgatgagtcagctgaaa attgtgacaaatcacttca tacccttttggagacaaattatgcacagttgcaactcttcgtgaaacct atggtgaaatggctgactgctgtgcaaaacaagaacctgagagaaatgaa tgcttcttgcaacacaaagatgacaacccaaacctcccccgattggtgag accagaggttgatgtgatgtgcactgcttttcat gacaatgaagagacat ttttgaaaaaatacttatatgaaattgccagaagacatccttacttttat gccccggaactccttttctttgctaaaaggtataaagctgcttttacaga atgttgccaagctgctgataaagctgcctgcctgttgccaaagctcgatg aacttcgggatgaagggaaggcttcgtctgccaa acagagactcaagtgt gccagtctccaaaaatttggagaaagagctttcaaagcatgggcagtagc tcgcctgagccagagatttcccaaagctgagtttgcagaagtttccaagt tagtgacagatcttaccaaagtccacacggaatgctgccatggagatctg cttgaatgtgctgatgacagggcggaccttgccaagtatatct gtgaaaa tcaagattcgatctccagtaaactgaaggaatgctgtgaaaaacctctgt tggaaaaatcccactgcattgccgaagtggaaaatgatgagatgcctget gacttgccttcattagctgctgattttgttgaaagtaaggatgtttgcaa aaactatgctgaggcaaaggatgtcttcctgggcatgt ttttgtatgaat atgcaagaaggcatcctgattactctgtcgtgctgctgctgagacttgcc aagacatatgaaaccactctagagaagtgctgtgccgctgcagatcctca tgaatgctatgccaaagtgttcgatgaatttaaacctcttgtggaagagc ctcagaatttaatcaaacaaaattgtgagctttttgagca gcttggagag tacaaattccagaatgcgctattagttcgttacaccaagaaagtacccca agtgtcaactccaactcttgtagaggtctcaagaaacctaggaaaagtgg gcagcaaatgttgtaaacatcctgaagcaaaaagaatgccctgtgcagaa gactatctatccgtggtcctgaaccagttatgtgtgttgcatgagaa aac gccagtaagtgacagagtcaccaaatgctgcacagaatccttggtgaaca ggcgaccatgcttttcagctctggaagtcgatgaaacatacgttcccaaa gagtttaatgctgaaacattcaccttccatgcagatatatgcacactttc tgagaaggagagacaaatcaagaaacaaactgcacttgttgagctc gtga aacacaagcccaaggcaacaaaagagcaactgaaagctgttatggatgat ttcgcagcttttgtagagaagtgctgcaaggctgacgataaggagacctg ctttgccgaggagggtaaaaaacttgttgcggccagtcaggccgccttag gcttaggaggtggtggatccggaggcggtggaagcggaggtggt ggatct ggaggcggtggaagcgcgcgcaacggagaccactgtccgctcgggcccgg gcgttgctgccgtctgcacacggtccgcgcgtcgctggaagacctgggct gggccgattgggtgctgtcgccacgggaggtgcaagtgaccatgtgcatc ggcgcgtgcccgagccagttccggggcggca aacatgcacgcgcagatcaa gacgagcctgcaccgcctgaagcccgacacggtgccagcgccctgctgcg tgcccgccagctacaatcccatggtgctcattcaaaagaccgacaccggg gtgtcgctccagacctatgatgacttgttagccaaagactgccactgcat atga (SEQ ID NO:111).

According to a preferred embodiment of the present invention, the second polypeptide

- 60 046387 chain contains the amino acid sequence SEQ ID NO: 12, which is encoded by the nucleic acid sequence SEQ ID NO: 11.

As discussed above, a heterodimer is provided that comprises a first polypeptide chain comprising the sequence SEQ ID NO: 112 and a second polypeptide chain comprising the sequence SEQ ID NO: 12.

II.G.2 HSA-(G4S)4-GDF15.

The definition of HSA-(G4S)4-GDF15 as used herein means a fusion protein comprising a GDF15 polypeptide linked to an HSA polypeptide by a linker which contains the sequence SEQ ID NO: 18 and which connects the N-terminus of the GDF15 polypeptide to the C-terminus of the HSA polypeptide.

Certain embodiments of the present invention provide a homodimer comprising two HSA-(G4S)4-GDF15 fusion proteins linked through an interchain disulfide bond between the respective GDF15 regions of the proteins.

More specifically, according to a particular embodiment of the present invention, the homodimer comprises:

(a) two HSA polypeptides (in each monomer) containing the sequence SEQ ID NO: 110;

(b) two GDF15 polypeptides (in each monomer) containing the sequence SEQ ID NO: 12, and (c) two polypeptide linkers (in each monomer) containing the sequence SEQ ID NO: 18, each of which connects the N-terminus of the GDF15 polypeptide to the C-terminus of the HAS polypeptide via a peptide bond.

In a preferred embodiment of the present invention, the fusion protein comprises the amino acid sequence SEQ ID NO: 112, which is encoded by the nucleic acid sequence SEQ ID NO: 111.

As discussed above, according to a specific embodiment of the present invention there is provided a homodimer that contains two fusion proteins containing the sequence SEQ ID NO: 112.

II.G.3 HSA-GSPAPAPGS-GDF15.

The definition of HSA-(GSPAPAPGS)-GDF15 in the present invention means a fusion protein comprising a GDF15 polypeptide connected to an HSA polypeptide through a linker that contains the sequence SEQ ID NO: 113 and which connects the N-terminus of the GDF15 polypeptide to the C-terminus of the HSA polypeptide.

Certain embodiments of the present invention provide a homodimer comprising two HSA-(GSPAPAPGS)-GDF15 fusion proteins linked through an interchain disulfide bond between the respective GDF15 regions of the proteins.

More specifically, according to a particular embodiment of the present invention, the homodimer comprises:

(a) two HSA polypeptides (in each monomer) containing the sequence SEQ ID NO: 110;

(b) two GDF15 polypeptides (in each monomer) containing the sequence SEQ ID NO: 12; and (c) two polypeptide linkers (in each monomer) containing the sequence: GSPAPAPGS (SEQ ID NO:113), each of which connects the N-terminus of the GDF-15 polypeptide to the C-terminus of the HSA polypeptide via a peptide bond.

According to a preferred embodiment of the present invention, the fusion protein contains the amino acid sequence (the linker is underlined by a double line):

DAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQCPFEDHVKLVNEVTEFA

KTCVADESAENCDKSLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNE

- 61 046387

DLPSL AADFVESKDVCKNYAEAKDVFLGMFLYEYARRHPDYSVVLLLRLA KTYETTLEKCCAAADPHECYAKVFDEFKPLVEEPQNLIKQNCELFEQLGE YKFQNALLVRYTKKVPQVSTPTLVEVSRNLGKVGSKCCKHPEAKRMPCAE DYLSWLNQLCVLHEKTPVSDRVTKCCTESLVNRRPCFSALEVDETYVPK E FNAE TFT FHADICTLSEKERQIKKQTALVE LVKHKPKATKE QLKAVMDD FAAFVEKCCKADDKE TC FAEEGKKLVAAS QAALGLGS PAPAPGSARNGDH CPLGPGRCCRLHTVRASLEDLGWADWVLSPREVQVTMCIGACPSQFRAAN MHAQIKTSLHRLKPDTVPAPCCVPASYNPMVLIQKTDTGVSLQTY DDLLA KDCHCI (SEQ ID NO:115), which is encoded by the nucleic acid sequence:

gats ctttttggagacaaattatgcacagttgcaactcttcgtgaaacct atggtgaaatggctgactgctgtgcaaaacaagaacctgagagaaatgaa tgcttcttgcaacacaaagatgacaacccaaacctcccccgattggtgag accagaggttgatgtgatgtgcactgcttttcatgacaatgaagagacat ttttgaa aaaatacttatatgaaattgccagaagacatccttacttttat gccccggaactccttttctttgctaaaaggtataaagctgcttttacaga atgttgccaagctgctgataaagctgcctgcctgttgccaaagctcgatg aacttcgggatgaagggaaggcttcgtctgccaaacagagactcaagtgt gccagt ctccaaaaatttggagaaagagcttttcaaagcatgggcagtagc tcgcctgagccagagatttcccaaagctgagtttgcagaagtttccaagt tagtgacagatcttaccaaagtccacacggaatgctgccatggagatctg cttgaatgtgctgatgacagggcggaccttgccaagtatatctgtgaaaa tcaagattcgat ctccagtaaactgaaggaatgctgtgaaaaacctctgt tggaaaaatcccactgcattgeegaagtggaaaatgatgagatgeetget gacttgccttcattagctgctgattttgttgaaagtaaggatgtttgcaa aaactatgctgaggcaaaggatgtcttcctgggcatgtttttgtatgaat atgcaagaagg catcctgattactctgtcgtgctgctgctgagacttgcc

- 62 046387 aagacatatgaaaccactctagagaagtgctgtgccgctgcagatcctca tgaatgctatgccaaagtgttcgatgaatttaaacctcttgtggaagagc ctcagaatttaatcaaacaaaattgtgagctttttgagcagcttggagag tacaaattccagaatgcgctattagttcgttaca ccaagaaagtacccca agtgtcaactccaactcttgtagaggtctcaagaaacctaggaaaagtgg gcagcaaatgttgtaaacatcctgaagcaaaaagaatgccctgtgcagaa gactatctatccgtggtcctgaaccagttatgtgtgttgcatgagaaaac gccagtaagtgacagagtcaccaaatgctgcacagaatcctt ggtgaaca ggcgaccatgcttttcagctctggaagtcgatgaaacatacgttcccaaa gagtttaatgctgaaacattcaccttccatgcagatatatgcacactttc tgagaaggagagacaaatcaagaaacaaactgcacttgttgagctcgtga aacacaagcccaaggcaacaaaagagcaactgaaagctgt tatggatgat ttcgcagcttttgtagagaagtgctgcaaggctgacgataaggagacctg ctttgccgaggagggtaaaaaacttgttgcggccagtcaggccgccttag gcttaggatccccagctccagctccaggaagcgcgcgcaacggagaccac tgtccgctcgggcccgggcgttgctgccgtctgca cacggtccgcgcgtc gctggaagacctgggctgggccgattgggtgctgtcgccacgggaggtgc aagtgaccatgtgcatcggcgcgtgcccgagccagttccgggcggcaaac atgcacgcgcagatcaagacgagcctgcaccgcctgaagcccgacacggt gccagcgccctgcgcgtgc ccgccagctacaatcccatggtgctcattc aaaagaccgacaccggggtgtcgctccagacctatgatgacttgttagcc aaagactgccactgcatatga (SEQ ID NO:114).

As discussed above, according to a specific embodiment of the present invention, there is provided a homodimer that contains two fusion proteins containing the sequence SEQ ID NO: 115.

II.G.4 HSA-GS(PAPAP)2GS-GDF15.

The definition of HSA-GS(PAPAP)2GS-GDF15 in the present invention means a fusion protein comprising a GDF15 polypeptide connected to an HSA polypeptide through a linker that contains the sequence of SEQ ID NO: 116 and which connects the N-terminus of the GDF15 polypeptide to the C-terminus of the HSA polypeptide.

According to certain embodiments of the present invention, there is provided a homodimer comprising two HSA-GS(PAPAP)2GS-GDF15 fusion proteins linked through an interchain disulfide bond between the corresponding GDF15 regions of the proteins.

More specifically, according to a particular embodiment of the present invention, the homodimer comprises:

(a) two HSA polypeptides (in each monomer) containing the sequence SEQ ID NO: 110;

(b) two GDF15 polypeptides (in each monomer) containing the sequence SEQ ID NO: 12; and (c) two polypeptide linkers (in each monomer) containing the sequence: GSPAPAPPAPAPGS (SEQ ID NO:116), each of which connects the N-terminus of the GDF-15 polypeptide to the C-terminus of the HSA polypeptide via a peptide bond.

According to a preferred embodiment of the present invention, the fusion protein contains the amino acid sequence (the linker is underlined by a double line):

- 63 046387

DAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQCPFEDHVKLVNEVTEFA KTCVADESAENCDKSLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNE CFLQHKDDNPNLPRLVRPEVDVMCTAFHDNEETFLKKYLYEIARRHPYFY APELLFFAKRYKAAFTECCQAADKAACLLPKLDELRDEGKASSAKQRLKC ASLQ KFGERAFKAWAVARLSQRFPKAEFAEVSKLVTDLTKVHTECCHGDL LECADDRADLAKYICENQDSISSKLKECCEKPLLEKSHCIAEVENDEMPA DLPSLAADFVESKDVCKNYAEAKDVFLGMFLYEYARRHPDYSWLLLRLA KTYETTLEKCCAAADPHECYAKVFDEFKPLVEEPQNLIKQNCELFEQLGE YKFQNALLVR YTKKVPQVSTPTLVEVSRNLGKVGSKCCKHPEAKRMPCAE DYLSWLNQLCVLHEKTPVSDRVTKCCTESLVNRRPCFSALEVDETYVPK EFNAETFTFHADICTLSEKERQIKKQTALVELVKHKPKATKEQLKAVMDD FAAFVEKCCKADDKE TC FAEE GKKLVAAS QAALGLGSPAPAPPAPAPGSA RNGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPREVQVTMCIGACPSQ FRAANMHAQIKTSLHRLKPDTVPAPCCVPASYNPMVLIQKTDTGVSLQTY DDLLAKDCHCI (SEQ ID NO:118), which is encoded by the nucleic acid sequence:

gatgcacacaagagtgaggttgctcatcgatttaaagatttgggagaaga aaatttcaaagccttggtgttgattgcctttgctcagtatcttcagcagt gtccatttgaagatcatgtaaaattagtgaatgaagtaactgaatttgca aaacatgtgttgctgatgagtcagctgaaaattgtgacaaatcacttca taccctttttggagacaaattatgcacagttgcaactcttcgtgaaacct atggtgaaatggctgactgctgtgcaaaacaagaacctgagagaaatgaa tgcttcttgcaacacaaagatgacaacccaaacctcccccgattggtgag accagaggttgatgtgatgtgcactgcttttcatgacaatgaagagacat tttt gcca gtctccaaaaatttggagaaagagctttcaaagcatgggcagtagc tcgcctgagccagagatttcccaaagctgagtttgcagaagtttccaagt tagtgacagatcttaccaaagtccacacggaatgctgccatggagatctg cttgaatgtgctgatgacagggcggaccttgccaagtatatctgtgaaaa tcaagattc gatctccagtaaactgaaggaatgctgtgaaaaacctctgt tggaaaaatcccactgcattgccgaagtggaaaatgatgagatgcctget gacttgccttcattagctgctgattttgttgaaagtaaggatgtttgcaa aaactatgctgaggcaaaggatgtcttcctgggcatgtttttgtatgaat atg caagaaggcatcctgattactctgtcgtgctgctgctgagacttgcc aagacatatgaaaccactctagagaagtgctgtgccgctgcagatcctca tgaatgctatgccaaagtgttcgatgaatttaaacctcttgtggaagagc ctcagaatttaatcaaacaaaattgtgagctttttgagcagcttggagag tacaaatt ccagaatgcgctattagttcgttacaccaagaaagtacccca agtgtcaactccaactcttgtagaggtctcaagaaacctaggaaaagtgg gcagcaaatgttgtaaacatcctgaagcaaaaagaatgccctgtgcagaa gactatctatccgtggtcctgaaccagttatgtgtgttgcatgagaaaac gccagtaagtgacaga gtcaccaaatgctgcacagaatccttggtgaaca ggcgaccatgcttttcagctctggaagtcgatgaaacatacgttcccaaa

- 64 046387 gagtttaatgctgaaacattcaccttccatgcagatatatgcacactttc tgagaaggagagacaaatcaagaaacaaactgcacttgttgagctcgtga aacacaagcccaaggcaacaaaagagcaactgaaagctgttatggatgat ttcgcagcttttgtagagaagtgctgcaagg ctgacgataaggagacctg ctttgccgaggagggtaaaaaacttgttgcggccagtcaggccgccttag gcttaggatccccagctccagctccacccgcacctgcccctggaagcgcg cgcaacggagaccactgtccgctcgggcccgggcgttgctgccgtctgca cacggtccgcgcgtcgctggaagacc tgggctgggccgattgggtgctgt cgccacgggaggtgcaagtgaccatgtgcatcggcgcgtgcccgagccag ttccgggcggcaaacatgcacgcgcagatcaagacgagcctgcaccgcct gaagcccgacacggtgccagcgccctgctgcgtgcccgccagctacaatc ccatggtgctcattca aaagaccgacaccggggtgtcgctccagacctat gatgacttgttagccaaagactgccactgcatatga (SEQ ID NO:117).

As discussed above, according to a specific embodiment of the present invention, there is provided a homodimer that contains two fusion proteins containing the sequence SEQ ID NO: 118.

II.G.5 HSA-GSAAQAAQQGS-GDF15.

The definition of HSA-GSAAQAAQQGS-GDF15 in the present invention means a fusion protein comprising a GDF15 polypeptide connected to an HSA polypeptide through a linker that contains the sequence SEQ ID NO: 119 and which connects the N-terminus of the GDF15 polypeptide to the C-terminus of the HSA polypeptide.

Certain embodiments of the present invention provide a homodimer comprising two HSA-GSAAQAAQQGS-GDF15 fusion proteins linked through an interchain disulfide bond between the corresponding GDF15 regions of the proteins.

More specifically, according to a particular embodiment of the present invention, the homodimer comprises:

(a) two HSA polypeptides (in each monomer) containing the sequence SEQ ID NO: 110;

(b) two GDF15 polypeptides (in each monomer) containing the sequence SEQ ID NO: 12; and (c) two polypeptide linkers (in each monomer) containing the sequence: GSAAQAAQQGS (SEQ ID NO:119), each of which connects the N-terminus of the GDF15 polypeptide to the C-terminus of the HSA polypeptide via a peptide bond.

According to a preferred embodiment of the present invention, the fusion protein contains the amino acid sequence (the linker is underlined by a double line):

DAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQCPFEDHVKLVNEVTEFA KTCVADESAENCDKSLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNE CFLQHKDDNPNLPRLVRPEVDVMCTAFHDNEETFLKKYLYEIARRHPYFY APELLFFAKRYKAAFTECCQAADKAACLLPKLDELRDEGKASSAKQRLKC ASLQ KFGERAFKAWAVARLSQRFPKAEFAEVSKLVTDLTKVHTECCHGDL LECADDRADLAKYICENQDSISSKLKECCEKPLLEKSHCIAEVENDEMPA DLPSLAADFVESKDVCKNYAEAKDVFLGMFLYEYARRHPDYSWLLLRLA KTYETTLEKCCAAADPHECYAKVFDEFKPLVEEPQNLIKQNCELFEQLGE YKFQNALLVR YTKKVPQVSTPTLVEVSRNLGKVGSKCCKHPEAKRMPCAE DYLSVVLNQLCVLHEKTPVSDRVTKCCTESLVNRRPCFSALEVDETYVPK E FNAE TFT FHADICTLSEKERQIKKQTALVE LVKHKPKATKE QLKAVMDD FAAFVEKCCKADDKETC FAEEGKKLVAASQAALGLGSAAQAAQQ GSARNG DHCPLGPGRCCRLHTVRASLEDLGWADWVLSPREVQVTMCIGACPSQFRA ANMHAQIKTSLHRLKPDTVPAPCCVPASYNPMVLIQKTDTGVSLQTYDDL LAKDCHCI (SEQ ID NO:121), which is encoded by the nucleic acid sequence:

- 65 046387 gatgcacacaagagtgaggttgctcatcgatttaaagatttgggagaaga aaatttcaaagccttggtgttgattgcctttgctcagtatcttcagcagt gtccatttgaagatcatgtaaaattagtgaatgaagtaactgaatttgca aaaacatgtgttgctgatgagtcagetgaaaatt gtgacaaatcacttea taccctttttggagacaaattatgcacagttgcaactcttcgtgaaacct atggtgaaatggctgactgctgtgcaaaacaagaacctgagagaaatgaa tgcttcttgcaacacaaagatgacaacccaaacctcccccgattggtgag accagaggttgatgtgatgtgcactgcttttcatga caatgaagagacat ttttgaaaaaatacttatatgaaattgccagaagacatccttacttttat gccccggaactccttttctttgctaaaaggtataaagctgcttttacaga atgttgccaagctgctgataaagctgcctgcctgttgccaaagctcgatg aacttcgggatgaagggaaggcttcgtctgccaaac agagactcaagtgt gccagtctccaaaaatttggagaaagagctttcaaagcatgggcagtagc tcgcctgagccagagatttcccaaagctgagtttgcagaagtttccaagt tagtgacagatcttaccaaagtccacacggaatgctgccatggagatctg cttgaatgtgctgatgacagggcggaccttgccaagtatatctg tgaaaa tcaagattcgatctccagtaaactgaaggaatgctgtgaaaaacctctgt tggaaaaatcccactgcattgeegaagtggaaaatgatgagatgeetget gacttgccttcattagctgctgattttgttgaaagtaaggatgtttgcaa aaactatgctgaggcaaaggatgtcttcctgggcatgtttt tgtatgaat atgcaagaaggcatcctgattactctgtcgtgctgctgctgagacttgcc aagacatatgaaaccactctagagaagtgctgtgccgctgcagatcctca tgaatgctatgccaaagtgttcgatgaatttaaacctcttgtggaagagc ctcagaatttaatcaaacaaaattgtgagctttttgagcagctt ggagag tacaaattccagaatgcgctattagttcgttacaccaagaaagtacccca agtgtcaactccaactcttgtagaggtctcaagaaacctaggaaaagtgg gcagcaaatgttgtaaacatcctgaagcaaaaagaatgccctgtgcagaa gactatctatccgtggtcctgaaccagttatgtgtgttgcatgagaaaac g ccagtaagtgacagagtcaccaaatgctgcacagaatccttggtgaaca ggcgaccatgcttttcagctctggaagtcgatgaaacatacgttcccaaa gagtttaatgctgaaacattcaccttccatgcagatatatgcacactttc tgagaaggagacaaatcaagaaacaaactgcacttgttgagctcgtga aacacaagcccaaggcaacaaaagagcaactgaaagctgttatggatgat ttcgcagcttttgtagagaagtgctgcaaggctgacgataaggagacctg ctttgccgaggagggtaaaaaacttgttgcggccagtcaggccgccttag gcttaggatccgccgctcaggctgcacagcaaggaagcgcgcgcaacgg a gaccactgtccgctcgggcccggggcgttgctgccgtctgcacacggtccg cgcgtcgctggaagacctgggctgggccgattgggtgctgtcgccacggg aggtgcaagtgaccatgtgcatcggcgcgtgcccgagccagttccgggcg gcaaacatgcacgcgcagatcaagacgagcct gcaccgcctgaagcccga cacggtgccagcgccctgctgcgtgcccgccagctacaatcccatggtgc tcattcaaaagaccgacaccggggtgtcgctccagacctatgatgacttg ttagccaaagactgccactgcatatga (SEQ ID NO :120).

As discussed above, according to a specific embodiment of the present invention there is provided a homodimer that contains two fusion proteins containing the sequence SEQ ID NO: 121.

II.G.6 HSA-GS(AAQAAQQ) ₂ GS-GDF15.

The definition of HSA-GS(AAQAAQQ) 2GS-GDF15 in the present invention means a fusion protein containing a GDF15 polypeptide connected to an HSA polypeptide through a linker, which

- 66 046387 contains the sequence SEQ ID NO: 122 and which connects the N-terminus of the GDF15 polypeptide to the C-terminus of the HSA polypeptide.

Certain embodiments of the present invention provide a homodimer comprising two HSA-GS(AAQAAQQ) _2GS -GDF15 fusion proteins linked through an interchain disulfide bond between the respective GDF15 regions of the proteins.

More specifically, according to a particular embodiment of the present invention, the homodimer comprises:

(a) two HSA polypeptides (in each monomer) containing the sequence SEQ ID NO: 110;

(b) two GDF15 polypeptides (in each monomer) containing the sequence SEQ ID NO: 12; and (c) two polypeptide linkers (in each monomer) containing the sequence: GSAAQAAQQAAQAAQQGS (SEQ ID NO:122), each of which connects the N-terminus of the GDF-15 polypeptide to the C-terminus of the HSA polypeptide via a peptide bond.

According to a preferred embodiment of the present invention, the fusion protein contains the amino acid sequence (the linker is underlined by a double line):

DAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQCPFEDHVKLVNEVTEFA KTCVADESAENCDKSLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNE CFLQHKDDNPNLPRLVRPEVDVMCTAFHDNEETFLKKYLYEIARRHPYFY APELLFFAKRYKAAFTECCQAADKAACLLPKLDELRDEGKASSAKQRLKC ASLQ KFGERAFKAWAVARLSQRFPKAEFAEVSKLVTDLTKVHTECCHGDL LECADDRADLAKYICENQDSISSKLKECCEKPLLEKSHCIAEVENDEMPA DLPSLAADFVESKDVCKNYAEAKDVFLGMFLYEYARRHPDYSWLLLRLA KTYETTLEKCCAAADPHECYAKVFDEFKPLVEEPQNLIKQNCELFEQLGE YK FQNAL LVRY T KKVP QVS T R T LVEVS RNL GKVG S KS SKN REAKRMP CAE DYLSWLNQLCVLHEKT PVS DRVTKCC TE S LVNRRPC FSALEVDE ТYVPK E FNAE T FT FHADICTLSEKERQIKKQTALVELVKHKPKATKE QLKAVMDD FAAFVEKSCKKADDKETСF AEEGККLVAASQAALGLGSAAQAAQQAAQAAQ QGZARNGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPREVQVTMCIGA CPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYNPMVLIQKTDTGVS LQTYDDLLAKDCHCI (SEQ ID NO:124) , which is encoded by the nucleic acid sequence:

gatgcacacaagagtgaggttgctcatcgatttaaagatttgggagaaga aaatttcaaagccttggtgttgattgcctttgctcagtatcttcagcagt gtccatttgaagatcatgtaaaattagtgaatgaagtaactgaatttgca aaacatgtgttgctgatgagtcagctgaaaattgtgacaaatcacttca taccctttttggagacaaattatgcacagttgcaactcttcgtgaaacct atggtgaaatggctgactgctgtgcaaaacaagaacctgagagaaatgaa

- 67 046387 tgcttcttgcaacacaaagatgacaacccaaacctcccccgattggtgag accagaggttgatgtgatgtgcactgcttttcatgacaatgaagagacat ttttgaaaaaatacttatatgaaattgccagaagacatccttacttttat gccccggaactccttttctttgctaaaaggtata aagctgcttttacaga atgttgccaagctgctgataaagctgcctgcctgttgccaaagctcgatg aacttcgggatgaagggaaggcttcgtctgccaaacagagactcaagtgt gccagtctccaaaaatttggagaaagagctttcaaagcatgggcagtagc tcgcctgagccagagatttcccaaagctgagttt gcagaagtttccaagt tagtgacagatcttaccaaagtccacacggaatgctgccatggagatctg cttgaatgtgctgatgacagggcggaccttgccaagtatatctgtgaaaa tcaagattcgatctccagtaaactgaaggaatgctgtgaaaaacctctgt tggaaaaatcccactgcattgccgaagtggaaaatga tgagatgcctget gacttgccttcattagctgctgattttgttgaaagtaaggatgtttgcaa aaactatgctgaggcaaaggatgtcttcctgggcatgtttttgtatgaat atgcaagaaggcatcctgattactctgtcgtgctgctgctgagacttgcc aagacatatgaaaccactctagagaagtgctgtgccgct gcagatcctca tgaatgctatgccaaagtgttcgatgaatttaaacctcttgtggaagagc ctcagaatttaatcaaacaaaattgtgagctttttgagcagcttggagag tacaaattccagaatgcgctattagttcgttacaccaagaaagtacccca agtgtcaactccaactcttgtagaggtctcaagaaacctaggaaaag tgg gcagcaaatgttgtaaacatcctgaagcaaaaagaatgccctgtgcagaa gactatctatccgtggtcctgaaccagttatgtgtgttgcatgagaaaac gccagtaagtgacagagtcaccaaatgctgcacagaatccttggtgaaca ggcgaccatgcttttcagctctggaagtcgatgaaacatacg ttcccaaa gagtttaatgctgaaacattcaccttccatgcagatatatgcacactttc tgagaaggagagacaaatcaagaaacaaactgcacttgttgagctcgtga aacacaagcccaaggcaacaaaagagcaactgaaagctgttatggatgat ttcgcagcttttgtagagaagtgctgcaaggctgacgataa ggagacctg ctttgccgaggagggtaaaaaacttgttgcggccagtcaggccgccttag gcttaggatccgccgctcaggctgcacagcaagcagcccaagcagctcag cagggaagcgcgcgcaacggagaccactgtccgctcgggcccgggcgttg ctgccgtctgcacacggtccgcgcgtcgctgga agacctgggctgggccg attgggtgctgtcgccacgggaggtgcaagtgaccatgtgcatcggcgcg tgcccgagccagttccgggcggcaaacatgcacgcgcagatcaagacgag cctgcaccgcctgaagcccgacacggtgccagcgccctgctgcgtgcccg ccagctacaatcccatggtgctcat tcaaaagaccgacaccggggtgtcg ctccagacctatgatgacttgttagccaaagactgccactgcatatga (SEQ ID NO:123).

As discussed above, according to a specific embodiment of the present invention, there is provided a homodimer that contains two fusion proteins containing the sequence SEQ ID NO: 124.

II.G.7 HSA-GGNAEAAAKEAAAKEAAAKAGG-GDF15.

The definition of HSA-GGNAEAAAKEAAAKEAAAKAGG-GDF15 in the present invention means a fusion protein comprising a GDF15 polypeptide connected to an HSA polypeptide through a linker that contains the sequence of SEQ ID NO: 125 and which connects the N-terminus of the GDF15 polypeptide to the C-terminus of the HSA polypeptide.

Certain embodiments of the present invention provide a homodimer comprising two HSA-GGNAEAAAKEAAAKEAAAKAGG-GDF15 fusion proteins linked through an interchain disulfide bond between the corresponding GDF15 regions of the proteins.

More specifically, according to a particular embodiment of the present invention, the homodimer comprises:

(a) two HSA polypeptides (in each monomer) containing the sequence SEQ ID NO: 110;

(b) two GDF15 polypeptides (in each monomer) containing the sequence SEQ ID NO: 12; And

- 68 046387 (c) two polypeptide linkers (in each monomer) containing the sequence: GGNAEAAAKEAAAKEAAAKAGG (SEQ ID NO:125), each of which connects the N-terminus of the GDF-15 polypeptide to the C-terminus of the HSA polypeptide through a peptide bond.

According to a preferred embodiment of the present invention, the fusion protein contains the amino acid sequence (the linker is underlined by a double line):

DAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQCPFEDHVKLVNEVTEFA KTCVADESAENCDKSLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNE CFLQHKDDNPNLPRLVRPEVDVMCTAFHDNEETFLKKYLYEIARRHPYFY APELLFFAKRYKAAFTECCQAADKAACLLPKLDELRDEGKASSAKQRLKC ASLQ KFGERAFKAWAVARLSQRFPKAEFAEVSKLVTDLTKVHTECCHGDL LECADDRADLAKYICENQDSISSKLKECCEKPLLEKSHCIAEVENDEMPA DLPSLAADFVESKDVCKNYAEAKDVFLGMFLYEYARRHPDYSWLLLRLA KTYETTLEKCCAAADPHECYAKVFDEFKPLVEEPQNLIKQNCELFEQLGE YKFQNALLVR YTKKVPQVSTPTLVEVSRNLGKVGSKCCKHPEAKRMPCAE DYLSWLNQLCVLHEKTPVSDRVTKCCTESLVNRRPCFSALEVDETYVPK EFNAETFTFHADICTLSEKERQIKKQTALVELVKHKPKATKEQLKAVMDD FAAFVEKCCKADDKETC FAEEGKKLVAAS QAALGLGGNAEAAAKEAAAKE AA AKEAAAKAGGARNGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPRE VQVTMCIGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYNPMVL IQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:127), which is encoded by the nucleic acid sequence:

gatgcacacaagagtgaggttgctcatcgatttaaagatttgggagaaga aaatttcaaagccttggtgttgattgcctttgctcagtatcttcagcagt gtccatttgaagateatgtaaaattagtgaatgaagtaactgaatttgca aaacatgtgttgctgatgagtcagctgaaaattgtgacaaatcacttca taccctttttggagacaaattatgcacagttgcaactcttcgtgaaacct atggtgaaatggctgactgctgtgcaaaacaagaacctgagagaaatgaa tgcttcttgcaacacaaagatgacaacccaaacctcccccgattggtgag accagaggttgatgtgatgtgcactgcttttcatgacaatgaagagacat tttt gcca gtctccaaaaatttggagaaagagctttcaaagcatgggcagtagc tcgcctgagccagagatttcccaaagctgagtttgcagaagtttccaagt tagtgacagatcttaccaaagtccacacggaatgctgccatggagatctg cttgaatgtgctgatgacagggcggaccttgccaagtatatctgtgaaaa tcaagattc gatctccagtaaactgaaggaatgctgtgaaaaacctctgt tggaaaaatcccactgcattgccgaagtggaaaatgatgagatgcctget gacttgccttcattagctgctgattttgttgaaagtaaggatgtttgcaa aaactatgctgaggcaaaggatgtcttcctgggcatgtttttgtatgaat atg caagaaggcatcctgattactctgtcgtgctgctgctgagacttgcc aagacatatgaaaccactctagagaagtgctgtgccgctgcagatcctca tgaatgctatgccaaagtgttcgatgaatttaaacctcttgtggaagagc ctcagaatttaatcaaacaaaattgtgagctttttgagcagcttggagag

- 69 046387 tacaaattccagaatgcgctattagttcgttacaccaagaaagtacccca agtgtcaactccaactcttgtagaggtctcaagaaacctaggaaaagtgg gcagcaaatgttgtaaacatcctgaagcaaaaagaatgccctgtgcagaa gactatctatccgtggtcctgaaccagttatgtgtgt tgcatgagaaaac gccagtaagtgacagagtcaccaaatgctgcacagaatccttggtgaaca ggcgaccatgcttttcagctctggaagtcgatgaaacatacgttcccaaa gagtttaatgctgaaacattcaccttccatgcagatatatgcacactttc tgagaaggagagacaaatcaagaaacaaactgcacttg ttgagctcgtga aacacaagcccaaggcaacaaaagagcaactgaaagctgttatggatgat ttcgcagcttttgtagagaagtgctgcaaggctgacgataaggagacctg ctttgccgaggagggtaaaaaacttgttgcggccagtcaggccgccttag gcttaggaggcaacgccgaggctgccgctaaggaagcc gctgccaaggag gccgcagcaaaagaggctgcagctaaggccggaggagcgcgcaacggaga ccactgtccgctcgggcccgggcgttgctgccgtctgcacacggtccgcg cgtcgctggaagacctgggctgggccgattgggtgctgtcgccacgggag gtgcaagtgaccatgcatcggcgc gtgcccgagccagttccggggcggc aaacatgcacgcgcagatcaagacgagcctgcaccgcctgaagcccgaca cggtgccagcgccctgctgcgtgcccgccagctacaatcccatggtgctc attcaaaagaccgacaccggggtgtcgctccagacctatgatgacttgtt agccaaagactgccactgcatat ga (SEQ ID NO:126).

As discussed above, according to a specific embodiment of the present invention, there is provided a homodimer that contains two fusion proteins containing the sequence SEQ ID NO: 127.

II.G.8 HSA-(G4S) ₆ -GDF15.

The definition of HSA-(G4S) ₆ -GDF15 in the present invention means a fusion protein comprising a GDF15 polypeptide connected to an HSA polypeptide through a linker that contains the sequence of SEQ ID NO: 128 and which connects the N-terminus of the GDF15 polypeptide to the C-terminus of the HSA polypeptide.

According to certain embodiments of the present invention, there is provided a homodimer comprising two HSA-(G4S) ₆ -GDF15 fusion proteins linked through an interchain disulfide bond between the respective GDF15 regions of the proteins.

More specifically, according to a particular embodiment of the present invention, the homodimer comprises:

(a) two HSA polypeptides (in each monomer) containing the sequence SEQ ID NO: 110;

(b) two GDF15 polypeptides (in each monomer) containing the sequence SEQ ID NO: 12; and (c) two polypeptide linkers (in each monomer) containing the sequence: GGGGSGGGGSGGGGSGGGGSGGGGSGGGGS (SEQ ID NO:128), each of which connects the N-terminus of the GDF-15 polypeptide to the C-terminus of the HSA polypeptide through a peptide bond.

According to a preferred embodiment of the present invention, the fusion protein contains the amino acid sequence (the linker is underlined by a double line):

- 70 046387

DAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQCPFEDHVKLVNEVTEFA DAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQCPFEDHVKLVNEVTEFA KTCVADESAENCDKSLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNE CFLQHKDDNPNLPRLVRPEVDVMCTAFHDNEETFLKKYLYEIARRHPYFY APELL FFAKRYKAAFTECCQAADKAACLLPKLDELRDEGKASSAKQRLKC ASLQKFGERAFKAWAVARLSQRFPKAEFAEVSKLVTDLTKVHTECCHGDL LECADDRADLAKYICENQDSISSKLKECCEKPLLEKSHCIAEVENDEMPA DLPSLAADFVESKDVCKNYAEAKDVFLGMFLYEYARRHPDYSWLLLRLA KTYETTLEKCCAAA DPHECYAKVFDEFKPLVEEPQNLIKQNCELFEQLGE YKFQNALLVRYTKKVPQVSTPTLVEVSRNLGKVGSKCCKHPEAKRMPCAE DYLSWLNQLCVLHEKTPVSDRVTKCCTESLVNRRPCFSALEVDETYVPK E FNAE TFT FHADICTLSEKERQIKKQTALVE LVKHKPKATKE QLKA VMDD FAAFVE KS CKADDKE T C FAE E GKKLVAAS OAALGLGGGGSGGGGSGGGGS GGGGSGGGGSGGGGSARNGDHCPLGPGRCCRLHTVRAS LE DLGWADWVL S PREVQVTMCIGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYNP MVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:130), which code is determined by the nucleic acid sequence:

gatgcacacaagagtgaggttgctcatcgatttaaagatttgggagaaga aaatttcaaagccttggtgttgattgcctttgctcagtatcttcagcagt gtccatttgaagatcatgtaaaattagtgaatgaagtaactgaatttgca aaacatgtgttgctgatgagtcagctgaaaattgtgacaaatcacttca taccctttttggagacaaattatgcacagttgcaactcttcgtgaaacct

- 71 046387 atggtgaaatggctgactgctgtgcaaaacaagaacctgagagaaatgaa tgcttcttgcaacacaaagatgacaacccaaacctcccccgattggtgag accagaggttgatgtgatgtgcactgcttttcatgacaatgaagagacat ttttgaaaaaatacttatatgaaattgccagaagacatcc ttacttttat gccccggaactccttttctttgctaaaaggtataaagctgcttttacaga atgttgccaagctgctgataaagctgcctgcctgttgccaaagctcgatg aacttcgggatgaagggaaggcttcgtctgccaaacagagactcaagtgt gccagtctccaaaaatttggagaaagagcttttcaa agcatgggcagtagc tcgcctgagccagagatttcccaaagctgagtttgcagaagtttccaagt tagtgacagatcttaccaaagtccacacggaatgctgccatggagatctg cttgaatgtgctgatgacagggcggaccttgccaagtatatctgtgaaaa tcaagattcgatctccagtaaactgaaggaatgctgtgaaa aacctctgt tggaaaaatcccactgcattgccgaagtggaaaatgatgagatgcctget gacttgccttcattagctgctgattttgttgaaagtaaggatgtttgcaa aaactatgctgaggcaaaggatgtcttcctgggcatgtttttgtatgaat atgcaagaaggcatcctgattactctgtcgtgctg ctgctgagacttgcc aagacatatgaaaccactctagagaagtgctgtgccgctgcagatcctca tgaatgctatgccaaagtgttcgatgaatttaaacctcttgtggaagagc ctcagaatttaatcaaacaaaattgtgagctttttgagcagcttggagag tacaaattccagaatgcgctattagttcgttacaccaagaa agtacccca agtgtcaactccaactcttgtagaggtctcaagaaacctaggaaaagtgg gcagcaaatgttgtaaacatcctgaagcaaaaagaatgccctgtgcagaa gactatctatccgtggtcctgaaccagttatgtgtgttgcatgagaaaac gccagtaagtgacagagtcaccaaatgctgcacagaatccttggtga aca ggcgaccatgcttttcagctctggaagtcgatgaaacatacgttcccaaa gagtttaatgctgaaacattcaccttccatgcagatatatgcacactttc tgagaaggagagacaaatcaagaaacaaactgcacttgttgagctcgtga aacacaagcccaaggcaacaaaagagcaactgaaagctgttatgg atgat ttcgcagcttttgtagagaagtgctgcaaggctgacgataaggagacctg ctttgccgaggagggtaaaaaacttgttgcggccagtcaggccgccttag gcttaggaggtggtggctctggaggcggtggaagcggaggcggtggatcc ggaggcggtggaagcggaggtggtggatctggaggcggtgga agcgcgcg caacggagaccactgtccgctcgggcccggggcgttgctgccgtctgcaca cggtccgcgcgtcgctggaagacctgggctgggccgattgggtgctgtcg ccacgggaggtgcaagtgaccatgtgcatcggcgcgtgcccgagccagtt ccgggcggcaaacatgcacgcgc agatcaagacgagcctgcaccgcctga agcccgacacggtgccagcgccctgctgcgtgcccgccagctacaatccc atggtgctcattcaaaagaccgacaccggggtgtcgctccagacctatga tgacttgttagccaaagactgccactgcatatga (SEQ ID NO:129).

As discussed above, according to a specific embodiment of the present invention, there is provided a homodimer that contains two fusion proteins containing the sequence SEQ ID NO: 130.

II.G.9 HSA-GS(AAQAAQQ)2GS-GDF15(N3D).

HSA-GS(AAQAAQQ)2GS-GDF15(N3D) as used herein means a fusion protein comprising a GDF15(N3D) polypeptide linked to an HSA polypeptide by a linker which contains the sequence SEQ ID NO: 122 and which connects the N-terminus of the GDF15 polypeptide (N3D) with the C-terminus of the HSA polypeptide.

According to certain embodiments of the present invention, there is provided a homodimer comprising two HSA-GS(AAQAAQQ) _2GS -GDF15(N3D) fusion proteins linked through an interchain disulfide bond between the respective GDF15 regions of the proteins.

- 72 046387

More specifically, according to a particular embodiment of the present invention, the homodimer comprises:

(a) two HSA polypeptides (in each monomer) containing the sequence SEQ ID NO: 110;

(b) two GDF15(N3D) polypeptides (in each monomer) containing the sequence SEQ ID NO: 52; and (c) two polypeptide linkers (in each monomer) containing the sequence SEQ ID NO: 122, each of which connects the N-terminus of the GDF15(N3D) polypeptide to the C-terminus of the HSA polypeptide via a peptide bond.

According to a preferred embodiment of the present invention, the fusion protein contains the amino acid sequence (the linker is underlined by a double line):

DAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQCPFEDHVKLVNEVTEFA KTCVADESAENCDKSLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNE CFLQHKDDNPNLPRLVRPEVDVMCTAFHDNEETFLKKYLYEIARRHPYFY APELLFFAKRYKAAFTECCQAADKAACLLPKLDELRDEGKASSAKQRLKC ASLQ KFGERAFKAWAVARLSQRFPKAEFAEVSKLVTDLTKVHTECCHGDL LECADDRADLAKYICENQDSISSKLKECCEKPLLEKSHCIAEVENDEMPA DLPSLAADFVESKDVCKNYAEAKDVFLGMFLYEYARRHPDYSWLLLRLA KTYETTLEKCCAAADPHECYAKVFDEFKPLVEEPQNLIKQNCELFEQLGE YKFQNALLVR YTKKVPQVSTPTLVEVSRNLGKVGSKCCKHPEAKRMPCAE DYLSWLNQLCVLHEKTPVSDRVTKCCTESLVNRRPCFSALEVDETYVPK EFNAETFTFHADICTLSEKERQIKKQTALVELVKHKPKATKEQLKAVMDD FAAFVEKCCKADDKE TS FAEEGKKLVAAS QAALGLGSAAQAAQQAAQ AAQ YG^ardgdhcplgpgrccrlhtvrasledlgwadwvlsprevqvtmciga CPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYNPMVLIQKTDTGVS LQTYDDLLAKDCHCI (SEQ ID NO:242), which is encoded by the nucleic acid sequence:

gats cataccctttttggagacaaattatgcacagttgcaactcttcgt gaaacctatggtgaaatggctgactgctgtgcaaaacaagaacctgagag aaatgaatgcttcttgcaacacaaagatgacaacccaaacctcccccgat tggtgagaccagaggttgatgtgatgtgcactgcttttcatgacaatgaa gagacattt ttgaaaaaatacttatatgaaattgccagaagacatcctta cttttatgccccggaactccttttcttttgctaaaaggtataaagctgctt ttacagaatgttgccaagctgctgataaagctgcctgcctgttgccaaag ctcgatgaacttcgggatgaagggaaggcttcgtctgccaaacagagact caagtg tgccagtctccaaaaatttggagaaagagctttcaaagcatggg cagtagctcgcctgagccagagatttcccaaagctgagtttgcagaagtt tccaagttagtgacagatcttaccaaagtccacacggaatgctgccatgg agatctgcttgaatgtgctgatgacagggcggaccttgccaagtatatct gtgaaaatcaagatt cgatctccagtaaactgaaggaatgctgtgaaaaa cctctgttggaaaaatcccactgcattgccgaagtggaaaatgatgagat gcctgctgacttgccttcattagctgctgattttgttgaaagtaaggatg tttgcaaaaactatgctgaggcaaaggatgtcttcctgggcatgtttttg tatga atatgcaagaaggcatcctgattactctgtcgtgctgctgctgag acttgccaagacatatgaaaccactctagagaagtgctgtgccgctgcag atcctcatgaatgctatgccaaagtgttcgatgaatttaaacctcttgtg

- 73 046387 gaagagcctcagaatttaatcaaacaaaattgtgagctttttgagcagct tggagagtacaaattccagaatgcgctattagttcgttacaccaagaaag taccccaagtgtcaactccaactcttgtagaggtctcaagaaacctagga aaagtgggcagcaaatgttgtaaacatcctgaagcaaaaaga atgccctg tgcagaagactatctatccgtggtcctgaaccagttatgtgtgttgcatg agaaaacgccagtaagtgacagagtcaccaaatgctgcacagaatccttg gtgaacaggcgaccatgcttttcagctctggaagtcgatgaaacatacgt tcccaaagagtttaatgctgaaacattcaccttccatgc agatatatgca cactttctgagaaggagagacaaatcaagaaacaaactgcacttgttgag ctcgtgaaacacaagcccaaggcaacaaaagagcaactgaaagctgttat ggatgatttcgcagcttttgtagagaagtgctgcaaggctgacgataagg agacctgctttgccgaggagggtaaaaaacttgttg cggccagtcaggcc gccttaggcttaggatccgccgctcaggctgcacagcaagcagcccaagc agctcagcagggaagcgcgcgcgacggagaccactgtccgctcgggcccg ggcgttgctgccgtctgcacacggtccgcgcgtcgctggaagacctgggc tgggccgattgggtgctgtcgccacgg gaggtgcaagtgaccatgtgcat cggcgcgtgcccgagccagttccgggcggcaaacatgcacgcgcagatca agacgagcctgcaccgcctgaagcccgacacggtgccagcgccctgctgc gtgcccgccagctacaatcccatggtgctcattcaaaagaccgacaccgg ggtgtcgctccagacctga tgacttgttagccaaagactgccactgca ta (SEQ ID NO:241).

As discussed above, according to a specific embodiment of the present invention there is provided a homodimer that contains two fusion proteins containing the sequence SEQ ID NO: 242.

II.H. Constructs with mutations to adjust binding affinity to FcyR.

Certain charged pair (delHinge) mutated multimers have been found to exhibit binding to the Fcy receptor (FcyR), particularly FcyRI and FcyRIII. See, for example, Example 7. In some cases, the binding affinity for FcyR was comparable to that observed for multimers containing a hinge region. This finding was surprising because the Fcy receptor interacts with the hinge region and these multimers are delHinge multimers, as described above, which lack all or part of the hinge region. Mutational analysis of Fc residues involved in binding to FcyR suggested that the major interaction site is located in the hinge region and CH2 domain (Tamm A, 1997, Int. Rev. Immunol. 16:57-85). See also publications Radaev S, et al., J. Biol. Chem. 276:16469-16477; Sondermann, P, et al., 2000, Nature 406:267-273.

Antibody-dependent cell-mediated cytotoxicity (ADCC), an immune response mediated primarily by natural killer (NK) cells, in humans depends on the interaction of FcyRs, particularly human FcyRIIIA, with the Fc domain of an antibody or Fc-containing protein. In ADCC, binding of Fc to FcyRIII on the NK cell surface activates the NK cell, which releases perforins and granzymes.

Accordingly, constructs have been proposed that contain additional modifications to modulate the interaction of the construct with FcyR. In one set of embodiments of the present invention, an asparagine to glycine mutation (N297G) is introduced into a native Fc or variant Fc, including the various Fc domains described above. The N297G mutation removes a conserved N-glycosylation site in the CH2 domain.

In another set of embodiments of the present invention, additional N-terminal amino acid residues are removed from an Fc domain from which all or part of the hinge region has been removed. For example, the amino acid sequence:

GGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVH NAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNG QPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV FSCSVMHEALHNH YTQKSLSLSPGK (SEQ ID NO:303)

- 74 046387 is obtained by deletion of amino acid residues N-terminal to the G236 Fc domain of wild-type IgG1. In some embodiments of the present invention, the terminal lysine (K447) in this embodiment of the Fc may optionally be removed. Amino acid sequence:

GPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHN

AKTKPREEQYNS ТYRWSVLTVLHQDWLNGKEYKCKVSNKAL PAPIECTI

SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQ

PENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHY

TQKSLSLSPGK (SEQ ID NO:304) is generated by deletion of amino acid residues N-terminal to the G237 Fc domain of wild-type IgG1. In some embodiments of the present invention, the terminal lysine (K447) in this embodiment of the Fc may optionally be removed. Amino acid sequence:

PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNA

KTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS

KAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP

ENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT QKSLSLSPGK (SEQ ID NO:305) is generated by deletion of amino acid residues N-terminal to the P238 Fc domain of wild-type IgG1. In some embodiments of the present invention, the terminal lysine (K447) in this embodiment of the Fc may optionally be removed.

According to one embodiment of the present invention, a DhCpmFc(-) domain has been introduced into which an asparagine to glycine (N297G) mutation has been introduced (in the present invention this domain is referred to as DhCpmFc(-)(N297G)). Another embodiment of the present invention provides a DhCpmFc(+) domain into which an asparagine to glycine (N297G) mutation has been introduced (in the present invention this domain is referred to as DhCpmFc(+)(N297G)).

According to another embodiment of the present invention, a DhCpmFc() (Y349C) domain has been introduced into which an asparagine to glycine (N297G) mutation has been introduced (in the present invention this domain is referred to as DhCpmFc(-)(N297G)(Y349C)). Another embodiment of the present invention provides a DhCpmFc(+)(S354C) domain into which an asparagine to glycine (N297G) mutation has been introduced (in the present invention this domain is referred to as DhCpmFc(+)(N297G)(S354C)).

According to another embodiment of the present invention, a DhCpmFc(+)(Y349C) domain has been introduced into which an asparagine to glycine (N297G) mutation has been introduced (in the present invention this domain is referred to as DhCpmFc(+)(N297G)(Y349C)). According to another embodiment of the present invention, a domain DhCpmFc(-)(S354C) has been introduced into which an asparagine to glycine (N297G) mutation has been introduced (in the present invention this domain is referred to as DhCpmFc())(N297G)(S354C)).

Another embodiment of the present invention provides a DhCpmFc(+)(L351C) domain into which an asparagine to glycine (N297G) mutation has been introduced (in the present invention this domain is referred to as DhCpmFc(+)(N297G)(L351C)). According to another embodiment of the present invention, a domain DhCpmFc(-)(L351C) has been introduced into which an asparagine to glycine (N297G) mutation has been introduced (in the present invention this domain is referred to as DhCpmFc())(N297G)(L351C)).

According to another embodiment of the present invention, a DhCpmFc(-) domain has been introduced into which an alanine to cysteine (A287C) mutation has been introduced (in the present invention this domain is referred to as DhCpmFc(-)(A287C)). According to another embodiment of the present invention, a DhCpmFc(+) domain has been introduced into which an alanine to cysteine (A287C) mutation has been introduced (in the present invention this domain is referred to as DhCpmFc(+)(A287C)).

According to another embodiment of the present invention, a DhCpmFc(-) domain has been introduced into which a mutation from leucine to cysteine (L306C) has been introduced (in the present invention this domain is referred to as DhCpmFc(-)(L306C)). According to another embodiment of the present invention, a DhCpmFc(+) domain has been introduced into which a mutation from leucine to cysteine (L306C) has been introduced (in the present invention this domain is referred to as DhCpmFc(+)(L306C)).

According to another embodiment of the present invention, a domain DhCpmFc() (A287C) has been introduced into which a mutation from tyrosine to cysteine (Y349C) has been introduced (in the present invention this domain is referred to as DhCpmFc(-)(A287C)(Y349C)). According to another embodiment of the present invention, there is provided a DhCpmFc(+)(A287C) domain into which a tyrosine mutation has been introduced to

- 75 046387 cysteine (Y349C) (in the present invention this domain is called DhCpmFc(+)(A287C)(Y349C)).

According to another embodiment of the present invention, a domain DhCpmFc() (A287C) has been introduced into which a serine to cysteine mutation (S354C) has been introduced (in the present invention this domain is referred to as DhCpmFc(-)(A287C)(S354C)). According to another embodiment of the present invention, a DhCpmFc(+)(A287C) domain has been introduced into which a serine to cysteine (S354C) mutation has been introduced (in the present invention this domain is referred to as DhCpmFc(+)(A287C)(S354C)).

According to another embodiment of the present invention, a domain DhCpmFc() (L306C) has been introduced into which a mutation from tyrosine to cysteine (Y349C) has been introduced (in the present invention this domain is referred to as DhCpmFc(-)(L306C)(Y349C)). According to another embodiment of the present invention, a DhCpmFc(+)(L306C) domain has been introduced into which a mutation from tyrosine to cysteine (Y349C) has been introduced (in the present invention this domain is referred to as DhCpmFc(+)(L306C)(Y349C)).

According to another embodiment of the present invention, a domain DhCpmFc() (L306C) has been introduced into which a serine to cysteine mutation (S354C) has been introduced (in the present invention this domain is referred to as DhCpmFc(-)(L306C)(S354C)). According to another embodiment of the present invention, a domain DhCpmFc(+)(L306C) has been introduced into which a serine to cysteine mutation (S354C) has been introduced (in the present invention this domain is referred to as DhCpmFc(+)(A287C)(L306C)).

According to another embodiment of the present invention, a DhCpmFc(-) domain is provided in which the 7 N-terminal amino acids have been removed (in the present invention this domain is referred to as Dh2CpmFc(-)). According to another embodiment of the present invention, a DhCpmFc(+) domain is provided in which the 7 N-terminal amino acids have been removed (in the present invention this domain is referred to as Dh2CpmFc(+)).

According to another embodiment of the present invention, a DhCpmFc() (Y349C) domain is provided in which the 7 N-terminal amino acids have been removed (in the present invention this domain is referred to as Dh2CpmFc(-)(Y349C)). According to another embodiment of the present invention, a DhCpmFc(+)(S354C) domain is provided in which the 7 N-terminal amino acids have been removed (in the present invention this domain is referred to as Dh2CpmFc(+)(S354C)).

According to another embodiment of the present invention, a DhCpmFc(+)(Y349C) domain is provided in which the 7 N-terminal amino acids have been removed (in the present invention this domain is referred to as Dh2CpmFc(+)(Y349C)). According to another embodiment of the present invention, a DhCpmFc(-)(S354C) domain is provided in which the 7 N-terminal amino acids have been removed (in the present invention this domain is referred to as Dh2CpmFc(-)(S354C)).

Another embodiment of the present invention provides a CpmFc(+) domain into which an asparagine to glycine (N297G) mutation has been introduced (in the present invention this domain is referred to as CpmFc(+)(N297G)). According to another embodiment of the present invention, a CpmFc(-) domain has been introduced into which an asparagine to glycine (N297G) mutation has been introduced (in the present invention this domain is referred to as CpmFc(-)(N297G)).

According to another embodiment of the present invention, a Dh2CpmFc(+) domain has been introduced into which an asparagine to glycine (N297G) mutation has been introduced (in the present invention this domain is referred to as Dh2CpmFc(+)(N297G)). According to another embodiment of the present invention, a Dh2CpmFc(-) domain has been introduced into which an asparagine to glycine (N297G) mutation has been introduced (in the present invention this domain is referred to as Dh2CpmFc(-)(N297G)).

According to another embodiment of the present invention, a domain Dh2CpmFc() (N297G) has been introduced into which an alanine to cysteine (A287C) mutation has been introduced (in the present invention this domain is referred to as Dh2CpmFc(-)(N297G)(A287C)). According to another embodiment of the present invention, a Dh2CpmFc(+)(N297G) domain has been introduced into which a mutation from leucine to cysteine (L306C) has been introduced (in the present invention this domain is referred to as Dh2CpmFc(+)(N297G)(L306C)).

According to another embodiment of the present invention, a domain Dh2CpmFc())(N297G)(A287C) has been introduced into which a mutation of tyrosine to cysteine (Y349C) has been introduced (in the present invention this domain is called Dh2CpmFc(-)(N297G)(A287C)(Y349C)) . According to another embodiment of the present invention, a domain Dh2CpmFc(+)(N297G)(L306C) has been introduced into which a serine to cysteine mutation (S354C) has been introduced (in the present invention this domain is called Dh2CpmFc(+)(N297G)(L306C)(S354C) ).

According to another embodiment of the present invention, a Dh2CpmFc(-) domain is provided in which two glycines have been added to the N-terminus (in the present invention this domain is referred to as GG-Dh2CpmFc(-)(N297G)). According to another embodiment of the present invention, a Dh2CpmFc(+) domain is provided in which two glycines have been added to the N-terminus (in the present invention this domain is referred to as GG-Dh2CpmFc(+)(N297G)).

According to another embodiment of the present invention, there is provided a GG-Dh2CpmFc() domain into which a mutation from tyrosine to cysteine (Y349C) has been introduced (in the present invention this domain is referred to as GG-Dh2CpmFc(-)(Y349C)). According to another embodiment of the present invention, a GG-Dh2CpmFc(+) domain has been introduced into which a serine to cysteine (S354C) mutation has been introduced (in the present invention, this domain is referred to as GG-Dh2CpmFc(+)(S354C)).

- 76 046387

According to another embodiment of the present invention, a GGDh2CpmFc(+) domain has been introduced into which a mutation from tyrosine to cysteine (Y349C) has been introduced (in the present invention this domain is referred to as GG-Dh2CpmFc(+)(Y349C)). According to another embodiment of the present invention, a domain GG-Dh2CpmFc(-) has been introduced into which a mutation of serine to cysteine (S354C) has been introduced (in the present invention this domain is referred to as GG-Dh2CpmFc(-)(S354C)).

According to another embodiment of the present invention, a Dh2CpmFc(-) domain is provided in which glycine has been added to the N-terminus (in the present invention this domain is referred to as Dh3CpmFc(-)(N297G)). According to another embodiment of the present invention, a Dh2CpmFc(+) domain is provided in which glycine has been added to the N-terminus (in the present invention this domain is referred to as Dh3CpmFc(+)).

According to another embodiment of the present invention, a Dh3CpmFc(-) domain has been introduced into which a mutation from tyrosine to cysteine (Y349C) has been introduced (in the present invention this domain is referred to as Dh3CpmFc(-)(Y349C)). According to another embodiment of the present invention, a Dh3CpmFc(+) domain has been introduced into which a serine to cysteine (S354C) mutation has been introduced (in the present invention this domain is referred to as Dh3CpmFc(+)(S354C)).

According to another embodiment of the present invention, an asparagine to glycine (N297G) mutation (referred to herein as DhMonoFc(N297G)) is introduced into the DhMonoFc domain.

II.H. 1 DhCpmFc(-)(N297G)-GDF15(Ndel3):DhCpmFc(+)(N297G).

The definition of DhCpmFc(-)(N297G)-GDF15(Ndel3):DhCpmFc(+)(N297G) in the present invention means a heterodimer that contains (i) a first polypeptide chain containing a GDF15(Ndel3) polypeptide, the N-terminus of which is connected directly to The C-terminus of the DhCpmFc(-)(N297G) domain, and (ii) a second polypeptide chain containing the DhCpmFc(+)(N297G) domain.

According to certain embodiments of the present invention, there is provided a tetramer that contains a dimer consisting of two heterodimers DhCpmFc(-)(N297G)GDF15(Ndel3):DhCpmFc(+)(N297G), in which the first two polypeptide chains of each heterodimer are connected through an interchain disulfide bond between the corresponding GDF15 regions of these circuits.

More specifically, according to a particular embodiment of the present invention, the tetramer comprises:

(a) two DhCpmFc(+)(N297G) domains (in each heterodimer) containing the sequence: APELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYGSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPSRKEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLKSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPG(SEQ ID NO:287), (b ) two DhCpmFc(-)(N297G) domains (in each heterodimer) containing the sequence: APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPG(SEQ ID NO:132), and (c) two GDF15(Ndel3) polypeptide (in each heterodimer) containing the sequence SEQ ID NO: 55.

According to a preferred embodiment of the present invention, the first polypeptide chain contains the amino acid sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYGSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPGGDHCPLGPGRCCRLHTVRASLEDLGWAD WVLSPR EVQVTMCIGAG P S Q FRAANMHAQIKT S LHRLКДТVPAPССVPAS YNPMV LIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:134), which is encoded by the nucleic acid sequence:

- 77 046387 gcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacc caaggacacccteatgatctcccggacccctgaggtcacatgcgtggtgg tggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggac ggcgtggaggtgcataatgccaagacaaagccgcgggaggag cagtacgg gagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggc tgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcc cccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccaca ggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtca gcctg acctgcctggtcaaaggcttctatcccagcgacatcgccgtggag tggggagagcaatgggcagccggagaacaactacgacaccacgcctcccgt gctggactccgacggctccttcttcctctatagcgacctcaccgtggaca agagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgag gctctgcacaacc actacacgcagaagagcctctccctgtctccggggtgg agaccactgtccgctcgggcccgggcgttgctgccgtctgcacacggtcc gcgcgtcgctggaagacctgggctgggccgattgggtgctgtcgccacgg gaggtgcaagtgaccatgtgcatcggcgcgtgcccgagccagttccggggc ggcaaacatgcacgcgcagatcaagacgagcctgcaccgcctgaagcccg acacggtgccagcgccctgctgcgtgcccgccagctacaatcccatggtg ctcattcaaaagaccgacaccggggtgtcgctccagacctatgatgactt gttagccaaagactgccactgcata (SEQ ID NO:133).

According to a preferred embodiment of the present invention, the second polypeptide chain contains the amino acid sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVD GVEVHNAKTKPREEQYGSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPSRKEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLKSDGSFFLYSKLTVDKSRW QQGNVFSCSVMHE ALHNHYTQKSLSLSPGK(SEQ ID NO:131), which is encoded by the nucleic acid sequence: gcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacc caaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtgg tggacgtgagccacgaagaccctgaggtcaagttcaactggtacgt ggac ggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacgg gagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggc tgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcc cccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccaca ggt gtacaccctgcccccatcccggaaggagatgaccaagaaccaggtca gcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggag tggggagagcaatgggcagccggagaacaactacaagaccacgcctcccgt getgaagtccgacggctccttcttoctetatagcaagctcaccgtggaca agagcaggtggcagcagg ggaacgtcttctcatgctccgtgatgcatgag gctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaa atga (SEQ ID NO:135).

As discussed above, a tetramer is provided containing two polypeptide chains that contain the sequence SEQ ID NO: 134, and two polypeptide chains that contain the sequence SEQ ID NO: 131.

II.H.2 DhCpmFc(-)(N297G)-GDF15(N3D):DhCpmFc(+)(N297G).

The definition of DhCpmFc(-)(N297G)-GDF15(N3D):DhCpmFc(+)(N297G) in the present invention means a heterodimer that contains (i) a first polypeptide chain containing the sequence of GDF15(N3D), the N-terminus of which is connected directly to C-terminus of the DhCpmFc(-)(N297G) domain, and (ii)

- 78 046387 second polypeptide chain containing the DhCpmFc(+)(N297G) domain.

According to certain embodiments of the present invention, there is provided a tetramer that contains a dimer consisting of two heterodimers DhCpmFc(-)(N297G)GDF15(N3D):DhCpmFc(+)(N297G), in which the first two polypeptide chains of each heterodimer are connected through an interchain disulfide bond between the corresponding GDF15 regions of these circuits.

More specifically, according to a particular embodiment of the present invention, the tetramer comprises:

(a) two DhCpmFc(+)(N297G) domains (in each heterodimer) containing the sequence SEQ ID NO: 287, (b) two DhCpmFc(-)(N297G) domains (in each heterodimer) containing the sequence SEQ ID NO: 132, and (c) two GDF15(N3D) polypeptides (in each heterodimer) containing the sequence SEQ ID NO: 52.

According to a preferred embodiment of the present invention, the first polypeptide chain contains the amino acid sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPGARDGDHCPLGPGRCCRLHTVRASLEDLG WADWVL S PREVQVTMCIGAG P S Q FRAANMHAQIKT S LHRLKPDTVPAPCCVPAS YN PMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:137), which is encoded by the nucleic acid sequence: gcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacc caaggacaccctcatgatctcccggacccctgagg tcacatgcgtggtgg tggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggac ggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacgg gagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggc tgaatggcaaggagtacaagtgcaaggtctccaacaa agccctcccagcc cccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccaca ggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtca gcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggag tggggagagcaatgggcagccggagaacaactacgacaccacgcctcccgt getggact ccgacggctccttcttoctetatagcgacctcaccgtggaca agagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgag gctctgcacaaccactacacgcagaagagcctctccctgtctccgggtgc gcgcgacggagaccactgtccgctcgggcccgggcgttgctgccgtctgc acacggtcc gcgcgtcgctggaagacctgggctgggccgattgggtgctg tcgccacgggaggtgcaagtgaccatgtgcatcggcgcgtgcccgagcca gttccgggcggcaaacatgcacgcgcagatcaagacgagcctgcaccgcc tgaagcccgacacggtgccagcgccctgctgcgtgcccgccagcta caat cccatggtgctcattcaaaagaccgacaccggggtgtcgctccagaccta tgatgacttgttagccaaagactgccactgcata (SEQ ID NO:136).

In a preferred embodiment of the present invention, the second polypeptide chain comprises the amino acid sequence SEQ ID NO: 131, which is encoded by the nucleic acid sequence SEQ ID NO: 135.

As discussed above, a tetramer is provided containing two polypeptide chains that contain the sequence SEQ ID NO: 137, and two polypeptide chains that contain the sequence SEQ ID NO: 131.

II.H.3 DhCpmFc(-)(N297G)-G4-GDF15(N3D):DhCpmFc(+)(N297G).

The definition of DhCpmFc(-)(N297G)-G ₄ -GDF15(N3D):DhCpmFc(+)(N297G) in the present invention means a heterodimer that contains (i) a first polypeptide chain containing a polypeptide

- 79 046387

GDF15(N3D) connected to the DhCpmFc(-)(N297G) domain by a linker which contains the sequence SEQ ID NO: 58 and which connects the N-terminus of the GDF15(N3D) polypeptide to the C-terminus of the DhCpmFc(-)(N297G) domain, and (ii) a second polypeptide chain containing the DhCpmFc(+)(N297G) domain.

According to certain embodiments of the present invention, there is provided a tetramer that contains a dimer consisting of two heterodimers DhCpmFc(-)(N297G)-G4GDF15(N3D):DhCpmFc(+)(N297G), in which the first two polypeptide chains of each heterodimer are connected through an interchain disulfide connections between the corresponding GDF15 regions of these circuits.

More specifically, according to a particular embodiment of the present invention, the tetramer comprises:

(a) two DhCpmFc(+)(N297G) domains (in each heterodimer) containing the sequence SEQ ID NO: 287, (b) two DhCpmFc(-)(N297G) domains (in each heterodimer) containing the sequence SEQ ID NO: 132, (c) two GDF15(N3D) polypeptides (in each heterodimer) containing the sequence SEQ ID NO: 52, and (d) two polypeptide linkers (in each heterodimer) containing the sequence SEQ ID NO: 58, each of which connects The N-terminus of the GDF15(N3D) polypeptide with the C-terminus of the DhCpmFc() (N297G) domain via a peptide bond.

According to a preferred embodiment of the present invention, the first polypeptide chain contains the amino acid sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYGSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPGQGGGARDGDHCPLGPGRCCRLHTVRASLED LGWA DWVLSPREVQVTMCIGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVP ASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:139), which is encoded by the nucleic acid sequence: gcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacc caaggacaccctcatgatctcccggacccctgaggtcacat gcgtggtgg tggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggac ggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacgg gagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggc tgaatggcaaggagtacaagtgcaaggtctccaacaaagccct cccagcc cccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccaca ggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtca gcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggag tggggagagcaatgggcagccggagaacaactacgacaccacgcctcccgt getggactccgac ggctccttcttoctetatagcgacctcaccgtggaca agagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgag gctctgcacaaccactacacgcagaagagcctctccctgtctccgggtgg aggtggtggagcgcgcgacggagaccactgtccgctcgggcccgggcgtt gctgccgtctgcaca g ccagctacaatcccatggtgctcattcaaaagaccgacaccggggtgtc gctccagacctatgatgacttgttagccaaagactgccactgcata (SEQ ID NO:138).

In a preferred embodiment of the present invention, the second polypeptide chain comprises the amino acid sequence SEQ ID NO: 131, which is encoded by the nucleic acid sequence SEQ ID NO: 135.

As discussed above, a tetramer is proposed containing two polypeptide chains that

- 80 046387 contain the sequence SEQ ID NO: 139, and two polypeptide chains that contain the sequence SEQ ID NO: 131.

II.H.4 DhCpmFc(-)(N297G)(Y349C)-GDF 15(Ndel3):DhCpmFc(+)(N297G)(S354C).

The definition of DhCpmFc(-)(N297G)(Y349C)-GDF15(Ndel3):DhCpmFc(+)(N297G)(S354C) in the present invention means a heterodimer that contains (i) a first polypeptide chain containing a GDF15(Ndel3) polypeptide, N - the end of which is connected directly to the C-terminus of the DhCpmFc() (N297G)(Y349C) domain, and (ii) a second polypeptide chain containing the DhCpmFc(+)(N297G)(S345C) domain. Cysteine clamp mutations allow the first and second polypeptide chains to be joined via an interchain disulfide bond between C349 of the first polypeptide chain and C354 of the second polypeptide chain.

According to certain embodiments of the present invention, there is provided a tetramer that contains a dimer consisting of two heterodimers DhCpmFc(-)(N297G)(Y349C)GDF15(Ndel3):DhCpmFc(+)(N297G)(S354C), in which the first two polypeptide chains of each heterodimers are connected via an interchain disulfide bond between the corresponding GDF15 regions of these chains.

More specifically, according to a particular embodiment of the present invention, the tetramer comprises:

(a) two DhCpmFc(+)(N297G)(S354C) domains (in each heterodimer) containing the sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYGSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPCRKEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLKSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPG (SEQ ID NO:288), (b ) two domains DhCpmFc(-)(N297G)(Y349C) (in each heterodimer) containing the sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYGSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVCTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPG (SEQ ID NO:141), and (c) two polypeptide and GDF15(Ndel3) (in each heterodimer) containing the sequence SEQ ID NO: 55.

According to a preferred embodiment of the present invention, the first polypeptide chain contains the amino acid sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYGSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVCTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPGGDHCPLGPGRCCRLHTVRASLEDLGWADW VLSPR EVQVTMCIGAC R S Q FRAANMHAQIKT S LHRLKPDTVPAPC CVPAS YNPMV LIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:143), which is encoded by the nucleic acid sequence:

- 81 046387 gcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacc caaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtgg tggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggac ggcgtggaggtgcataatgccaagacaaagccgcgggaggagca gtacgg cagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggc tgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcc cccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccaca ggtgtgcaccctgcccccatcccgggaggagatgaccaagaaccaggtca gcctg acctgcctggtcaaaggcttctatcccagcgacatcgccgtggag tggggagagcaatgggcagccggagaacaactacgacaccacgcctcccgt getggactccgacggctccttcttoctetatagcgacctcaccgtggaca agagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgag gctctgcacaaccactac acgcagaagagcctctccctgtctccgggtgg agaccactgtccgctcgggcccgggcgttgctgccgtctgcacacggtcc gcgcgtcgctggaagacctgggctgggccgattgggtgctgtcgccacgg gaggtgcaagtgaccatgtgcatcggcgcgtgcccgagccagttccggggc ggca aacatgcacgcgcagatcaagacgagcctgcaccgcctgaagcccg acacggtgccagcgccctgctgcgtgcccgccagctacaatcccatggtg ctcattcaaaagaccgacaccggggtgtcgctccagacctatgatgactt gttagccaaagactgccactgcata (SEQ ID NO:142).

According to a preferred embodiment of the present invention, the second polypeptide chain contains the amino acid sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVD GVEVHNAKTKPREEQYGSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPCRKEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLKSDGSFFLYSKLTVDKSRW QQGNVFSCSVMHE ALHNHYTQKSLSLSPGK (SEQ ID NO:140), which is encoded by the nucleic acid sequence: gccccagagctgcttggtggaccatccgtgttcctgtttcctccaaagcc gaaggacaccctgatgatctcaagaactccggaagtgacttgcgtcgtcg tggacgtgtcacatgaggatccagaggtcaagtt caattggtatgtggac ggagtggaagtgcataacgccaagaccaaaccccgcgaagaacagtacgg gagcacctaccgcgtggtgagcgtccttactgtgctccaccaggactggc ttaatgggaaggaatacaagtgtaaggtgtccaacaaggccctccccgct cccatcgaaaagaccatctcaaaggcaaaggggcaaccaagggaacct ca agtgtacaccctgcctccgtgcaggaaggagatgaccaagaaccaggtca gcctgacttgtctcgtgaagggcttctatcccagcgatattgctgtggaa tgggagtcaaatggccagcccgagaataactacaaaactaccccacccgt gctgaaatctgatgggtccttcttcctttactccaagctgaccgtggaca aga gccgctggcaacaaggcaatgtctttagctgctcagtgatgcatgag gctctccataatcactacactcagaagtcactgtccctgtctccgggtaa a (SEQ ID NO:144).

As discussed above, a tetramer is provided containing two polypeptide chains that contain the sequence SEQ ID NO: 143, and two polypeptide chains that contain the sequence SEQ ID NO: 140.

II.H.5 DhCpmFc(-)(N297G)(Y349C)-GDF15(N3D):DhCpmFc(+)(N297G)(S354C).

The definition of DhCpmFc(-)(N297G)(Y349C)-GDF15(N3D):DhCpmFc(+)(N297G)(S354C) in the present invention means a heterodimer that contains (i) a first polypeptide chain containing a GDF15(N3D) polypeptide, N - the end of which is connected directly to the C-terminus of the DhCpmFc() (N297G)(Y349C) domain, and (ii) a second polypeptide chain containing the DhCpmFc(+)(N297G)(S345C) domain.

- 82 046387

Cysteine clamp mutations allow the first and second polypeptide chains to be joined via an interchain disulfide bond between C349 of the first polypeptide chain and C354 of the second polypeptide chain.

According to certain embodiments of the present invention, there is provided a tetramer that contains a dimer consisting of two heterodimers DhCpmFc(-)(N297G)(Y349C)GDF15(N3D):DhCpmFc(+)(N297G)(S354C), in which the first two polypeptide chains of each heterodimers are connected via an interchain disulfide bond between the corresponding GDF15 regions of these chains.

More specifically, according to a particular embodiment of the present invention, the tetramer comprises:

(a) two DhCpmFc(+)(N297G)(S354C) domains (in each heterodimer) containing the sequence SEQ ID NO: 288, (b) two DhCpmFc(-)(N297G)(Y349C) domains containing the sequence SEQ ID NO: : 141, and (c) two GDF15(N3D) polypeptides (in each heterodimer) containing the sequence SEQ ID NO: 52.

According to a preferred embodiment of the present invention, the first polypeptide chain contains the amino acid sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVD GVEVHNAKTKPREEQYGSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVCTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFS CSVMHE ALHNHYTQKSLSLSPGARDGDHCPLGPGRCCRLHTVRASLEDLGWADWVL S PREVQVTMCIGAG R S Q FRAANMHAQIKT S LHRLKPD TVPAPCCVPAS YN PMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:146), which is encoded by the nucleic acid sequence: gcacctgaactcctggggggaccgtcagtct tcctcttccccccaaaacc caaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtgg tggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggac ggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacgg gagcacgtaccgtgtggtcagcgtcctcaccgtcct gcaccaggactggc tgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcc cccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccaca ggtgtgcaccctgcccccatcccgggaggagatgaccaagaaccaggtca gcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggag tg ggagagcaatgggcagccggagaacaactacgacaccacgcctcccgt gctggactccgacggctccttcttcctctatagcgacctcaccgtggaca agagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgag gctctgcacaaccactacacgcagaagagcctctccctgtctccgggtgc gcgcgacggag accactgtccgctcgggcccggggcgttgctgccgtctgc acacggtccgcgcgtcgctggaagacctgggctgggccgattgggtgctg tcgccacgggaggtgcaagtgaccatgtgcatcggcgcgtgcccgagcca gttccgggcggcaaacatgcacgcgcagatcaagacgagcctgcaccg cc tgaagcccgacacggtgccagcgccctgctgcgtgcccgccagctacaat cccatggtgctcattcaaaagaccgacaccggggtgtcgctccagaccta tgatgacttgttagccaaagactgccactgcata ( SEQ ID NO:145).

In a preferred embodiment of the present invention, the second polypeptide chain comprises the amino acid sequence SEQ ID NO: 140, which is encoded by the nucleic acid sequence SEQ ID NO: 144.

As discussed above, a tetramer is provided containing two polypeptide chains that contain the sequence of SEQ ID NO: 146, and two polypeptide chains that contain the sequence of SEQ ID NO: 140.

II.H.6 DhCpmFc(-)(N297G)(L351C) -GDF15(Ndel3):DhCpmFc(+)(N297G)(L351C).

The definition of DhCpmFc(-)(N297G)(L351C)-GDF15(Ndel3):DhCpmFc(+)(N297G)(L351C) in the present invention means a heterodimer that contains (i) a first polypeptide chain containing a GDF15(Ndel3) polypeptide, N -the end of which is connected directly to the C-terminus of the DhCpmFc domain(

- 83 046387 )(N297G)(L351C), and (ii) a second polypeptide chain containing the DhCpmFc(+)(N297G)(L351C) domain. Cysteine clamp mutations allow the first and second polypeptide chains to be joined via an interchain disulfide bond between C351 of the first polypeptide chain and C351 of the second polypeptide chain.

According to certain embodiments of the present invention, there is provided a tetramer that contains a dimer consisting of two heterodimers DhCpmFc(-)(N297G)(L351C)GDF15(Ndel3):DhCpmFc(+)(N297G)(L351C), in which the first two polypeptide chains of each heterodimers are connected via an interchain disulfide bond between the corresponding GDF15 regions of these chains.

More specifically, according to a particular embodiment of the present invention, the tetramer comprises:

(a) two DhCpmFc(+)(N297G)(L351C) domains (in each heterodimer) containing the sequence:

APELLGGPSVFLFPPKPKDTLMI SRTPEVTCVWDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYGSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPA

PIEKTISKAKGQPREPQVYTCPPSREEMTKNQVSLTCLVKGFYPSDIAVE

WESNGQPENNYKTTPPVLKSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE

ALHNHYTQKSLSLSPG (SEQ ID NO:289), (b) two DhCpmFc(-)(N297G)(L351C) domains (in each heterodimer) containing the sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYGSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPA

PIEKTISKAKGQPREPQVYTCPPSREEMTKNQVSLTCLVKGFYPSDIAVE

WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHE

ALHNHYTQKSLSLSPG (SEQ ID NO:148), and (c) two GDF15(Ndel3) polypeptides (in each heterodimer) containing the sequence SEQ ID NO: 55.

According to a preferred embodiment of the present invention, the first polypeptide chain contains the amino acid sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYGSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPA

PIEKTISKAKGQPREPQVYTCPPSRKEMTKNQVSLTCLVKGFYPSDIAVE

WESNGQPENNYKTTPPVLKSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE

ALHNHYTQKSLSLSPGARNGDHCPLGPGRCCRLHTVRASLEDLGWADWVL

S PREVQVTMCIGAG P S Q FRAANMHAQIKT S LHRLKPDTVPAPCCVPAS YN

PMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:150), which is encoded by the nucleic acid sequence:

- 84 046387 gcgccggaactgctgggcggcccgagcgtgtttctgtttccgccgaaacc gaaagataccctgatgattagccgcaccccggaagtgacctgcgtggtgg tggatgtgagccatgaagatccggaagtgaaatttaactggtatgtggat ggcgtggaagtgcataacgcgaaa accaaaccgcgcgaagaacagtatgg cagcacctatcgcgtggtgagcgtgctgaccgtgctgcatcaggattggc tgaacggcaaagaatataaatgcaaagtgagcaacaaagcgctgccggcg ccgattgaaaaaaccattagcaaagcgaaaggccagccgcgcgaaccgca ggtgtatacctgcccgccgag ccgcaaagaaatgaccaaaaaccaggtga gcctgacctgcctggtgaaaggcttttatccgagcgatattgcggtggaa tgggaaagcaacggccagccggaaaacaactataaaaccaccccgccggt gctgaaaagcgatggcagcttttttctgtatagcaaactgaccgtggata aaagccgctggcagcagggcaacg tgtttagctgcagcgtgatgcatgaa gcgctgcataaccattatacccagaaaagcctgagcctgagcccgggcgc gcgcaacggcgatcattgcccgctgggcccgggccgctgctgccgcctgc ataccgtgcgcgcgagcctggaagatctgggctgggcggattgggtgctg agcccgcgcga agtgcaggtgaccatgtgcattggcgcgtgcccgagcca gtttcgcgcggcgaacatgcatgcgcagattaaaaccagcctgcatcgcc tgaaaccggataccgtgccggcgccgtgctgcgtgccggcgagctataac ccgatggtgctgattcagaaaaccgataccggcgtgagcctgcagaccta tga tgatctgctggcgaaagattgccattgcatt (SEQ ID NO:149).

According to a preferred embodiment of the present invention, the second polypeptide chain contains the amino acid sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVD GVEVHNAKTKPREEQYGSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTCPPSREEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLKSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHE ALHNHYTQKSLSLSPGK (SEQ ID NO:147), which is encoded by the nucleic acid sequence:

gcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacc caaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtgg tggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggac ggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacgg gagcacgtacc gtgtggtcagcgtcctcaccgtcctgcaccaggactggc tgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcc cccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccaca ggtgtacacctgtcccccatcccgggaggagatgaccaagaaccaggtca gcctgacctgcctggtcaaagg cttctatcccagcgacatcgccgtggag tgggagagcaatgggcagccggagaacaactacgacaccacgcctcccgt gctggactccgacggctccttcttcctctatagcgacctcaccgtggaca agagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgag gctctgcacaaccactacacgcagaagagcctct ccctgtctccggggtaa (SEQ ID NO:151).

As discussed above, a tetramer is provided containing two polypeptide chains that contain the sequence SEQ ID NO: 150, and two polypeptide chains that contain the sequence SEQ ID NO: 147.

II.H.7 DhCpmFc(-)(N297G)(L351C)-GDF15(N3D):DhCpmFc(+)(N297G)(L351C).

The definition of DhCpmFc(-)(N297G)(L351C)-GDF15(N3D):DhCpmFc(+)(N297G)(L351C) in the present invention means a heterodimer that contains (i) a first polypeptide chain containing a GDF15(N3D) polypeptide, N - the end of which is connected directly to the C-terminus of the DhCpmFc() (N297G)(L351C) domain via a peptide bond, and (ii) a second polypeptide chain containing the domain

- 85 046387

DhCpmFc(+)(N297G)(L351C). Cysteine clamp mutations allow the first and second polypeptide chains to be joined via an interchain disulfide bond between C351 of the first polypeptide chain and C351 of the second polypeptide chain.

According to certain embodiments of the present invention, there is provided a tetramer that contains a dimer consisting of two heterodimers DhCpmFc(-)(N297G)(L351C)GDF15(N3D):DhCpmFc(+)(N297G)(L351C), in which the first two polypeptide chains of each heterodimers are connected via an interchain disulfide bond between the corresponding GDF15 regions of these chains.

More specifically, according to a particular embodiment of the present invention, the tetramer comprises:

(a) two DhCpmFc(+)(N297G)(L351C) domains (in each heterodimer) containing the sequence SEQ ID NO: 289, (b) two DhCpmFc(-)(N297G)(L351C) domains (in each heterodimer), containing the sequence SEQ ID NO: 148, and (c) two GDF15(N3D) polypeptides (in each heterodimer) containing the sequence SEQ ID NO: 52.

According to a preferred embodiment of the present invention, the first polypeptide chain contains the amino acid sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVD GVEVHNAKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTCPPSRKEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLKSDGSFFLYSKLTVDKSR WQQGNVFSCSVMHE ALHNHYTQKSLSLSPGARDGDHCPLGPGRCCRLHTVRASLEDLGWADWVL SPREVQVTMCIGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYN PMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:153), which is encoded by the nucleic acid sequence:

gcgccggaactgctgggcggcccgagcgtgtttctgtttccgccgaaacc gaaagataccctgatgattagccgcaccccggaagtgacctgcgtggtgg tggatgtgagccatgaagatccggaagtgaaatttaactggtatgtggat ggcgtggaagtgcataacgcgaaaaccaaaccgcgcgaagaac agtatgg cagcacctatcgcgtggtgagcgtgctgaccgtgctgcatcaggattggc tgaacggcaaagaatataaatgcaaagtgagcaacaaagcgctgccggcg ccgattgaaaaaaccattagcaaagcgaaaggccagccgcgcgaaccgca ggtgtatacctgcccgccgagccgcaaagaaatgaccaaa aaccaggtga gcctgacctgcctggtgaaaggcttttatccgagcgatattgcggtggaa tgggaaagcaacggccagccggaaaacaactataaaaccaccccgccggt gctgaaaagcgatggcagcttttttctgtatagcaaactgaccgtggata aaagccgctggcagcagggcaacgtgtttagctgcagcg tgatgcatgaa gcgctgcataaccattatacccagaaaagcctgagcctgagcccgggcgc gcgcgatggcgatcattgcccgctgggcccgggccgctgctgccgcctgc ataccgtgcgcgcgagcctggaagatctgggctgggcggattgggtgctg agcccgcgcgaagtgcaggtgaccatg tgcattggcgcgtgcccgagcca gtttcgcgcggcgaacatgcatgcgcagattaaaaccagcctgcatcgcc tgaaaccggataccgtgccggcgccgtgctgcgtgccggcgagctataac ccgatggtgctgattcagaaaaccgataccggcgtgagcctgcagaccta tgatgatctgctggcgaa agattgccattgcatt (SEQ ID NO:152).

In a preferred embodiment of the present invention, the second polypeptide chain comprises the amino acid sequence SEQ ID NO: 147, which is encoded by the nucleic acid sequence SEQ ID NO: 151.

As discussed above, a tetramer is provided containing two polypeptide chains that contain the sequence SEQ ID NO: 153, and two polypeptide chains that contain the sequence SEQ ID NO: 147.

- 86 046387

II.H.8 DhCpmFc(-)(N297G)(A287C)-GDF15(Ndel3):DhCpmFc(+)(N297G)(L306C).

The definition of DhCpmFc(-)(N297G)(A287C)-GDF15(Ndel3):DhCpmFc(+)(N297G)(L306C) in the present invention means a heterodimer that contains (i) a first polypeptide chain containing a GDF15(Ndel3) polypeptide, N - the end of which is connected directly to the C-terminus of the DhCpmFc() (N297G)(A287C) domain, and (ii) a second polypeptide chain containing the DhCpmFc(+)(N297G)(L306C) domain.

According to certain embodiments of the present invention, there is provided a tetramer that contains a dimer consisting of two heterodimers DhCpmFc(-)(N297G)(A287C)GDF15(Ndel3):DhCpmFc(+)(N297G)(L306C), in which the first two polypeptide chains of each heterodimers are connected via an interchain disulfide bond between the corresponding GDF15 regions of these chains.

More specifically, according to a particular embodiment of the present invention, the tetramer comprises:

(a) two DhCpmFc(+)(N297G)(L306C) domains (in each heterodimer) containing the sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVD

GVEVHNCKTKPREEQYGSTYRWSVCTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPSRKEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLKSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPG (SEQ ID NO:290), (b) two DhCpmFc(-)(N297G)(A287C) domains (in each heterodimer) containing the sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNCKTKPREEQYGSTYRWSVCTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPG (SEQ ID NO:268), and (c) two polypeptide and GDF15(Ndel3) (in each heterodimer) containing the sequence SEQ ID NO: 55.

According to a preferred embodiment of the present invention, the first polypeptide chain contains the amino acid sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVD

GVEVHNCKTKPREEQYGSTYRWSVCTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPGGDHCPLGPGRCCRLHTVRASLEDLGWADW VLSPR EVQVTMCIGAC R S Q FRAANMHAQIKT S LHRLKPDTVPAPCCVPAS YNPMV LIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:269), which is encoded by the nucleic acid sequence:

- 87 046387 gcacctgaactcctggggggaccgtcagtcttcctcttccccc caaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgc gtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggta cgtggacggcgtggaggtgcataattgcaagacaaagccgcgggaggagc agtacggcane tgcctggtcaaaggcttctatcccagcgacatcgc cgtggagtggggagagcaatgggcagccggagaacaactacgacaccacgc ctcccgtgetggactccgacggctccttcttoctetatagcgacctcacc gtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgat gcatgaggctctgcacaaccactacac gcagaagagcctctccctgtctc cgggtggagaccactgtccgctcgggcccgggcgttgctgccgtctgcac acggtccgcgcgtcgctggaagacctgggctgggccgattgggtgctgtc gccacgggaggtgcaagtgaccatgtgcatcggcgcgtgcccgagccagt tccgggcggcaaacat gcacgcgcagatcaagacgagcctgcaccgcctg aagcccgacacggtgccagcgccctgctgcgtgcccgccagctacaatcc catggtgctcattcaaaagaccgacaccggggtgtcgctccagacctatg atgacttgttagccaaagactgccactgcata (SEQ ID NO:270).

According to a preferred embodiment of the present invention, the second polypeptide chain contains the amino acid sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVD GVEVHNCKTKPREEQYGSTYRWSVCTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPSRKEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLKSDGSFFLYSKLTVDKSRW QQGNVFSCSVMHE ALHNHYTQKSLSLSPGK (SEQ ID NO:267), which is encoded by the nucleic acid sequence: gcacctgaactcctggggggaccgtcagtcttcctcttccccc caaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgc gtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggta Ic gtggacggcgtggaggtgcataattgcaagacaaagccgcgggaggagc agtacggcagcacgtaccgtgtggtcagcgtctgcaccgtcctgcaccag gactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccct cccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgag aaccacagg tgtacaccctgcccccatcccggaaggagatgaccaagaac caggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgc cgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgc ctcccgtgctgaagtccgacggctccttcttcctctatagcaagctcacc gtggacaagagcaggtgg cagcaggggaacgtcttctcatgctccgtgat gcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctc cgggtaaa (SEQ ID NO:271).

As discussed above, a tetramer is provided containing two polypeptide chains that contain the sequence of SEQ ID NO: 269, and two polypeptide chains that contain the sequence of SEQ ID NO: 267.

II.H.9 DhCpmFc(-)(N297G)(A287C)-GDF15(N3D):DhCpmFc(+)(N297G)(L306C).

The definition of DhCpmFc(-)(N297G)(A287C)-GDF15(N3D):DhCpmFc(+)(N297G)(L306C) in the present invention means a heterodimer that contains (i) a first polypeptide chain containing a GDF15(N3D) polypeptide, N -the end of which is connected directly to the C-terminus of the DhCpmFc domain(

- 88 046387 )(N297G)(A287C), and (ii) a second polypeptide chain containing the DhCpmFc(+)(N297G)(L306C) domain.

According to certain embodiments of the present invention, there is provided a tetramer that contains a dimer consisting of two heterodimers DhCpmFc(-)(N297G)(A287C)GDF15(N3D):DhCpmFc(+)(N297G)(L306C), in which the first two polypeptide chains of each heterodimers are connected via an interchain disulfide bond between the corresponding GDF15 regions of these chains.

More specifically, according to a particular embodiment of the present invention, the tetramer comprises:

(a) two DhCpmFc(+)(N297G)(L306C) domains (in each heterodimer) containing the sequence SEQ ID NO: 290, (b) two DhCpmFc(-)(N297G)(A287C) domains (in each heterodimer), containing the sequence SEQ ID NO: 268, and (c) two GDF15(N3D) polypeptides (in each heterodimer) containing the sequence SEQ ID NO: 52.

According to a preferred embodiment of the present invention, the first polypeptide chain contains the amino acid sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVD GVEVHNCKTKPREEQYGSTYRVVSVCTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQG NVFSCSVMHE ALHNHYTQKSLSLSPGARDGDHCPLGPGRCCRLHTVRASLEDLGWADWVL S PREVQVTMCIGAC R S Q FRAANMHAQIKT S LHRLKPDTVPAPCCVPAS YN PMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:272), which is encoded by the nucleic acid sequence: gcacctgaactcctggggaccgtcagt cttcctcttssee caaaacccaaggacacccteatgatctcccggacccctgaggtcacatgc gtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggta cgtggacggcgtggaggtgcataattgcaagacaaagccgcgggaggagc agtacggcagcacgtaccgtgtggtcagcgtctgcaccgt cctgcaccag gactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccct cccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgag aaccacaggtgtacaccctgcccccatcccgggaggagatgaccaagaac caggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgc cgtggagt ggggagagcaatgggcagccggagaacaactacgacaccacgc ctcccgtgctggactccgacggctccttcttcctctatagcgacctcacc gtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgat gcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctc cggggtgcgcgcgacgg agaccactgtccgctcgggcccggggcgttgctgc cgtctgcacacggtccgcgcgtcgctggaagacctgggctgggccgattg ggtgctgtcgccacgggaggtgcaagtgaccatgtgcatcggcgcgtgcc cgagccagttccgggcggcaaacatgcacgcgcagatcaagacgagcctg caccgcctgaagcccgacacggtgccagcgccctgctgcgtgcccgccag ctacaatcecatggtgctcattcaaaagaccgacaccggggtgtcgctec agacctatgatgacttgttagccaaagactgccactgcata (SEQ ID NO:273).

In a preferred embodiment of the present invention, the second polypeptide chain comprises the amino acid sequence SEQ ID NO: 267, which is encoded by the nucleic acid sequence SEQ ID NO: 271.

As discussed above, a tetramer is provided containing two polypeptide chains that contain the sequence SEQ ID NO: 272, and two polypeptide chains that contain the sequence SEQ ID NO: 267.

II.H.10 DhCpmFc(-)(N297G)(A287C)(Y349C)-GDF15(Ndel3):DhCpmFc(+)(N297G)(L306C)(S354C).

The definition of DhCpmFc(-)(N297G)(A287C)(Y349C)-GDF15(Ndel3):DhCpmFc(+)(N297G)(L306C) (S354C) in the present invention means a heterodimer that contains (i) a first polypeptide chain containing a polypeptide GDF15(Ndel3), the N-terminus of which is connected directly to the C-terminus of the domain

- 89 046387

DhCpmFc(-)(N297G)(A287C)(Y349C), and (ii) a second polypeptide chain containing the DhCpmFc(+)(N297G)(L306C)(S354C) domain.

According to certain embodiments of the present invention, there is provided a tetramer that contains a dimer consisting of two heterodimers DhCpmFc(-)(N297G)(A287C)(Y349C)GDF15(Ndel3):DhCpmFc(+)(N297G)(L306C)(S354C), in in which the first two polypeptide chains of each heterodimer are connected through an interchain disulfide bond between the corresponding GDF15 regions of these chains.

More specifically, according to a particular embodiment of the present invention, the tetramer comprises:

(a) two DhCpmFc(+)(N297G)(L306C)(Y349C) domains (in each heterodimer) containing the sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNCKTKPREEQYGSTYRVVSVCTVLHQDWLNGKEYKCKVSNKALPA

PIEKTISKAKGQPREPQVYTLPPCRKEMTKNQVSLTCLVKGFYPSDIAVE

WESNGQPENNYKTTPPVLKSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE

ALHNHYTQKSLSLSPG (SEQ ID NO:291), (b) two DhCpmFc(-)(N297G)(A287C)(S354C) domains (in each heterodimer) containing the sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVD

GVEVHNCKTKPREEQYGSTYRVVSVCTVLHQDWLNGKEYKCKVSNKALPA

PIEKTISKAKGQPREPQVCTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE

WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHE

ALHNHYTQKSLSLSPG (SEQ ID NO:275), and (c) two GDF15(Ndel3) polypeptides (in each heterodimer) containing the sequence SEQ ID NO:55.

According to a preferred embodiment of the present invention, the first polypeptide chain contains the amino acid sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVD GVEVHNCKTKPREEQYGSTYRWSVCTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVCTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCS VMHE ALHNHYTQKSLSLSPGGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPR EVQVTMCIGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYNPMV LIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:276), which is encoded by the nucleic acid sequence: gcacctgaactcctggggggaccgtcagtcttcctcttccccc caaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgc gtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggta cgtggacggcgtggaggtgcataattgcaagacaaagccgcgggaggagc agtacggcagcacgtaccgtgtggtcagcgtctgcaccgtcctgcaccag gactgg ctgaatggcaaggagtacaagtgcaaggtctccaacaaagccct cccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgag aaccacaggtgtgcaccctgcccccatcccgggaggagatgaccaagaac caggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgc cgtggagtggagagcaatggg cagccggagaacaactacgacaccacgc ctcccgtgctggactccgacggctccttcttcctctatagcgacctcacc gtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgat gcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctc cgggtggagaccactgtccgctcgggcccgggc gttgctgccgtctgcac acggtccgcgcgtcgctggaagacctgggctgggccgattgggtgctgtc gccacgggaggtgcaagtgaccatgtgcatcggcgcgtgcccgagccagt tccgggcggcaaacatgcacgcgcagatcaagacgagcctgcaccgcctg

- 90 046387 aagcccgacacggtgccagcgccctgctgcgtgcccgccagctacaatcc catggtgctcattcaaaagaccgacaccggggtgtcgctccagacctatg atgacttgttagccaaagactgccactgcata (SEQ ID NO:277).

According to a preferred embodiment of the present invention, the second polypeptide chain contains the amino acid sequence:

APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVD

GVEVHNCKTKPREEQYGSTYRWSVCTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPCRKEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLKSDGSFFLYSKLTVDKSRWQGNVFSCSVMHE ALHNHYTQKSLSLSPGK (SEQ ID NO:274), which code is expressed by the nucleic acid sequence: gcacctgaactcctggggggaccgtcagtcttcctcttccccc caaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgc gtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggta cgtggacggcgtggaggtgcataattgcaagacaaagccgcgggaggagc agt acggcagcacgtaccgtgtggtcagcgtctgcaccgtgctccaccag gactggcttaatgggaaggaatacaagtgtaaggtgtccaacaaggccct ccccgctcccatcgaaaagaccatctcaaaggcaaaggggcaaccaaggg aacctcaagtgtacaccctgcctccgtgcaggaaggagatgaccaagaac caggtcagcctg acttgtctcgtgaagggcttctatcccagcgatattgc tgtggaatgggagtcaaatggccagcccgagaataactacaaaactaccc cacccgtgctgaaatctgatgggtccttcttcctttactccaagctgacc gtggacaagagccgctggcaacaaggcaatgtctttagctgctcagtgat gcatgaggctctccataatc actacactcagaagtcactgtccctgtctc cgggtaaa (SEQ ID NO:278).

As discussed above, a tetramer is provided containing two polypeptide chains that contain the sequence of SEQ ID NO: 276, and two polypeptide chains that contain the sequence of SEQ ID NO: 274.

II.H. 11 DhCpmFc(-)(N297G)(A287C)(Y349C)-GDF15(N3D):DhCpmFc(+)(N297G)(L306C)(S354C).

The definition of DhCpmFc(-)(N297G)(A287C)(Y349C)GDF15(N3D):DhCpmFc(+)(N297G)(L306C)(S354C) in the present invention means a heterodimer that contains (i) a first polypeptide chain containing a GDF15 polypeptide (N3D), the N-terminus of which is connected directly to the C-terminus of the DhCpmFc(-)(N297G)(A287C)(Y349C) domain, and (ii) a second polypeptide chain containing the DhCpmFc(+)(N297G)(L306C)( domain) S354C).

According to certain embodiments of the present invention, there is provided a tetramer that contains a dimer consisting of two heterodimers DhCpmFc(-)(N297G)(A287C)(Y349C)GDF15(N3D):DhCpmFc(+)(N297G)(L306C)(S354C), in in which the first two polypeptide chains of each heterodimer are connected through an interchain disulfide bond between the corresponding GDF15 regions of these chains.

More specifically, according to a particular embodiment of the present invention, the tetramer comprises:

(a) two DhCpmFc(+)(N297G)(L306C)(Y349C) domains (in each heterodimer) containing the sequence SEQ ID NO: 291, (b) two DhCpmFc(-)(N297G)(A287C)(S354C) domains (in each heterodimer) containing the sequence SEQ ID NO: 275, and (c) two GDF15(N3D) polypeptides (in each heterodimer) containing the sequence SEQ ID NO: 52.

According to a preferred embodiment of the present invention, the first polypeptide chain contains the amino acid sequence:

- 91 046387

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVD GVEVHNCKTKPREEQYGSTYRWSVCTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVCTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCS VMHE ALHNHYTQKSLSLSPGARDGDHCPLGPGRCCRLHTVRASLEDLGWADWVL S PREVQVTMCIGAG PS QFRAANMHAQIKT S LHRLKPDTVPAPCCVPAS YN PMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:279), which is encoded by the nucleic acid sequence:

gcacctgaactcctggggggaccgtcagtcttcctcttccccc caaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgc gtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggta cgtggacggcgtggaggtgcataattgcaagacaaagccgcgggaggagc agtacggcagcacgt accgtgtggtcagcgtctgcaccgtcctgcaccag gactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccct cccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgag aaccacaggtgtgcaccctgcccccatcccgggaggagatgaccaagaac caggtcagcctgacctgcctggtcaaagg cttctatcccagcgacatcgc cgtggagtgggagagcaatgggcagccggagaacaactacgacaccacgc ctcccgtgetggactccgacggctccttcttoctetatagcgacctcacc gtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgat gcatgaggctctgcacaaccactacacgcagaagagcctctccct gtctc cgggtgcgcgcgacggagaccactgtccgctcgggcccgggcgttgctgc cgtctgcacacggtccgcgcgtcgctggaagacctgggctgggccgattg ggtgctgtcgccacgggaggtgcaagtgaccatgtgcatcggcgcgtgcc cgagccagttccgggcggcaaacat gcacgcgcagatcaagacgagcctg caccgcctgaagcccgacacggtgccagcgccctgctgcgtgcccgccag ctacaatcecatggtgctcattcaaaagaccgacaccggggtgtcgctec agacctatgatgacttgttagccaaagactgccactgcata (SEQ ID NO:280)

In a preferred embodiment of the present invention, the second polypeptide chain comprises the amino acid sequence SEQ ID NO: 274, which is encoded by the nucleic acid sequence SEQ ID NO: 278.

As discussed above, a tetramer is provided containing two polypeptide chains that contain the sequence SEQ ID NO: 279, and two polypeptide chains that contain the sequence SEQ ID NO: 274.

P.N.12 Dh2CpmFc(-)-GDF15(Ndel3):Dh2CpmFc(+).

The definition of Dh2CpmFc(-)-GDF15(Ndel3):Dh2CpmFc(+) in the present invention means a heterodimer that contains (i) a first polypeptide chain containing a GDF15(Ndel3) polypeptide, the N-terminus of which is connected directly to the C-terminus of the Dh2CpmFc(-) domain , and (ii) a second polypeptide chain containing the Dh2CpmFc(+) domain.

According to certain embodiments of the present invention, there is provided a tetramer that contains a dimer consisting of two heterodimers Dh2CpmFc(-)-GDF15(Ndel3):Dh2CpmFc(+), in which the first two polypeptide chains of each heterodimer are connected through an interchain disulfide bond between the corresponding GDF15 data regions chains.

More specifically, according to a particular embodiment of the present invention, the tetramer comprises:

(a) two Dh2CpmFc(+) domains (in each heterodimer) containing the sequence:

PSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNA KTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSRKEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYKTTPPVLKSDGSFFLYSKLTVDKSRWQQ GNVFSCSVMHEALHNHYT QKSLSLSPG(SEQ ID NO:292), (b) two Dh2CpmFc(-) domains (in each heterodimer) containing the sequence:

- 92 046387

PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNA KTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNV FSCSVMHEALHNHYT QKSLSLSPG(SEQ ID NO:155), (c) two GDF15(Ndel3) polypeptides (in each heterodimer) containing the sequence SEQ ID NO: 55.

According to a preferred embodiment of the present invention, the first polypeptide chain contains the amino acid sequence:

PSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNA KTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFS CSVMHEALHNHYT QKSLSLSPGGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPREVQVTMC IGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYNPMVLIQKTDT GVSLQTYDDLLAKDCHCI (SEQ ID NO:157), which is encoded by the nucleic acid sequence:

c gtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagt gcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctcc aaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatc ccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaag gcttctatcccagcgacatc gccgtggagtgggagagcaatgggcagccg gagaacaactacgacaccacgcctcccgtgctggactccgacggctcctt cttcctctatagcgacctcaccgtggacaagagcaggtggcagcagggga acgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacg cagaagagcctctccctgtctccggggtggag accactgtccgctcgggcc cggggcgttgctgccgtctgcacacggtccgcgcgtcgctggaagacctgg gctgggccgattgggtgctgtcgccacgggaggtgcaagtgaccatgtgc atcggcgcgtgcccgagccagttccgggcggcaaacatgcacgcgcagat caagacgagcctgcacc gcctgaagcccgacacggtgccagcgccctgct gcgtgcccgccagctacaatcccatggtgctcattcaaaagaccgacacc ggggtgtcgctccagacctatgatgacttgttagccaaagactgccactg cata (SEQ ID NO:156).

According to a preferred embodiment of the present invention, the second polypeptide chain contains the amino acid sequence:

PSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNA KTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSRKEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYKTTPPVLKSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYT QKSLSLSPGK(SEQ ID NO:154), which is encoded by the nucleic acid sequence:

- 93 046387 ccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctc ccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagacc ctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgcc aagacaaagccgcgggaggagcagtacaacagcacg taccgtgtggtcag cgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagt gcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctctcc aaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatc ccggaaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaag gcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccg gagaacaactacaagaccacgcctcccgtgctgaagtccgacggctcctt cttoctetatagcaagctcaccgtggacaagagcaggtggcagcagggga acgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacg cagaagagcctct ccctgtctccgggtaaatga (SEQ ID NO:158)

As discussed above, a tetramer is provided containing two polypeptide chains that contain the sequence of SEQ ID NO: 157, and two polypeptide chains that contain the sequence of SEQ ID NO: 154.

I.N.13 Dh2CpmFc(-)-GDF15(N3D):Dh2CpmFc(+).

The definition of Dh2CpmFc(-)-GDF15(N3D):Dh2CpmFc(+) in the present invention means a heterodimer that contains (i) a first polypeptide chain containing a GDF15(N3D) polypeptide, the N-terminus of which is connected directly to the C-terminus of the Dh2CpmFc(-) domain via a peptide bond, and (ii) a second polypeptide chain containing a Dh2CpmFc(+) domain.

According to certain embodiments of the present invention, there is provided a tetramer that contains a dimer consisting of two heterodimers Dh2CpmFc(-)-GDF15(N3D):DhCpmFc(+), in which the first two polypeptide chains of each heterodimer are connected through an interchain disulfide bond between the corresponding GDF15 data regions chains.

More specifically, according to a particular embodiment of the present invention, the tetramer comprises:

(a) two Dh2CpmFc(+) domains (in each heterodimer) containing the sequence SEQ ID NO: 292, (b) two Dh2CpmFc(-) domains (in each heterodimer) containing the sequence SEQ ID NO: 155, and (c) two GDF15(N3D) polypeptides (in each heterodimer) containing the sequence SEQ ID NO: 52.

According to a preferred embodiment of the present invention, the first polypeptide chain contains the amino acid sequence:

PSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNA KTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFS CSVMHEALHNHYT QKSLSLSPGARDGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPREVQV TMCIGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYNPMVLIQK TDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:160), which is encoded by the nucleic acid sequence:

- 94 046387 ccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctc ccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagacc ctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgcc aagacaaagccgcgggaggagcagtacaacagcacg taccgtgtggtcag cgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagt gcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctctcc aaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatc ccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaag g cttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccg gagaacaactacgacaccacgcctcccgtgctggactccgacggctcctt cttcctctatagcgacctcaccgtggacaagagcaggtggcagcagggga acgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacg cagaagagcctct ccctgtctccgggtgcgcgcgacggagaccactgtcc gctcgggcccgggcgttgctgccgtctgcacacggtccgcgcgtcgctgg aagacctgggctgggccgattgggtgctgtcgccacgggaggtgcaagtg accatgtgcatcggcgcgtgcccgagccagttccgggcggcaaacatg ca cgcgcagatcaagacgagcctgcaccgcctgaagcccgacacggtgccag cgccctgctgcgtgcccgccagctacaatcccatggtgctcattcaaaag accgacaccggggtgtcgctccagacctatgatgacttgttagccaaaga ctgccactgcata (SEQ ID NO:159).

In a preferred embodiment of the present invention, the second polypeptide chain comprises the amino acid sequence SEQ ID NO: 154, which is encoded by the nucleic acid sequence SEQ ID NO: 158.

As discussed above, a tetramer is provided containing two polypeptide chains that contain the sequence SEQ ID NO: 160, and two polypeptide chains that contain the sequence SEQ ID NO: 154.

II.H.14 Dh2CpmFc(-)(Y349C)-GDF15(Ndel3):Dh2CpmFc(+)(S354C).

The definition of Dh2CpmFc(-)(Y349C)-GDF15(Ndel3):Dh2CpmFc(+)(S354C) in the present invention means a heterodimer that contains (i) a first polypeptide chain containing a GDF15(Ndel3) polypeptide, the N-terminus of which is connected directly to The C-terminus of the Dh2CpmFc(-)(Y349C) domain, and (ii) a second polypeptide chain containing the Dh2CpmFc(+)(S345C) domain. Cysteine clamp mutations allow the first and second polypeptide chains to be joined via an interchain disulfide bond between C349 of the first polypeptide chain and C354 of the second polypeptide chain.

According to certain embodiments of the present invention, there is provided a tetramer that contains a dimer consisting of two heterodimers Dh2CpmFc(-)(Y349C)GDF15(Ndel3):Dh2CpmFc(+)(S354C), in which the first two polypeptide chains of each heterodimer are connected through an interchain disulfide bond between the corresponding GDF15 regions of these circuits.

More specifically, according to a particular embodiment of the present invention, the tetramer comprises:

(a) two Dh2CpmFc(+)(S354C) domains (in each heterodimer) containing the sequence:

PSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNA

KTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPCRKEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYKTTPPVLKSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT QKSLSLSPG (SEQ ID NO:293), (b) two domain a Dh2CpmFc(-)(Y349C) (in each heterodimer) containing the sequence:

PSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNA

KTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVCTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHEALHNHYT

QKSLSLSPG (SEQ ID NO:162), and

- 95 046387 (c) two GDF15(Ndel3) polypeptides (in each heterodimer) containing the sequence SEQ ID NO: 55.

According to a preferred embodiment of the present invention, the first polypeptide chain contains the amino acid sequence:

PSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNA

KTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVCTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHEALHNHYT QKSLSLSPGGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPREV QVTMC IGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYNPMVLIQKTDT GVSLQTYDDLLAKDCHCI (SEQ ID NO:164), which is encoded by the nucleic acid sequence: ccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctc ccggacccctgaggtcacatgcgtggtggtggacgtgagccacga agacc ctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgcc aagacaaagccgcgggaggagcagtacaacagcacgtaccgtgtggtcag cgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagt gcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctcc aaag ccaaagggcagccccgagaaccacaggtgtgcaccctgcccccatc ccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaag gcttctatcccagcgacatcgccgtggagtggggagagcaatgggcagccg gagaacaactacgacaccacgcctcccgtgctggactccgacggctcctt cttcctctatagcg acctcaccgtggacaagagcaggtggcagcagggga acgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacg cagaagagcctctccctgtctccgggtggagaccactgtccgctcgggcc cgggcgttgctgccgtctgcacacggtccgcgcgtcgctggaagacctgg gctgggccgattgggtg ctgtcgccacgggaggtgcaagtgaccatgtgc atcggcgcgtgcccgagccagttccgggcggcaaacatgcacgcgcagat caagacgagcctgcaccgcctgaagcccgacacggtgccagcgccctgct gcgtgcccgccagctacaatcccatggtgctcattcaaaagaccgacacc ggggtgtc gctccagacctatgatgacttgttagccaaagactgccactg cata (SEQ ID NO:163).

According to a preferred embodiment of the present invention, the second polypeptide chain contains the amino acid sequence:

PSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNA KTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPCRKEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYKTTPPVLKSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYT QKSLSLSPGK (SEQ ID NO:161), which is encoded by the nucleic acid sequence:

- 96 046387 ccatccgtgttcctgtttcctccaaagccgaaggacaccctgatgatctc aagaactccggaagtgacttgcgtcgtcgtggacgtgtcacatgaggatc cagaggtcaagttcaattggtatgtggacggagtggaagtgcataacgcc aagaccaaaccccgcgaagaacagtacaatagcacc taccgcgtggtgag cgtccttactgtgctccaccaggactggcttaatgggaaggaatacaagt gtaaggtgtccaacaaggccctccccgctcccatcgaaaagaccatctca aaggcaaaggggcaaccaagggaacctcaagtgtacaccctgcctccgtg caggaaggagatgaccaagaaccaggtcagcctgacttgtctcgtga agg gcttctatcccagcgatattgctgtggaatgggagtcaaatggccagccc gagaataactacaaaactaccccacccgtgctgaaatctgatgggtcctt cttcctttactccaagctgaccgtggacaagagccgctggcaacaaggca atgtctttagctgctcagtgatgcatgaggctctccataatcactacact cagaagtcact gtccctgtctccgggtaaa (SEQ ID NO:165).

As discussed above, a tetramer is provided containing two polypeptide chains that contain the sequence of SEQ ID NO: 164, and two polypeptide chains that contain the sequence of SEQ ID NO: 161.

II.H.15 Dh2CpmFc(-)(Y349C)-GDF15(N3D):Dh2CpmFc(+)(S354C).

The definition of Dh2CpmFc(-)(Y349C)-GDF15(N3D):Dh2CpmFc(+)(S354C) in the present invention means a heterodimer that contains (i) a first polypeptide chain containing a GDF15(N3D) polypeptide, the N-terminus of which is connected directly to The C-terminus of the Dh2CpmFc(-)(Y349C) domain, and (ii) a second polypeptide chain containing the Dh2CpmFc(+)(S345C) domain. Cysteine clamp mutations allow the first and second polypeptide chains to be joined via an interchain disulfide bond between C349 of the first polypeptide chain and C354 of the second polypeptide chain.

According to certain embodiments of the present invention, there is provided a tetramer that contains a dimer consisting of two heterodimers Dh2CpmFc(-)(Y349C)GDF15(N3D):Dh2CpmFc(+)(S354C), in which the first two polypeptide chains of each heterodimer are connected through an interchain disulfide bond between the corresponding GDF15 regions of these circuits.

More specifically, according to a particular embodiment of the present invention, the tetramer comprises:

(a) two Dh2CpmFc(+)(S354C) domains (in each heterodimer) containing the sequence SEQ ID NO: 293, (b) two Dh2CpmFc(-)(Y349C) domains (in each heterodimer) containing the sequence SEQ ID NO: 162, and (c) two GDF15(N3D) polypeptides (in each heterodimer) containing the sequence SEQ ID NO: 52.

According to a preferred embodiment of the present invention, the first polypeptide chain contains the amino acid sequence:

PSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNA

KTKPREEQYNS ТYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVCTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHEALHNHYT QKSLSLSPGARDGDHCPLGPGRCCRLHTVRASLEDLGWADWVLS PREVQV TMCIGAO R S Q FRAANMHAQIKT S LHRLKPDTVPAPCCVPAS YNPMVLIQK TDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:167), which is encoded by the nucleic acid sequence:

- 97 046387 ccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctc ccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagacc ctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgcc aagacaaagccgcgggaggagcagtacaacagcacg taccgtgtggtcag cgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagt gcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctctcc aaagccaaagggcagccccgagaaccacaggtgtgcaccctgcccccatc ccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaag gcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccg gagaacaactacgacaccacgcctcccgtgctggactccgacggctcctt cttcctctatagcgacctcaccgtggacaagagcaggtggcagcagggga acgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacg cagaagagcct ctccctgtctccgggtgcgcgcgacggagaccactgtcc gctcgggcccgggcgttgctgccgtctgcacacggtccgcgcgtcgctgg aagacctgggctgggccgattgggtgctgtcgccacgggaggtgcaagtg accatgtgcatcggcgcgtgcccgagccagttccgggcggcaaacat gca cgcgcagatcaagacgagcctgcaccgcctgaagcccgacacggtgccag cgccctgctgcgtgcccgccagctacaatcccatggtgctcattcaaaag accgacaccggggtgtcgctccagacctatgatgacttgttagccaaaga ctgccactgcata (SEQ ID NO:166).

According to a preferred embodiment of the present invention, the second monomer contains the amino acid sequence SEQ ID NO: 161, which is encoded by the nucleic acid sequence SEQ ID NO: 165.

As discussed above, a tetramer is provided containing two polypeptide chains that contain the sequence SEQ ID NO: 167, and two polypeptide chains that contain the sequence SEQ ID NO: 161.

II.H.16 CpmFc(-)(N297G)-GDF15(Ndel3): CpmFc(+)(N297G).

The definition of CpmFc(-)(N297G)-GDF15(Ndel3):DhCpmFc(+)(N297G) in the present invention means a heterodimer that contains (i) a first polypeptide chain containing a GDF15(Ndel3) polypeptide, the N-terminus of which is connected directly to The C-terminus of the CpmFc(-)(N297G) domain, and (ii) a second polypeptide chain containing the CpmFc(+)(N297G) domain.

According to certain embodiments of the present invention, there is provided a tetramer that contains a dimer consisting of two heterodimers CpmFc(-)(N297G)GDF15(Ndel3):CpmFc(+)(N297G), in which the first two polypeptide chains of each heterodimer are connected through an interchain disulfide bond between the corresponding GDF15 regions of these circuits.

More specifically, according to a particular embodiment of the present invention, the tetramer comprises:

(a) two CpmFc(+)(N297G) domains (in each heterodimer) containing the sequence (part of the hinge region is included in parentheses):

(DKTHTCPPCP)APELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYGSTYRWSVLTVLHQDWLNGKE YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRKEMTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPVLKSDGSFF LYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO:294), (b) two CpmFc(-)(N297G) domains (in each heterodimer) containing the sequence (part of the hinge region is included in parentheses):

- 98 046387 (DKTHTCPPCP) APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYGSTYRWSVLTVLHQDWLNGKE YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCL VKGFYPSDIAVEWESNGQP ENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO:169), _and (c) two GDF15(Ndel3) polypeptides (in each heterodimer) containing the sequence SEQ ID NO: 55.

According to a preferred embodiment of the present invention, the first polypeptide chain contains the amino acid sequence:

(DKTHTCPPCP)APELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYGSTYRWSVLTVLHQDWLNGKE YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYDTTPPVLDSDGSFFLYSDL TVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPGGDHCPLGPGRCCRLHTVRASLE DLGWADWVL S PREVQVTMCIGAC P S Q FRAANMHAQIKT S LHRLKPDTVPA PCCVPASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:171), which is encoded by the nucleic acid sequence: gacaaaactcacacatg cccaccgtgcccagcacctgaactcc tggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctc atgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagcca cgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgc ataatgccaagacaaagccgcgggaggagcagtac ggcagcacgtaccgt gtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaagga gtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaa ccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctg cccccatcccgggaggagatgaccaagaaccaggtcagcctgacctgcct ggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatg ggcagccggagaacaactacgacaccacgcctcccgtgctggactccgac ggctccttcttcctctatagcgacctcaccgtggacaagagcaggtggca gcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaacc actacacg cagaagagcctctccctgtctccgggtggagaccactgtccg ctcgggcccgggcgttgctgccgtctgcacacggtccgcgcgtcgctgga agacctgggctgggccgattgggtgctgtcgccacgggaggtgcaagtga ccatgtgcatcggcgcgtgcccgagccagttccgggcggcaaacat gcac gcgcagatcaagacgagcctgcaccgcctgaagcccgacacggtgccagc gccctgctgcgtgcccgccagctacaatcccatggtgctcattcaaaaga ccgacaccggggtgtcgctccagacctatgatgacttgttagccaaagac tgccactgcata (SEQ ID NO:170).

According to a preferred embodiment of the present invention, the second polypeptide chain contains the amino acid sequence:

(DKTHTCPPCP) APELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYGSTYRWSVLTVLHQDWLNGKE YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRKEMTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPVLKSDGSFF LYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO:168), which is encoded by the nucleic acid sequence:

- 99 046387 gacaaaactcacacatgcccaccgtgcccagcacctgaactcc tggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctc atgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagcca cgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggt gc ataatgccaagacaaagccgcgggaggagcagtacggcagcacgtaccgt gtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaagga gtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaa ccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctg cccccatccc ggaaggagatgaccaagaaccaggtcagcctgacctgcct ggtcaaaggcttctatcccagcgacatcgccgtggagtggggagagcaatg ggcagccggagaacaactacaagaccacgcctcccgtgctgaagtccgac ggctccttcttcctctatagcaagctcaccgtggacaagagcaggtggca gcaggggaacgtctt ctcatgctccgtgatgcatgaggctctgcacaacc actacacgcagaagagcctctccctgtctccgggtaaa (SEQ ID NO:172).

As discussed above, a tetramer is provided containing two polypeptide chains that contain the sequence SEQ ID NO: 171, and two polypeptide chains that contain the sequence SEQ ID NO: 168.

I.N.17 CpmFc(-)(N297G)-GDF15(N3D):CpmFc(+)(N297G).

The definition of CpmFc(-)(N297G)-GDF15(N3D):DhCpmFc(+)(N297G) in the present invention means a heterodimer that contains (i) a first polypeptide chain containing a GDF15(N3D) polypeptide, the N-terminus of which is connected directly to The C-terminus of the CpmFc(-)(N297G) domain, and (ii) a second polypeptide chain containing the CpmFc(+)(N297G) domain.

According to certain embodiments of the present invention, there is provided a tetramer that contains a dimer consisting of two heterodimers CpmFc(-)(N297G)GDF15(N3D):CpmFc(+)(N297G), in which the first two polypeptide chains of each heterodimer are connected through an interchain disulfide bond between the corresponding GDF15 regions of these circuits.

More specifically, according to a particular embodiment of the present invention, the tetramer comprises:

(a) two CpmFc(+)(N297G) domains (in each heterodimer) containing the sequence SEQ ID NO: 294, (b) two CpmFc(-)(N297G) domains (in each heterodimer) containing the sequence SEQ ID NO: 169, and (c) two GDF15(N3D) polypeptides (in each heterodimer) containing the sequence SEQ ID NO: 52.

According to a preferred embodiment of the present invention, the first polypeptide chain contains the amino acid sequence:

(DKTHTCPPCP) APELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYGSTYRWSVLTVLHQDWLNGKE YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYDTTPPVLDSDGSFFLYSDL TVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPGARDGDHCPLGPGRCCRLHTVRA SLEDLGWADWVLSPREVQVTMCIGACPSQFRAANMHAQIKTSLHRLKPDT VPAPCCVPASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ IDNO:174), which is encoded by the nucleic acid sequence:

- 100 046387 gacaaaactcacacatgcccaccgtgcccagcacctgaactcc tggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctc atgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagcca cgaagaccctgaggtcaagttcaactggtacgtggacggcgtggagg tgc ataatgccaagacaaagccgcgggaggagcagtacggcagcacgtaccgt gtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaagga gtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaa ccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctg cccccatcc cgggaggagatgaccaagaaccaggtcagcctgacctgcct ggtcaaaggcttctatcccagcgacatcgccgtggagtggggagagcaatg ggcagccggagaacaactacgacaccacgcctcccgtgctggactccgac ggctccttcttcctctatagcgacctcaccgtggacaagagcaggtggca gcaggggaacgtctt ctcatgctccgtgatgcatgaggctctgcacaacc actacacgcagaagagcctctccctgtctccgggtgcgcgcgacggagac cactgtccgctcgggcccgggcgttgctgccgtctgcacacggtccgcgc gtcgctggaagacctgggctgggccgattgggtgctgtcgccacgggagg tgcaagtgacca tgtgcatcggcgcgtgcccgagccagttccggggcggca aacatgcacgcgcagatcaagacgagcctgcaccgcctgaagcccgacac ggtgccagcgccctgctgcgtgcccgccagctacaatcccatggtgctca ttcaaaagaccgacaccggggtgtcgctccagacctatgatgacttgtta gcca aagactgccactgcata (SEQ ID NO:173).

In a preferred embodiment of the present invention, the second polypeptide chain comprises the amino acid sequence SEQ ID NO: 168, which is encoded by a nucleic acid sequence comprising the sequence SEQ ID NO: 172.

As discussed above, a tetramer is provided containing two polypeptide chains that contain the sequence SEQ ID NO: 174, and two polypeptide chains that contain the sequence SEQ ID NO: 168.

II.H.18 Dh2CpmFc(-)(N297G)-GDF15(Ndel3):Dh2CpmFc(+)(N297G).

The definition of Dh2CpmFc(-)(N297G)-GDF15(Ndel3):Dh2CpmFc(+)(N297G) in the present invention means a heterodimer that contains (i) a first polypeptide chain containing a GDF15(Ndel3) polypeptide, the N-terminus of which is connected directly to The C-terminus of the Dh2CpmFc(-)(N297G) domain, and (ii) a second polypeptide chain containing the Dh2CpmFc(+)(N297G) domain.

According to certain embodiments of the present invention, there is provided a tetramer that contains a dimer consisting of two heterodimers Dh2CpmFc(-)(N297G)GDF15(Ndel3):Dh2CpmFc(+)(N297G), in which the first two polypeptide chains of each heterodimer are connected through an interchain disulfide bond between the corresponding GDF15 regions of these circuits.

More specifically, according to a particular embodiment of the present invention, the tetramer comprises:

(a) two Dh2CpmFc(+)(N297G) domains (in each heterodimer) containing the sequence: PSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNA

KTKPREEQYGSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSRKEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYKTTPPVLKSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT QKSLSLSPG(SEQ ID NO:295), (b) two domains Dh2CpmFc(-)(N297G) (in each heterodimer), containing the sequence: PSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNA

KTKPREEQYGSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS

KAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP

ENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHEALHNHYT

QKSLSLSPG(SEQ ID NO:176), and (c) two GDF15(Ndel3) polypeptides (in each heterodimer) containing the sequence SEQ ID NO:55.

- 101 046387

According to a preferred embodiment of the present invention, the first polypeptide chain contains the amino acid sequence:

PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNA KTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNV FSCSVMHEALHNHYT QKSLSLSPGGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPREVQVTMC IGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYNPMVLIQKTDT GVSLQTYDDLLAKDCHCI (SEQ ID NO:178), which is encoded by the nucleic acid sequence: ccgtcagtcttcctcttccccccaaaacccaagg acacccteatgatetc ccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagacc ctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgcc aagacaaagccgcgggaggagcagtacgggagcacgtaccgtgtggtcag cgtcctcaccgtcctgcaccaggactggctgaatggcaa ggagtacaagt gcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctcc aaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatc ccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaag gcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccg gagaa caactacgacaccacgcctcccgtgctggactccgacggctcctt cttcctctatagcgacctcaccgtggacaagagcaggtggcagcagggga acgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacg cagaagagcctctccctgtctccgggtggagaccactgtccgctegggee cgggcgttgctgccg tctgcacacggtccgcgcgtcgctggaagacctgg gctgggccgattgggtgctgtcgccacgggaggtgcaagtgaccatgtgc atcggcgcgtgcccgagccagttccgggcggcaaacatgcacgcgcagat caagacgagcctgcaccgcctgaagcccgacacggtgccagcgccctgct gc gtgcccgccagetacaatcecatggtgctcattcaaaagaccgacacc ggggtgtcgctccagacctatgatgacttgttagccaaagactgccactg cata (SEQ ID NO:177).

According to a preferred embodiment of the present invention, the second polypeptide chain contains the amino acid sequence:

PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNA KTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSRKEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYKTTPPVLKSDGSFFLYSKLTVDKSRW QQGNVFSCSVMHEALHNHYT QKSLSLSPGK(SEQ ID NO:175), which is encoded by the nucleic acid sequence:

- 102 046387 ccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctc ccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagacc ctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgcc aagacaaagccgcgggaggagcagtacggggagca cgtaccgtgtggtcag cgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagt gcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctcc aaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatc ccggaaggagatgaccaagaaccaggtcagcctgacctgcctggtca aag gcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccg gagaacaactacaagaccacgcctcccgtgctgaagtccgacggctcctt cttcctctatagcaagctcaccgtggacaagagcaggtggcagcagggga acgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacg cagaagag cctctccctgtctccgggtaaatga (SEQ ID NO:179).

As discussed above, a tetramer is provided containing two polypeptide chains that contain the sequence SEQ ID NO: 178, and two polypeptide chains that contain the sequence SEQ ID NO: 175.

II.H.19 Dh2CpmFc(-)(N297G)-GDF15(N3D):Dh2CpmFc(+)(N297G).

The definition of Dh2CpmFc(-)(N297G)-GDF15(N3D):DhCpmFc(+)(N297G) in the present invention means a heterodimer that contains (i) a first polypeptide chain containing a GDF15(N3D) polypeptide, the N-terminus of which is connected directly to The C-terminus of the Dh2CpmFc(-)(N297G) domain, and (ii) a second polypeptide chain containing the Dh2CpmFc(+)(N297G) domain.

According to certain embodiments of the present invention, there is provided a tetramer that contains a dimer consisting of two heterodimers Dh2CpmFc(-)(N297G)GDF15(N3D):Dh2CpmFc(+)(N297G), in which the first two polypeptide chains of each heterodimer are connected through an interchain disulfide bond between the corresponding GDF15 regions of these circuits.

More specifically, according to a particular embodiment of the present invention, the tetramer comprises:

(a) two Dh2CpmFc(+)(N297G) domains (in each heterodimer) containing the sequence SEQ ID NO: 295, (b) two Dh2CpmFc(-)(N297G) domains (in each heterodimer) containing the sequence SEQ ID NO: 176, and (c) two GDF15(N3D) polypeptides (in each heterodimer) containing the sequence SEQ ID NO: 52.

According to a preferred embodiment of the present invention, the first polypeptide chain contains the amino acid sequence:

PSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNA KTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFS CSVMHEALHNHYT QKSLSLSPGARDGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPREVQV TMCIGAG P S Q FRAANMHAQIKT S LHRLKPDTVPAPCCVPAS YNPMVLIQK TDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:181), which is encoded by the nucleic acid sequence:

- 103 046387 ccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctc ccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagacc ctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgcc aagacaaagccgcgggaggagcagtacggggagca cgtaccgtgtggtcag cgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagt gcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctcc aaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatc ccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaa ag gcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccg gagaacaactacgacaccacgcctcccgtgctggactccgacggctcctt cttoctetatagcgacctcaccgtggacaagagcaggtggcagcagggga acgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacg cagaagagcct ctccctgtctccgggtgcgcgcgacggagaccactgtcc gctcgggcccgggcgttgctgccgtctgcacacggtccgcgcgtcgctgg aagacctgggctgggccgattgggtgctgtcgccacgggaggtgcaagtg accatgtgcatcggcgcgtgcccgagccagttccgggcggcaaacat gca cgcgcagatcaagacgagcctgcaccgcctgaagcccgacacggtgccag cgccctgctgcgtgcccgccagctacaatcccatggtgctcattcaaaag accgacaccggggtgtcgctccagacctatgatgacttgttagccaaaga ctgccactgcata (SEQ ID NO:180).

In a preferred embodiment of the present invention, the second polypeptide chain comprises the amino acid sequence SEQ ID NO: 175, which is encoded by the nucleic acid sequence SEQ ID NO: 179.

As discussed above, a tetramer is provided containing two polypeptide chains that contain the sequence SEQ ID NO: 181, and two polypeptide chains that contain the sequence SEQ ID NO: 175.

II.H.20 Dh2CpmFc(-)(N297G)(Y349C)-GDF15(Ndel3):Dh2CpmFc(+)(N297G)(S354C).

The definition of Dh2CpmFc(-)(N297G)(Y349C)-GDF15(Ndel3):Dh2CpmFc(+)(N297G)(S354C) in the present invention means a heterodimer that contains (i) a first polypeptide chain containing a GDF15(Ndel3) polypeptide, N - the end of which is connected directly to the C-terminus of the Dh2CpmFc(-)(N297G)(Y349C) polypeptide, and (ii) a second polypeptide chain containing the Dh2CpmFc(+)(N297G)(S345C) domain. Cysteine clamp mutations allow the first and second polypeptide chains to be joined via an interchain disulfide bond between C349 of the first polypeptide chain and C354 of the second polypeptide chain.

According to certain embodiments of the present invention, there is provided a tetramer that contains a dimer consisting of two heterodimers Dh2CpmFc(-)(N297G)(Y349C)GDF15(Ndel3):Dh2CpmFc(+)(N297G)(S354C), in which the first two polypeptide chains of each heterodimers are connected via an interchain disulfide bond between the corresponding GDF15 regions of these chains.

More specifically, according to a particular embodiment of the present invention, the tetramer comprises:

(a) two Dh2CpmFc(+)(N297G)(S354C) domains (in each heterodimer) containing the sequence:

PSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNA KTKPREEQYGSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPCRKEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYKTTPPVLKSDGSFFLYSKLTVDKSRWQQ GNVFSCSVMHEALHNHYT QKSLSLSPG (SEQ ID NO:296), (b) two Dh2CpmFc(-)(N297G)(Y349C) domains (in each heterodimer) containing the sequence:

- 104 046387

PSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNA KTKPREEQYGSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVCTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVM HEALHNHYT QKSLSLSPG (SEQ ID NO:183), (c) two GDF15(Ndel3) polypeptides (in each heterodimer) containing the sequence SEQ ID NO: 55.

According to a preferred embodiment of the present invention, the first polypeptide chain contains the amino acid sequence:

PSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNA KTKPREEQYGSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVCTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVM HEALHNHYT QKSLSLSPGGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPREVQVTMC IGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYNPMVLIQKTDT GVSLQTYDDLLAKDCHCI (SEQ ID NO:185), which is encoded by the nucleic acid sequence:

ccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctc ccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagacc ctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgcc aagacaaagccgcgggaggagcagtacggcagcacgtaccgtgtggtcag cgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagt gcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctctcc aaagccaaagggcagccccgagaaccacaggtgtgcaccctgcccccatc ccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaag gcttctatcccagcga catcgccgtggagtgggagagcaatgggcagccg gagaacaactacgacaccacgcctcccgtgctggactccgacggctcctt cttcctctatagcgacctcaccgtggacaagagcaggtggcagcagggga acgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacg cagaagagcctctccctgtctccggggt ggagaccactgtccgctcgggcc cgggcgttgctgccgtctgcacacggtccgcgcgtcgctggaagacctgg gctgggccgattgggtgctgtcgccacgggaggtgcaagtgaccatgtgc atcggcgcgtgcccgagccagttccgggcggcaaacatgcacgcgcagat caagacgagcctg caccgcctgaagcccgacacggtgccagcgccctgct gcgtgcccgccagctacaatcccatggtgctcattcaaaagaccgacacc ggggtgtcgctccagacctatgatgacttgttagccaaagactgccactg cata (SEQ ID NO:184).

According to a preferred embodiment of the present invention, the second polypeptide chain contains the amino acid sequence:

PSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNA KTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPCRKEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYKTTPPVLKSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYT QKSLSLSPGK (SEQ ID NO:182), which is encoded by the nucleic acid sequence:

- 105 046387 ccatccgtgttcctgtttcctccaaagccgaaggacaccctgatgatctc aagaactccggaagtgacttgcgtcgtcgtggacgtgtcacatgaggatc cagaggtcaagttcaattggtatgtggacggagtggaagtgcataacgcc aagaccaaaccccgcgaagaacagtacgggag cacctaccgcgtggtgag cgtccttactgtgctccaccaggactggcttaatgggaaggaatacaagt gtaaggtgtccaacaaggccctccccgctcccatcgaaaagaccatctca aaggcaaaggggcaaccaagggaacctcaagtgtacaccctgcctccgtg caggaaggatgaccaagaaccaggtcagcctgacttgtctcg tgaagg gcttctatcccagcgatattgctgtggaatgggagtcaaatggccagccc gagaataactacaaaactaccccacccgtgctgaaatctgatgggtcctt cttcctttactccaagctgaccgtggacaagagccgctggcaacaaggca atgtctttagctgctcagtgatgcatgaggctctccataatcactacact cagaagt cactgtccctgtctccgggtaaa (SEQ ID NO:186).

As discussed above, a tetramer is provided containing two polypeptide chains that contain the sequence of SEQ ID NO: 185, and two polypeptide chains that contain the sequence of SEQ ID NO: 182.

II.H.21 Dh2CpmFc(-)(N297G)(Y349C)-GDF15(N3D):Dh2CpmFc(+)(N297G)(S354C).

The definition of Dh2CpmFc(-)(N297G)(Y349C)-GDF15(N3D):Dh2CpmFc(+)(N297G)(S354C) in the present invention means a heterodimer that contains (i) a first polypeptide chain containing a GDF15(N3D) polypeptide, N - the end of which is connected directly to the C-terminus of the Dh2CpmFc() (N297G)(Y349C) domain, and (ii) a second polypeptide chain containing the Dh2CpmFc(+)(N297G)(S345C) domain. Cysteine clamp mutations allow the first and second polypeptide chains to be joined via an interchain disulfide bond between C349 of the first polypeptide and C354 of the second polypeptide.

According to certain embodiments of the present invention, there is provided a tetramer that contains a dimer consisting of two heterodimers Dh2CpmFc(-)(N297G)(Y349C)GDF15(N3D):Dh2CpmFc(+)(N297G)(S354C), in which the first two polypeptide chains of each heterodimers are connected via an interchain disulfide bond between the corresponding GDF15 regions of these chains.

More specifically, according to a particular embodiment of the present invention, the tetramer comprises:

(a) two Dh2CpmFc(+)(N297G)(S354C) domains (in each heterodimer) containing the sequence SEQ ID NO: 296, (b) two Dh2CpmFc(-)(N297G)(Y349C) domains (in each heterodimer), containing the sequence SEQ ID NO: 183, and (c) two GDF15(N3D) polypeptides (in each heterodimer) containing the sequence SEQ ID NO: 52.

According to a preferred embodiment of the present invention, the first polypeptide chain contains the amino acid sequence:

PSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNA

KTKPREEQYGSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVCTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHEALHNHYT QKSLSLSPGARDGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPR EVQV TMCIGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYNPMVLIQK TDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:188), which is encoded by the nucleic acid sequence: ccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctc

- 106 046387 ccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagacc ctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgcc aagacaaagccgcgggaggagcagtacgggagcacgtaccgtgtggtcag cgtcctcaccgtcctgcaccaggactggct gaatggcaaggagtacaagt gcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctcc aaagccaaagggcagccccgagaaccacaggtgtgcaccctgcccccatc ccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaag gcttctatcccagcgacatcgccgtggagtgggagagcaatgggca gccg gagaacaactacgacaccacgcctcccgtgctggactccgacggctcctt cttcctctatagcgacctcaccgtggacaagagcaggtggcagcagggga acgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacg cagaagagcctctccctgtctccgggtgcgcgcgacggagaccactgtcc gctc gggcccgggcgttgctgccgtctgcacacggtccgcgcgtcgctgg aagacctgggctgggccgattgggtgctgtcgccacgggaggtgcaagtg accatgtgcatcggcgcgtgcccgagccagttccgggcggcaaacatgca cgcgcagatcaagacgagcctgcaccgcctgaagcccgaca cggtgccag cgccctgctgcgtgcccgccagctacaatcccatggtgctcattcaaaag accgacaccggggtgtcgctccagacctatgatgacttgttagccaaaga ctgccactgcata (SEQ ID NO:187).

In a preferred embodiment of the present invention, the second polypeptide chain comprises the amino acid sequence SEQ ID NO: 182, which is encoded by the nucleic acid sequence SEQ ID NO: 186.

As discussed above, a tetramer is provided containing two polypeptide chains that contain the sequence SEQ ID NO: 188, and two polypeptide chains that contain the sequence SEQ ID NO: 182.

II.H.22 Dh2CpmFc(-)(N297G)(A287C) -GDF15(Ndel3):Dh2CpmFc(+)(N297G)(L306C).

The definition of Dh2CpmFc(-)(N297G)(A287C)-GDF15(Ndel3):Dh2CpmFc(+)(N297G)(L306C) in the present invention means a heterodimer that contains (i) a first polypeptide chain containing a GDF15(Ndel3) polypeptide, N the -end of which is connected directly to the C-terminus of the Dh2CpmFc(-)(N297G)(A287C) domain, and (ii) a second polypeptide chain containing the Dh2CpmFc(+)(N297G)(L306C) domain. Cysteine clamp mutations allow the first and second polypeptide chains to be connected via an interchain disulfide bond between C287 of the first monomer and C306 of the second monomer.

According to certain embodiments of the present invention, there is provided a tetramer that contains a dimer consisting of two heterodimers Dh2CpmFc(-)(N297G)(A287C)GDF15(Ndel3):Dh2CpmFc(+)(N297G)(L306C), in which the first two polypeptide chains of each heterodimers are connected via an interchain disulfide bond between the corresponding GDF15 regions of these chains.

More specifically, according to a specific embodiment of the present invention there is provided a tetramer that contains:

(a) two Dh2CpmFc(+)(N297G)(L306C) domains (in each heterodimer) containing the sequence:

PSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNC

KTKPREEQYGS ТYRVVSVCTVLHQDWLNGKEYKCKVSNKALPAPIECTIS KAKGQPREPQVYTLPPSRKEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYKTTPPVLKSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT QKSLSLSPG (SEQ ID NO:297), (b) two Dh2CpmFc(-)(N297G)(A287C) (in each heterodimer), containing the sequence: PSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNC

KTKPREEQYGSTYRWSVCTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHEALHNHYT QKSLSLSPG (SEQ ID NO:192), and (c) two GDF1 polypeptides 5(Ndel3) (in each heterodimer) containing the sequence SEQ

- 107 046387

ID NO: 55.

According to a preferred embodiment of the present invention, the first polypeptide chain contains the amino acid sequence:

PSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNC KTKPREEQYGSTYRWSVCTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVM HEALHNHYT QKSLSLSPGGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPREVQVTMC IGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYNPMVLIQKTDT

GVSLQTYDDLLAKDCHCI (SEQ ID NO:194), which is encoded by the nucleic acid sequence:

ccgtcagtcttcctcttccccccaaaacccaaggacaccctca tgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccac gaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgca taattgcaagacaaagccgcgggaggagcagtacggcagcacgtaccgtg tggtcag cgtctgcaccgtcctgcaccaggactggctgaatggcaaggag tacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaac catctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgc ccccatcccgggaggagatgaccaagaaccaggtcagcctgacctgcctg gtcaaaggcttctatcccagcga catcgccgtggagtgggagagcaatgg gcagccggagaacaactacgacaccacgcctcccgtgctggactccgacg gctccttcttcctctatagcgacctcaccgtggacaagagcaggtggcag caggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaacca ctacacgcagaagagcctctccctgtctccggg tggagaccactgtccgc tcgggcccgggcgttgctgccgtctgcacacggtccgcgcgtcgctggaa gacctgggctgggccgattgggtgctgtcgccacgggaggtgcaagtgac catgtgcatcggcgcgtgcccgagccagttccgggcggcaaacatgcacg cgcagatcaagacgagcc tgcaccgcctgaagcccgacacggtgccagcg ccctgctgcgtgcccgccagctacaatcccatggtgctcattcaaaagac cgacaccggggtgtcgctccagacctatgatgacttgttagccaaagact gccactgcata(SEQ ID NO:193).

According to a preferred embodiment of the present invention, the second polypeptide chain contains the amino acid sequence:

PSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNC

KTKPREEQYGSTYRWSVCTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSRKEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYKTTPPVLKSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT

QKSLSLSPGK (SEQ ID NO:191), which is encoded by the nucleic acid sequence:

ccgtcagtcttcctcttccccccaaaacccaaggacaccctca

- 108 046387 tgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccac gaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgca taattgcaagacaaagccgcgggaggagcagtacggcagcacgtaccgtg tggtcagcgtctgcaccgtcctgcacca ggactggctgaatggcaaggag tacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaac catctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgc ccccatcccggaaggagatgaccaagaaccaggtcagcctgacctgcctg gtcaaaggcttctatcccagcgacatcgccgtggagtgggagag caatgg gcagccggagaacaactacaagaccacgcctcccgtgctgaagtccgacg getccttcttoctetatagcaagctcaccgtggacaagagcaggtggcag caggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaacca ctacacgcagaagagcctctccctgtctccgggtaaa (SEQ ID NO:195).

As discussed above, a tetramer is provided containing two polypeptide chains that contain the sequence SEQ ID NO: 194, and two polypeptide chains that contain the sequence SEQ ID NO: 191.

II.H.23 Dh2CpmFc(-)(N297G)(A287C) -GDF15(N3D):Dh2CpmFc(+)(N297G)(L306C).

The definition of Dh2CpmFc(-)(N297G)(A287C)-GDF15(N3D):Dh2CpmFc(+)(N297G)(L306C) in the present invention means a heterodimer that contains (i) a first polypeptide chain containing a GDF15(N3D) polypeptide, N - the end of which is connected directly to the C-terminus of the Dh2CpmFc() (N297G)(A287C) domain, and (ii) a second polypeptide chain containing the Dh2CpmFc(+)(N297G)(L306C) domain. Cysteine clamp mutations allow the first and second polypeptide chains to be connected via an interchain disulfide bond between C287 of the first polypeptide chain and C306 of the second polypeptide chain.

According to certain embodiments of the present invention, there is provided a tetramer that contains a dimer consisting of two heterodimers Dh2CpmFc(-)(N297G)(A287C)GDF15(N3D):Dh2CpmFc(+)(N297G)(L306C), in which the first two polypeptide chains of each heterodimers are connected via an interchain disulfide bond between the corresponding GDF15 regions of these chains.

More specifically, according to a specific embodiment of the present invention there is provided a tetramer that contains:

(a) two Dh2CpmFc(+)(N297G)(L306C) domains (in each heterodimer) containing the sequence SEQ ID NO: 297, (b) two Dh2CpmFc(-)(N297G)(A287C) domains (in each heterodimer), containing the sequence SEQ ID NO: 192, and (c) two GDF15(N3D) polypeptides (in each heterodimer) containing the sequence SEQ ID NO: 52.

According to a preferred embodiment of the present invention, the first polypeptide chain contains the amino acid sequence:

PSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNC KTKPREEQYGSTYRVVSVCTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFS CSVMHEALHNHYT QKSLSLSPGARDGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPREVQV TMCIGACPS QFRAANMHAQIKT S LHRLKPDTVPAPCCVPASYNPMVLIQK TDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:197), which is encoded by the nucleic acid sequence:

- 109 046387 ccgtcagtcttcctcttccccccaaaacccaaggacaccctca tgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccac gaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgca taattgcaagacaaagccgcgggaggagcagtacggcagca cgtaccgtg tggtcagcgtctgcaccgtcctgcaccaggactggctgaatggcaaggag tacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaac catctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgc ccccatcccgggaggagatgaccaagaaccaggtcagcctgacctgcctg gtca aaggcttctatcccagcgacatcgccgtggagtgggagagcaatgg gcagccggagaacaactacgacaccacgcctcccgtgctggactccgacg gctccttcttcctctatagcgacctcaccgtggacaagagcaggtggcag caggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaacca ctacacgcagaaga gcctctccctgtctccgggtgcgcgcgacggagacc actgtccgctcgggcccgggcgttgctgccgtctgcacacggtccgcgcg tcgctggaagacctgggctgggccgattgggtgctgtcgccacgggaggt gcaagtgaccatgtgcatcggcgcgtgcccgagccagttccggggcggca acatgcacgcgcagatcaagacgagcctgcaccgcctgaagcccgacacg gtgccagcgccctgctgcgtgcccgccagctacaatcccatggtgctcat tcaaaagaccgacaccggggtgtcgctccagacctatgatgacttgttag ccaaagactgccactgcata (SEQ ID NO:196).

In a preferred embodiment of the present invention, the second polypeptide chain comprises the amino acid sequence SEQ ID NO: 191, which is encoded by the nucleic acid sequence SEQ ID NO: 195.

As discussed above, a tetramer is provided containing two polypeptide chains that contain the sequence SEQ ID NO: 197, and two polypeptide chains that contain the sequence SEQ ID NO: 191.

II.H.24 Dh2CpmFc(-)(N297G)(A287C)(Y349C)-GDF15(Ndel3):Dh2CpmFc(+)(N297G)(L306C)(S354C).

The definition of Dh2CpmFc(-)(N297G)(A287C)(Y349C)GDF15(Ndel3):Dh2CpmFc(+)(N297G)(L306C)(S354C) in the present invention means a heterodimer that contains (i) a first polypeptide chain containing a GDF15 polypeptide (Ndel3), the N-terminus of which is connected directly to the C-terminus of the Dh2CpmFc(-)(N297G)(A287C)(Y349C) domain, and (ii) a second polypeptide chain containing the Dh2CpmFc(+)(N297G)(L306C)( domain) S354C). Cysteine clamp mutations allow the first and second polypeptide chains to be connected via an interchain disulfide bond between C287 of the first polypeptide chain and C306 of the second polypeptide chain and between C349 of the first polypeptide chain and C349 of the second polypeptide chain.

According to certain embodiments of the present invention, there is provided a tetramer that contains a dimer consisting of two heterodimers Dh2CpmFc(-)(N297G)(A287C)(Y349C)GDF15(Ndel3):Dh2CpmFc(+)(N297G)(L306C)(S354C), in in which the first two polypeptide chains of each heterodimer are connected through an interchain disulfide bond between the corresponding GDF15 regions of these chains.

More specifically, according to a specific embodiment of the present invention there is provided a tetramer that contains:

(a) two Dh2CpmFc(+)(N297G)(L306C)(S354C) domains (in each heterodimer) containing the sequence:

PSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNC KTKPREEQYGSTYRWSVCTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPCRKEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYKTTPPVLKSDGSFFLYSKLTVDKSRWQQG NVFSCSVMHEALHNHYT QKSLSLSPG (SEQ ID NO:298), (b) two Dh2CpmFc(-)(N297G)(A287C)(Y349C) domains (in each heterodimer) containing the sequence:

- 110 046387

PSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNC KTKPREEQYGSTYRWSVCTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVCTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVM HEALHNHYT QKSLSLSPG (SEQ ID NO:199), (c) two GDF15(Ndel3) polypeptides (in each heterodimer) containing the sequence SEQ ID NO: 55.

According to a preferred embodiment of the present invention, the first polypeptide chain contains the amino acid sequence:

PSVFLFPPKPKDTLMISRT PE VT CVWDVS NOT DPE VKFNW YVDGVE VHNC KTKPREEQYGS ТYRWSVCTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVCTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQG NVFSCSVMHEALHNHYT QKSLSLSPGGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPREVQVTMC IGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYNPMVLIQKTDT GVSLQTYDDLLAKDCHCI (SEQ ID NO:201), which is encoded by the nucleic acid sequence:

ccgtcagtcttcctcttccccccaaaacccaaggacaccctca tgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccac gaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgca taattgcaagacaaagccgcgggaggagcagtacggcagcacgtaccgtg tggtcag cgtctgcaccgtcctgcaccaggactggctgaatggcaaggag tacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaac catctccaaagccaaagggcagccccgagaaccacaggtgtgcaccctgc ccccatcccgggaggagatgaccaagaaccaggtcagcctgacctgcctg gtcaaaggcttctatcccagc gacatcgccgtggagtgggagagcaatgg gcagccggagaacaactacgacaccacgcctcccgtgctggactccgacg gctccttcttcctctatagcgacctcaccgtggacaagagcaggtggcag caggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaacca ctacacgcagaagagcctctccctgtctccg ggtggagaccactgtccgc tcgggcccggggcgttgctgccgtctgcacacggtccgcgcgtcgctggaa gacctgggctgggccgattgggtgctgtcgccacgggaggtgcaagtgac catgtgcatcggcgcgtgcccgagccagttccgggcggcaaacatgcacg cgcagatcaagacgag cctgcaccgcctgaagcccgacacggtgccagcg ccctgctgcgtgcccgccagctacaatcccatggtgctcattcaaaagac cgacaccggggtgtcgctccagacctatgatgacttgttagccaaagact gccactgcata (SEQ ID NO:200).

According to a preferred embodiment of the present invention, the second polypeptide chain contains the amino acid sequence:

PSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNW YVDGVE VHNC KTKPREEQYGSTYRWSVCTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPCRKEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYKTTPPVLKSDGSFFLYSKLTVDKSRWQQG NVFSCSVMHEALHNHYT QKSLSLSPGK (SEQ ID NO:198), which is encoded by the nucleic acid sequence:

- 111 046387 ccgtcagtcttcctcttccccccaaaacccaaggacaccctca tgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccac gaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgca taattgcaagacaaagccgcgggaggagcagtacggcagca gt caaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgg gcagccggagaacaactacaagaccacgcctcccgtgctgaagtccgacg getccttcttoctetatagcaagctcaccgtggacaagagcaggtggcag caggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaacca ctacacgcagaagag cctctccctgtctccggggtaaa (SEQ ID NO:202).

As discussed above, a tetramer is provided containing two polypeptide chains that contain the sequence SEQ ID NO: 201, and two polypeptide chains that contain the sequence SEQ ID NO: 198.

II.H.25 Dh2CpmFc(-)(N297G)(A287C)(Y349C)-GDF15(N3D):Dh2CpmFc(+)(N297G)(L306C)(S354C).

The definition of Dh2CpmFc(-)(N297G)(A287C)(Y349C)GDF15(N3D):Dh2CpmFc(+)(N297G)(L306C)(S354C) in the present invention means a heterodimer that contains (i) a first monomer containing a GDF15( N3D), the N-terminus of which is connected directly to the C-terminus of the Dh2CpmFc(-)(N297G)(A287C)(Y349C) domain, and (ii) a second polypeptide chain containing the Dh2CpmFc(+)(N297G)(L306C)(S354C) domain ). Cysteine clamp mutations allow the first and second polypeptide chains to be connected via an interchain disulfide bond between C287 of the first polypeptide chain and C306 of the second polypeptide chain and between C349 of the first polypeptide chain and C349 of the second polypeptide chain.

According to certain embodiments of the present invention, there is provided a tetramer that contains a dimer consisting of two heterodimers Dh2CpmFc(-)(N297G)(A287C)(Y349C)GDF15(N3D):Dh2CpmFc(+)(N297G)(L306C)(S354C), in in which the first two polypeptide chains of each heterodimer are connected through an interchain disulfide bond between the corresponding GDF15 regions of these chains.

More specifically, according to a specific embodiment of the present invention there is provided a tetramer that contains:

(a) two Dh2CpmFc(+)(N297G)(L306C)(S354C) domains (in each heterodimer) containing the sequence SEQ ID NO: 298, (b) two Dh2CpmFc(-)(N297G)(A287C)(Y349C) domains (in each heterodimer) containing the sequence SEQ ID NO: 199, and (c) two GDF15(N3D) polypeptides (in each heterodimer) containing the sequence (SEQ ID NO: 52).

According to a preferred embodiment of the present invention, the first polypeptide chain contains the amino acid sequence:

P SVFL FP PKPKD T LMIS RT REVT CWVDVS NOT D PE VKFNW YVDGVE VHNC

KTKPREEQYGS ТYRWSVCTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVCTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHEALHNHYT QKSLSLSPGARDGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPR EVQV TMCIGACPS QFRAANMHAQIKT S LHRLKPDTVPAPCCVPAS YNPMVLIQK TDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:204), which is encoded by the nucleic acid sequence:

- 112 046387 ccgtcagtcttcctcttccccccaaaacccaaggacaccctca tgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccac gaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgca taattgcaagacaaagccgcgggaggagcagtacggcagca gt caaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgg gcagccggagaacaactacgacaccacgcctcccgtgctggactccgacg gctccttcttcctctatagcgacctcaccgtggacaagagcaggtggcag caggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaacca ctacacgcaga agagcctctccctgtctccgggtgcgcgcgacggagacc actgtccgctcgggcccgggcgttgctgccgtctgcacacggtccgcgcg tcgctggaagacctgggctgggccgattgggtgctgtcgccacgggaggt gcaagtgaccatgtgcatcggcgcgtgcccgagccagttccgggcgg caa acatgcacgcgcagatcaagacgagcctgcaccgcctgaagcccgacacg gtgccagcgccctgctgcgtgcccgccagctacaatcccatggtgctcat tcaaaagaccgacaccggggtgtcgctccagacctatgatgacttgttag ccaaagactgccactgcata (SEQ ID NO:203).

In a preferred embodiment of the present invention, the second polypeptide chain comprises the amino acid sequence SEQ ID NO: 198, which is encoded by the nucleic acid sequence SEQ ID NO: 202.

As discussed above, a tetramer is provided containing two polypeptide chains that contain the sequence SEQ ID NO: 204, and two polypeptide chains that contain the sequence SEQ ID NO: 198.

II.H.26 GG-Dh2CpmFc(-)-GDF15(Ndel3):GG-Dh2CpmFc(+).

The definition of GG-Dh2CpmFc(-)-GDF15(Ndel3):GG-Dh2CpmFc(+) in the present invention means a heterodimer that contains (i) a first polypeptide chain containing a GDF15(Ndel3) polypeptide, the N-terminus of which is connected directly to the C- the end of the GG-Dh2CpmFc(-) domain, and (ii) a second polypeptide chain containing the GG-Dh2CpmFc(+) domain.

According to certain embodiments of the present invention, there is provided a tetramer that contains a dimer consisting of two heterodimers GG-Dh2CpmFc(-)-GDF15(Ndel3):GGDh2CpmFc(+), in which the first two polypeptide chains of each heterodimer are connected through an interchain disulfide bond between the respective regions GDF15 data circuits.

More specifically, according to a particular embodiment of the present invention, the tetramer comprises:

(a) two GG-Dh2CpmFc(+) domains (in each heterodimer) containing the sequence:

GGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVH

NAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVYTLPPSRKEMTKNQVSLTCLVKGFYPSDIAVEWESNG QPENNYKTTPPVLKSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNH

YTQKSLSLSPG (SEQ ID NO:299), (b) two GG-Dh2CpmFc(-) domains (in each heterodimer) containing the sequence:

GGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVH NAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNG QPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCS VMHEALHNH

YTQKSLSLSPG (SEQ ID NO:206), and (c) two GDF15(Ndel3) polypeptides (in each heterodimer) containing the sequence SEQ ID NO: 55.

According to a preferred embodiment of the present invention, the first polypeptide

- 113 046387 chain contains the amino acid sequence:

GGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVH NAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNG QPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFS CSVMHEALHNH YTQKSLSLSPGGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPREVQVT MCIGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYNPMVLIQKT DTGVSLQTYDDLLAKDCHCI (SEQ ID NO:208), which is encoded by the nucleic acid sequence: ggtggcccgtcagtcctcctcttccccccaaaacc caaggaca ccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtg agccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtgga ggtgcataatgccaagacaaagccgcgggaggagcagtacaacagcacgt accgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaat ggc aaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcga gaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtaca ccctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacc tgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagag caatgggcagcc ggagaacaactacgacaccacgcctcccgtgctggact ccgacggctccttcttcctctatagcgacctcaccgtggacaagagcagg tggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgca caaccactacacgcagaagagcctctccctgtctccgggtggagaccact gtccgctcgggcccggggcgttg ctgccgtctgcacacggtccgcgcgtcg ctggaagacctgggctgggccgattgggtgctgtcgccacgggaggtgca agtgaccatgtgcatcggcgcgtgcccgagccagttccgggcggcaaaca tgcacgcgcagatcaagacgagcctgcaccgcctgaagcccgacacggtg ccagc (SEQ ID NQ:207).

According to an embodiment of the present invention that utilizes the VH21 signal sequence, in a preferred embodiment of the present invention, the first polypeptide chain comprises the amino acid sequence (signal sequence is underlined):

MEWSWVFLFFLSVTTGVHSGGPSVFLFPPKPKDTLMISRTPEVTCVWDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNG KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT CLVKGFYPSDIAVEWESNGQPENNYDTTPPVLDSDGSFFLYSDL TVDKSR WQQGNVFSCSI/MHEALHNHYTQKSLSLSPGGDHCPLGPGRCCRLHTVRAS LEDLGWADWVLSPREVQVTMCIGACPSQFRAANMHAQIKTSLHRLKPDTV PAPCCVPASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:243), which is encoded by the nucleic acid sequence (signal sequence underlined):

- 114 046387 atggaatggagctgggtctttctcttcttcctgtcagtaacgactggtgt ccactccggtggcccgtcagtcttcctcttccccccaaaacccaaggaca ccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtg agccacgaagaccctgaggtcaagttcaactggt acgtggacggcgtgga ggtgcataatgccaagacaaagccgcgggaggagcagtacaacagcacgt accgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggc aaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcga gaaaaccatctccaaagccaaagggcagccccgagaaccaca ggtgtaca ccctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacc tgcctggtcaaaggcttctatcccagcgacatcgccgtggagtggggagag caatgggcagccggagaacaactacgacaccacgcctcccgtgctggact ccgacggctccttcttoctetatagcgacctcaccgtggacaagagcagg tggca gcaggggaacgtcttctcatgctccgtgatgcatgaggctctgca caaccactacacgcagaagagcctctccctgtctccgggtggagaccact gtccgctcgggcccgggcgttgctgccgtctgcacacggtccgcgcgtcg ctggaagacctgggctgggccgattgggtgctgtcgccacgggaggtgca ag tgaccatgtgcatcggcgcgtgcccgagccagttccgggcggcaaaca tgcacgcgcagatcaagacgagcctgcaccgcctgaagcccgacacggtg ccagcgccctgctgcgtgcccgccagctacaatcccatggtgctcattca aaagaccgacaccggggtgtcgctccagacctatgatgacttgt tagcca aagactgccactgcata (SEQ ID NO:244).

According to a preferred embodiment of the present invention, the second polypeptide chain contains the amino acid sequence:

GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVH NAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVYTLPPSRKEMTKNQVSLTCLVKGFYPSDIAVEWESNG QPENNYKTTPPVLKSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNH YTQKSLSLSPGK (SEQ ID NO:205), which is encoded by the nucleic acid sequence: ggtggcccgtcagtcttcctcttccccccaaaacccaaggaca ccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtg agccacgaagaccctgaggtcaagttcaactggtacgtggacggcg tgga ggtgcataatgccaagacaaagccgcgggaggagcagtacaacagcacgt accgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggc aaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcga gaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtaca ccct gcccccatcccggaaggagatgaccaagaaccaggtcagcctgacc tgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagag caatgggcagccggagaacaactacaagaccacgcctcccgtgctgaagt ccgacggctccttcttoctetatagcaagctcaccgtggacaagagcagg tggcagcaggggaacg tcttctcatgctccgtgatgcatgaggctctgca caaccactacacgcagaagagcctctccctgtctccgggtaaa (SEQ ID NO:209).

According to an embodiment of the present invention that utilizes the VH21 signal sequence, in a preferred embodiment of the present invention, the second polypeptide chain comprises the amino acid sequence (signal sequence is underlined):

- 115 046387

MEWSWVFLFFLSVTTGVHSGGPSVFLFPPKPKDTLMISRTPEVTCVWDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNG KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRKEMTKNQVSLT CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLKSDGSFF LYSKLTVDKSR WQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO:245), which is encoded by the nucleic acid sequence (signal sequence underlined): atggaatggagctgggtctttctcttcttcctgtcagtaacgactggtgt ccactccggtggcccgtcagtcttcctcttccccccaaaacccaaggaca ccct catgatctcccggacccctgaggtcacatgcgtggtggtggacgtg agccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtgga ggtgcataatgccaagacaaagccgcgggaggagcagtacaacagcacgt accgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggc aaggagta caagtgcaaggtctccaacaaagccctcccagcccccatcga gaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtaca ccctgcccccatcccggaaggagatgaccaagaaccaggtcagcctgacc tgcctggtcaaaggcttctatcccagcgacatcgccgtggagtggggagag caatgggcagccggagaacaacta caagaccacgcctcccgtgctgaagt ccgacggctccttcttoctetatagcaagctcaccgtggacaagagcagg tggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgca caaccactacacgcagaagagcctctccctgtctccgggtaaa (SEQ ID NO:246).

As discussed above, a tetramer is provided containing two polypeptide chains that contain the sequence of SEQ ID NO: 208, and two polypeptide chains that contain the sequence of SEQ ID NO: 205.

II.H.27 GG-Dh2CpmFc(-)-GDF15(N3D):GG-Dh2CpmFc(+).

The definition of GG-Dh2CpmFc(-)-GDF15(N3D):GG-DhCpmFc(+) in the present invention means a heterodimer that contains (i) a first polypeptide chain containing a GDF15(N3D) polypeptide, the N-terminus of which is connected directly to the C- the end of the GG-Dh2CpmFc(-) domain, and (ii) a second polypeptide chain containing the GG-DhCpmFc(+) domain.

According to certain embodiments of the present invention, there is provided a tetramer that contains a dimer consisting of two heterodimers GG-Dh2CpmFc(-)-GDF15(N3D):GGDh2CpmFc(+), in which the first two polypeptide chains of each heterodimer are connected through an interchain disulfide bond between the respective regions GDF15 data circuits.

More specifically, according to a particular embodiment of the present invention, the tetramer comprises:

(a) two GG-Dh2CpmFc(+) domains (in each heterodimer) containing the sequence SEQ ID NO: 299, (b) two GG-Dh2CpmFc(-) domains (in each heterodimer) containing the sequence SEQ ID NO: 206, and (c) two GDF15(N3D) polypeptides (in each heterodimer) containing the sequence SEQ ID NO: 52.

According to a preferred embodiment of the present invention, the first polypeptide chain contains the amino acid sequence:

GGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVH NAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNG QPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCS VMHEALHNH YTQKSLSLSPGARDGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPREV QVTMCIGAC R S Q FRAANMHAQIKTSLHRLKPD ТVPAPC CVPAS YNPMVLI QKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:211) which is encoded by the nucleic acid sequence:

- 116 046387 ggtggcccgtcagtcttcctcttccccccaaaacccaaggaca ccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtg agccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtgga ggtgcataatgccaagacaaagccgcgggaggagcagtaca acagcacgt accgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggc aaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcga gaaaaccatctctccaaagccaaagggcagccccgagaaccacaggtgtaca ccctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacc tgcc tggtcaaaggcttctatcccagcgacatcgccgtggagtgggagag caatgggcagccggagaacaactacgacaccacgcctcccgtgctggact ccgacggctccttcttcctctatagcgacctcaccgtggacaagagcagg tggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgca caaccactacacgc agaagagcctctccctgtctccggggtgcgcgcgacg gagaccactgtccgctcgggcccgggcgttgctgccgtctgcacacggtc cgcgcgtcgctggaagacctgggctgggccgattgggtgctgtcgccacg ggaggtgcaagtgaccatgtgcatcggcgcgtgcccgagccagttcc ggg cggcaaacatgcacgcgcagatcaagacgagcctgcaccgcctgaagccc gacacggtgccagcgccctgctgcgtgcccgccagctacaatcccatggt gctcattcaaaagaccgacaccggggtgtcgctccagacctatgatgact tgttagccaaagactgccactgcata (SEQ ID NQ:210).

According to an embodiment of the present invention that utilizes the VH21 signal sequence, in a preferred embodiment of the present invention, the first polypeptide chain comprises the amino acid sequence (signal sequence is underlined):

MEWSWVFLFFLSVTTGVHSGGPSVFL FPPKPKDTLMISRT PE VT CVWDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNG KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT CLVKGFYPSDIAVEWESNGQPENNYDTTPPVLDSDGSFF LYSDLTVDKSR WQQGNVFSCSVMHEALHNHYTQKSLSLSPGARDGDHCPLGPGRCCRLHTV RAS LE DLGWADWVL S PREVQVTMCIGAG R S Q FRAANMHAQIKT S LHRLKP DTVPAPCCVPASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:247), which is encoded by a nucleic acid sequence (signal sequence is underlined):

- 117 046387 atggaatggagctgggtctttctcttcttcctgtcagtaacgactggtgt ccactccggtggcccgtcagtcttcctcttccccccaaaacccaaggaca ccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtg agccacgaagaccctgaggtcaagttcaactggt acgtggacggcgtgga ggtgcataatgccaagacaaagccgcgggaggagcagtacaacagcacgt accgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggc aaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcga gaaaaccatctccaaagccaaagggcagccccgagaaccaca ggtgtaca ccctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacc tgcctggtcaaaggcttctatcccagcgacatcgccgtggagtggggagag caatgggcagccggagaacaactacgacaccacgcctcccgtgctggact ccgacggctccttcttcctctatagcgacctcaccgtggacaagagcagg tgg cagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgca caaccactacacgcagaagagcctctccctgtctccgggtgcgcgcgacg gagaccactgtccgctcgggcccgggcgttgctgccgtctgcacacggtc cgcgcgtcgctggaagacctgggctgggccgattgggtgctgtcg ccacg ggaggtgcaagtgaccatgtgcatcggcgcgtgcccgagccagttccggg cggcaaacatgcacgcgcagatcaagacgagcctgcaccgcctgaagccc gacacggtgccagcgccctgctgcgtgcccgccagctacaatcccatggt gctcattcaaaagaccgacaccggggtgtcgctccagacct atgatgact tgttagccaaagactgccactgcata (SEQ ID NO:248).

In a preferred embodiment of the present invention, the second polypeptide chain comprises the amino acid sequence SEQ ID NO: 205, which is encoded by the nucleic acid sequence SEQ ID NO: 209.

According to an embodiment of the present invention using the VH21 signal sequence, in a preferred embodiment of the present invention, the second polypeptide chain comprises the amino acid sequence SEQ ID NO: 245, which is encoded by the nucleic acid sequence SEQ ID NO: 246.

As discussed above, a tetramer is provided containing two polypeptide chains that contain the sequence SEQ ID NO: 211, and two polypeptide chains that contain the sequence SEQ ID NO: 205.

II.H.28 GG-Dh2CpmFc(-)(Y349C)-GDF15(Ndel3):GG-Dh2CpmFc(+)(S354C).

The definition of GG-Dh2CpmFc(-)(Y349C)-GDF15(Ndel3):GG-Dh2CpmFc(+)(S354C) in the present invention means a heterodimer that contains (i) a first polypeptide chain containing a GDF15(Ndel3) polypeptide, N-terminus which is connected directly to the C-terminus of the GG-Dh2CpmFc() (Y349C) domain, and (ii) a second polypeptide chain containing the GG-Dh2CpmFc(+)(S345C) domain. Cysteine clamp mutations allow the first and second polypeptide chains to be joined via an interchain disulfide bond between C349 of the first polypeptide chain and C354 of the second polypeptide chain.

According to certain embodiments of the present invention, there is provided a tetramer that contains a dimer consisting of two heterodimers GG-Dh2CpmFc(-)(Y349C)-GDF15(Ndel3):GGDh2CpmFc(+)(S354C), in which the first two polypeptide chains of each heterodimer are connected by interchain disulfide bond between the corresponding GDF15 regions of these chains.

More specifically, according to a particular embodiment of the present invention, the tetramer comprises:

(a) two GG-Dh2CpmFc(+)(S354C) (in each heterodimer) containing the sequence: GGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVH

(b) two circuits GG-Dh2CpmFc(-)(Y349C) (in each heterodimer), containing the sequence:

- 118 046387

GGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVH NAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVCTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNG QPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVM HEALHNH

YTQKSLSLSPG (SEQ ID NO:213), and (c) two GDF15(Ndel3) polypeptides (in each heterodimer) containing the sequence SEQ ID NO: 55.

According to a preferred embodiment of the present invention, the first polypeptide chain contains the amino acid sequence:

GGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVH

NAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVCTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNG QPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHEALHNH YTQKSLSLSPGGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPREV QVT MCIGAG R S Q FRAANMHAQIKT S LHRLKPDTVPAPC CVPAS YNPMVLIQKT DTGVSLQTYDDLLAKDCHCI (SEQ ID NO:215), which is encoded by the nucleic acid sequence: ggtggcccgtcagtcttcctcttccccccaaaacccaaggaca ccctcatgatctcccggacccctgaggtcacatgcgtggtggtggac gtg agccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtgga ggtgcataatgccaagacaaagccgcgggaggagcagtacaacagcacgt accgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggc aaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcga gaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtgca ccctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacc tgcctggtcaaaggcttctatcccagcgacatcgccgtggagtggggagag caatgggcagccggagaacaactacgacaccacgcctcccgtgctggact ccgacggctccttct toctetatagcgacctcaccgtggacaagagcagg tggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgca caaccactacacgcagaagagcctctccctgtctccgggtggagaccact gtccgctcgggcccgggcgttgctgccgtctgcacacggtccgcgcgtcg ctggaagacctgggctg ggccgattgggtgctgtcgccacgggaggtgca agtgaccatgtgcatcggcgcgtgcccgagccagttccgggcggcaaaca tgcacgcgcagatcaagacgagcctgcaccgcctgaagcccgacacggtg ccagcgccctgctgegtgcccgccagctacaatcecatggtgetcattea aaagaccgac accggggtgtcgctccagacctatgatgacttgttagcca aagactgccactgcata (SEQ ID NO:214).

According to an embodiment of the present invention that utilizes the VH21 signal sequence, in a preferred embodiment of the present invention, the first polypeptide chain comprises the amino acid sequence (signal sequence is underlined):

MEWSWVFLFFLSVTTGVHSGGPSVFL FPPKPKDTLMISRT PE VT CVWDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNG KEYKCKVSNKALPAPIEKTISKAKGQPREPQVCTLPPSREEMTKNQVSLT CLVKGFYPSDIAVEWESNGQPENNYDTTPPVLDSDGSFFLY SDLTVDKSR WQQGNVFSCSVMHEALHNHYTQKSLSLSPGGDHCPLGPGRCCRLHTVRAS LEDLGWADWVLSPREVQVTMCIGACPSQFRAANMHAQIKTSLHRLKPDTV PAPCCVPASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI(SEQ ID NO:249),

- 119 046387 which is encoded by a nucleic acid sequence (signal sequence is underlined):

atggaatggagctgggtctttctcttcttcctgtcagtaacgactggtgt ccactccggtggcccgtcagtcttcctcttccccccaaaacccaaggaca ccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtg agccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtgga ggtgcataatgccaagacaaagccgcgggaggagcagtacaacagcacgt accgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggc aaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcga gaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtgca ccctgcccc catcccgggaggagatgaccaagaaccaggtcagcctgacc tgcctggtcaaaggcttctatcccagcgacatcgccgtggagtggggagag caatgggcagccggagaacaactacgacaccacgcctcccgtgctggact ccgacggctccttcttcctctatagcgacctcaccgtggacaagagcagg tggcagcaggggaacgtctt ctcatgctccgtgatgcatgaggctctgca caaccactacacgcagaagagcctctccctgtctccgggtggagaccact gtccgctcgggcccgggcgttgctgccgtctgcacacggtccgcgcgtcg ctggaagacctgggctgggccgattgggtgctgtcgccacgggaggtgca agtgaccatgtgcatcgg cgcgtgcccgagccagttccgggcggcaaaca tgcacgcgcagatcaagacgagcctgcaccgcctgaagcccgacacggtg ccagcgccctgctgcgtgcccgccagctacaatcccatggtgctcattca aaagaccgacaccggggtgtcgctccagacctatgatgacttgttagcca aagactgccactgcat a (SEQ ID NO:250).

According to a preferred embodiment of the present invention, the second polypeptide chain contains the amino acid sequence:

GGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVH NAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVYTLPPCRKEMTKNQVSLTCLVKGFYPSDIAVEWESNG QPENNYKTTPPVLKSDGSFFLYSKLTVDKSRWQQ GNVFSCSVMHEALHNH YTQKSLSLSPGK (SEQ ID NO:212), which is encoded by the nucleic acid sequence: ggtggcccgtcagtcttcctcttccccccaaaacccaaggaca ccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtg agccacgaagaccctgaggtcaagttcaactggtacgtggacggcgt gga ggtgcataatgccaagacaaagccgcgggaggagcagtacaacagcacgt accgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggc aaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcga gaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtaca ccctg cccccatgccggaaggagatgaccaagaaccaggtcagcctgacc tgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagag caatgggcagccggagaacaactacaagaccacgcctcccgtgctgaagt ccgacggctccttcttoctetatagcaagctcaccgtggacaagagcagg tggcagcaggggaacgt cttctcatgctccgtgatgcatgaggctctgca caaccactacacgcagaagagcctctccctgtctccgggtaaa (SEQ ID NO:216) .

According to an embodiment of the present invention that utilizes the VH21 signal sequence, in a preferred embodiment of the present invention, the second polypeptide chain comprises the amino acid sequence (signal sequence is underlined):

- 120 046387

MEWSWVFLFFLSVTTGVHSGGP SVFLFPPKPKDTLMIS RT PE VT CVWDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNG KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPCRKEMTKNQVSLT CLVKGFYPSDIAVEWESNGQPENNYKTTPPVL KSDGSFFLYSKLTVDKSR WQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO:251), which is encoded by the nucleic acid sequence (signal sequence underlined): atggaatggagctgggtctttctcttcttcctgtcagtaacgactggtgt ccactccggtggcccgtcagtcttcctcttccccccaaaacccaagga ca ccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtg agccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtgga ggtgcataatgccaagacaaagccgcgggaggagcagtacaacagcacgt accgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggc a aggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcga gaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtaca ccctgcccccatgccggaaggagatgaccaagaaccaggtcagcctgacc tgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagag caatgggcagccggaga acaactacaagaccacgcctcccgtgctgaagt ccgacggctccttcttoctetatagcaagctcaccgtggacaagagcagg tggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgca caaccactacacgcagaagagcctctccctgtctccgggtaaa (SEQ ID

NO:252).

As discussed above, a tetramer is provided containing two polypeptide chains that contain the sequence of SEQ ID NO: 215, and two polypeptide chains that contain the sequence of SEQ ID NO: 212.

I.N.29 GG-Dh2CpmFc(-)(Y349C)-GDF15(N3D):GG-Dh2CpmFc(+)(S354C).

The definition of GG-Dh2CpmFc(-)(Y349C)-GDF15(N3D):GG-Dh2CpmFc(+)(S354C) in the present invention means a heterodimer that contains (i) a first polypeptide chain containing a GDF15(N3D) polypeptide, N-terminus which is connected directly to the C-terminus of the GG-Dh2CpmFc() (Y349C) domain, and (ii) a second polypeptide chain containing the GG-Dh2CpmFc(+)(S345C) domain. Cysteine clamp mutations allow the first and second polypeptide chains to be joined via an interchain disulfide bond between C349 of the first polypeptide chain and C354 of the second polypeptide chain.

According to certain embodiments of the present invention, there is provided a tetramer that contains a dimer consisting of two heterodimers GG-Dh2CpmFc(-)(Y349C)-GDF15(N3D):GGDh2CpmFc(+)(S354C), in which the first two polypeptide chains of each heterodimer are connected by interchain disulfide bond between the corresponding GDF15 regions of these chains.

More specifically, according to a particular embodiment of the present invention, the tetramer comprises:

(a) two GG-Dh2CpmFc(+)(S354C) domains (in each heterodimer) containing the sequence SEQ ID NO: 300, (b) two GG-Dh2CpmFc(-)(Y349C) domains (in each heterodimer) containing the sequence SEQ ID NO: 213, and (c) two GDF15(N3D) polypeptides (in each heterodimer) containing the sequence SEQ ID NO: 52.

According to a preferred embodiment of the present invention, the first polypeptide chain contains the amino acid sequence:

- 121 046387

GGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVH NAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVCTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNG QPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVM HEALHNH YTQKSLSLSPGARDGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPREV QVTMCIGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYNPMVLI QKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:218) which is encoded by the nucleic acid sequence:

ggtggcccgtcagtcttcctcttccccccaaaacccaaggaca ccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtg agccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtgga ggtgcataatgccaagacaaagccgcgggaggagcagtacaacagcacgt accgtgt ggtcagcgtcctcaccgtcctgcaccaggactggctgaatggc aaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcga gaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtgca ccctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacc tgcctggtcaaaggcttctat cccagcgacatcgccgtggagtgggagag caatgggcagccggagaacaactacgacaccacgcctcccgtgctggact ccgacggctccttcttcctctatagcgacctcaccgtggacaagagcagg tggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgca caaccactacacgcagaagagcctctccctgtct ccgggtgcgcgcgacg gagaccactgtccgctcgggcccgggcgttgctgccgtctgcacacggtc cgcgcgtcgctggaagacctgggctgggccgattgggtgctgtcgccacg ggaggtgcaagtgaccatgtgcatcggcgcgtgcccgagccagttccggg cggcaaacatgcac (SEQ ID NO:217).

According to an embodiment of the present invention that utilizes the VH21 signal sequence, in a preferred embodiment of the present invention, the first polypeptide chain comprises the amino acid sequence (signal sequence is underlined):

MEWSWVFLFFLSVTTGVHS GGP S VFL EP PKPKDT LMIS RT PE VT CVWDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNG KEYKCKVSNKALPAPIEKTISKAKGQPREPQVCTLPPSREEMTKNQVSLT CLVKGFYPSDIAVEWESNGQPENNYDTTPPVLDSD GSFFLYSDLTVDKSR WQQGNVFSCSVMHEALHNHYTQKSLSLSPGARDGDHCPLGPGRCCRLHTV RASLEDLGWADWVLSPREVQVTMCIGACPSQFRAANMHAQIKTSLHRLKP

DTVPAPCCVPASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI(SEQ ID NO:253), which is encoded by the nucleic acid sequence (signal sequence underlined):

- 122 046387 atggaatggagctgggtctttctcttcttcctgtcagtaacgactggtgt ccactccggtggcccgtcagtcttcctcttccccccaaaacccaaggaca cccteatgatctcccggacccctgaggtcacatgcgtggtggtggacgtg agccacgaagaccctgaggtcaagttcaactggt acgtggacggcgtgga ggtgcataatgccaagacaaagccgcgggaggagcagtacaacagcacgt accgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggc aaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcga gaaaaccatctccaaagccaaagggcagccccgagaaccaca ggtgtgca ccctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacc tgcctggtcaaaggcttctatcccagcgacatcgccgtggagtggggagag caatgggcagccggagaacaactacgacaccacgcctcccgtgctggact ccgacggctccttcttoctetatagcgacctcaccgtggacaagagcagg tgg cagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgca caaccactacacgcagaagagcctctccctgtctccgggtgcgcgcgacg gagaccactgtccgctcgggcccgggcgttgctgccgtctgcacacggtc cgcgcgtcgctggaagacctgggctgggccgattgggtgctgtcg ccacg ggaggtgcaagtgaccatgtgcatcggcgcgtgcccgagccagttccggg cggcaaacatgcacgcgcagatcaagacgagcctgcaccgcctgaagccc gacacggtgccagcgccctgctgcgtgcccgccagctacaatcccatggt gctcattcaaaagaccgacaccggggtgtcgctccagacct atgatgact tgttagccaaagactgccactgcata (SEQ ID NO:254).

In a preferred embodiment of the present invention, the second polypeptide chain comprises the amino acid sequence SEQ ID NO: 212, which is encoded by the nucleic acid sequence SEQ ID NO: 218.

According to an embodiment of the present invention using the VH21 signal sequence, in a preferred embodiment of the present invention, the second polypeptide chain comprises the amino acid sequence SEQ ID NO: 251, which is encoded by the nucleic acid sequence SEQ ID NO: 252.

As discussed above, a tetramer is provided containing two polypeptide chains that contain the sequence SEQ ID NO: 218, and two polypeptide chains that contain the sequence SEQ ID NO: 212.

I.N.30 Dh3CpmFc(-)-GDF 15(Ndel3):Dh3CpmFc(+).

The definition of Dh3CpmFc(-)-GDF15(Ndel3):Dh3CpmFc(+) in the present invention means a heterodimer that contains (i) a first polypeptide chain containing a GDF15(Ndel3) polypeptide, the N-terminus of which is connected directly to the C-terminus of the Dh3CpmFc(-) domain , and (ii) a second polypeptide chain containing the Dh3CpmFc(+) domain.

According to certain embodiments of the present invention, there is provided a tetramer that contains a dimer consisting of two heterodimers Dh3CpmFc(-)-GDF15(Ndel3):Dh3CpmFc(+), in which the first two polypeptide chains of each heterodimer are connected through an interchain disulfide bond between the corresponding GDF15 data regions chains.

More specifically, according to a particular embodiment of the present invention, the tetramer comprises:

(a) two Dh3CpmFc(+) domains (in each heterodimer) containing the sequence: GPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHN

AKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI SKAKGQPREPQVYTLPPSRKEMTKNQVSLTCLVKGFYPSDIAVEWESNGQ PENNYKTTPPVLKSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHY TQKSLSLSPG (SEQ ID NO:301), (b) two D domains h3CpmFc(-) (in each heterodimer) containing the sequence:

- 123 046387

GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHN

AKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI

SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQ

PENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHEALHNHY

TQKSLSLSPG (SEQ ID NO:220), _and (c) two GDF15(Ndel3) polypeptides (in each heterodimer) containing the sequence SEQ ID NO: 55.

According to a preferred embodiment of the present invention, the first polypeptide chain contains the amino acid sequence:

GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHN

AKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQ PENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHEALHNHY TQKSLSLSPGGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPREV QVTM CIGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYNPMVLIQKTD TGVSLQTYDDLLAKDCHCI (SEQ ID NO:222), which is encoded by the nucleic acid sequence: ggcccgtcagtcttcctcttccccccaaaaccca aggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtg gacgtgagcca cgaagaccctgaggtcaagttcaactggtacgtggacgg cgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaaca gcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctg aatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccc catcgagaaaaccatctccaa agccaaagggcagccccgagaaccacagg tgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtcagc ctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtg ggagagcaatgggcagccggagaacaactacgacaccacgcctcccgtgc tggactccgacggctccttcttcctctatagcg acctcaccgtggacaag agcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggc tctgcacaaccactacacgcagaagagcctctccctgtctccgggtggag accactgtccgctcgggcccgggcgttgctgccgtctgcacacggtccgc gcgtcgctggaagacctgggctggggccgattg ggtgctgtcgccacggga ggtgcaagtgaccatgtgcatcggcgcgtgcccgagccagttccgggcgg caaacatgcacgcgcagatcaagacgagcctgcaccgcctgaagcccgac acggtgccagcgccctgctgcgtgcccgccagctacaatcccatggtgct cattcaaaagaccgacaccggggtg tcgctccagacctatgatgacttgt tagccaaagactgccactgcata (SEQ ID NO:221).

According to an embodiment of the present invention that utilizes a VK1 signal sequence, in a preferred embodiment of the present invention, the first polypeptide chain comprises the amino acid sequence (signal sequence is underlined):

- 124 046387

MDMRVPAQLLGLLLLWLRGARCGP S VFL FPPKPKDTLMISRT PE VT US DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWL NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVS LTCLVKGFYPSDIAVEWESNGQPENNYDTTPPVLD SDGSFFLYSDLTVDK SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGDHCPLGPGRCCRLHTVR ASLEDLGWADWVLSPREVQVTMCIGACPSQFRAANMHAQIKTSLHRLKPD

TVPAPCCVPASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:255), which is encoded by the nucleic acid sequence (signal sequence underlined):

atggacatgaggtgcccgctcagctcctggggctcctgctgctgtggct gagaggtgcgcgctgtggcccgtcagtcttcctcttccccccaaaaccca aggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtg gacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacgg cg tggaggtgcataatgccaagacaaagccgcgggaggagcagtacaaca gcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctg aatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccc catcgagaaaaccatctccaaagccaaagggcagccccgagaaccacagg tgtacaccctgcccc catcccgggaggagatgaccaagaaccaggtcagc ctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtg ggagagcaatgggcagccggagaacaactacgacaccacgcctcccgtgc tggactccgacggctccttcttcctctatagcgacctcaccgtggacaag agcaggtggcagcaggggaacg tcttctcatgctccgtgatgcatgaggc tctgcacaaccactacacgcagaagagcctctccctgtctccgggtggag accactgtccgctcgggcccgggcgttgctgccgtctgcacacggtccgc gcgtcgctggaagacctgggctgggccgattgggtgctgtcgccacggga ggtgcaagtgaccatgt gcatcggcgcgtgcccgagccagttccggggcgg caaacatgcacgcgcagatcaagacgagcctgcaccgcctgaagcccgac acggtgccagcgccctgctgcgtgcccgccagctacaatcccatggtgct cattcaaaagaccgacaccggggtgtcgctccagacctatgatgacttgt tagccaaagactgccact gcata (SEQ ID NO:256).

According to a preferred embodiment of the present invention, the second polypeptide chain contains the amino acid sequence:

GPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHN AKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI SKAKGQPREPQVYTLPPSRKEMTKNQVSLTCLVKGFYPSDIAVEWESNGQ PENNYKTTPPVLKSDGSFFLYSKLTVDKSRWQQG NVFSCSVMHEALHNHY TQKSLSLSPGK (SEQ ID NO:219), which is encoded by the nucleic acid sequence:

- 125 046387 ggcccgtcagtcttcctcttccccccaaaaccca aggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtg gacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacgg cgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaaca gca cgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctg aatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccc catcgagaaaaccatctccaaagccaaagggcagccccgagaaccacagg tgtacaccctgcccccatcccggaaggagatgaccaagaaccaggtcagc ctgacctgcctggtca aaggcttctatcccagcgacatcgccgtggagtg ggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgc tgaagtccgacggctccttcttoctetatagcaagctcaccgtggacaag agcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggc tctgcacaaccactacacgcagaaga gcctctccctgtctccggggtaaa (SEQ ID NO:223).

According to an embodiment of the present invention that uses a VK1 signal sequence, in a preferred embodiment of the present invention, the second polypeptide chain comprises the amino acid sequence (signal sequence is underlined):

MDMRVPAQLLGLLLLWLRGARCGPSVFLFP PKPKDTLMISRT PEVT CVW DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWL NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRKEMTKNQVS LTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV LKSDGSFFLYSKLTVDK SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO:257), which is encoded by the nucleic acid sequence (signal sequence underlined):

atggacatgaggtgcccgctcagctcctggggctcctgctgctgtggct gagaggtgcgcgctgtggcccgtcagtcttcctcttccccccaaaaccca aggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtg gacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacgg cg tggaggtgcataatgccaagacaaagccgcgggaggagcagtacaaca gcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctg aatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccc catcgagaaaaccatctccaaagccaaagggcagccccgagaaccacagg tgtacaccctgcccc catcccggaaggagatgaccaagaaccaggtcagc ctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtg ggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgc tgaagtccgacggctccttcttcctctatagcaagctcaccgtggacaag agcaggtggcagcaggggaac gtcttctcatgctccgtgatgcatgaggc tctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa (SEQ ID NO:258).

As discussed above, a tetramer is provided containing two polypeptide chains that contain the sequence SEQ ID NO: 222, and two polypeptide chains that contain the sequence SEQ ID NO: 219.

P.N.31 Dh3CpmFc(-)-GDF15(N3D):Dh3CpmFc(+).

The definition of Dh3CpmFc(-)-GDF15(N3D):Dh3CpmFc(+) in the present invention means a heterodimer that contains (i) a first polypeptide chain containing a GDF15(N3D) polypeptide, the N-terminus of which is connected directly to the C-terminus of the Dh3CpmFc(-) domain , and (ii) a second polypeptide chain containing the Dh3CpmFc(+) domain.

According to certain embodiments of the present invention, there is provided a tetramer that

- 126 046387 contains a dimer consisting of two heterodimers Dh3CpmFc(-)-GDF15(N3D):Dh3CpmFc(+), in which the first two polypeptide chains of each heterodimer are connected through an interchain disulfide bond between the corresponding GDF15 regions of these chains.

More specifically, according to a particular embodiment of the present invention, the tetramer comprises:

(a) two Dh3CpmFc(+) domains (in each heterodimer) containing the sequence SEQ ID NO: 301, (b) two Dh3CpmFc(-) domains (in each heterodimer) containing the sequence SEQ ID NO: 220, and (c) two GDF15(N3D) polypeptide (in each heterodimer) containing the sequence SEQ ID NO: 52.

According to a preferred embodiment of the present invention, the first polypeptide chain contains the amino acid sequence:

GPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHN AKTKPREEQYNS ТYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIECTI SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQ PENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNV FSCSVMHEALHNHY TQKSLSLSPGARDGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPREVQ VTMCIGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYNPMVLIQ KTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:225), which is encoded by the nucleic acid sequence: atggacatgagggtgcccgctcagctcctggggctcc tgctgctgtggct gagaggtgcgcgctgtggcccgtcagtcttcctcttccccccaaaaccca aggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtg gacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacgg cgtggaggtgcataatgccaagacaaagccgcgggaggagca gtacaaca gcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctg aatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccc catcgagaaaaccatctccaaagccaaagggcagccccgagaaccacagg tgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtcagc ctgacct gcctggtcaaaggcttctatcccagcgacatcgccgtggagtg ggagagcaatgggcagccggagaacaactacgacaccacgcctcccgtgc tggactccgacggctccttcttcctctatagcgacctcaccgtggacaag agcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggc tctgcacaacc actacacgcagaagagcctctccctgtctccgggtgcgc gcgacggagaccactgtccgctcgggcccgggcgttgctgccgtctgcac acggtccgcgcgtcgctggaagacctgggctgggccgattgggtgctgtc gccacgggaggtgcaagtgaccatgtgcatcggcgcgtgcccgagccagt tccgggcggcaaacatgcacgcgcagatcaagacgagcctgcaccgcctg aagcccgacacggtgccagcgccctgctgcgtgcccgccagctacaatcc catggtgctcattcaaaagaccgacaccggggtgtcgctccagacctatg atgacttgttagccaaagactgccactgcata (SEQ ID NO:224) .

According to an embodiment of the present invention that utilizes a VK1 signal sequence, in a preferred embodiment of the present invention, the first polypeptide chain comprises the amino acid sequence (signal sequence is underlined):

- 127 046387

MDMRVPAQLLGLLLLWLRGARCGPSVFLFPPKPKDTLMISRT PEVT CVW DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWL NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVS LTCLVKGFYPSDIAVEWESNGQPENNYDTTPPVLDSD GSFFLYSDLTVDK SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGARDGDHCPLGPGRCCRLH TVRAS LE DLGWADWVL S PREVQVTMCIGAG P S Q FRAANMHAQIKT S LHRL KPDTVPAPCCVPASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI(SEQ ID

NO:259), which is encoded by a nucleic acid sequence (signal sequence underlined): atggacatgaggtgcccgctcagctcctggggctcctgctgctgtggct gagaggtgcgcgctgtggcccgtcagtcttcctcttccccccaaaaccca aggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtg gacgt gagccacgaagaccctgaggtcaagttcaactggtacgtggacgg cgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaaca gcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctg aatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccc catcgagaaaaccat ctccaaagccaaagggcagccccgagaaccacagg tgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtcagc ctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtg ggagagcaatgggcagccggagaacaactacgacaccacgcctcccgtgc tggactccgacggctccttcttcctcta tagcgacctcaccgtggacaag agcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggc tctgcacaaccactacacgcagaagagcctctccctgtctccgggtgcgc gcgacggagaccactgtccgctcgggcccgggcgttgctgccgtctgcac acggtccgcgcgtcgctggaagacc tgggctgggccgattgggtgctgtc gccacgggaggtgcaagtgaccatgtgcatcggcgcgtgcccgagccagt tccgggcggcaaacatgcacgcgcagatcaagacgagcctgcaccgcctg aagcccgacacggtgccagcgccctgctgcgtgcccgccagctacaatcc catggtgctcattcaa aagaccgacaccggggtgtcgctccagacctatg atgacttgttagccaaagactgccactgcata (SEQ ID NO:260).

In a preferred embodiment of the present invention, the second polypeptide chain comprises the amino acid sequence SEQ ID NO: 219, which is encoded by the nucleic acid sequence SEQ ID NO: 223.

According to an embodiment of the present invention that utilizes a VK1 signal sequence, in a preferred embodiment of the present invention, the second polypeptide chain comprises the amino acid sequence SEQ ID NO: 257, which is encoded by the nucleic acid sequence SEQ ID NO: 258.

As discussed above, a tetramer is provided containing two polypeptide chains that contain the sequence SEQ ID NO: 225, and two polypeptide chains that contain the sequence SEQ ID NO: 219.

II.H.32 Dh3CpmFc(-)(Y349C)-GDF15(Ndel3):Dh3CpmFc(+)(S354C).

The definition of Dh3CpmFc(-)(Y349C)-GDF15(Ndel3):Dh3CpmFc(+)(S354C) in the present invention means a heterodimer that contains (i) a first polypeptide chain containing a GDF15(Ndel3) polypeptide, the N-terminus of which is connected directly to The C-terminus of the Dh3CpmFc(-)(Y349C) domain, and (ii) a second polypeptide chain containing the Dh3CpmFc(+)(S345C) domain. Cysteine clamp mutations allow the first and second polypeptide chains to be joined via an interchain disulfide bond between C349 of the first polypeptide and C354 of the second polypeptide.

According to certain embodiments of the present invention, there is provided a tetramer that contains a dimer consisting of two heterodimers Dh3CpmFc(-)(Y349C)GDF15(Ndel3):Dh3CpmFc(+)(S354C), in which the first two polypeptide chains of each heterodimer are connected through an interchain disulfide bond between respective areas

- 128 046387

GDF15 data circuits.

More specifically, according to a particular embodiment of the present invention, the tetramer comprises:

(a) two Dh3CpmFc(+)(S354C) domains (in each heterodimer) containing the sequence: GPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHN

IAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI SKAKGQPREPQVYTLPPCRKEMTKNQVSLTCLVKGFYPSDIAVEWESNGQ PENNYKTTPPVLKSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHY TQKSLSLSPG (SEQ ID NO:302), (b) two domains Dh3CpmFc(-)(Y349C) (in each heterodimer), containing the sequence:

GPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHN

AKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI

SKAKGQPREPQVCTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQ

PENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHEALHNHY

TQKSLSLSPG (SEQ ID NO:227), and (c) two GDF15(Ndel3) polypeptides (in each heterodimer) containing the sequence SEQ ID NO: 55.

According to a preferred embodiment of the present invention, the first polypeptide chain contains the amino acid sequence:

GPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHN

AKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI SKAKGQPREPQVCTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQ PENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHEALHNHY TQKSLSLSPGGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPREVQ VTM CIGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYNPMVLIQKTD TGVSLQTYDDLLAKDCHCI (SEQ ID NO:229), which is encoded by the nucleic acid sequence:

atggacatgaggtgcccgctcagctcctggggctcctgctgctgtggct gagaggtgcgcgctgtggcccgtcagtcttcctcttccccccaaaaccca aggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtg gacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacgg cg tggaggtgcataatgccaagacaaagccgcgggaggagcagtacaaca gcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctg aatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccc catcgagaaaaccatctccaaagccaaagggcagccccgagaaccacagg tgtgcaccctgcc cccatcccgggaggagatgaccaagaaccaggtcagc ctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtg ggagagcaatgggcagccggagaacaactacgacaccacgcctcccgtgc tggactccgacggctccttcttoctetatagcgacctcaccgtggacaag agcaggtggcagcaggggaacg tcttctcatgctccgtgatgcatgaggc tctgcacaaccactacacgcagaagagcctctccctgtctccgggtggag

- 129 046387 accactgtccgctcgggcccggggcgttgctgccgtctgcacacggtccgc gcgtcgctggaagacctgggctgggccgattgggtgctgtcgccacggga ggtgcaagtgaccatgtgcatcggcgcgtgcccgagccagttccgggcgg caaacatgcacgc gcagatcaagacgagcctgcaccgcctgaagcccgac acggtgccagcgccctgctgcgtgcccgccagctacaatcccatggtgct cattcaaaagaccgacaccggggtgtcgctccagacctatgatgacttgt tagccaaagactgccactgcata (SEQ ID NO:228).

According to an embodiment of the present invention that utilizes a VK1 signal sequence, in a preferred embodiment of the present invention, the first polypeptide chain comprises the amino acid sequence (signal sequence is underlined):

MDMRVPAQLLGLLLLWLRGARCGP SVFL FP PKPKD T LMIS RT REVT СWV DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWL NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVCTLPPSREEMTKNQVS LTCLVKGFYPSDIAVEWESNGQPENNYDT TPPVLDSDGSFFLYSDLTVDK SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGDHCPLGPGRCCRLHTVR ASLEDLGWADWVLSPREVQVTMCIGACPSQFRAANMHAQIKTSLHRLKPD TVPAPCCVPASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ IDNO:261), which is encoded by a nucleic acid sequence (signal sequence underlined):

atggacatgaggtgcccgctcagctcctggggctcctgctgctgtggct gagaggtgcgcgctgtggcccgtcagtcttcctcttccccccaaaaccca aggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtg gacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacgg cg tggaggtgcataatgccaagacaaagccgcgggaggagcagtacaaca gcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctg aatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccc catcgagaaaaccatctccaaagccaaagggcagccccgagaaccacagg tgtgcaccctgcc cccatcccgggaggagatgaccaagaaccaggtcagc ctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtg ggagagcaatgggcagccggagaacaactacgacaccacgcctcccgtgc tggactccgacggctccttcttcctctatagcgacctcaccgtggacaag agcaggtggcagcaggggaac gtcttctcatgctccgtgatgcatgaggc tctgcacaaccactacacgcagaagagcctctccctgtctccgggtggag accactgtccgctcgggcccgggcgttgctgccgtctgcacacggtccgc gcgtcgctggaagacctgggctgggccgattgggtgctgtcgccacggga ggtgcaagtgaccatg tgcatcggcgcgtgcccgagccagttccggggcgg caaacatgcacgcgcagatcaagacgagcctgcaccgcctgaagcccgac acggtgccagcgccctgctgcgtgcccgccagctacaatcccatggtgct cattcaaaagaccgacaccggggtgtcgctccagacctatgatgacttgt tagaagactgcc actngcata (SEQ ID NO:262).

According to a preferred embodiment of the present invention, the second polypeptide chain contains the amino acid sequence:

- 130 046387

GPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHN AKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI SKAKGQPREPQVYTLPPCRKEMTKNQVSLTCLVKGFYPSDIAVEWESNGQ PENNYKTTPPVLKSDGSFFLYSKLTVDKSRWQQG NVFSCSVMHEALHNHY TQKSLSLSPGK (SEQ ID NO:226), which is encoded by the nucleic acid sequence: ggcccgtcagtcttcctcttccccccaaaaccca aggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtg gacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacgg cgtggaggt gcataatgccaagacaaagccgcgggaggagcagtacaaca gcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctg aatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccc catcgagaaaaccatctccaaagccaaagggcagccccgagaaccacagg tgtacaccctgcccccatgccgga aggagatgaccaagaaccaggtcagc ctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtg ggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgc tgaagtccgacggctccttcttcctctatagcaagctcaccgtggacaag agcaggtggcagcaggggaacgtcttct catgctccgtgatgcatgaggc tctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa (SEQ ID NO: 230).

According to an embodiment of the present invention that uses a VK1 signal sequence, in a preferred embodiment of the present invention, the second polypeptide chain comprises the amino acid sequence (signal sequence is underlined):

MpMRVPAQLLGLLLLWLRGARCGP SVFL FPPKPKDTLMISRT REVT CVW DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWL NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPCRKEMTKNQVS LTCLVKGFYPSDIAVEWESNGQPENNYKTT PPVLKSDGSFFLYSKLTVDK SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO:263), which is encoded by the nucleic acid sequence (signal sequence underlined):

atggacatgaggtgcccgctcagctcctggggctcctgctgctgtggct gagaggtgcgcgctgtggcccgtcagtcttcctcttccccccaaaaccca aggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtg gacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacgg cg tggaggtgcataatgccaagacaaagccgcgggaggagcagtacaaca gcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctg aatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccc catcgagaaaaccatctccaaagccaaagggcagccccgagaaccacagg tgtacaccctgcccc catgccggaaggagatgaccaagaaccaggtcagc ctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtg

- 131 046387 ggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgc tgaagtccgacggctccttcttoctetatagcaagctcaccgtggacaag agcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggc tctgcacaaccactacacgcagaagagcctctccctgtct ccgggtaaa (SEQ ID NO:264) .

As discussed above, a tetramer is provided containing two polypeptide chains that contain the sequence SEQ ID NO: 229, and two polypeptide chains that contain the sequence SEQ ID NO: 226.

II.H.33 Dh3 CpmFc(-)(Y3 49C)-GDF 15(N3D):Dh3 CpmFc(+)(S354C).

The definition of Dh3CpmFc(-)(Y349C)-GDF15(N3D):Dh3CpmFc(+)(S354C) in the present invention means a heterodimer that contains (i) a first polypeptide chain containing a GDF15(N3D) polypeptide, the N-terminus of which is connected directly to The C-terminus of the Dh3CpmFc(-)(Y349C) domain, and (ii) a second polypeptide chain containing the Dh3CpmFc(+)(S345C) domain. Cysteine clamp mutations allow the first and second polypeptide chains to be joined via an interchain disulfide bond between C349 of the first polypeptide chain and C354 of the second polypeptide chain.

According to certain embodiments of the present invention, there is provided a tetramer that contains a dimer consisting of two heterodimers Dh3CpmFc(-)(Y349C)GDF15(N3D):Dh3CpmFc(+)(S354C), in which the first two polypeptide chains of each heterodimer are connected through an interchain disulfide bond between the corresponding GDF15 regions of these circuits.

More specifically, according to a particular embodiment of the present invention, the tetramer comprises:

(a) two Dh3CpmFc(+)(S354C) domains (in each heterodimer) containing the sequence SEQ ID NO: 302, (b) two Dh3CpmFc(-)(Y349C) domains (in each heterodimer) containing the sequence SEQ ID NO: 227, and (c) two GDF15(N3D) polypeptides (in each heterodimer) containing the sequence SEQ ID NO: 52.

According to a preferred embodiment of the present invention, the first polypeptide chain contains the amino acid sequence:

GPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHN

AKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI

SKAKGQPREPQVCTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQ

PENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHEALHNHY

TQKSLSLSPGARDGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPREVQ

VTMCIGACPS QFRAANMHAQIKT S LHRLKPDTVPAPCCVPASYNPMVLIQ

KTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO: 232), which is encoded by the nucleic acid sequence:

- 132 046387 ggcccgtcagtcttcctcttccccccaaaaccca aggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtg gacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacgg cgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaaca gca cgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctg aatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccc catcgagaaaaccatctccaaagccaaagggcagccccgagaaccacagg tgtgcaccctgcccccatcccgggaggagatgaccaagaaccaggtcagc ctgacctgcctggtca aaggcttctatcccagcgacatcgccgtggagtg ggagagcaatgggcagccggagaacaactacgacaccacgcctcccgtgc tggactccgacggctccttcttoctetatagcgacctcaccgtggacaag agcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggc tctgcacaaccactacacgcagaaga gcctctccctgtctccgggtgcgc gcgacggagaccactgtccgctcgggcccgggcgttgctgccgtctgcac acggtccgcgcgtcgctggaagacctgggctgggccgattgggtgctgtc gccacgggaggtgcaagtgaccatgtgcatcggcgcgtgcccgagccagt tccgggcggca aacatgcacgcgcagatcaagacgagcctgcaccgcctg aagcccgacacggtgccagcgccctgctgcgtgcccgccagctacaatcc catggtgctcattcaaaagaccgacaccggggtgtcgctccagacctatg atgacttgttagccaaagactgccactgcata (SEQ ID NO:231).

According to an embodiment of the present invention that utilizes a VK1 signal sequence, in a preferred embodiment of the present invention, the first polypeptide chain comprises the amino acid sequence (signal sequence is underlined):

MDMRVPAQLLGLLLLWLRGARCGPSVFL FPPKPKDTLMISRT PE VT CVW DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWL NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVCTLPPSREEMTKNQVS LTCLVKGFYPSDIAVEWESNGQPENNYDTTPPVLDSD GSFFLYSDLTVDK SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGARDGDHCPLGPGRCCRLH ТVRAS LE DLGWADWVL S PREVQVTMCIGAG R S Q FRAANMHAQIKT S LHRL KPDTVPAPCCVPASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:265) which is encoded by a nucleic acid sequence (signal sequence is underlined):

- 133 046387 atggacatgagggtgcccgctcagctcctggggctcctgctgctgtggct gagaggtgcgcgctgtggcccgtcagtcttcctcttccccccaaaaccca aggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtg gacgtgagccacgaagaccctgaggtcaagtt caactggtacgtggacgg cgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaaca gcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctg aatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccc catcgagaaaaccatctccaaagccaaagggcagccccgagaacc acagg tgtgcaccctgcccccatcccgggaggagatgaccaagaaccaggtcagc ctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtg ggagagcaatgggcagccggagaacaactacgacaccacgcctcccgtgc tggactccgacggctccttcttcctctatagcgacctcaccgtggacaag a gcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggc tctgcacaaccactacacgcagaagagcctctccctgtctccgggtgcgc gcgacggagaccactgtccgctcgggcccgggcgttgctgccgtctgcac acggtccgcgcgtcgctggaagacctgggctgggccgattggggtgct gtc gccacgggaggtgcaagtgaccatgtgcatcggcgcgtgcccgagccagt tccgggcggcaaacatgcacgcgcagatcaagacgagcctgcaccgcctg aagcccgacacggtgccagcgccctgctgcgtgcccgccagctacaatcc catggtgctcattcaaaagaccgacaccggggtgtcgct ccagacctatg atgacttgttagccaaagactgccactgcata (SEQ ID NO:266).

In a preferred embodiment of the present invention, the second polypeptide chain comprises the amino acid sequence SEQ ID NO: 226, which is encoded by the nucleic acid sequence SEQ ID NO: 230.

According to an embodiment of the present invention that utilizes a VK1 signal sequence, in a preferred embodiment of the present invention, the second polypeptide chain comprises the amino acid sequence SEQ ID NO: 263, which is encoded by the nucleic acid sequence SEQ ID NO: 264.

As discussed above, a tetramer is provided containing two polypeptide chains that contain the sequence SEQ ID NO: 232, and two polypeptide chains that contain the sequence SEQ ID NO: 226.

II.H.34 DhMonoFc(N297G)-GDF15.

The definition of DhMonoFc(N297G)-GDF15 in the present invention means a fusion protein containing a GDF15 polypeptide, the N-terminus of which is connected directly to the C-terminus of the DhMonoFc(N297G) domain via a peptide bond.

Certain embodiments of the present invention provide a homodimer comprising two such fusion proteins linked through an interchain disulfide bond between the corresponding GDF15 polypeptides of the proteins.

More specifically, according to a particular embodiment of the present invention, the homodimer comprises:

(a) two DhMonoFc(N297G) domains (in each monomer) containing the sequence: APELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVD

GVEVHNAKTKPREEQYGSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVTTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPG (SEQ ID NO:233); and (b) two GDF15 polypeptides (in each heterodimer) containing the sequence SEQ ID NO: 12.

According to a preferred embodiment of the present invention, a fusion protein with

- 134 046387 contains the amino acid sequence:

APELLGGPSVFLFPPKPKDTLMI SRTPEVTCVWDVSHEDPEVKFNWYVD GVEVHNAKTKPREEQYGSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVTTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNV FSCSVMHE ALHNHYTQKSLSLSPGARNGDHCPLGPGRCCRLHTVRASLEDLGWADWVL S PREVQVTMCIGAC P S Q FRAANMHAQIKT S LHRLKPDTVPAPC CVPAS YN PMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:235), which is encoded by the nucleic acid sequence: gcacctgaactcctggggaccgtcagt cttcctcttccccc caaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgc gtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggta cgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagc agtacggcagcacgtaccgtgtggtcagcgtcctcaccgt cctgcaccag gactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccct cccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgag aaccacaggtgaccaccctgcccccatcccgggaggagatgaccaagaac caggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgc cgtggagtg ggagagcaatgggcagccggagaacaactacgacaccacgc ctcccgtgctggactccgacggctccttcttcctctatagcgacctcacc gtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgat gcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctc cggggtgcgcgcaacggagacc actgtccgctcgggcccggggcgttgctgc cgtctgcacacggtccgcgcgtcgctggaagacctgggctgggccgattg ggtgctgtcgccacgggaggtgcaagtgaccatgtgcatcggcgcgtgcc cgagccagttccgggcggcaaacatgcacgcgcagatcaagacgagcctg cacc gcctgaagcccgacacggtgccagcgccctgctgcgtgcccgccag ctacaatcccatggtgctcattcaaaagaccgacaccggggtgtcgctcc agacctatgatgacttgttagccaaagactgccactgcata ( SEQ ID NO:234).

As discussed above, according to a specific embodiment of the present invention there is provided a homodimer that contains two monomers containing the sequence SEQ ID NO: 235.

P.N.35 DhMonoFc(N297G)-(G ₄ S) ₄ -GDF 15.

The definition of DhMonoFc(N297G)-(G ₄ S) ₄ -GDF15 in the present invention means a fusion protein comprising a GDF15 polypeptide connected to a DhMonoFc(N297G) domain by a linker that contains the sequence SEQ ID NO: 18 and that connects the N-terminus of the polypeptide GDF15 with the C-terminal DhMonoFc(N297G) domain via a peptide bond.

Certain embodiments of the present invention provide a homodimer comprising two such fusion proteins linked through an interchain disulfide bond between the corresponding GDF15 polypeptides of the proteins.

More specifically, according to a particular embodiment of the present invention, the homodimer comprises:

(a) two DhMonoFc(N297G) domains (in each monomer) containing the sequence: APELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVD GVEVHNAKTKPREEQYGSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVTTLPPSREEMTKNQVSLTCLVKGFY PSDIAVE WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPG (SEQ ID NO:236);

(b) two GDF15 polypeptides (in each monomer) containing the sequence SEQ ID NO: 12;

- 135 046387 and

(c) two polypeptide linkers (in each monomer) containing the sequence SEQ ID NO: 18, each of which connects the N-terminus of the GDF15 polypeptide to the C-terminus of the DhMonoFc(N297G) domain via peptide bonds.

According to a preferred embodiment of the present invention, the fusion protein contains the amino acid sequence (the linker is underlined by a double line):

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVD GVEVHNAKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVTTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNV FSCSVMHE AL HNHY T QKSLSLSP GGGGGSGGGGSGGGGSGGGGSARNGDHCPLGРGRC CRLHTVRASLEDLGWADWVLSPREVQVTMCIGACPSQFRAANMHAQIKTS LHRLKPDTVPAPCCVPASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:238), which is encoded by the nucleic acid sequence: gcacctgaactcctgggg ggaccgtcagtcttcctcttccccc caaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgc gtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggta cgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagc agtacggcagcacgtaccgtgtggtcagcg tcctcaccgtcctgcaccag gactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccct cccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgag aaccacaggtgaccaccctgcccccatcccgggaggagatgaccaagaac caggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgc cgtggagtggggagagcaatgggcagccggagaacaactacgacaccacgc ctcccgtgctggactccgacggctccttcttcctctatagcgacctcacc gtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgat gcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctc cgggtggagg tggtggatccggaggcggtggaagcggaggtggtggatct ggaggcggtggaagcgcgcgcaacggagaccactgtccgctcgggcccgg gcgttgctgccgtctgcacacggtccgcgcgtcgctggaagacctgggct gggccgattgggtgctgtcgccacgggaggtgcaagtgaccatgtgcatc ggcgcgtgcccgagccagttccgggcggcaaacatgcacgcgcagatcaa gacgagcctgcaccgcctgaagcccgacacggtgccagcgccctgctgcg tgcccgccagctacaatcccatggtgctcattcaaaagaccgacaccggg gtgtcgctccagacctatgatgacttgttagccaaagactgccact gcata (SEQ ID NO :237).

As discussed above, according to a specific embodiment of the present invention there is provided a homodimer that contains two monomers containing the sequence SEQ ID NO: 238.

II.H.36 DhMonoFc(N297G)-G ₄ -GDF15.

The definition of DhMonoFc(N297G)-G ₄ -GDF15 in the present invention means a fusion protein comprising a GDF15 polypeptide connected to a DhMonoFc(N297G) domain by a linker which contains the sequence SEQ ID NO: 58 and which connects the N-terminus of the GDF15 polypeptide to the C- end of the DhMonoFc(N297G) domain via a peptide bond.

Certain embodiments of the present invention provide a homodimer comprising two such fusion proteins linked through an interchain disulfide bond between the corresponding GDF15 polypeptides of the proteins.

More specifically, according to a particular embodiment of the present invention, the homodimer comprises:

(a) two DhMonoFc(N297G) domains (in each monomer) containing the sequence SEQ ID

- 136 046387

NO: 236;

(b) two GDF15 polypeptides (in each monomer) containing the sequence SEQ ID NO: 12; and (c) two polypeptide linkers (in each monomer) containing the sequence SEQ ID NO: 58, each of which connects the N-terminus of the GDF15 polypeptide to the C-terminus of the DhMonoFc(N297G) domain via peptide bonds.

According to a preferred embodiment of the present invention, the fusion protein contains the amino acid sequence (the linker is underlined by a double line):

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVD GVEVHNAKTKPREEQYGSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVTTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFS CSVMHE ALHNHYTQKSLSLSPGgGQGARNGDHCPLGPGRCCRLHTVRASLEDLGWA DWVLSPREVQVTMCIGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVP ASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:240), which is encoded by the nucleic acid sequence: gcacctgaactcctggggggaccgtcagtctt cctcttccccc caaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgc gtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggta cgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagc agtacggcagcacgtaccgtgtggtcagcgtcctcaccgtcct gcaccag gactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccct cccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgag aaccacaggtgaccaccctgcccccatcccgggaggagatgaccaagaac caggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgc cgtggagtgggaga gcaatgggcagccggagaacaactacgacaccacgc ctcccgtgetggactccgacggctccttcttoctetatagcgacctcacc gtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgat gcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctc cgggtggaggtggtggagcgcgcaac ggagaccactgtccgctcgggccc gggcgttgctgccgtctgcacacggtccgcgcgtcgctggaagacctggg ctgggccgattgggtgctgtcgccacgggaggtgcaagtgaccatgtgca tcggcgcgtgcccgagccagttccgggcggcaaacatgcacgcgcagatc aagacgacc tgcaccgcctgaagcccgacacggtgccagcgccctgctg cgtgcccgccagctacaatcccatggtgctcattcaaaagaccgacaccg gggtgtcgctccagacctatgatgacttgttagccaaagactgccactgc ata (SEQ ID NO:239).

As discussed above, according to a specific embodiment of the present invention there is provided a homodimer that contains two monomers containing the sequence SEQ ID NO: 240.

III. GDF15 polypeptides and constructs containing GDF15, including mutant forms of GDF15.

As disclosed herein, GDF15 polypeptides (including full-length and mature forms of human GDF15) and constructs containing GDF15 described in the present invention can be designed and/or produced using standard molecular biology techniques for generating mutant forms of GDF15 polypeptides and constructs , proposed in the present invention. In various examples, a nucleic acid sequence encoding a mutant form of the GDF15 polypeptides and constructs provided herein, which may contain all or a portion of SEQ ID NOs: 4, 8, or 12, can be isolated and/or amplified from genomic DNA or cDNA with using appropriate oligonucleotide primers. Primers can be designed based on the nucleic acid sequence and amino acid sequence proposed in the present invention according to standard real-time polymerase chain reaction amplification techniques. The amplified GDF15 mutant polypeptide nucleic acid can then be cloned into a suitable vector and characterized by DNA sequence analysis.

Oligonucleotides for use as probes in the isolation or amplification of all or part of the mutant forms of GDF15 polypeptides and constructs proposed in the present invention,

- 137 046387 can be designed and obtained using standard synthesis techniques, for example, automatic DNA synthesis devices, or can be isolated from a longer DNA sequence.

III.A. Polypeptide and polynucleotide sequences of GDF15.

GDF15 is expressed in vivo as a contiguous amino acid sequence containing a signal sequence, a prodomain, and an active domain.

The amino acid sequence of full-length human GDF15, 308 amino acids long, is:

MPGQELRTVNGSQMLLVLLVLSWLPHGGALLSLAEASRASFPGPSELHSED SRFRELRKRYEDLLTRLRANQSWEDSNTDLVPAPAVRILTPEVRLGSGGH LHLRISRAALPEGLPEASRLHRALFRLSPTASRSWDVTRPLRRQLSLARP QAPALHLRLSPPPSQSDQLLAESSSARPQLELHLHLRPQAARGRRRARARNG DHCPLGPGRCCRLHTVRASLEDL GWADWVLSPREVQVTMCIGACPSQFRA ANMHAQIKTSLHRLKPDTVPAPCCVPASYNPMVLIQKTDTGVSLQTYDDL LAKDCHCI (SEQ ID NO:4) and is encoded by the DNA sequence: atgcccgggcaagaactcaggacggtgaatggctctcagatgctcctggt gttgctggtgctctcgtggctgccgcatggggcgccctgtct ctggccg aggcgagccgcgcaagtttcccggggaccctcagagttgcactccgaagac tccagattccgagagttgcggaaacgctacgaggacctgctaaccaggct gcgggccaaccagagctgggaagattcgaacaccgacctcgtcccggccc ctgcagtccggatactcacgccagaagtgcggctgggatccggcggccac ctgcacctgcgtatctctcgggccgcccttcccgaggggctccccgaggc ctcccgccttcaccgggctctgttccggctgtccccgacggcgtcaaggt cgtgggacgtgacacgaccgctgcggcgtcagctcagccttgcaagaccc caggcgcccgcgctgcacctgcgactgtcgccgccg ccgtcgcagtcgga ccaactgctggcagaatcttcgtccgcacggccccagctggagttgcact tgcggccgcaagccgccaggggcgccgcagagcgcgtgcgcgcaacggg gaccactgtccgctcgggcccgggcgttgctgccgtctgcacacggtccg cgcgtcgctggaagacctggg ctgggccgattgggtgctgtcgccacggg aggtgcaagtgaccatgtgcatcggcgcgtgcccgagccagttccgggcg gcaaacatgcacgcgcagatcaagacgagcctgcaccgcctgaagcccga cacggtgccagcgccctgctgcgtgcccgccagctacaatcccatggtgc tcattcaaa agaccgacaccggggtgtcgctccagacctatgatgacttg ttagccaaagactgccactgcatatga (SEQ ID NO:3).

The amino acid sequence of full-length mouse GDF15, 303 amino acids long, is:

MAPPALQAQPPGGSQLRFLLFLLLLLLLLSWPSQGDALAMPEQRPSGPES QLNADELRGRFQDLLSRLHANQSREDSNSEPSPDPAVRILSPEVRLGSHG QLLLRVNRASLSQGLPEAYRVHRALLLLTPTARPWDITRPLKRALSLRGP RAPALRLRLTPPPDLAMLPSGGTQLELRLRVAAGRGRRSAHAHPRDSCPL GPGRCCHLETVQATLEDLGW SDWVLSPRQLQLSMCVGECPHLYRSANTHA QIKARLHGLQPDKVPAPCCVPSSYTPWLMHRTDSGVSLQTYDDLVARGC HCA (SEQ ID NO:6) and is encoded by the DNA sequence:

- 138 046387 atggccccgcccgcgctccaggcccagcctccaggcggctctcaactgag gttcctgctgttcctgctgctgttgctgctgctgctgtcatggccatcgc agggggacgccctggcaatgcctgaacagcgaccctccggccctgagtcc caactcaacgccgacgagctacggggtcgctt ccaggacctgctgagccg gctgcatgccaaccagagccgagaggactcgaactcagaaccaagtcctg acccagctgtccggatactcagtccagaggtgagattggggtcccacggc cagctgctactccgcgtcaaccgggcgtcgctgagtcagggtctccccga agcctaccgcgtgcaccgagcgctgctcctgctgacgccgac ggcccgcc cctgggacatcactaggcccctgaagcgtgcgctcagcctccggggaccc cgtgctcccgcattacgcctgcgcctgacgccgcctccggacctggctat gctgccctctggcggcacgcagctggaactgcgcttacgggtagccgccg gcagggggcgccgaagcgcgcatgcgcacccaagagactcg tgcccactg ggtccggggcgctgctgtcacttggagactgtgcaggcaactcttgaaga cttgggctggagcgactgggtgctgtccccgcgccagctgcagctgagca tgtgcgtgggcgagtgtccccacctgtatcgctccgcgaacacgcatgcg cagatcaaagcacgcctgcatggcctgcagcc tgacaaggtgcctgcccc gtgctgtgtcccctccagctacaccccggtggttcttatgcacaggacag acagtggtgtgtcactgcagacttatgatgacctggtggcccggggctgc cactgcgcttga (SEQ ID NO:5).

The amino acid sequence of human GDF15 after cleavage of the 29-residue signal sequence is:

LSLAEASRASFPGPSELHSEDSRFRELRKRYEDLLTRLRANQSWEDSNTD LVPAPAVRILTPEVRLGSGGHLHLRISRAALPEGLPEASRLHRALFRLSP TASRSWDVTRPLRRQLSLARPQAPALHLRLLSPPPSQSDQLLAESSSARPQ LELHLRPQAARGRRRARARNGDHCPLGPGRCCRLHTVRASLEDLGWADWV LSPREVQVTMCIGACPSQFR AANMHAQIKTSLHRLKPDTVPAPCCVPASY NPMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO:8) and is encoded by the DNA sequence: ctgtctctggccgaggcgagccgcgcaagtttcccgggaccctcagagtt gcactccgaagactccagattccgagagttgcggaaacgctacgaggacc tgctaaccaggctgcggg ccaaccagagctgggaagattcgaacaccgac ctcgtcccggcccctgcagtccggatactcacgccagaagtgcggctggg atccggcggccacctgcacctgcgtatctctcgggccgcccttcccgagg ggctccccgaggcctcccgccttcaccgggctctgttccggctgtccccg acggcgtcaaggtcgtgggac gtgacacgaccgctgcggcgtcagctcag ccttgcaagaccccaggcgcccgcgctgcacctgcgactgtcgccgccgc cgtcgcagtcggaccaactgctggcagaatcttcgtccgcacggccccag ctggagttgcacttgcggccgcaagccgccaggggcgccgcagagcgcg tgcgc gcaacggggaccactgtccgctcgggcccggggcgttgctgccgtc tgcacacggtccgcgcgtcgctggaagacctgggctgggccgattgggtg ctgtcgccacgggaggtgcaagtgaccatgtgcatcggcgcgtgcccgag ccagttccgggcggcaaacatgcacgcgcagatcaagac gagcctgcacc gcctgaagcccgacacggtgccagcgccctgctgcgtgcccgccagctac aatcccatggtgctcattcaaaagaccgacaccggggtgtcgctccagac ctatgatgacttgttagccaaagactgccactgcatatga (SEQ ID NO:7) Amino acid sequence of mouse GDF15 after signal sequence cleavage 32 residues long is:

- 139 046387

SQGDALAMPEQRPSGPESQLNADELRGRFQDLLSRLHANQSREDSNSEPS PDPAVRILSPEVRLGSHGQLLLRVNRASLSQGLPEAYRVHRALLLLTPTA RPWDITRPLKRALSLRGPRAPALRLRLTPPPDLAMLPSGGTQLELRLRVA AGRGRRSAHAHPRDSCPLGPGRCCHLETVQATLEDLGWSDWVLSPRQLQL SMCVGECPHLYRS ANTHAQIKARLHGLQPDKVPAPCCVPSSYTPWLMHR TDSGVSLQTYDDLVARGCHCA (SEQ ID NO:10) and is encoded by the DNA sequence: tcgcagggggacgccctggcaatgcctgaacagcgaccctccggccctga gtcccaactcaacgccgacgagctacggggtcgcttccaggacctgctga gccggctgcatgccaaccagagccgagaggactc gaactcagaaccaagt cctgacccagctgtccggatactcagtccagaggtgagattggggtccca cggccagctgctactccgcgtcaaccgggcgtcgctgagtcagggtctcc ccgaagcctaccgcgtgcaccgagcgctgctcctgctgacgccgacggcc cgcccctgggacatcactaggcccctgaagcgtgcgct cagcctccgggg accccgtgctcccgcattacgcctgcgcctgacgccgcctccggacctgg ctatgctgccctctggcggcacgcagctggaactgcgcttacgggtagcc gccggcagggggcgccgaagcgcgcatgcgcacccaagagactcgtgccc actgggtccggggcgctgctgtcacttggagactgt gcaggcaactcttg aagacttgggctggagcgactgggtgctgtccccgcgccagctgcagctg agcatgtgcgtgggcgagtgtccccacctgtatcgctccgcgaacacgca tgcgcagatcaaagcacgcctgcatggcctgcagcctgacaaggtgcctg ccccgtgctgtgtcccctccag ctacaccccggtggttcttatgcacagg acagacagtggtgtgtcactgcagacttatgatgacctggtggcccgggg ctgccactgcgcttga (SEQ ID NO:9)

The biologically active form of GDF15 contains a homodimer containing two mature GDF15 monomers, each containing SEQ ID NO: 12. The monomer that undergoes homodimerization to form the native mature human GDF15 dimer is encoded by the nucleic acid sequence:

gcgcgcaacggggaccactgtccgctcgggcccggggcgttgctgccgtct gcacacggtccgcgcgtcgctggaagacctgggctgggccgattgggtgc tgtcgccacgggaggtgcaagtgaccatgtgcatcggcgcgtgcccgagc cagttccgggcggcaaacatgcacgcgcaga tcaagacgagcctgcaccg cctgaagcccgacacggtgccagcgccctgctgcgtgcccgccagctaca atcccatggtgctcattcaaaagaccgacaccggggtgtcgctccagacc tatgatgacttgttagccaaagactgccactgcatatga (SEQ ID NO:11) and contains the amino acid sequence:

ARNGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPREVQVTMCIGACPS QFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYNPMVLIQKTDTGVSLQT YDDLLAKDCHCI (SEQ ID NO:12).

Thus, the native mature human GDF15 dimer contains two covalently linked monomers containing SEQ ID NO: 12.

The amino acid sequence of the recombinant active form of human GDF15, which contains a homodimer containing nine cysteines in each monomer to form one interchain disulfide bond and four intrachain disulfide bonds, is (sequence shown with the optional N-terminal methionine residue in parentheses):

(M)ARNGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPREVQVTMCIGA CPSQERAANMHAQIKTSLHRLKPDTVPAPCCVPASYNPMVLIQKTDTGVS LQTYDDLLAKDCHCI (SEQ ID NO:189) and is encoded by the DNA sequence (shown with the optional N-terminal methionine codon in parentheses):

- 140 046387 (atg)gcgcgcaacggggaccactgtccgctcgggcccgggcgttgctgc cgtctgcacacggtccgcgcgtcgctggaagacctgggctgggccgattg ggtgctgtcgccacgggaggtgcaagtgaccatgtgcatcggcgcgtgcc cgagccagttcc gggcggcaaacatgcacgcgcagatcaagacgagcctg caccgcctgaagcccgacacggtgccagcgccctgctgcgtgcccgccag ctacaatcccatggtgctcattcaaaagaccgacaccggggtgtcgctcc agacctatgatgacttgttagccaaagactgccactgcatataa (SEQ ID NO:190).

The amino acid sequence of the recombinant active form of mouse GDF15, which contains a homodimer containing nine cysteines in each monomer to form one interchain disulfide bond and four intrachain disulfide bonds, is:

(M)SAHAHPRDSCPLGPGRCCHLETVQATLEDLGWSDWVLSPRQLQLSMC

VGECPHLYRSANTHAQIKARLHGLQPDKVPAPCCVPSSYTPWLMHRTDS

GVSLQTYDDLVARGCHCA (SEQ ID NO:14) and is encoded by the DNA sequence:

(atg)agcgcgcatgcgcacccaagagactcgtgcccactgggtccgggg cgctgctgtcacctggagactgtgcaggcaactcttgaagacttgggctg gagcgactgggtgttgtccccgcgccagctgcagctgagcatgtgcgtgg gcgagtgtccccacctgtatcgctccgcgaacacgcatgc gcagatcaaa gcacgcctgcatggcctgcagcctgacaaggtgcctgccccgtgctgtgt cccctccagctacaccccggtggttcttatgcacaggacagacagtggtg tgtcactgcagacttatgatgacctggtggcccggggctgccactgcgct tga (SEQ ID NO:13).

As defined herein, the term GDF15 polypeptide means a GDF polypeptide containing the human amino acid sequences SEQ ID NO: 4, 8 and 12. The term GDF15 mutant polypeptide, however, includes polypeptides containing an amino acid sequence that differs from the amino acid sequence of naturally occurring GDF polypeptide sequences, e.g., SEQ ID NOs: 4, 8 and 12, by one or more amino acids such that the sequence is at least 85% identical to SEQ ID NOs: 4, 8 and 12. GDF15 polypeptides can be prepared by introducing one or more amino acid substitutions, conservative or non-conservative, and by using natural or non-naturally occurring amino acids at specific positions of the GDF15 polypeptide, or by deleting specific residues or collections of residues.

A conservative amino acid substitution may involve replacing a native amino acid residue (i.e., a residue found at a given position in a wild-type GDF15 polypeptide sequence) with a non-native residue (i.e., a residue that is not found at a given position in a wild-type GDF15 polypeptide sequence), thereby there is little or no effect on the polarity or charge of the amino acid residue at a given position. Conservative amino acid substitutions also include non-naturally occurring amino acid residues (as defined herein) that are typically introduced through chemical peptide synthesis rather than synthesis in biological systems. These residues include peptidomimetics and other reversible or inverted forms of amino acid groups.

Naturally occurring residues can be divided into classes based on common side chain properties:

(1) hydrophobic: norleucine, Met, Ala, Val, Leu, Ile;

(2) neutral hydrophilic: Cys, Ser, Thr;

(3) acidic: Asp, Glu;

(4) basic: Asn, Gln, His, Lys, Arg;

(5) residues affecting chain orientation: Gly, Pro; and (6) aromatic: Trp, Tyr, Phe.

Additional amino acid groups can also be prepared using principles described, for example, in Creighton (1984) PROTEINS: STRUCTURE AND MOLECULAR PROPERTIES (2d Ed. 1993), W.H. Freeman and Company. In some cases, further characterization of substitutions based on two or more of these properties may be useful (eg, a substitution with a small polar residue, such as a Thr residue, may represent a highly conserved substitution in the appropriate context).

Conservative substitutions may involve replacing a member of one of these classes with another member of either

- 141 046387 of the same class. Non-conservative substitutions may involve replacing a member of one of these classes with a member of another class.

Synthetic, rare or modified amino acid residues known to have similar physiological properties to residues from the groups described above can be used as a conservative replacement for a particular amino acid residue in a sequence. For example, a D-Arg residue may act as a replacement for a typical L-Arg residue. It is also possible that a particular substitution can be described in the context of two or more of the classes described above (e.g., a substitution with a small and hydrophobic residue means the replacement of one amino acid with residue(s) that are found in both of the above classes or with other synthetic, rare or modified residues, which are known in the art to have similar physiological properties to such residues satisfying both definitions).

Nucleic acid sequences encoding the mutant GDF15 polypeptide of the present invention, including sequences that are degenerate of SEQ ID NOs: 3, 7, 11 and 15, and sequences that encode polypeptide variants of SEQ ID NOs: 4, 8 and 12 constitute other aspects of the present invention.

III.B. Vectors suitable for the expression of GDF15 polypeptides and constructs containing GDF15, including mutant forms of GDF15.

For the expression of nucleic acid sequences encoding a polypeptide containing the GDF15 region, the corresponding coding sequences, for example, SEQ ID NO: 3, 7 and 11, can be cloned into a suitable vector, and after introduction into a suitable host, the sequence can be expressed to produce the encoded polypeptide according to standard cloning and expression techniques known in the art (for example, as described in Sambrook, J., Fritsh, E. F., and Maniatis, T. Molecular Cloning: A Laboratory Manual 2nd, ed., Cold Spring Harbor Laboratory, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1989). The present invention also relates to such vectors containing the nucleic acid sequence according to the present invention.

Vector means a delivery vehicle that (a) promotes the expression of a nucleic acid sequence encoding a polypeptide; (b) facilitates the production of a polypeptide from a nucleic acid; (c) promotes transfection/transformation of target cells with nucleic acid; (d) promotes replication of the nucleic acid sequence; (e) promotes nucleic acid stability; (f) facilitates the detection of nucleic acid and/or transformed/transfected cells; and/or (g) otherwise endows the nucleic acid encoding the polypeptide with a preferred biological and/or physicochemical function. The vector can be any suitable vector, including chromosomal, non-chromosomal vectors and synthetic nucleic acid vectors (a nucleic acid sequence containing a suitable set of expression control elements). Examples of such vectors include SV40 derivatives, bacterial plasmids, phage DNA, baculovirus, yeast plasmids, vectors derived from combinations of plasmids and phage DNA, and viral nucleic acid (RNA or DNA) vectors.

A recombinant expression vector can be prepared to express a polypeptide containing the GDF15 region in prokaryotic (eg, E. coli) or eukaryotic cells (eg, insect cells, use of baculovirus expression vectors, yeast cells, or mammalian cells). Typical host cells include hosts commonly used for cloning and expression, including Escherichia coli strains TOP10F', TOP10, DH10B, DH5a, HB101, W3110, BL21(DE3) and BL21(DE3)pLysS, BLUESCRIPT ( Stratagene), mammalian cell line vectors CHO, CHO-K1, HEK293, 293-EBNA pIN (Van Heeke & Schuster, J. Biol. Chem. 264: 5503-5509 (1989); pET vectors (Novagen, Madison Wis.). Alternatively, the recombinant expression vector can be transcribed and translated in vitro, for example, using a T7 promoter regulatory sequence and T7 polymerase, as well as an in vitro translation system.The vector preferably contains a promoter located upstream of a cloning site containing a nucleic acid sequence encoding the polypeptide Examples of promoters that can be turned on and off include the lac promoter, T7 promoter, trc promoter, tac promoter and trp promoter.

Thus, the present invention provides vectors containing a nucleic acid sequence encoding a polypeptide containing the GDF15 region that facilitate the expression of a polypeptide or construct of interest. According to various embodiments of the present invention, the vectors contain an operably linked nucleotide sequence that regulates the expression of a polypeptide containing the GDF15 region. The vector may contain or be associated with any suitable promoter, enhancer and other elements facilitating expression. Examples of such elements include strong expression promoters (eg, human CMV IE promoter/enhancer, RSV promoter, SV40 promoter, SL3-3 promoter, MMTV promoter or HIV LTR promoter, EF1alpha promoter, CAG promoter), efficient poly(A) terms

- 142 046387 routing sequences, the origin of replication of the plasmid product in E. coli, the antibiotic resistance gene as a selectable marker and/or the corresponding cloning site (for example, a polylinker). Vectors may also contain an inducible promoter rather than a constitutive promoter such as CMV IE. In one aspect of the present invention, a nucleic acid comprising a sequence encoding a polypeptide comprising a GDF15 region is operably linked to a tissue-specific promoter that drives expression of the sequence in a metabolically appropriate tissue, such as liver or pancreatic tissue.

III. C. Host cells.

According to another aspect of the present invention, host cells are provided containing the nucleic acids and vectors disclosed in the present invention. In various embodiments of the present invention, the vector or nucleic acid is inserted into the genome of the host cell, whereas in other embodiments, the vector or nucleic acid is extrachromosomal.

Proposed are recombinant cells, such as yeast, bacteria (eg, E. coli), and mammalian cells (eg, immortalized mammalian cells), containing such a nucleic acid, vector, or combinations of any one or all of these components. In various embodiments of the present invention, the cells contain a non-integrated nucleic acid, such as a plasmid, cosmid, phagemid, or linear expression element, that contains a coding sequence for expression of a polypeptide containing the GDF15 region.

A vector containing a nucleic acid sequence that encodes a polypeptide containing the GDF15 region can be introduced into a host cell by transformation or transfection. Methods for transforming a cell with an expression vector are well known.

The nucleic acid that encodes a polypeptide containing the GDF15 region can be located in a host cell or animal host and/or delivered to the host cell or animal host via a viral vector. Any suitable viral vector can be used as the vector. The viral vector may contain any number of viral polynucleotides, alone or in combination with one or more viral proteins, that facilitate delivery, replication and/or expression of the nucleic acid of the present invention in the desired host cell. The viral vector may be a polynucleotide containing all or part of the viral genome, a viral protein/nucleic acid conjugate, a virus-like particle (VLP), or an intact viral particle containing viral nucleic acids and a nucleic acid that encodes a polypeptide containing the GDF15 region. The viral particle-based viral vector may comprise a wild-type viral particle or a modified viral particle. The viral vector may be a vector that requires the presence of another vector or a wild-type virus for replication and/or expression (eg, the viral vector may be a helper-dependent virus), such as an amplicon of an adenoviral vector. Typically, such viral vectors consist of a wild-type viral particle or a viral particle modified in its protein and/or nucleic acid content to increase transgenic potency or promote transfection and/or nucleic acid expression (examples of such vectors include herpesvirus amplicons/AAB amplicons, adeno-associated virus). Typically, the viral vector is similar to and/or derived from a virus that normally infects humans. Suitable viral vector particles in this regard include, for example, adenoviral vector particles (including any virus of the Adenoviridae family or a virus derived from a virus of the Adenoviridae family), adeno-associated virus vector particles (AAB vector) or other parvoviruses and parvoviral vector particles, papillomavirus vector particles, flavivirus vectors, alphavirus vectors, herpesvirus vectors, poxvirus vectors, retroviral vectors, including lentiviral vectors.

III.D. Isolation of a GDF15 polypeptide, a construct containing a GDF15 polypeptide or a mutant form of a GDF15 polypeptide.

A polypeptide containing the GDF15 region can be isolated using standard protein purification techniques. A polypeptide containing the GDF15 region can be isolated from a cell that has been engineered to express a polypeptide containing the GDF15 region, for example, from a cell that does not naturally express native GDF15.

Protein purification methods that can be used to isolate a polypeptide containing the GDF15 region, as well as the necessary substances and reagents, are known in the art. Examples of methods for purifying a polypeptide containing the GDF15 region are provided in the present invention in the examples below. Additional purification methods that can be used to isolate a polypeptide containing the GDF15 region can be found in publications such as Bootcov MR, 1997, Proc. Natl. Acad. Sci. USA 94:11514-9, Fairlie WD, 2000, Gene 254: 67-76.

IV. Pharmaceutical compositions containing a GDF15 polypeptide, a construct containing a GDF15 polypeptide or a mutant form of a GDF15 polypeptide.

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Pharmaceutical compositions are provided containing a monomer or multimer containing a polypeptide that contains the GDF15 region. Such polypeptide pharmaceutical compositions may contain a therapeutically effective amount of a polypeptide that contains a monomer or multimer containing polypeptide that contains the GDF15 region, in admixture with a pharmaceutically or physiologically acceptable dosage form agent selected according to the route of administration. The term pharmaceutically acceptable carrier or physiologically acceptable carrier as used herein means one or more dosage formulated substances suitable for effecting or enhancing delivery of a monomer or multimer containing polypeptide that contains a GDF15 region into the body of a human or non-human subject. . The term includes any and all solvents, dispersion media, coating agents, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like which are physiologically compatible. Examples of pharmaceutically acceptable carriers include one or more carriers selected from water, saline, phosphate-buffered saline, dextrose, glycerol, ethanol and the like, and combinations thereof. In some cases, it is preferable to include isotonic agents such as sugars, polyhydric alcohols such as mannitol, sorbitol, or sodium chloride in the pharmaceutical composition. Pharmaceutically acceptable agents such as wetting agents or minor amounts of auxiliary agents such as wetting or emulsifying agents, preservatives or buffers that increase the shelf life or potency of the monomer or multimer containing polypeptide that contains the GDF15 region may also act as a carrier or may form an integral part of the carrier. Suitable pharmaceutically acceptable carriers are preferably non-toxic to the recipient at the dosages and concentrations used.

The pharmaceutical composition may contain formulation agent(s) to modify, maintain or maintain, for example, pH, osmolarity, viscosity, clarity, color, isotonicity, odor, sterility, stability, degree of dissolution or release, absorption or penetration of the composition. Suitable substances for the formulation of the dosage form include, but are not limited to, amino acids (such as glycine, glutamine, asparagine, arginine or lysine), antimicrobial agents, antioxidants (such as ascorbic acid, sodium sulfite or sodium hydrogen sulfite), buffers (such as borate , bicarbonate, Tris-HCl, citrate, phosphate buffers or other organic acids), excipients (such as mannitol or glycine), chelating agents (such as ethylenediaminetetraacetic acid (EDTA)), complexing agents (such as caffeine, polyvinylpyrrolidone, beta-cyclodextrin or hydroxypropyl-beta-cyclodextrin), fillers, monosaccharides, disaccharides and other carbohydrates (such as glucose, mannose or dextrins), proteins (such as free serum albumin, gelatin or immunoglobulins), coloring agents, flavoring agents and diluents, emulsifying agents, hydrophilic polymers (such as polyvinylpyrrolidone), low molecular weight polypeptides, salt-forming counterions (such as sodium), preservatives (such as benzalkonium chloride, benzoic acid, salicylic acid, thimerosal, phenethyl alcohol, methylparaben, propylparaben, chlorhexidine, sorbic acid or hydrogen peroxide ), solvents (such as glycerin, propylene glycol, or polyethylene glycol), sugar alcohols (such as mannitol or sorbitol), suspending agents, surfactants, or wetting agents (such as Pluronics; PEG; sorbitan esters; polysorbates such as Polysorbate 20 or Polysorbate 80; Triton; tromethamine; lecithin; cholesterol or tyloxapol), stability enhancing substances (such as sucrose or sorbitol), tonicity increasing substances (such as alkali metal halides - preferably sodium or potassium chloride - or mannitol, sorbitol), delivery vehicles, diluents, excipients and /or pharmaceutical excipients (see, for example, REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY, 19th edition, (1995); Berge et al., J. Pharm. Sci., 6661), 1-19 (1977). Additional relevant principles, methods and materials are described, for example, in Lieberman et al., PHARMACEUTICAL DOSAGE FORMS-DISPERSE SYSTEMS (2nd ed., vol. 3, 1998); Ansel et al., PHARMACEUTICAL DOSAGE FORMS & DRUG DELIVERY SYSTEMS (7th ed. 2000); Martindale, THE EXTRA PHARMACOPEIA (31st edition), Remington's PHARMACEUTICAL SCIENCES (16th-20th and subsequent editions); The Pharmacological Basis of Therapeutics, Goodman and Gilman, Eds. (9th ed.--1996); Wilson and Gisvolds' TEXTBOOK OF ORGANIC MEDICINAL AND PHARMACEUTICAL CHEMISTRY, Delgado and Remers, Eds. (10th ed., 1998). Principles for preparing pharmaceutically acceptable compositions are also described, for example, in Aulton, PHARMACEUTICS: THE SCIENCE OF DOSAGE FORM DESIGN, Churchill Livingstone (New York) (1988), EXTEMPORANEOUS ORAL LIQUID DOSAGE PREPARATIONS, CSHP (1998)).

The optimal pharmaceutical composition will be determined by one skilled in the art depending on, for example, the intended route of administration, delivery format and desired dosage (see, for example, Remington's PHARMACEUTICAL SCIENCES manual, supra). Such compositions may influence physiological state, stability, in vivo release rate,

- 144 046387 rate of in vivo clearance of a GDF15 polypeptide, a construct containing a GDF15 polypeptide or a mutant form of a GDF15 polypeptide.

The primary excipient or carrier in a pharmaceutical composition may be aqueous or non-aqueous in nature. For example, a suitable excipient or carrier for injection may be water, physiological saline, or artificial cerebrospinal fluid, to which may be added other substances conventionally used in compositions for parenteral administration. Neutral buffered saline or saline mixed with free serum albumin are additional examples of excipients. Other examples of pharmaceutical compositions include a Tris buffer of approximately pH 7.0-8.5 or an acetate buffer of approximately pH 4.0-5.5, which may further contain sorbitol or a suitable analogue thereof. In one embodiment of the present invention, compositions containing a GDF15 polypeptide, a construct containing a GDF15 polypeptide, or a mutant form of a GDF15 polypeptide can be prepared in a storage form by mixing a selected composition of the desired purity with optional formulation agents (Remington's PHARMACEUTICAL SCIENCES, supra ) in the form of a lyophilized tablet or aqueous solution. Moreover, a product containing a monomer or multimer containing a polypeptide that contains the GDF15 region can be formulated in the form of a lyophilisate using appropriate excipients such as sucrose.

Pharmaceutical compositions based on the polypeptide may be selected for parenteral delivery. Alternatively, the compositions may be selected for inhalation or for delivery through the gastrointestinal tract, for example, for oral delivery. The preparation of such a pharmaceutically acceptable composition is within the skill of one skilled in the art.

The components of the dosage form are present in concentrations that are acceptable at the site of administration. For example, buffers are used to maintain the pH of the composition at a physiological level or at a slightly lower pH level, typically in the pH range of about 5 to about 8.

If parenteral administration is contemplated, therapeutic compositions for use according to the present invention may be in the form of a pyrogen-free, parenterally acceptable aqueous solution containing the desired GDF15 polypeptide, a construct containing the GDF15 polypeptide, or a mutant form of the GDF15 polypeptide, in a pharmaceutically acceptable excipient. A particularly suitable vehicle for parenteral injection is sterile distilled water in which the GDF15 polypeptide, a monomer-containing construct, or a multimer containing polypeptide that contains the GDF15 region, is formulated as a sterile isotonic solution, suitably preserved. Preparation of another drug may involve formulation of the desired molecule with a vehicle, such as injectable microspheres, biodegradable particles, polymeric compounds (such as polylactic acid or polyglycolic acid), beads or liposomes, providing a controlled or sustained release of the product, which can then be delivered by injection with slow absorption. You can also use hyaluronic acid, which can promote longer circulation. Other suitable methods for administering the desired molecule include the use of implantable drug delivery devices.

According to one embodiment of the present invention, the pharmaceutical composition can be formulated into an inhalation formulation. For example, a monomer or multimer containing a polypeptide that contains the GDF15 region can be formulated as a dry powder for inhalation. Inhalation solutions containing a monomer or multimer containing a polypeptide that contains the GDF15 region can also be formulated with a nebulizer for delivery in aerosol form. According to another embodiment of the present invention, the solutions can be sprayed. Pulmonary administration is also described in international publication No. WO 94/20069, which describes pulmonary delivery of chemically modified proteins.

It is also contemplated that certain formulations may be administered orally. According to one embodiment of the present invention, the monomer or multimer that contains the polypeptide containing the GDF15 region that is administered in this manner can be formulated with or without the addition of such carriers as are typically used in the formulation of solid dosage forms such as tablets and capsules. media data. For example, a capsule may be designed to release the active portion of the formulation at a specific site in the gastrointestinal tract when bioavailability is greatest and pre-systemic degradation is minimal. Additional agents may be added to facilitate absorption of the monomer or multimer containing the polypeptide that contains the GDF15 region. Diluents, flavoring agents, low melting waxes, vegetable oils, lubricants, suspending agents, disintegrating agents and binders may also be used.

The other pharmaceutical composition may contain an effective amount of monomer or

- 145 046387 a multimer containing a polypeptide which contains the GDF15 region, mixed with non-toxic excipients suitable for the production of tablets. By dissolving the tablets in sterile water or other suitable excipient, single-dose solutions can be prepared. Suitable excipients include, but are not limited to, inert diluents such as calcium carbonate, sodium carbonate or bicarbonate, lactose or calcium phosphate; or binders such as starch, gelatin or gum acacia; or lubricants such as magnesium stearate, stearic acid or talc.

Additional pharmaceutical compositions containing a monomer or multimer containing a polypeptide that contains the GDF15 region will be apparent to one skilled in the art, including sustained or controlled delivery formulations containing a monomer or multimer containing a polypeptide that contains the GDF15 region. Techniques for preparing a variety of other delayed or controlled delivery formulations, such as the use of liposome-based carriers, biodegradable microparticles or porous beads and delayed absorption injections, are also known to one skilled in the art (see, for example, International Publication No. WO 93/ 15722, which describes controlled-release porous polymer microparticles for the delivery of pharmaceutical compositions, as well as Wischke & Schwendeman, 2008, Int. J. Pharm. 364: 298-327 and Freiberg & Zhu, 2004, Int. J. Pharm. 282 : 1-18, which discusses the preparation and use of microspheres/microparticles). As described in the present invention, the hydrogel is an example of a delayed or controlled delivery formulation.

Additional examples of sustained release formulations include semi-permeable polymer matrices in the form of molded articles, such as films, or microcapsules. Sustained release matrices may contain polyesters, hydrogels, polylactides (US Patent No. 3,773,919 and European Patent No. 0 058 481), copolymers of L-glutamic acid and gamma-ethyl-L-glutamate (Sidman et al., 1983, Biopolymers 22: 547-56 ), poly(2-hydroxyethyl methacrylate) (Langer et al., 1981, J. Biomed. Mater. Res. 15: 167-277 and Langer, 1982, Chem. Tech. 12: 98-105), ethylene vinyl acetate (Langer et al., supra) or poly-E(-)-3-hydroxybutyric acid (European patent no. 0 133 988). Sustained release compositions may also contain liposomes, which can be prepared by any of the methods known in the art. See, for example, Epstein et al., 1985, Proc. Natl. Acad. Sci. U.S.A. 82: 3688-92; and European patents nos. 0 036 676, 0 088 046 and 0 143 949.

A pharmaceutical composition containing a monomer or multimer containing a polypeptide that contains a GDF15 region that is used for in vivo administration will generally need to be sterile. Sterility can be achieved by filtration through sterile filtration membranes. If the composition is lyophilized, sterilization using this method can be carried out before or after lyophilization and reconstitution. The composition for parenteral administration can be stored in lyophilized form or in solution. In addition, parenteral compositions are typically placed in a container having a sterile entry port, such as an intravenous solution bag or vial having a stopper pierceable by a hypodermic needle.

Once the pharmaceutical composition has been formulated, it can be stored in sterile vials as a solution, suspension, gel, emulsion, solid, or as a dehydrogenated or lyophilized powder. Such formulations may be stored in a ready-to-use form or in a form (eg, lyophilized) requiring reconstitution before administration.

According to a specific embodiment, the present invention is directed to kits for producing a single dose administration unit. The kits may each contain a first container containing a dried protein and a second container containing an aqueous formulation. Also included within the scope of the present invention are kits containing single-chamber or multi-chamber prefilled syringes (eg, liquid syringes or lyophilisate syringes).

The effective amount of a pharmaceutical composition that contains a monomer or multimer containing a polypeptide that contains the GDF15 region intended for therapeutic use depends, for example, on the therapeutic context and purposes. One of ordinary skill in the art will appreciate that appropriate dose levels for treatment will thus vary in part depending on the molecule being delivered, the indication for which the monomer or multimer containing polypeptide that contains the GDF15 region is used, the route of administration and the size (body weight , body surface or organ size) and the condition (age and general health) of the patient. Accordingly, the physician may titrate the dose and modify the route of administration to achieve optimal therapeutic effect. A typical dose may vary from about 0.1 μg/kg to about 100 mg/kg or more, depending on the factors mentioned above. According to other embodiments of the present invention, the dose may range from 0.1 μg/kg to about 100 mg/kg; or from 1 μg/kg to about 100 mg/kg; or be 5 mcg/kg, 10 mcg/kg, 15 mcg/kg, 20 mcg/kg, 25 mcg/kg, 30 mcg/kg, 35 mcg/kg, 40 mcg/kg, 45 mcg/kg, 50 mcg/ kg, 55 mcg/kg, 60 mcg/kg, 65 mcg/kg, 70 mcg/kg, 75 mcg/kg, 100 mcg/kg, 200 mcg/kg or up to approximately 10 mg/kg.

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The frequency of dosing depends on the pharmacokinetic parameters of the monomer or multimer containing polypeptide that contains the GDF15 region in the formulation used. Typically, the physician will administer the composition until a dose is reached that produces the desired effect. Therefore, the composition can be administered as a single dose, as two or more doses (which may or may not contain the same amount of the desired molecule) over time, or as a continuous infusion via an implantable device or catheter. Subsequent adjustment of the appropriate dose can be carried out in a conventional manner by one of ordinary skill in the art, and such adjustment is consistent with tasks routinely performed by one of ordinary skill in the art. Appropriate doses can be established using appropriate dose-response data.

Routes of administration of the pharmaceutical composition are in accordance with known methods and include, for example, the oral route; administration by injection, intravenous, intraperitoneal, intracerebral (intraparenchymal), intracerebroventricular, intramuscular, intraocular, intraarterial, intraportal, or intralesional routes; administration using sustained release systems (which can also be injected); or administration using implantable devices. If necessary, the compositions can be administered by bolus injection or continuously by infusion, or using an implantable device.

Alternatively or additionally, the composition can be administered topically by implantation of a membrane, sponge, or other suitable material into which the desired molecule has been absorbed or encapsulated. In the case of an implantable device, the device can be implanted into any suitable tissue or organ, and delivery of the desired molecule can be through diffusion, bolus administration with timed release, or continuous administration.

A variety of different approaches can be used to deliver a drug, for example a monomer or multimer containing a polypeptide that contains the GDF15 region, at a predetermined rate so that the concentration of the drug can be maintained at a desired therapeutically effective level over an extended period. In one example, a hydrogel containing a polymer such as gelatin (eg, bovine gelatin, human gelatin, or gelatin from another source) or a naturally occurring or synthetically produced polymer may be used. Any percentage of polymer (eg gelatin) can be used in the hydrogel, for example 5, 10, 15 or 20%. The selection of the appropriate concentration may depend on a variety of factors, such as the desired therapeutic profile and the pharmacokinetic profile of the therapeutic molecule.

Examples of polymers that may be contained in the hydrogel include polyethylene glycol (PEG), polyethylene oxide, polyethylene oxide-co-polypropylene oxide, block copolymers or random co-polyethylene oxide copolymers, polyvinyl alcohol, poly(vinylpyrrolidinone), poly(amino acids), dextran, heparin, polysaccharides , polyesters and similar polymers.

Another factor to consider when preparing hydrogel-based formulations is the degree of cross-linking between the hydrogel and the cross-linking agent. According to one embodiment of the present invention, cross-linking can be achieved through a methacrylation reaction that uses methacrylic anhydride. In some cases, a high degree of cross-linking may be desirable, while in others a lower degree of cross-linking is preferred. In some cases, a greater degree of cross-linking provides a longer sustained release. A greater degree of cross-linking may result in a stiffer hydrogel and a longer period over which drug delivery occurs.

Any ratio of polymer to cross-linking agent (eg, methacrylic anhydride) can be used to produce a hydrogel with the desired properties. For example, the ratio of polymer to cross-linker may be, for example, 8:1, 16:1, 24:1 or 32:1. For example, when the hydrogel polymer is gelatin and the cross-linker is methacrylate, ratios of 8:1, 16:1, 24:1, or 32:1 can be used for methacrylic anhydride:gelatin.

V. Therapeutic applications of the GDF15 polypeptide, a construct containing the GDF15 polypeptide or a mutant form of the GDF15 polypeptide.

A monomer or multimer containing a polypeptide that contains the GDF15 region can be used to treat, diagnose or alleviate a metabolic condition or disorder. In one embodiment of the present invention, the metabolic disorder being treated is diabetes, such as type 2 diabetes. According to another embodiment of the present invention, the metabolic condition or disorder is obesity. According to other embodiments of the present invention, the metabolic condition or disorder

- 147 046387 represents dyslipidemia, increased glucose levels, increased insulin levels or diabetic nephropathy. For example, a metabolic condition or disorder that can be treated or ameliorated using a monomer or multimer containing a polypeptide that contains the GDF15 region includes a condition in which a human subject has a fasting blood glucose level of 125 mg/dL or more, for example, 130 , 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200 or more than 200 mg/dl. Blood glucose levels can be determined in the postprandial or fasting state or randomly. The metabolic condition or disorder may also include a condition in which the subject is at increased risk of developing the metabolic condition. In the case of a human subject, such conditions include a fasting blood glucose level of 100 mg/dL. Conditions that can be treated using a pharmaceutical composition containing a mutant GDF15 polypeptide can also be found in American Diabetes Association Standards of Medical Care in Diabetes Care-2011, American Diabetes Association, Diabetes Care Vol. 34, No. Supplement 1, S11-S61, 2010.

In practical application, a metabolic disorder or condition, such as type 2 diabetes, increased glucose levels, increased insulin levels, dyslipidemia, obesity or diabetic nephropathy, can be treated by administering to a patient in need of such treatment a therapeutically effective dose of a GDF15 polypeptide, a construct comprising a monomer or multimer containing a polypeptide that contains the GDF15 region. Administration can be carried out as described in the present invention, for example, by intravenous (IV) injection, intraperitoneal (IP) injection, subcutaneous injection, intramuscular injection, or orally in the form of a tablet or liquid formulation. In some cases, the therapeutically effective or preferred dose of a monomer or multimer containing a polypeptide that contains the GDF15 region can be determined by a physician. The therapeutically effective dose of a monomer or multimer containing a polypeptide that contains the GDF15 region depends, among other things, on the schedule of administration, the single dose of the agent administered, whether the monomer or multimer containing a polypeptide that contains the GDF15 region is administered in combination with other therapeutic agents, immune status and health of the recipient. The term "therapeutically effective dose" as used herein means an amount of monomer or multimer containing polypeptide that contains the GDF15 region that produces a biological or medical response in a tissue system, animal or human, wherein said response is determined by the investigator, physician, or other physician, and said the response involves alleviating or alleviating the symptoms of the disease or disorder being treated. Those. this term means an amount of monomer or multimer containing polypeptide that contains the GDF15 region that maintains an observed level of one or more desired biological or medical responses, for example, a decrease in blood glucose, insulin, triglyceride or cholesterol levels; reducing body weight; or improvement in glucose tolerance, energy expenditure, or insulin sensitivity.

It should be noted that the therapeutically effective dose of a monomer or multimer containing a polypeptide that contains the GDF15 region may also vary depending on the desired result. Thus, for example, in cases in which a reduction in blood glucose levels is indicated, the dose of a monomer or multimer containing a polypeptide that contains the GDF15 region will suitably be higher than the dose at which a relative reduction in blood glucose levels is desired. Conversely, in cases in which a higher blood glucose level is indicated, the dose of a monomer or multimer containing a polypeptide that contains the GDF15 region will be correspondingly less than the dose at which a relatively higher blood glucose level is desired.

In various embodiments of the present invention, the subject is a human whose blood glucose level is 100 mg/dL or greater and who may be treated with a monomer or multimer containing a polypeptide that contains the GDF15 region.

According to one embodiment of the present invention, the method of the present invention includes a first measured baseline level of one or more metabolically significant compounds, such as glucose, insulin, cholesterol, lipid, in a subject. Then, a pharmaceutical composition containing a monomer or multimer containing a polypeptide that contains the GDF15 region is administered to the subject. After a desired period of time, the level of one or more metabolically significant compounds (eg, glucose, insulin, cholesterol, blood lipid) in the subject is again determined. The two levels can then be compared to determine the relative change in metabolically significant compounds in the subject. Depending on the result of this comparison, a different dose of a pharmaceutical composition containing a monomer or multimer containing a polypeptide that contains the GDF15 region may be administered to achieve the desired level of one or more metabolically significant compounds.

It should be noted that a pharmaceutical composition containing a monomer or multimer containing a polypeptide that contains the GDF15 region can be co-administered with another compound. The nature and properties of the compound that is co-administered with the monomer or multimer contains

- 148 046387 polypeptide that contains the GDF15 region depends on the nature of the condition that is being treated or that needs to be alleviated. A non-limiting list of examples of compounds that can be administered in combination with a pharmaceutical composition containing a monomer or multimer containing a polypeptide that contains the GDF15 region include rosiglitazone, pioglitazone, repaglinide, nateglitinide, metformin, exenatide, stiagliptin, pramlintide, glipizide, glimeprirideacarbose and miglitol.

VI. Sets.

Kits for implementing the disclosed methods in practice are also provided. Such kits may contain a pharmaceutical composition, such as the compositions described in the present invention, including nucleic acids encoding the peptides or proteins provided in the present invention, vectors and cells containing such nucleic acids, and pharmaceutical compositions that contain such compounds, containing nucleic acid, which may be offered in a sterile container. Optionally, the kits may also include or be available to the patient or health care provider with instructions on how to use the pharmaceutical composition of the invention to treat a metabolic disorder.

According to one aspect of the present invention, the kit includes (a) a pharmaceutical composition containing a therapeutically effective amount of a monomer or multimer containing a polypeptide that contains a GDF15 region; and (b) one or more pharmaceutical composition containers. Such a kit may also include instructions for its use; the instructions may be tailored to the specific metabolic disorder being treated. Instructions may describe the application process and the nature of the materials provided in the kit. In certain embodiments of the present invention, the kits include instructions for a patient to administer an administration to treat a metabolic disorder, such as increased glucose levels, increased insulin levels, obesity, type 2 diabetes, dyslipidemia, or diabetic nephropathy.

The instructions may be printed on a medium such as paper or plastic, etc., and may be provided in the kits as an insert, on a label on the container of the kit or its components (eg, attached to the packaging), etc. In other embodiments of the present invention, the instructions are provided in the form of a data file for electronic storage provided on a suitable computer-readable storage medium, such as a CD-ROM, floppy disk, etc. In other embodiments of the present invention, there are no actual instructions in the set, but methods are provided for obtaining instructions from a remote source, such as over the Internet. An example of such an implementation is a set that includes a web address at which instructions can be viewed and/or from which instructions can be downloaded.

It is often desirable that some or all of the kit components be packaged in appropriate packaging to maintain sterility. The components of the kit may be packaged into a kit containing unit to form a separate, easy to use unit, wherein said kit containing unit, such as a box or similar structure, may be a sealed container, for example, to further maintain the sterility of some or all of the components of the kit, or may be an unsealed container.

Examples

The following examples, including experiments performed and results obtained, are offered for illustrative purposes only and should not be construed as limiting the present invention.

Example 1.

Preparation of the Fc-GDF15 molecule.

Fusions of GDF15 to knob/holeFc, HemiFc, charged pair (delHinge) Fc, and charged pair (delHinge) cysteine clamp Fc sequences were stably expressed in the serum-free, suspension-adapted cell line CHO-K1. GDF15-Fc molecules were cloned into a stable expression vector containing the puromycin resistance gene, while the Fc chains were cloned into an expression vector containing the hygromycin resistance gene (Selexis, Inc.). Plasmids were transfected in a 1:1 ratio using Lipofectamine LTX, and cell selection was performed 2 days after transfection in proprietary growth medium containing 10 μg/ml puromycin and 600 μg/ml hygromycin. The medium was changed 2 times a week during selection. When cell viability reached approximately 90%, the culture was scaled up to fed-batch production scale. Cells were seeded at a concentration of 1e6Aim in a proprietary production medium and fed on days 3, 6 and 8. The conditioned medium (CM) produced by the cells was collected on day 10 and filtered. Final viability rates were typically approximately 90%.

Fc-GDF15 was isolated from the filtered conditioning medium using a two-step chromatographic procedure. Approximately 5 L of CS was applied directly to a GE MabSelect SuRe column, which was pre-equilibrated with Dulbecco's phosphate buffered saline (PBS). The bound protein was subjected to three washing steps: first, with 3 column volumes (CV) of PBS; next

- 149 046387 blowing - 1st OK 20 mM Tris, 100 mM sodium chloride, pH 7.4; and finally, 3 OK 500 mM L-arginine, pH 7.5. These washing steps removed unbound or weakly bound media components and host cell contaminants. The column was then re-equilibrated with 5% of 20 mM Tris, 100 mM sodium chloride at pH 7.4, returning the UV absorbance to baseline. The target protein was eluted with 100 mM acetic acid at pH 3.6 and collected in the bulk. The total protein mass was rapidly titrated over a pH range of 5.0 to 5.5 with 1 M Tris-HCl, pH 9.2.

The pH-adjusted total protein mass was then applied to a GE SP Sepharose HP column that had been pre-equilibrated with 20 mM MES at pH 6.0. After this, the bound protein was washed with 5 OC of equilibration buffer, and then eluted with 20 OC with a linear gradient of 0-50% 0-400 mM sodium chloride in 20 mM MES at pH 6.0. Fractions were collected during elution and analyzed by analytical size exclusion chromatography (Superdex 200) to determine the appropriate fractions to collect the homogeneous product. SP HP chromatography removes related product impurities such as free Fc, aggregated forms and Fc-GDF15 multimers.

Then, the SP HP total mass buffer was changed by dialysis to 10 mM sodium acetate, 5% proline, pH 5.2. The product was concentrated to a concentration of approximately 15 mg/ml using a Sartorius Vivaspin 20 centrifugation device with a molecular weight cutoff of ten kilodaltons. The product was then sterilized by filtration and the resulting solution containing purified Fc-GDF15 molecules was stored at 5°C. The identity and purity of the final products were assessed using mass spectral analysis, sodium dodecyl sulfate-polyacrylamide gel electrophoresis and size exclusion high-performance liquid chromatography.

The purification method described above was used to purify DhMonoFc-GDF15 fusion proteins. However, it was found that introducing the H6D mutation into DhMonoFc-GDF15 caused the formation of soluble aggregates upon SP elution. Consequently, purification of DhMonoFc-GFF15(H6D) involved an additional step of size exclusion chromatography (Superdex 200 using 20 mM phosphate, 250 mM NaCl, pH 6.8), followed by loading onto Q-sepharose HP and eluting with a 0 to 0 gradient. 6 M NaCl in 20 mM tris, pH 8.5.

Example 2.

Preparation of GDF15-HSA and DhMonoFc molecules.

GDF15 fusions with HSA and DhMonoFc sequences were stably expressed in CHO-S cells (Invitrogen). For each of the homodimer-forming constructs, the coding sequence was cloned into a stable expression vector containing the puromycin resistance gene (Selexis, Inc.). In the case of the HSA-(G ₄ S) ₄ -GDF15:GDF15 heterodimer, the HSA-(G ₄ S) ₄ GDF15 fusion sequence was cloned into an expression vector containing the puromycin resistance gene, and the GDF15 sequence was cloned into an expression vector containing the hygromycin resistance gene . Parental CHO-S cells were maintained in CD-CHO medium (Invitrogen) supplemented with 8 mM L-glutamine and transfected with 4 μg of plasmid DNA using the Lipofectamine LTX transfection kit (Invitrogen) according to the manufacturer's instructions. In the case of the HSA-(G ₄ S) ₄ -GDF15:GDF15 heterodimer, the two plasmids were mixed before transfection in a 1:1 ratio. Stable cell lines were selected using 10 μg/ml puromycin (homodimers) or 10 μg/ml puromycin and 400 μg/ml hygromycin (heterodimers). After recovery, which was determined by a viability rate of >90% using a Vi-Cell counter (Beckman Coulter), stable CHO-S cell lines were expanded and seeded for batch production in shake flasks or for fed-batch production in WAVE bioreactors (GE Healthcare). For both processes, cells were seeded at a concentration of 1e6 viable cells/ml in growth medium. The products of the batch process were collected by centrifugation on day 6, while the products of the fed-batch process were fed on days 3, 6 and 8. The CM formed by the cells was collected by centrifugation on day 10 and filtered.

HSA-GDF15 fusion proteins were purified from filtered conditioning media using two chromatography steps. Filtered conditioned medium containing the HSA-GDF15 fusion protein was applied to a Cibracon Blue Sepharose HP column equilibrated with 20 mM phosphate, 150 mM NaCl, pH 7.4. The column was then washed with equilibration buffer to obtain a baseline level of UV absorbance. The product and contaminants were eluted with a buffer containing 20 mM phosphate, 2 M NaCl, and the eluates were then collected and analyzed by SDS-PAGE with Coomassie staining to determine which fractions of the eluate contained the polypeptide migrating with estimated molecular weight of the HSA-GDF15 fusion protein. After the Blue Sepharose step, pooled product-containing fractions were dialyzed against 10 mM Tris, pH 8.0. The dialysis step allowed the HSA-GDF15 fusion protein to bind when applied to an anion exchange chromatography resin. The final chromatography step was Q-Sepharose HP chromatography using a linear gradient (0 to 0.6 M NaCl in 10 mM Tris, pH 8.0) to elute the bound fusion protein. The eluate was collected from QSepharose HP in the form of fractions and then analyzed by DNS-PAGE and analytical exclusion

- 150 046387 chromatography to determine appropriate fractions for pooling. Analysis by LCMS (liquid chromatography/mass spectrometry) and SDS-PAGE was performed to confirm the identity of each protein. Then, by means of dialysis, the buffer in the resulting total mass was changed to 10 mM sodium acetate, 9% sucrose, pH 4.5, the product was subjected to sterilizing filtration, and then stored at a temperature of 5°C or frozen.

DhMonoFc-GDF15 fusion proteins were purified as described in Example 2 above for the other Fc-GDF15 fusion proteins.

Example 3.

Suppression of food intake in gluttonous ob/ob mice using GDF15-fusion Fc polypeptides and GDF15-fusion HSA polypeptides.

GDF15 reduces food intake in gluttonous ob/ob mice; Dietary intake analysis was used to evaluate the efficacy of different forms of GDF15 analogues. Since the half-life of the human GDF15 polypeptide in mouse has been observed to be approximately 3 hours, an Fc fusion strategy has been used to increase the half-life of the protein. Various multimers containing a polypeptide that contains the GDF15 region were prepared, and the in vivo activity of these multimers was analyzed by administering the multimer to glutinous leptin-deficient ob/ob mice and measuring the ability of a particular multimer containing a polypeptide that contains the GDF15 region to suppress food intake. in these animals. A test multimer containing polypeptide that contains the GDF15 region was administered to 7-8 week old ob/ob mice (Jackson Laboratory) by subcutaneous injection on day 0 at 4-5 p.m. After the injection, the animals were transferred to cages in which the amount of food was previously measured, and food intake was measured the next day at 9-10 o'clock.

The results of illustrative experiments are presented in figures 6-53. These experiments indicate that the described multimers containing GDF15 regions demonstrate a reduction in food intake in ob/ob mice with greater activity than the native mature 4GDF15 homodimer.

Example 4.

Chronic efficacy of GDF15 constructs in DIO mice.

Specific multimers containing GDF15 regions were administered chronically and subcutaneously to DIO mice once a week. The constructs have demonstrated efficacy in improving various metabolic parameters, including body weight, blood glucose levels and glucose tolerance, serum insulin levels, serum cholesterol levels, serum triglyceride levels, and oral lipid tolerance.

Example 5.

Activity of GDF15 constructs in vivo.

C57Bl/6 males were fed a high-fat 60% fat diet for 15 weeks and divided into different treatment groups, with animals in each group having similar body weights and levels of glucose, insulin, triglyceride and cholesterol before treatment. Animals were injected subcutaneously with proteins or vehicle (buffer) weekly for 5 weeks. Three different protein dose levels were used: 10, 1, 0.1 nmol/kg, equivalent to 1.25, 0.125, 0.0125 mg/kg. The study was conducted over a 5-week period, with the last dose administered on day 28.

Body weight was measured weekly during 5 weeks of treatment and drug washout. One oral glucose tolerance test (OGTT) was performed 2 weeks after the first protein injection in animals that were fasted for 4 hours. Another oral glucose tolerance test (OGTT) was performed 5 weeks after the first protein injection in animals that were fasted for 16 hours. During OGTT, animals were administered a 2 g/kg glucose solution orally, and glucose levels were measured at time points 0, 15, 30, 60, 120 min. using an AlphaTRAK glucometer (Abbott). The area under curve (AUC) of glucose levels during OGTT was calculated to compare glucose tolerance between treatment groups. Serum samples were collected 3 weeks after the first protein injection and were used to measure insulin, triglyceride and cholesterol levels, as well as levels of test compounds. Insulin levels were measured using an immunoassay kit (Alpco). Triglyceride and cholesterol levels were measured using enzymatic assays (Wako).

The results are presented in Fig. 54-59 (asterisks indicate statistical significance). These experiments demonstrated that the described multimers containing GDF15 regions reduced the AUC of glucose levels during OGTT (Figs. 55 and 59), reduced body weight (Fig. 54), reduced insulin levels (Fig. 56), reduced cholesterol levels (Fig. 58) and reduce triglyceride levels (Fig. 57).

Example 6.

Temperature stability of GDF15 structures.

The temperature stability of selected GDF15 designs was assessed by differential scanning calorimetry on a MicroCal Capillary VP-DSC system, in which the temperature difference between the reference cell and the sample cell is continuously measured and calibrated to units of high power

- 151 046387 sti. The data channel is referred to in the present invention as the PM signal or the power difference (PM) between the reference cell and the sample cell. The unfolding of a protein molecule appears on a DSC thermogram as an endothermic transition and can be characterized using the temperature transition midpoints (Tm). The samples were heated in the range from 10°C to 100°C with a heating rate of 60°^hour. The pre-scan time was 15 minutes, the filtering period was 10 seconds. The concentrations used in the DSC experiments were approximately 1.0 mg/mL. Data analysis for baseline correction and determination of Tm values was performed using MicroCal Origin 7 software.

In particular, the dimer DhCpmFc(-)-GDF15(N3D):DhCpmFc(+) was compared with the dimer Dh3CpmFc(-)GDF15(N3D):DhCpmFc(+); the dimer DhCpmFc(-)-GDF15(Ndel3):DhCpmFc(+) was compared with the dimer Dh3CpmFc(-)-GDF15(Ndel3):DhCpmFc(+); the dimer DhCpmFc(-)(Y349C)-GDF15(N3D):DhCpmFc(+)(S354C) was compared with the dimer Dh3CpmFc(-)(Y349C)-GDF15(N3D):DhCpmFc(+)(S354C); and the dimer DhCpmFc()(Y349C)-GDF15(Ndel3):DhCpmFc(+)(S354C) was compared with the dimer Dh3CpmFc(-)(Y349C)GDF15(Ndel3):DhCpmFc(+)(S354C). The results are presented in Fig. 61. These experiments indicate that the Dh3CpmFc domains are more stable than the corresponding DhCpmFc domains.

Example 7.

Fcy receptor binding assay.

The binding activity to Fcy receptors of selected GDF15 constructs was analyzed on a BIA3000 instrument. Each Fcy receptor was captured on the surface of CM5 coated with anti-His antibody (capture retention level ~200 RU response units). GDF15 constructs were diluted to a concentration of 250 nM in sample buffer (0.1 mg/ml BSA, 0.005% P20, PBS). Each GDF15 construct was injected over surfaces with Fcy receptor and captured anti-His antibodies at a rate of 50 μl/min. within 3 minutes. After 5 min dissociation in instrument assay buffer (0.005% P20 in PBS), the surface of each Fcy receptor was regenerated by injecting 8 mM glycine, pH 1.5, 1 M NaCl for 30 seconds, followed by injection of 10 mM glycine, pH 1.5 within 30 seconds. The resulting sensorgrams were analyzed using BIAcore BIAEvaluation software (v. 4.1). Binding responses in EO units were read 10 seconds before the end of the injection.

In particular, binding to FcyRI, FcyRIIIA and FcyRIIA was determined for the dimer DhCpmFc(-)GDF15(Ndel3):DhCpmFc(+), dimer DhCpmFc(-)(Y349C)-GDF15(Ndel3): DhCpmFc(+)(S354C); dimer Dh3CpmFc(-)-GDF15(Ndel3); dimer Dh3CpmFc(-)(Y349C)-GDF15(Ndel3)-Dh3CpmFc(+)(S354C); dimer Dh3CpmFc(-)-GDF15(N3D); and the dimer Dh3CpmFc(-)(Y349C)-GDF15(N3D):Dh3CpmFc(+)(S354C).

The results are presented in Fig. 60. These experiments indicate that the Dh3CpmFc domains essentially abolish binding to FcyRI, FcyRIIIA and FcyRIIA.

Although the present invention has been described in terms of various embodiments, it should be understood that various variations and modifications will be apparent to one skilled in the art. It is therefore intended that the appended claims cover all such equivalent variations that fall within the claimed scope of the present invention. Additionally, section headings are used herein for organizational purposes only and should not be construed as limiting the subject matter described.

All publications referenced in the present invention are expressly incorporated by reference into this application for all purposes.

Sequence List <110> AMGEN INC.

<120> DESIGNS BASED ON DIFFERENTIATION AND GROWTH FACTOR 15 (GDF-15) <130> A-1850-WO-PCT <140>

<141>

<150> 61/860,723 <151> 2013-07-31 <160> 305 <170> PatentIn version 3.5

- 152 046387 <210> 1 <211> 4 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic peptide <400> 1

Arg Gly Arg Arg 1 <210> 2 <211> 7 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=description of artificial sequence: synthetic peptide <400> 2

Arg Gly Arg Arg Arg Ala Arg <210> 3 <211> 927 <212> DNA <213> Homo sapiens <400> 3 atgcccgggc aagaactcag gacggtgaat ggctctcaga tgctcctggt gttgctggtg60 ctctcgtggc tgccgcatgg gggcgccctg tctctggccg aggc gagccg cgcaagtttc120 ccgggaccct cagagttgca ctccgaagac tccagattcc gagagttgcg gaaacgctac180 gaggacctgc taaccaggct gcgggccaac cagagctggg aagattcgaa caccgacctc240 gtcccggccc ctgcagtccg gatactcacg ccagaagtgc ggctgggatc cggcggccac300 ctgcacctgc gtatctctcg ggccgccctt cccgaggggc tccccgaggc ctcccgcctt360 caccgggctc tgttccggct gtccccgacg gcgtcaaggt cgtgggacgt gacacgaccg420 ctgcggcgtc agctcagcct tgcaagaccc caggcgcccg cgctgcacct gcgactgtcg480 ccgccgccgt cgcagtcgga ccaactgctg gcagaatctt cgtccgcacg gccccagctg540 gagttgcact t gcggccgca agccgccagg gggcgccgca gagcgcgtgc gcgcaacggg600 gaccactgtc cgctcgggcc cgggcgttgc tgccgtctgc acacggtccg cgcgtcgctg660 gaagacctgg gctgggccga ttgggtgctg tcgccacggg aggtgcaagt gaccatgt gc720 atcggcgcgt gcccgagcca gttccgggcg gcaaacatgc acgcgcagat caagacgagc780

- 153 046387 ctgcaccgcc tgaagcccga cacggtgcca gcgccctgct gcgtgcccgc cagctacaat cccatggtgc tcattcaaaa gaccgacacc ggggtgtcgc tccagaccta tgatgacttg ttagccaaag actgccactg catatga

840

900

927 <210>

<211>

<212>

<213>

308 PRT Homo sapiens <400>

Met

Pro

Gly

Gln

Glu 5

Leu

Arg

Thr

Val

Asn

Gly

Ser

Gln

Met

Leu

Leu

Val

Leu

Leu

Val 20

Leu

Ser

Trp

Leu

Pro 25

His

Gly

Gly

Ala

Leu

Ser

Leu

Ala

Glu

Ala 35

Ser

Arg

Ala

Ser

Phe 40

Pro

Gly

Pro

Ser

Glu 45

Leu

His

Ser

Glu

Asp 50

Ser

Arg

Phe

Arg

Glu 55

Leu

Arg

Lys

Arg

Tyr 60

Glu

Asp

Leu

Leu

Thr 65

Arg

Leu

Arg

Ala

Asn 70

Gln

Ser

Trp

Glu

Asp 75

Ser

Asn

Thr

Asp

Leu 80

Val

Pro

Ala

Pro

Ala 85

Val

Arg

Ile

Leu

Thr

Pro

Glu

Val

Arg

Leu 95

Gly

Ser

Gly

Gly

His

100

Leu

His

Leu

Arg

Ile

105

Ser

Arg

Ala

Ala

Leu

110

Pro

Glu

Gly

Leu

Pro

115

Glu

Ala

Ser

Arg

Leu

120

His

Arg

Ala

Leu

Phe

125

Arg

Leu

Ser

Pro

Thr

130

Ala

Ser

Arg

Ser

Trp 135

Asp

Val

Thr

Arg

Pro

140

Leu

Arg

Arg

Gln

Leu

145

Ser

Leu

Ala

Arg

Pro

150

Gln

Ala

Pro

Ala

Leu

155

His

Leu

Arg

Leu

Ser 160

Pro

Pro

Pro

Ser

Gln

165

Ser

Asp

Gln

Leu

Leu

170

Ala

Glu

Ser

Ser

Ser

175

Ala

Arg

Pro

Gln

Leu

180

Glu

Leu

His

Leu

Arg

185

Pro

Gln

Ala

Ala

Arg 190

Gly

Arg

Arg

Arg

Ala

195

Arg

Ala

Arg

Asn

Gly 200

Asp

His

Cys

Pro

Gly

Pro

Gly

Leu

205

- 154 046387

Arg Cys Cys Arg Leu His Thr Val Arg Ala Ser Leu Glu Asp Leu Gly 210 215220

Trp Ala Asp Trp Val Leu Ser Pro Arg Glu Val Gln Val Thr MetCys

225 230 235240

Ile Gly Ala Cys Pro Ser Gln Phe Arg Ala Ala Asn Met His AlaGln

245 250255

Ile Lys Thr Ser Leu His Arg Leu Lys Pro Asp Thr Val Pro Ala Pro 260 265270

Cys Cys Val Pro Ala Ser Tyr Asn Pro Met Val Leu Ile Gln Lys Thr 275 280285

Asp Thr Gly Val Ser Leu Gln Thr Tyr Asp Asp Leu Leu Ala Lys Asp 290 295300

Cys His Cys Ile 305 <210> 5 <211> 912 <212> DNA <213> Mus sp. <400> 5

atggccccgc ccgcgctcca ggcccagcct ccaggcggct ctcaactgag gttcctgctg 60 ttcctgctgc tgttgctgct gctgctgtca tggccatcgc aggggacgc cctggcaatg 120 cctgaacagc gaccctccgg ccctgagtcc caactcaacg ccgacgagct acggggtcgc 180 ttccaggacc tgctgagccg gctgcatgcc aaccagagcc gagaggactc gaactcagaa 240 ccaagtcctg acccagctgt ccggatactc agtccagagg tgagattggg gtcccacggc 300 cagctgctac tccgcgtcaa ccgggcgtcg ctgagtcagg gtctccccga agcctaccgc 360 gtgcaccgag cgctgctcct gctgacgccg acggcccgcc cctgggacat cactaggccc 420 ctgaagcgtg cgctcagcct ccggggaccc cgtgctcccg cattacgcct gcgcctgacg 480 ccgcctccgg acctggctat gctgccctct ggcggcacgc agctggaact gcgcttacgg 540 gtagccgccg gcaggggggcg ccgaagcgcg catgcgcacc caagagactc gtgcccactg 600 ggtccggggc gctgctgtca cttggagact gtgcaggcaa ctcttgaaga cttggggctgg 660 agcgactggg tgctgtcccc gcgccagctg cagctgagca tgtgcgtggg cgagtgtccc 720 cacctgtatc gctccgcgaa cacgcatgcg cagatcaaag cacgcctgca tggcctgcag 780 cctgacaagg tgcctgcccc gtgctgtgtc ccctccagct acaccccggt ggttcttatg 840

- 155 046387 cacaggacag acagtggtgt gtcactgcag acttatgatg acctggtggc ccggggctgc

900 cactgcgctt ga

912 <210>

<211>

<212>

<213>

303

PRT

Mus sp.

<400>

Met 1

Ala

Pro

Pro

Ala 5

Leu

Gln

Ala

Gln

Pro 10

Pro

Gly

Gly

Ser

Gln 15

Leu

Arg

Phe

Leu

Leu 20

Phe

Leu

Leu

Leu

Leu 25

Leu

Leu

Leu

Leu

Ser 30

Trp

Pro

Ser

Gln

Gly 35

Asp

Ala

Leu

Ala

Met 40

Pro

Glu

Gln

Arg

Pro 45

Ser

Gly

Pro

Glu

Ser 50

Gln

Leu

Asn

Ala

Asp 55

Glu

Leu

Arg

Gly

Arg 60

Phe

Gln

Asp

Leu

Leu 65

Ser

Arg

Leu

His

Ala 70

Asn

Gln

Ser

Arg

Glu 75

Asp

Ser

Asn

Ser

Glu 80

Pro

Ser

Pro

Asp

Pro 85

Ala

Val

Arg

Ile

Leu 90

Ser

Pro

Glu

Val

Arg 95

Leu

Gly

Ser

His

Gly 100

Gln

Leu

Leu

Leu

Arg 105

Val

Asn

Arg

Ala

Ser

110

Leu

Ser

Gln

Gly

Leu

115

Pro

Glu

Ala

Tyr

Arg

120

Val

His

Arg

Ala

Leu

125

Leu

Leu

Leu

Thr

Pro

130

Thr

Ala

Arg

Pro

Trp 135

Asp

Ile

Thr

Arg

Pro

140

Leu

Lys

Arg

Ala

Leu

145

Ser

Leu

Arg

Gly

Pro

150

Arg

Ala

Pro

Ala

Leu

155

Arg

Leu

Arg

Leu

Thr

160

Pro

Pro

Pro

Asp

Leu

165

Ala

Met

Leu

Pro

Ser

170

Gly

Gly

Thr

Gln

Leu

175

Glu

Leu

Arg

Leu

Arg 180

Val

Ala

Ala

Gly

Arg 185

Gly

Arg

Arg

Ser

Ala

190

His

Ala

His

Pro

Arg 195

Asp

Ser

Cys

Pro

Leu

200

Gly

Pro

Gly

Arg

Cys 205

Cys

His

Leu

- 156 046387

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

210 215220

Leu Ser Pro Arg Gln Leu Gln Leu Ser Met Cys Val Gly Glu Cys Pro

225 230 235240

His Leu Tyr Arg Ser Ala Asn Thr His Ala Gln Ile Lys Ala Arg Leu

245 250255

His Gly Leu Gln Pro Asp Lys Val Pro Ala Pro Cys Cys Val Pro Ser

260 265270

Ser Tyr Thr Pro Val Val Leu Met His Arg Thr Asp Ser Gly Val Ser

275 280285

Leu Gln Thr Tyr Asp Asp Leu Val Ala Arg Gly Cys His Cys Ala

290 295300

<210> 7 <211> 840 <212> DNA <213> Homo sapiens <400> 7 ctgtctctgg ccgaggcgag ccgcgcaagt ttcccggggac cctcagagtt gcactccgaa 60 gactccagat tccgagagtt gcggaaacgc tacgaggacc tgctaaccag gctgcgggcc 120 aaccagagct gggaagattc gaacaccgac ctcgtcccgg cccctgcagt ccggatactc 180 acgccagaag tgcggctggg atccggcggc cacctgcacc tgcgtatctc tcggggccgcc 240 cttcccgagg ggctccccga ggcctcccgc cttcaccgggg ctctgttccg gctgtccccg 300 acggcgtcaa ggtcgtggga cgtgacacga ccgctgcggc gtcagctcag ccttgcaaga 360 ccccaggcgc ccgcgctgca cctgcgactg tcgccgccgc cgtcgcagtc ggaccaactg 420 ctggcagaat cttcgtccgc acggccccag ctggagttgc acttgcggcc gcaagccgcc 480 aggggggcgcc gcagagcgcg tgcgcgcaac ggggaccact gtccgctcgg gccgggcgt 540 tgctgccgtc tgcacacggt ccgcgcgtcg ctggaagacc tgggctgggc cgattgggtg 600 ctgtcgccac gggaggtgca agtgaccatg tgcatcggcg cgtgcccgag ccagttccgg 660 gcggcaaaca tgcacgcgca gatcaagacg agcctgcacc gcctgaagcc cgacacggtg 720 ccagcgccct gctgcgtgcc cgccagctac aatcccatgg tgctcattca aaagaccgac 780 accggggtgt cgctccagac ctatgatgac ttgttagcca aagactgcca ctgcatatga 840

<210> 8 <211> 279 <212> PRT

- 157 046387 <213> Homo sapiens <400> 8

Leu Ser Leu Ala Glu 1 5

Leu His Ser Glu Asp

Ala Ser Arg Ala Ser

Ser Arg Phe Arg Glu 25

Phe Pro Gly Pro Ser 15

Leu Arg Lys Arg Tyr

Asp Leu Leu Thr Arg 35

Leu Arg Ala Asn Gln 40

Ser Trp Glu Asp Ser 45

Thr Asp Leu Val Pro 50

Ala Pro Ala Val Arg 55

Ile Leu Thr Pro Glu

Arg Leu Gly Ser Gly 65

Gly His Leu His Leu 70

Arg Ile Ser Arg Ala 75

Leu Pro Glu Gly Leu

Pro Glu Ala Ser Arg

Leu His Arg Ala Leu

Arg Leu Ser Pro Thr

100

Ala Ser Arg Ser Trp

105

Asp Val Thr Arg Pro

110

Arg Arg Gln Leu Ser 115

Leu Ala Arg Pro Gln

120

Ala Pro Ala Leu His

125

Arg Leu Ser Pro Pro

130

Pro Ser Gln Ser Asp

135

Gln Leu Leu Ala Glu

140

Ser Ser Ala Arg Pro 145

Gln Leu Glu Leu His 150

Leu Arg Pro Gln Ala 155

Arg Gly Arg Arg Arg

165

Ala Arg Ala Arg Asn

170

Gly Asp His Cys Pro

175

Gly Pro Gly Arg Cys

180

Cys Arg Leu His Thr

185

Val Arg Ala Ser Leu

190

Asp Leu Gly Trp Ala 195

Asp Trp Val Leu Ser 200

Pro Arg Glu Val Gln

205

Thr Met Cys Ile Gly

210

Ala Cys Pro Ser Gln 215

Phe Arg Ala Ala Asn 220

His Ala Gln Ile Lys 225

Thr Ser Leu His Arg 230

Leu Lys Pro Asp Thr 235

Glu

Glu

Asn

Val

Ala 80

Phe

Leu

Leu

Ser

Ala 160

Leu

Glu

Val

Met

Val 240

- 158 046387

Pro Ala Pro Cys Cys Val Pro Ala

245

Ser Tyr Asn Pro Met Val Leu Ile

250

255

Gln Lys Thr Asp Thr Gly Val 260

Ser Leu Gln Thr Tyr Asp Asp Leu Leu

265

270

Ala Lys Asp Cys His Cys Ile 275 <210> 9 <211> 816 <212> DNA <213> Mus sp.

<400> 9 tcgcaggggg aacgccgacg agccgagagg gaggtgagat cagggtctcc cgcccctggg cccgcattac acgcagctgg cacccaagag gcaactcttg agcatgtgcg aaagcacgcc agctacaccc gatgacctgg acgccctggc agctacgggg actcgaactc tggggtccca ccgaag ccta acatcactag gcctgcgcct aactgcgctt actcgtgccc aagacttggg tgggcgagtg tgcatggcct cggtggttct tggcccgggg aatgcctgaa tcgcttccag agaaccaagt cggccagctg ccgcgtgcac gcccctgaag gacgccgcct acgggtagcc actgggtccg ctggag cgac tccccacctg gcagcctgac tatgcacagg ctgccactgc cagcgaccct gacctgctga cctgacccag ctactccgcg cgagcgctgc cgtgcgctca ccggacctgg gccggcaggg gggcgctgct tgggtgctgt tatcgctccg aaggtgcctg acagacagtg gcttga ccggccctga gccggctgca ctgtccggat tcaaccgggc tcctgctgac gcctccgggg ctatgctgcc ggcgccgaag gtcact tgga ccccgcgcca cgaacacgca ccccgtgctg gtgtgtcact gtcccaactc tgccaaccag actcagtcca gtcgctgagt gccgacggcc accccgtgct ctctggcggc cgcgcatgcg gactgtgcag gctgcagctg tgcgcagatc tgtcccctcc gcagacttat

120

180

240

300

360

420

480

540

600

660

720

780

816 <210> 10 <211> 271 <212> PRT <213> Mus sp.

<400>

Ser

Gln

Gly

Asp

Ala 5

Leu

Ala

Met

Pro

Glu

Gln

Arg

Pro

Ser

Gly

Pro

Glu

Ser

Gln

Leu 20

Asn

Ala

Asp

Glu

Leu 25

Arg

Gly

Arg

Phe

Gln 30

Asp

Leu

Leu

Ser

Arg 35

Leu

His

Ala

Asn

Gln 40

Ser

Arg

Glu

Asp

Ser 45

Asn

Ser

Glu

- 159 046387

Pro Ser Pro Asp Pro 50

Ala Val Arg Ile Leu 55

Ser Pro Glu Val Arg 60

Gly Ser His Gly Gln 65

Leu Leu Leu Arg Val 70

Asn Arg Ala Ser Leu 75

Gln Gly Leu Pro Glu

Ala Tyr Arg Val His

Arg Ala Leu Leu Leu

Thr Pro Thr Ala Arg

100

Pro Trp Asp Ile Thr

105

Arg Pro Leu Lys Arg

110

Leu Ser Leu Arg Gly 115

Pro Arg Ala Pro Ala

120

Leu Arg Leu Arg Leu 125

Pro Pro Pro Asp Leu

130

Ala Met Leu Pro Ser

135

Gly Gly Thr Gln Leu 140

Leu Arg Leu Arg Val 145

Ala Ala Gly Arg Gly 150

Arg Arg Ser Ala His 155

His Pro Arg Asp Ser

165

Cys Pro Leu Gly Pro

170

Gly Arg Cys Cys His

175

Glu Thr Val Gln Ala

180

Thr Leu Glu Asp Leu

185

Gly Trp Ser Asp Trp

190

Leu Ser Pro Arg Gln

195

Leu Gln Leu Ser Met

200

Cys Val Gly Glu Cys

205

His Leu Tyr Arg Ser 210

Ala Asn Thr His Ala

215

Gln Ile Lys Ala Arg

220

His Gly Leu Gln Pro 225

Asp Lys Val Pro Ala 230

Pro Cys Cys Val Pro 235

Ser Tyr Thr Pro Val

245

Val Leu Met His Arg

250

Thr Asp Ser Gly Val

255

Leu

Ser 80

Leu

Ala

Thr

Glu

Ala 160

Leu

Val

Pro

Leu

Ser 240

Ser

Leu Gln Thr Tyr Asp

260

Asp Leu Val Ala Arg

265

Gly Cys His Cys Ala

270 <210> 11 <211> 339 <212> DNA <213> Homo sapiens

- 160 046387 <400> 11 gcgcgcaacg gggaccactg tccgctcggg cccgggcgtt gctgccgtct gcacacggtc60 cgcgcgtcgc tggaagacct gggctgggcc gattgggtgc tgtcgccacg ggaggtgcaa120 gtgaccatgt gcatcggcg c gtgcccgagc cagttccggg cggcaaacat gcacgcgcag180 atcaagacga gcctgcaccg cctgaagccc gacacggtgc cagcgccctg ctgcgtgccc240 gccagctaca atcccatggt gctcattcaa aagaccgaca ccggggtgtc gctccagacc300 tatgatgact tgttag ccaa agactgccac tgcatatga339 <210> 12 <211> 112 < 212> PRT <213> Homo sapiens <400> 12

Ala Arg Asn Gly Asp His Cys Pro Leu Gly Pro Gly Arg Cys Cys Arg

5 1015

Leu His Thr Val Arg Ala Ser Leu Glu Asp Leu Gly Trp Ala AspTrp

2530

Val Leu Ser Pro Arg Glu Val Gln Val Thr Met Cys Ile Gly Ala Cys

4045

Pro Ser Gln Phe Arg Ala Ala Asn Met His Ala Gln Ile Lys Thr Ser 50 5560

Leu His Arg Leu Lys Pro Asp Thr Val Pro Ala Pro Cys Cys Val Pro 65 70 7580

Ala Ser Tyr Asn Pro Met Val Leu Ile Gln Lys Thr Asp Thr Gly Val 85 9095

Ser Leu Gln Thr Tyr Asp Asp Leu Leu Ala Lys Asp Cys His Cys Ile

100 105110 <210> 13 <211> 351 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide <400> 13 atgagcgcgc atgcgcaccc aagagactcg tgcccactgg gtccggggcg ctgctgtcac 60 ctggagactg tgcaggcaac tcttgaagac ttgggctgga gcgactgggt gttgtccccg 120

- 161 046387

cgccagctgc agctgagcat gtgcgtggggc gagtgtcccc acctgtatcg ctccgcgaac 180 acgcatgcgc agatcaaagc acgcctgcat ggcctgcagc ctgacaaggt gcctgccccg 240 tgctgtgtcc cctccagcta caccccggtg gttcttatgc acaggacaga cagtggtgtg 300 tcactgcaga cttatgatga cctggtggcc cggggctgcc actgcgcttg a 351

<210> 14 <211> 116 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 14

Met Ser Ala His Ala His Pro Arg Asp Ser Cys Pro Leu Gly Pro Gly

5 1015

Arg Cys Cys His Leu Glu Thr Val Gln Ala Thr Leu Glu Asp LeuGly

2530

Trp Ser Asp Trp Val Leu Ser Pro Arg Gln Leu Gln Leu Ser Met Cys 35 4045

Val Gly Glu Cys Pro His Leu Tyr Arg Ser Ala Asn Thr His Ala Gln 50 5560

Ile Lys Ala Arg Leu His Gly Leu Gln Pro Asp Lys Val Pro Ala Pro 65 70 7580

Cys Cys Val Pro Ser Ser Tyr Thr Pro Val Val Leu Met His Arg Thr 85 9095

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

100 105110

Cys His Cys Ala

115 <210> 15 <211> 12 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=description of artificial sequence: synthetic peptide <400> 15

- 162 046387

Glu Arg Lys Ser Ser Val Glu Cys Pro Pro Cys Pro 1 5 10 <210> 16 <211> 216 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 16

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

5 1015

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

2530

Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 4045

Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 5560

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

70 7580

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

9095

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

100 105110

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

115 120125

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

130 135140

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

145 150 155160

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

165 170175

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

180 185190

- 163 046387

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

210 215 <210> 17 <211> 217 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 17

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

5 1015

Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 2530

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

4045

Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 5560

Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 7580

Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 9095

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

100 105110

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

115 120125

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

130 135140

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

145 150 155160

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

165 170175

- 164 046387

Val Ser Lys Leu Thr Val Asp Lys

180

Ser Arg Trp Gln Gln Gly Asn Val

185 190

Phe Ser Cys

195

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

200 205

Lys Ser Leu Ser Leu Ser Pro Gly Lys

210 215 <210> 18 <211> 20 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic peptide <400> 18

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

5 10 15

Gly Gly Gly Ser <210> 19 <211> 1047 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=description of artificial sequence: synthetic polynucleotide

<400> 19 gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 180 ccgcgggagg agcagtacaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 ccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtacacc 360 ctgcccccat cccgggatga gctgaccaag aaccaggtca gcctgtggtg cctggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tggggagagca atggggcagcc ggagaacaac 480 tacaagacca cgcctcccgt gctggactcc gacggctcct tcttcctcta cagcaagctc 540 accgtggac agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccggggtgg aggtggtgga 660

- 165 046387

tccggagaggcg gtggaagcgg aggtggtgga tctggaggcg gtggaagcgc gcgcaacgga 720 gaccactgtc cgctcgggcc cgggcgttgc tgccgtctgc acacggtccg cgcgtcgctg 780 gaagacctgg gctgggccga ttgggtgctg tcgccacggg aggtgcaagt gaccatgtgc 840 atcggcgcgt gcccgagcca gttccggggcg gcaaacatgc acgcgcagat caagacgagc 900 ctgcaccgcc tgaagcccga cacggtgcca gcgccctgct gcgtgcccgc cagctacaat 960 cccatggtgc tcattcaaaa gaccgacacc ggggtgtcgc tccagaccta tgatgacttg 1020 ttagccaaag actgccactg catatga 1047

<210> 20 <211> 348 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 20

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

5 1015

Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 2530

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

4045

Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 5560

Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 7580

Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 9095

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

100 105110

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

115 120125

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

130 135140

- 166 046387

Ser 145

Asp

Ile

Ala

Val

Glu

150

Trp

Glu

Ser

Asn

Gly

155

Gln

Pro

Glu

Asn

Asn

160

Tyr

Lys

Thr

Thr

Pro

165

Pro

Val

Leu

Asp

Ser

170

Asp

Gly

Ser

Phe

Phe

175

Leu

Tyr

Ser

Lys

Leu

180

Thr

Val

Asp

Lys

Ser

185

Arg

Trp

Gln

Gln

Gly

190

Asn

Val

Phe

Ser

Cys 195

Ser

Val

Met

His

Glu

200

Ala

Leu

His

Asn

His

205

Tyr

Thr

Gln

Lys

Ser

210

Leu

Ser

Leu

Ser

Pro

215

Gly

Gly

Gly

Gly

Gly

220

Ser

Gly

Gly

Gly

Gly

225

Ser

Gly

Gly

Gly

Gly

230

Ser

Gly

Gly

Gly

Gly

235

Ser

Ala

Arg

Asn

Gly

240

Asp

His

Cys

Pro

Leu

245

Gly

Pro

Gly

Arg

Cys 250

Cys

Arg

Leu

His

Thr

255

Val

Arg

Ala

Ser

Leu

260

Glu

Asp

Leu

Gly

Trp 265

Ala

Asp

Trp

Val

Leu

270

Ser

Pro

Arg

Glu

Val

275

Gln

Val

Thr

Met

Cys 280

Ile

Gly

Ala

Cys

Pro

285

Ser

Gln

Phe

Arg

Ala

290

Ala

Asn

Met

His

Ala

295

Gln

Ile

Lys

Thr

Ser 300

Leu

His

Arg

Leu

Lys

305

Pro

Asp

Thr

Val

Pro

310

Ala

Pro

Cys

Cys

Val

315

Pro

Ala

Ser

Tyr

Asn

320

Pro

Met

Val

Leu

Ile

325

Gln

Lys

Thr

Asp

Thr

330

Gly

Val

Ser

Leu

Gln

335

Thr

Tyr

Asp

Asp

Leu

340

Leu

Ala

Lys

Asp

Cys 345

His

Cys

Ile <210>

<211>

<212>

<213>

654

DNA

Artificial sequence <220>

<221>

<223>

source/note=''description of artificial sequence: synthetic polynucleotide <400>

- 167 046387

gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 180 ccgcgggagg agcagtacaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 ccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtacacc 360 ctgcccccat cccgggatga gctgaccaag aaccaggtca gcctgagctg cgcggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tggggagagca atggggcagcc ggagaacaac 480 tacaagacca cgcctcccgt gctggactcc gacggctcct tcttcctcgt cagcaagctc 540 accgtggac agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccgggtaa atga 654

<210> 22 <211> 216 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 22

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

5 1015

Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 2530

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

4045

Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 5560

Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 7580

Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 9095

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

100 105110

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

- 168 046387

Thr

Lys 130

115

Asn

Gln

Val

Ser

Leu

135

120

Thr

Cys

Leu

Val

Lys 140

125

Gly

Phe

Tyr

Pro

Ser

145

Asp

Ile

Ala

Val

Glu

150

Trp

Glu

Ser

Asn

Gly 155

Gln

Pro

Glu

Asn

Asn

160

Tyr

Asp

Thr

Thr

Pro

165

Pro

Val

Leu

Asp

Ser

170

Asp

Gly

Ser

Phe

Phe

175

Leu

Tyr

Ser

Asp

Leu

180

Thr

Val

Asp

Lys

Ser

185

Arg

Trp

Gln

Gln

Gly 190

Asn

Val

Phe

Ser

Cys 195

Ser

Val

Met

His

Glu

200

Ala

Leu

His

Asn

His

205

Tyr

Thr

Gln

Lys Ser Leu Ser Leu Ser Pro Gly

210 215 <210> 23 <211> 1046 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide

<400> 23 cacctgaact cctgggggga ccgtcagtct tcctcttccc cccaaaaccc aaggacacc 60 tcatgatctc ccggacccct gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc 120 ctgaggtcaa gttcaactgg tacgtggacg gcgtggaggt gcataatgcc aagacaaagc 180 cgcggggaga gcagtacaac agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc 240 aggactggct gaatggcaag gagtacaagt gcaaggtctc caacaaagcc ctcccagccc 300 ccatcgagaa aaccatctcc aaagccaaag ggcagccccg agaaccacag gtgaccacc 360 tgcccccatc ccggggagg atgaccaaga accaggtcag cctgacctgc ctggtcaaag 420 gcttctatcc cagcgacatc gccgtggagt ggggagagcaa tggggcagccg gagaacaact 480 acgacaccac gcctcccgtg ctggactccg acggctcctt cttcctctat agcgacctca 540 ccgtggacaa gagcaggtgg cagcagggga acgtcttctc atgctccgtg atgcatgagg 600 ctctgcacaa ccactacacg cagaagagcc tctccctgtc tccggggtgga ggtggtggat 660 ccggaggcgg tggaagcgga ggtggtggat ctggaggcgg tggaagcgcg cgcaacggag 720 accactgtcc gctcgggccc gggcgttgct gccgtctgca cacggtccgc gcgtcgctgg 780

- 169 046387

aagacctggg ctggggccgat tgggtgctgt cgccacggga ggtgcaagtg accatgtgca 840 tcggcgcgtg cccgagccag ttccggggcgg caaacatgca cgcgcagatc aagacgagcc 900 tgcaccgcct gaagcccgac acggtgccag cgccctgctg cgtgcccgcc agctacaatc 960 ccatggtgct cattcaaaag accgacaccg gggtgtcgct ccagacctat gatgacttgt 1020 tagccaaaga ctgccactgc atatga 1046

<210> 24 <211> 348 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 24

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

5 1015

Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 2530

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

4045

Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 5560

Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 7580

Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 9095

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

100 105110

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

115 120125

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

130 135140

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

145 150 155160

- 170 046387

Tyr

Asp

Thr

Thr

Pro

165

Pro

Val

Leu

Asp

Ser

170

Asp

Gly

Ser

Phe

Phe

175

Leu

Tyr

Ser

Asp

Leu

180

Thr

Val

Asp

Lys

Ser

185

Arg

Trp

Gln

Gln

Gly 190

Asn

Val

Phe

Ser

Cys 195

Ser

Val

Met

His

Glu

200

Ala

Leu

His

Asn

His

205

Tyr

Thr

Gln

Lys

Ser

210

Leu

Ser

Leu

Ser

Pro

215

Gly

Gly

Gly

Gly

Gly 220

Ser

Gly

Gly

Gly

Gly 225

Ser

Gly

Gly

Gly

Gly 230

Ser

Gly

Gly

Gly

Gly 235

Ser

Ala

Arg

Asn

Gly 240

Asp

His

Cys

Pro

Leu

245

Gly

Pro

Gly

Arg

Cys 250

Cys

Arg

Leu

His

Thr

255

Val

Arg

Ala

Ser

Leu

260

Glu

Asp

Leu

Gly

Trp

265

Ala

Asp

Trp

Val

Leu

270

Ser

Pro

Arg

Glu

Val

275

Gln

Val

Thr

Met

Cys 280

Ile

Gly

Ala

Cys

Pro

285

Ser

Gln

Phe

Arg

Ala

290

Ala

Asn

Met

His

Ala

295

Gln

Ile

Lys

Thr

Ser

300

Leu

His

Arg

Leu

Lys

305

Pro

Asp

Thr

Val

Pro

310

Ala

Pro

Cys

Cys

Val

315

Pro

Ala

Ser

Tyr

Asn

320

Pro

Met

Val

Leu

Ile

325

Gln

Lys

Thr

Asp

Thr

330

Gly

Val

Ser

Leu

Gln

335

Thr

Tyr

Asp

Asp

Leu

340

Leu

Ala

Lys

Asp

Cys 345

His

Cys

Ile <210> 25 <211> 112 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=’’description of artificial sequence: synthetic polypeptide <400> 25

Ala Arg Asn Gly Asp Asp Cys Pro Leu Gly Pro Gly Arg Cys Cys Arg

5 10 15

- 171 046387

Leu His Thr Val Arg Ala Ser Leu

Glu Asp Leu Gly Trp Ala Asp Trp 25 30

Val Leu Ser Pro Arg Glu Val Gln

40

Val Thr Met Cys Ile Gly Ala Cys 45

Pro Ser Gln Phe Arg Ala Ala Asn

55

Met His Ala Gln Ile Lys Thr Ser 60

Leu His Arg Leu Lys Pro Asp Thr 65 70

Val Pro Ala Pro Cys Cys Val Pro

80

Ala Ser Tyr Asn Pro Met Val Leu 85

Ile Gln Lys Thr Asp Thr Gly Val

95

Ser Leu Gln Thr Tyr Asp Asp Leu

100

Leu Ala Lys Asp Cys His Cys Ile

105 110 <210> 26 <211> 1047 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide <400> 26

gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 180 ccgcgggagg agcagtacaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 ccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgaccacc 360 ctgcccccat cccggggaga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tggggagagca atggggcagcc ggagaacaac 480 tacgacacca cgcctcccgt gctggactcc gacggctcct tcttcctcta tagcgacctc 540 accgtggac agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccggggtgg aggtggtgga 660 tccggagaggcg gtggaagcgg aggtggtgga tctggaggcg gtggaagcgc gcgcaacgga 720 gacgactgtc cgctcgggcc cggggcgttgc tgccgtctgc acacggtccg cgcgtcgctg 780 gaagacctgg gctggggccga ttgggtgctg tcgccacggg aggtgcaagt gaccatgtgc 840

- 172 046387

atcggcgcgt gccccgagcca gttccggggcg gcaaacatgc acgcgcagat caagacgagc 900 ctgcaccgcc tgaagcccga cacggtgcca gcgccctgct gcgtgcccgc cagctacaat 960 cccatggtgc tcattcaaaa gaccgacacc ggggtgtcgc tccagaccta tgatgacttg 1020 ttagccaaag actgccactg catatga 1047

<210> 27 <211> 348 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 27

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

5 1015

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

2530

Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 4045

Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 5560

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

70 7580

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

9095

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

100 105110

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

115 120125

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

130 135140

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

145 150 155160

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

165 170175

- 173 046387

Tyr

Ser

Asp

Leu

180

Thr

Val

Asp

Lys

Ser

185

Arg

Trp

Gln

Gln

Gly 190

Asn

Val

Phe

Ser

Cys 195

Ser

Val

Met

His

Glu

200

Ala

Leu

His

Asn

His

205

Tyr

Thr

Gln

Lys

Ser

210

Leu

Ser

Leu

Ser

Pro

215

Gly

Gly

Gly

Gly

Gly 220

Ser

Gly

Gly

Gly

Gly 225

Ser

Gly

Gly

Gly

Gly 230

Ser

Gly

Gly

Gly

Gly

235

Ser

Ala

Arg

Asn

Gly 240

Asp

Asp

Cys

Pro

Leu

245

Gly

Pro

Gly

Arg

Cys 250

Cys

Arg

Leu

His

Thr

255

Val

Arg

Ala

Ser

Leu

260

Glu

Asp

Leu

Gly

Trp 265

Ala

Asp

Trp

Val

Leu

270

Ser

Pro

Arg

Glu

Val

275

Gln

Val

Thr

Met

Cys 280

Ile

Gly

Ala

Cys

Pro

285

Ser

Gln

Phe

Arg

Ala

290

Ala

Asn

Met

His

Ala

295

Gln

Ile

Lys

Thr

Ser

300

Leu

His

Arg

Leu

Lys

305

Pro

Asp

Thr

Val

Pro

310

Ala

Pro

Cys

Cys

Val

315

Pro

Ala

Ser

Tyr

Asn

320

Pro

Met

Val

Leu

Ile

325

Gln

Lys

Thr

Asp

Thr

330

Gly

Val

Ser

Leu

Gln

335

Thr

Tyr

Asp

Asp

Leu

340

Leu

Ala

Lys

Asp

Cys 345

His

Cys

Ile <210> 28 <211> 230 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 28

Gly Gly Gly Glu Arg Lys Ser Ser Val Glu Cys Pro Pro Cys Pro Ala

5 1015

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

2530

- 174 046387

Asp Thr Leu Met Ile Ser Arg Thr

40

Pro Glu Val

Thr Cys Val Val Val

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

5560

Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe 65 70 7580

Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gln Asp 85 9095

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

100 105110

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

115 120125

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

130 135140

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

145 150 155160

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

165 170175

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

180 185190

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

195 200205

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

210 215220

Leu Ser Leu Ser Pro Gly

225230 <210> 29 <211> 227 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide

- 175 046387 <400> 29

Glu Arg Lys Ser Ser 1 5

Val Glu Cys Pro Pro

Cys Pro Ala Pro Pro

Ala Gly Pro Ser Val

Phe Leu Phe Pro Pro

Lys Pro Lys Asp Thr

Met Ile Ser Arg Thr 35

Pro Glu Val Thr Cys 40

Val Val Val Asp Val 45

His Glu Asp Pro Glu 50

Val Gln Phe Asn Trp 55

Tyr Val Asp Gly Val 60

Val His Asn Ala Lys 65

Thr Lys Pro Arg Glu 70

Glu Gln Phe Asn Ser 75

Phe Arg Val Val Ser 85

Val Leu Thr Val Val

His Gln Asp Trp Leu

Gly Lys Glu Tyr Lys

100

Cys Lys Val Ser Asn

105

Lys Gly Leu Pro Ala

110

Ile Glu Lys Thr Ile 115

Ser Lys Thr Lys Gly 120

Gln Pro Arg Glu Pro 125

Val Tyr Thr Leu Pro

130

Pro Ser Arg Glu Glu 135

Met Thr Lys Asn Gln 140

Ser Leu Thr Cys Leu 145

Val Lys Gly Phe Tyr 150

Pro Ser Asp Ile Ala 155

Glu Trp Glu Ser Asn

165

Gly Gln Pro Glu Asn

170

Asn Tyr Lys Thr Thr

175

Pro Met Leu Asp Ser

180

Asp Gly Ser Phe Phe

185

Leu Tyr Ser Lys Leu

190

Val Asp Lys Ser Arg

195

Trp Gln Gln Gly Asn

200

Val Phe Ser Cys Ser 205

Met His Glu Ala Leu

210

His Asn His Tyr Thr

215

Gln Lys Ser Leu Ser 220

Val

Leu

Ser

Glu

Thr 80

Asn

Pro

Gln

Val

Val 160

Pro

Thr

Val

Leu

Ser Pro Gly 225 <210> 30 <211> 21

- 176 046387 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic peptide <400> 30

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

5 10 15

Gly Gly Gly Gly Ser <210> 31 <211> 1833 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide

<400> 31 ggaggtggag agcgcaaatc ttctgtcgag tgccaccgt gccagcacc acctgtggca 60 ggaccgtcag tcttcctctt ccccccaaaa cccaaggaca ccctcatgat ctcccggacc 120 cctgaggtca cgtgcgtggt ggtggacgtg agccacgaag accccgaggt ccagttcaac 180 tggtacgtgg acggcgtgga ggtgcataat gccaagacaa aaccacggga ggagcagttc 240 aacagcacgt tccgtgtggt cagcgtcctc accgttgtgc accaggactg gctgaacggc 300 aaggagtaca agtgcaaggt ctccaacaaa ggcctcccag ccccatcga gaaaaccatc 360 tccaaaacca aagggcagcc ccgagaacca caggtgtaca ccctgccccc atcccggggag 420 gagatgacca agaaccaggt cagcctgacc tgcctggtca aaggcttcta ccccagcgac 480 atcgccgtgg agggggagag caatggggcag ccggagaaca actacaagac cacacctccc 540 atgctggact ccgacggctc cttcttcctc tacagcaagc tcaccgtgga caagagcagg 600 tggcagcagg ggaacgtctt ctcatgctcc gtgatgcatg aggctctgca caaccactac 660 acgcagaaga gcctctccct gtctccggggt ggaggtggcg gtagcggtgg cggaggttca 720 ggtggcggcg gaagcggtgg aggaggttca gagcggaaat ccagcgttga atgtcctccg 780 tgccctgctc cacccgtcgc ggggcctagt gtcttccttt tccctccaaa accaaaggat 840 acactgatga tcagccggac ccccgaggtt acgtgcgtcg tcgtcgatgt ctcccacgag 900 gatccagagg tccaattcaa ctggtacgtg gacggggtcg aggtgcataa tgcaaagaca 960 aagccacggg aagagcagtt taactctact ttccgcgtgg tttctgtgct gaccgtggtg 1020 caccaagatt ggctcaacgg caaggagtac aagtgcaagg taagcaataa ggggctccct 1080

- 177 046387

gcccccattg agaagactat ctccaagaca aagggacagc cacgcgagcc acaagtctat 1140 acactcccc cttcccgcga agaaatgacc aagaatcagg ttagcctgac atgcttggtt 1200 aagggtttct acccctctga catagccgtg gagtggggaga gcaatggaca accagagaac 1260 aactacaaga ccaccccacc catgctggat agcgacggtt cattctttct gtatagtaag 1320 cttaccgtgg acaagtcccg gtggcaacaa ggaaatgtct tttcatgctc tgtgatgcac 1380 gaggccttgc ataatcacta tactcagaag agcttgagcc tcagccccgg atctggaggt 1440 ggcggatccg ggggcggtgg aagcggaggt ggtggatcgg gagggcggtgg aagcgcgcgc 1500 aacggcgacc actgtccgct cggggcccgga cgttgctgcc gtctgcacac ggtccgcgcg 1560 tcgctggaag acctggggctg ggccgattgg gtgctgtcgc caggggggt gcaagtgacc 1620 atgtgcatcg gcgcgtgccc gagccagttc cggggcggcaa acatgcacgc gcagatcaag 1680 acgagcctgc accgcctgaa gccccgacacg gtgccagcgc cctgctgcgt gcccgccagc 1740 tacaatccca tggtgctcat tcaaaagacc gacaccgggg tgtcgctcca gacctatgat 1800 gacttgttag ccaaagactg ccactgcata tga 1833

<210> 32 <211> 610 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 32

Gly Gly Gly Glu Arg Lys Ser Ser Val Glu Cys Pro Pro Cys Pro Ala

5 1015

Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 20 2530

Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 35 4045

Asp Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp 50 5560

Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe 65 70 7580

Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gln Asp 85 9095

- 178 046387

Trp Leu Asn Gly Lys

100

Glu Tyr Lys Cys Lys

105

Val Ser Asn Lys Gly

110

Pro Ala Pro Ile Glu

115

Lys Thr Ile Ser Lys

120

Thr Lys Gly Gln Pro

125

Glu Pro Gln Val Tyr

130

Thr Leu Pro Pro Ser

135

Arg Glu Glu Met Thr 140

Asn Gln Val Ser Leu 145

Thr Cys Leu Val Lys 150

Gly Phe Tyr Pro Ser 155

Ile Ala Val Glu Trp

165

Glu Ser Asn Gly Gln

170

Pro Glu Asn Asn Tyr

175

Thr Thr Pro Pro Met

180

Leu Asp Ser Asp Gly

185

Ser Phe Phe Leu Tyr

190

Lys Leu Thr Val Asp

195

Lys Ser Arg Trp Gln

200

Gln Gly Asn Val Phe 205

Cys Ser Val Met His

210

Glu Ala Leu His Asn

215

His Tyr Thr Gln Lys

220

Leu Ser Leu Ser Pro 225

Gly Gly Gly Gly Gly 230

Ser Gly Gly Gly Gly 235

Gly Gly Gly Gly Ser

245

Gly Gly Gly Gly Ser

250

Glu Arg Lys Ser Ser

255

Glu Cys Pro Pro Cys

260

Pro Ala Pro Pro Val

265

Ala Gly Pro Ser Val

270

Leu Phe Pro Pro Lys

275

Pro Lys Asp Thr Leu 280

Met Ile Ser Arg Thr 285

Glu Val Thr Cys Val

290

Val Val Asp Val Ser

295

His Glu Asp Pro Glu

300

Gln Phe Asn Trp Tyr 305

Val Asp Gly Val Glu 310

Val His Asn Ala Lys 315

Lys Pro Arg Glu Glu

325

Gln Phe Asn Ser Thr

330

Phe Arg Val Val Ser

335

Leu Thr Val Val His

340

Gln Asp Trp Leu Asn

345

Gly Lys Glu Tyr Lys

350

Leu

Arg

Lys

Asp 160

Lys

Ser

Ser

Ser

Ser 240

Val

Phe

Pro

Val

Thr 320

Val

Cys

- 179 046387

Lys Val Ser Asn Lys

355

Gly Leu Pro Ala Pro 360

Ile Glu Lys Thr Ile

365

Lys Thr Lys Gly Gln

370

Pro Arg Glu Pro Gln 375

Val Tyr Thr Leu Pro

380

Ser Arg Glu Glu Met 385

Thr Lys Asn Gln Val 390

Ser Leu Thr Cys Leu 395

Lys Gly Phe Tyr Pro

405

Ser Asp Ile Ala Val

410

Glu Trp Glu Ser Asn

415

Gln Pro Glu Asn Asn

420

Tyr Lys Thr Thr Pro

425

Pro Met Leu Asp Ser

430

Gly Ser Phe Phe Leu 435

Tyr Ser Lys Leu Thr 440

Val Asp Lys Ser Arg

445

Gln Gln Gly Asn Val

450

Phe Ser Cys Ser Val 455

Met His Glu Ala Leu

460

Asn His Tyr Thr Gln 465

Lys Ser Leu Ser Leu 470

Ser Pro Gly Ser Gly 475

Gly Gly Ser Gly Gly

485

Gly Gly Ser Gly Gly

490

Gly Gly Ser Gly Gly

495

Gly Ser Ala Arg Asn

500

Gly Asp His Cys Pro

505

Leu Gly Pro Gly Arg

510

Cys Arg Leu His Thr 515

Val Arg Ala Ser Leu

520

Glu Asp Leu Gly Trp 525

Asp Trp Val Leu Ser

530

Pro Arg Glu Val Gln

535

Val Thr Met Cys Ile

540

Ala Cys Pro Ser Gln 545

Phe Arg Ala Ala Asn 550

Met His Ala Gln Ile 555

Thr Ser Leu His Arg

565

Leu Lys Pro Asp Thr

570

Val Pro Ala Pro Cys

575

Val Pro Ala Ser Tyr

580

Asn Pro Met Val Leu

585

Ile Gln Lys Thr Asp

590

Gly Val Ser Leu Gln

595

Thr Tyr Asp Asp Leu 600

Leu Ala Lys Asp Cys 605

Ser

Pro

Val 400

Gly

Asp

Trp

His

Gly 480

Gly

Cys

Ala

Gly

Lys 560

Cys

Thr

His

- 180 046387

Cys Ile

610 <210> 33 <211> 218 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 33

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

5 1015

Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr 20 2530

Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe Asn 35 4045

Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 50 5560

Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val 65 70 7580

Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 85 9095

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

100 105110

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

115 120125

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

130 135140

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

145 150 155160

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

165 170175

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

180 185190

- 181 046387

Asn Val Phe Ser Cys 195

Ser Val Met

200

His Glu Ala Leu His Asn His Tyr

205

Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

210 215 <210> 34 <211> 25 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=’’description of artificial sequence: synthetic peptide <400> 34

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

5 10 15

Gly Gly Gly Ser Gly Gly Gly Gly Ser 20 25 <210> 35 <211> 215 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=description of artificial sequence: synthetic polypeptide <400> 35

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

5 1015

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val 20 2530

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

4045

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln 50 5560

Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gln 65 70 7580

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly 85 9095

- 182 046387

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

100 105110

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

115 120125

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

130 135140

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

145 150 155160

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

165 170175

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

180 185190

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

195 200205

Ser Leu Ser Leu Ser Pro Gly 210215 <210> 36 <211> 1809 <212> DNA <213> Artificial Sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide

<400> 36 ggcggtggag ctccgccggt ggctggaccc tcagtgttcc tctttccacc gaagccgaag 60 gacaccctta tgattagccg gaccccagag gtcacttgcg tcgtcgtgga cgtgtcccat 120 gaggatcccg aagtgcagtt taactggtat gtggacggag tggaggtcca taacgccaag 180 accaagccaa gggaagaaca gttcaatagc accttccgggg tggtgtccgt gctcaccgtg 240 gtgcatcaag actggctgaa tggcaaagag tacaaatgta aggtgtcaaa caaggggctc 300 ccagccccta ttgaaaagac catctcaaag actaagggac agccacgcga acctcaagtg 360 tataccctcc cgccttcacg cgaagaaatg actaagaatc aggtcagcct tacttgtctg 420 gtcaagggct tctacccgag cgacattgca gtcgaatggg agagcaatgg tcagccagag 480 aataactaca agaccactcc tcccatgctt gataggatg gaagcttttt cctttacagc 540 aagcttactg tggataagtc tcgctggcaa cagggaaatg tgttcagctg ttcagtgatg 600

- 183 046387

catgaagcac tccacaatca ttacacccag aagtcactca gcctctcacc cggagaggagga 660 ggcggttctg gtggaggagg gtctggaggt gggagggagcg gcggaggcgg gtctggcggt 720 ggtgggtctg aggaagtc atcagtggaa tgccccacat gccctgctcc tcccgtggcc 780 ggtccgagcg tgtttctctt cccacctaag cccaaggaca ctctgatgat ctcacggact 840 ccggaagtga cttgtgtggt ggtggacgtg tctcatgagg accctgaagt gcagttcaac 900 tggtacgtgg acggcgtgga ggtgcacaat gctaagacca agcctagaga ggaacagttc 960 aattccacct ttcgcgtggt gagcgtcctg accgtcgtgc accaggactg gcttaacgga 1020 aaggaataca agtgcaaggt gtccaacaaa ggccttccag ctcccattga gaaaaccatc 1080 tctaaaacta agggtcaacc aagggaaccc caagtctaca ccctccctcc gtctagagaa 1140 gagatgacca aaaaccaggt gtccctgacc tgtctggtga agggattta cccctcagac 1200 atcgccgtgg agtgggaaag caacggacag cccgaaaaca actataagac tacccctcct 1260 atgctggact cagacggatc tttcttcctc tatagcaagc tcactgtgga caaatccaga 1320 tggcaacaag ggaatgtgtt ctcatgcagc gtgatgcacg aggctcttca caaccactat 1380 acccagaaga gcctgtctct ttcacctggt tccggaggtg gtgggagcgg aggggtgga 1440 tcaggtggtg gagggtccgg aggcggagga tccgcacgga atggcgacca ctgtccactg 1500 ggacccggaa gatgttgtcg cctccacacc gtgaggggcct ctctggagga ccttggctgg 1560 gccgactggg tcctgtcacc tcgggaggtc caagtcacca tgtgtatcgg agcctgcccc 1620 agccaattca gagcagcaaa tatgcacgca cagattaaga ccagcctgca tcggcttaaa 1680 cctgatactg tgccggctcc ttgttgcgtg ccagcatctt acaacccgat ggtgctgats 1740 cagaaaaccg ataccggtgt ctccctccag acttacgacg acctccttgc aaaggactgc 1800

1809 cattgcatc <210> 37 <211> 591 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 37

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

5 10 15

Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr 20 25 30

- 184 046387

Cys Val Val Val Asp Val Ser His Glu

40

Trp Tyr Val Asp Gly Val Glu Val His

55

Glu Glu Gln Phe Asn Ser Thr Phe Arg 65 70

Val His Gln Asp Trp Leu Asn Gly Lys 85

Asn Lys Gly Leu Pro Ala Pro Ile Glu

100 105

Gly Gln Pro Arg Glu Pro Gln Val Tyr

115 120

Glu Met Thr Lys Asn Gln Val Ser Leu

130 135

Tyr Pro Ser Asp Ile Ala Val Glu Trp

145 150

Asn Asn Tyr Lys Thr Thr Pro Pro Met

165

Phe Leu Tyr Ser Lys Leu Thr Val Asp

180 185

Asn Val Phe Ser Cys Ser Val Met His

195 200

Thr Gln Lys Ser Leu Ser Leu Ser Pro

210 215

Gly Gly Gly Ser Gly Gly Gly Gly Ser

225 230

Gly Gly Ser Ala Pro Pro Val Ala Gly

245

Pro Lys Pro Lys Asp Thr Leu Met Ile

260 265

Cys Val Val Val Asp Val Ser His Glu

275 280

Pro Glu Val Gln Phe Asn

Ala Lys Thr Lys Pro Arg 60

Val Ser Val Leu Thr Val

80

Tyr Lys Cys Lys Val Ser 95

Thr Ile Ser Lys Thr Lys

110

Leu Pro Pro Ser Arg Glu

125

Cys Leu Val Lys Gly Phe

140

Ser Asn Gly Gln Pro Glu

155 160

Asp Ser Asp Gly Ser Phe

175

Ser Arg Trp Gln Gln Gly

190

Ala Leu His Asn His Tyr

205

Gly Gly Gly Gly Ser Gly

220

Gly Gly Gly Ser Gly Gly

235 240

Ser Val Phe Leu Phe Pro

255

Arg Thr Pro Glu Val Thr

270

Pro Glu Val Gln Phe Asn

285

- 185 046387

Trp

Glu 305

Val

Asn

Gly

Glu

Tyr 385

Asn

Phe

Asn

Thr

Gly 465

Arg

His

Leu

Ser

Tyr Val Asp Gly Val 290

Glu Gln Phe Asn Ser

310

His Gln Asp Trp Leu

325

Lys Gly Leu Pro Ala

340

Gln Pro Arg Glu Pro

355

Met Thr Lys Asn Gln 370

Pro Ser Asp Ile Ala

390

Asn Tyr Lys Thr Thr

405

Leu Tyr Ser Lys Leu 420

Val Phe Ser Cys Ser

435

Gln Lys Ser Leu Ser 450

Gly Gly Gly Ser Gly

470

Asn Gly Asp His Cys

485

Thr Val Arg Ala Ser 500

Ser Pro Arg Glu Val

515

Gln Phe Arg Ala Ala 530

Glu Val His Asn Ala 295

Thr Phe Arg Val Val

315

Asn Gly Lys Glu Tyr

330

Pro Ile Glu Lys Thr 345

Gln Val Tyr Thr Leu

360

Val Ser Leu Thr Cys 375

Val Glu Trp Glu Ser

395

Pro Pro Met Leu Asp

410

Thr Val Asp Lys Ser 425

Val Met His Glu Ala

440

Leu Ser Pro Gly Ser 455

Gly Gly Gly Ser Gly

475

Pro Leu Gly Pro Gly

490

Leu Glu Asp Leu Gly 505

Gln Val Thr Met Cys 520

Asn Met His Ala Gln 535

Lys Thr Lys Pro Arg 300

Ser Val Leu Thr Val

320

Lys Cys Lys Val Ser

335

Ile Ser Lys Thr Lys 350

Pro Pro Ser Arg Glu

365

Leu Val Lys Gly Phe 380

Asn Gly Gln Pro Glu

400

Ser Asp Gly Ser Phe

415

Arg Trp Gln Gln Gly

430

Leu His Asn His Tyr 445

Gly Gly Gly Gly Ser 460

Gly Gly Gly Ser Ala

480

Arg Cys Cys Arg Leu

495

Trp Ala Asp Trp Val 510

Ile Gly Ala Cys Pro

525

Ile Lys Thr Ser Leu 540

- 186 046387

His Arg Leu Lys Pro Asp Thr Val

545 550

Pro Ala Pro Cys Cys Val Pro Ala

555 560

Ser Tyr Asn Pro Met Val

565

Leu Ile Gln Lys Thr Asp Thr Gly Val

570 575

Ser

Leu Gln Thr Tyr Asp Asp Leu Leu Ala Lys Asp Cys His Cys

580 585 590

Ile <210> 38 <211> 216 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 38

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

5 1015

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

2530

Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 4045

Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 5560

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

70 7580

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

9095

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

100 105110

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

115 120125

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

130 135140

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

145 150 155160

- 187 046387

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

165 170175

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

180 185190

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

195 200205

Lys Ser Leu Ser Leu Ser Pro Gly

210215 <210> 39 <211> 217 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 39

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

5 1015

Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 2530

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

4045

Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 5560

Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 7580

Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 9095

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

100 105110

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

115 120125

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

130 135140

- 188 046387

Ser 145

Asp

Ile

Ala

Val

Glu

150

Trp

Glu

Ser

Asn

Gly 155

Gln

Pro

Glu

Asn

Asn

160

Tyr

Asp

Thr

Thr

Pro

165

Pro

Val

Leu

Asp

Ser

170

Asp

Gly

Ser

Phe

Phe

175

Leu

Tyr

Ser

Asp

Leu

180

Thr

Val

Asp

Lys

Ser

185

Arg

Trp

Gln

Gln

Gly 190

Asn

Val

Phe

Ser

Cys 195

Ser

Val

Met

His

Glu

200

Ala

Leu

His

Asn

His

205

Tyr

Thr

Gln

Lys

Ser

210

Leu

Ser

Leu

Ser

Pro

215

Gly

Lys <210> 40 <211> 23 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic peptide <400> 40

Gly Ser Gly Ser Ala Thr Gly Gly Ser Gly Ser Val Ala Ser Ser Gly

5 10 15

Ser Gly Ser Ala Thr His Leu <210> 41 <211> 1053 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=description of artificial sequence: synthetic polynucleotide

<400> 41 gccccagagc tgcttggtgg accatccgtg ttcctgtttc ctccaaagcc gaaggacacc 60 ctgatgatct caagaactcc ggaagtgact tgcgtcgtcg tggacgtgtc acatgaggat 120 ccagaggtca agttcaattg gtatgtggac ggagtggaag tgcataacgc caagaccaaa 180 ccccgcgaag aacagtacaa tagcacctac cgcgtggtga gcgtccttac tgtgctccac 240 caggactggc ttaatgggaa ggaatacaag tgtaaggtgt ccaacaaggc cctccccgct 300 cccatcgaaa agaccatctc aaaggcaaag gggcaaccaa gggaacctca agtgtacacc 360

- 189 046387

ctgcctccga gcaggaagga gatgaccaag aaccaggtca gcctgacttg tctcgtgaag 420 ggcttctatc ccagcgatat tgctgtggaa tggggagtcaa atggccagcc cgagaataac 480 tacaaaacta ccccacccgt gctgaaatct gatgggtcct tcttccttta ctccaagctg 540 accgtggac agagccgctg gcaacaaggc aatgtcttta gctgctcagt gatgcatgag 600 gctctccata atcactacac tcagaagtca ctgtccctgt cacctggcgg atccggttct 660 gctactggtg gttccggctc cgtcgcaagc tctggttcag gcagtgcgac tcatctggca 720 cggaacgggg accattgtcc cctggggacct ggtcggtgct gccggcttca caccgtcaga 780 gcctctctgg aggaccttgg atgggctgat tgggtgctga gccctcggga ggtgcaagtc 840 accatgtgca tcggggcctg ccctagccag ttccgcgcag ccaacatgca cgctcagatc 900 aaaacctctc ttcacagact gaagcccgac accgtgccag caccttgctg tgtgccggcc 960 tcttataacc ccatggtcct cattcagaaa accgacaccg gagtgtcact tcagacttac 1020 gatgacctcc tggccaagga ctgccactgc ata 1053

<210> 42 <211> 351 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 42

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

5 1015

Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 2530

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

4045

Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 5560

Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 7580

Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 9095

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

100 105110

- 190 046387

Pro Arg Glu

115

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

120 125

Thr Lys Asn

130

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

135 140

Ser Asp Ile 145

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

150 155

Tyr Lys Thr

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

165 170 175

Tyr Ser Lys

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

180 185 190

Phe Ser Cys

195

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

200 205

Lys Ser Leu

210

Ser Leu Ser Pro Gly Gly Ser Gly Ser Ala Thr Gly

215 220

Ser Gly Ser 225

Val Ala Ser Ser Gly Ser Gly Ser Ala Thr His Leu

230 235

Arg Asn Gly

Asp His Cys Pro Leu Gly Pro Gly Arg Cys Cys Arg

245 250 255

His Thr Val

Arg Ala Ser Leu Glu Asp Leu Gly Trp Ala Asp Trp

260 265 270

Leu Ser Pro

275

Arg Glu Val Gln Val Thr Met Cys Ile Gly Ala Cys

280 285

Ser Gln Phe

290

Arg Ala Ala Asn Met His Ala Gln Ile Lys Thr Ser

295 300

His Arg Leu 305

Lys Pro Asp Thr Val Pro Ala Pro Cys Cys Val Pro

310 315

Ser Tyr Asn

Pro Met Val Leu Ile Gln Lys Thr Asp Thr Gly Val

325 330 335

Met

Pro

Asn 160

Leu

Val

Gln

Gly

Ala 240

Leu

Val

Pro

Leu

Ala 320

Ser

Leu Gln Thr

Tyr Asp Asp Leu Leu Ala Lys Asp Cys His Cys Ile

340 345 350 <210> 43

- 191 046387 <211> 651 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide

<400> 43 gcgccggaac tgctggggcgg cccgagcgtg tttctgtttc cgccgaaacc gaaagatacc 60 ctgatgatta gccgcacccc ggaagtgacc tgcgtggtgg tggatgtgag ccatgaagat 120 ccggaagtga aatttaactg gtatgtggat ggcgtggaag tgcataacgc gaaaaccaaa 180 ccgcgcgaag aacagtataa cagcacctat cgcgtggtga gcgtgctgac cgtgctgcat 240 caggattggc tgaacggcaa agaatataaa tgcaaagtga gcaacaaagc gctgccggcg 300 ccgattgaaa aaaccattag caaagcgaaa ggccagccgc gcgaaccgca ggtgtatacc 360 ctgccgccga gccgcgaaga aatgaccaaa aaccaggtga gcctgacctg cctggtgaaa 420 ggcttttatc cgagcgatat tgcggtggaa tgggaaagca acggccagcc ggaaaacaac 480 tatgatacca ccccgccggt gctggatagc gatggcagct tttttctgta tagcgatctg 540 accgtggata aaagccgctg gcagcagggc aacgtgttta gctgcagcgt gatgcatgaa 600 gcgctgcata accattatac ccagaaaagc ctgagcctga gcccggggcaa a 651

<210> 44 <211> 216 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=description of artificial sequence: synthetic polypeptide <400> 44

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

5 1015

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

2530

Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 4045

Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 5560

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

70 7580

- 192 046387

Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 9095

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

100 105110

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

115 120125

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

130 135140

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

145 150 155160

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

165 170175

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

180 185190

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

195 200205

Lys Ser Leu Ser Leu Ser Pro Gly

210215 <210> 45 <211> 984 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide

<400> 45 gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 180 ccgcgggagg agcagtacaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 ccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgaccacc 360 ctgcccccat cccggggaga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tggggagagca atggggcagcc ggagaacaac 480

- 193 046387

tacgacacca cgcctcccgt gctggactcc gacggctcct tcttcctcta tagcgacctc 540 accgtggac agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccgggtgc gcgcaacgga 660 gaccactgtc cgctcgggcc cggggcgttgc tgccgtctgc acacggtccg cgcgtcgctg 720 gaagacctgg gctggggccga ttgggtgctg tcgccacggg aggtgcaagt gaccatgtgc 780 atcggcgcgt gcccgagcca gttccggggcg gcaaacatgc acgcgcagat caagacgagc 840 ctgcaccgcc tgaagcccga cacggtgcca gcgccctgct gcgtgcccgc cagctacaat 900 cccatggtgc tcattcaaaa gaccgacacc ggggtgtcgc tccagaccta tgatgacttg 960 ttagccaaag actgccactg cata 984

<210> 46 <211> 328 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 46

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

5 1015

Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 2530

Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 4045

Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 5560

Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 7580

Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 9095

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

100 105110

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

115 120125

- 194 046387

Thr Lys Asn Gln Val Ser Leu Thr

130 135

Cys Leu Val

Lys Gly Phe Tyr Pro

140

Ser Asp Ile Ala Val Glu Trp Glu

145 150

Ser Asn Gly Gln Pro Glu Asn Asn

155 160

Tyr Asp Thr Thr Pro Pro Val

165

Leu Asp

Ser Asp Gly Ser Phe Phe Leu

170 175

Tyr Ser Asp 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 Ala Arg Asn Gly Asp His Cys Pro

210 215 220

Leu Gly Pro Gly Arg Cys Cys Arg Leu His Thr Val Arg Ala Ser Leu

225 230 235 240

Glu Asp Leu Gly Trp Ala Asp Trp Val Leu Ser Pro Arg Glu Val Gln

245 250 255

Val Thr Met Cys

260

Ile Gly Ala Cys Pro Ser Gln Phe Arg Ala Ala Asn

265 270

Met His Ala Gln

275

Ile Lys Thr Ser Leu His Arg Leu Lys Pro Asp Thr

280 285

Val Pro Ala Pro Cys Cys Val Pro Ala

290 295

Ser Tyr Asn Pro Met Val Leu

300

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

305 310 315 320

Leu Ala Lys Asp Cys His Cys Ile

325 <210> 47 <211> 217 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 47

- 195 046387

Ala Pro Glu Leu Leu

5

Gly Gly Pro Ser Val

Phe Leu Phe Pro Pro

Pro Lys Asp Thr Leu

Met Ile Ser Arg Thr

Pro Glu Val Thr Cys

Val Val Asp Val Ser 35

His Glu Asp Pro Glu 40

Val Lys Phe Asn Trp 45

Val Asp Gly Val Glu 50

Val His Asn Ala Lys 55

Thr Lys Pro Arg Glu 60

Gln Tyr Asn Ser Thr 65

Tyr Arg Val Val Ser 70

Val Leu Thr Val Leu 75

Gln Asp Trp Leu Asn

Gly Lys Glu Tyr Lys

Cys Lys Val Ser Asn 95

Ala Leu Pro Ala Pro

100

Ile Glu Lys Thr Ile

105

Ser Lys Ala Lys Gly

110

Pro Arg Glu Pro Gln 115

Val Tyr Thr Leu Pro

120

Pro Ser Arg Lys Glu 125

Thr Lys Asn Gln Val

130

Ser Leu Thr Cys Leu 135

Val Lys Gly Phe Tyr

140

Ser Asp Ile Ala Val 145

Glu Trp Glu Ser Asn 150

Gly Gln Pro Glu Asn 155

Tyr Lys Thr Thr Pro

165

Pro Val Leu Lys Ser

170

Asp Gly Ser Phe Phe

175

Tyr Ser Lys Leu Thr

180

Val Asp Lys Ser Arg

185

Trp Gln Gln Gly Asn

190

Phe Ser Cys Ser Val 195

Met His Glu Ala Leu

200

His Asn His Tyr Thr 205

Lys

Val

Tyr

Glu

His 80

Lys

Gln

Met

Pro

Asn 160

Leu

Val

Gln

Lys Ser Leu Ser Leu 210

Ser Pro Gly Lys

215 <210> 48 <211> 216 <212> PRT <213> Artificial sequence <220>

<221> source

- 196 046387 <223>

/note=''description of the artificial sequence:

synthetic polypeptide <400> 48

Ala Pro Glu Leu 1

Leu Gly Gly Pro 5

Ser Val Phe Leu

Phe Pro Pro Lys 15

Pro Lys Asp Thr

Leu Met Ile Ser

Arg Thr Pro Glu 25

Val Thr Cys Val 30

Val Val Asp Val

Ser His Glu Asp 40

Pro Glu Val Lys

Phe Asn Trp Tyr 45

Val Asp Gly Val 50

Glu Val His Asn

Ala Lys Thr Lys 60

Pro Arg Glu Glu

Gln Tyr Asn Ser 65

Thr Tyr Arg Val 70

Val Ser Val Leu

Thr Val Leu His

Gln Asp Trp Leu

Asn Gly Lys Glu 85

Tyr Lys Cys Lys 90

Val Ser Asn Lys

Ala Leu Pro Ala

100

Pro Ile Glu Lys

Thr Ile Ser Lys 105

Ala Lys Gly Gln 110

Pro Arg Glu Pro

115

Gln Val Tyr Thr

120

Leu Pro Pro Ser

Arg Glu Glu Met 125

Thr Lys Asn Gln 130

Val Ser Leu Thr

135

Cys Leu Val Lys

140

Gly Phe Tyr Pro

Ser Asp Ile Ala 145

Val Glu Trp Glu

150

Ser Asn Gly Gln

155

Pro Glu Asn Asn

160

Tyr Asp Thr Thr

Pro Pro Val Leu 165

Asp Ser Asp Gly

170

Ser Phe Phe Leu

175

Tyr Ser Asp Leu

180

Thr Val Asp Lys

Ser Arg Trp Gln 185

Gln Gly Asn Val

190

Phe Ser Cys Ser

195

Val Met His Glu

200

Ala Leu His Asn

His Tyr Thr Gln 205

Lys Ser Leu Ser Leu Ser Pro Gly

210 215 <210> 49 <211> 984 <212> DNA

- 197 046387 <213> Artificial sequence <220>

<221> source <223> /note=description of artificial sequence: synthetic polynucleotide” <400> 49

gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 180 ccgcgggagg agcagtacaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 ccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtacacc 360 ctgcccccat cccggggaga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tggggagagca atggggcagcc ggagaacaac 480 tacgacacca cgcctcccgt gctggactcc gacggctcct tcttcctcta tagcgacctc 540 accgtggac agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccgggtgc gcgcaacgga 660 gaccactgtc cgctcgggcc cggggcgttgc tgccgtctgc acacggtccg cgcgtcgctg 720 gaagacctgg gctggggccga ttgggtgctg tcgccacggg aggtgcaagt gaccatgtgc 780 atcggcgcgt gcccgagcca gttccggggcg gcaaacatgc acgcgcagat caagacgagc 840 ctgcaccgcc tgaagcccga cacggtgcca gcgccctgct gcgtgcccgc cagctacaat 900 cccatggtgc tcattcaaaa gaccgacacc ggggtgtcgc tccagaccta tgatgacttg 960 ttagccaaag actgccactg cata 984

<210> 50 <211> 328 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=description of artificial sequence: synthetic polypeptide” <400> 50

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

5 10 15

Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 25 30

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

- 198 046387

40 45

Val

Gln 65

Gln

Ala

Pro

Thr

Ser 145

Tyr

Tyr

Phe

Lys

Leu 225

Glu

Val

Met

Asp Gly Val Glu Val 50

His Asn Ala Lys Thr 55

Lys Pro Arg Glu Glu 60

Tyr Asn Ser Thr Tyr

Arg Val Val Ser Val 75

Leu Thr Val Leu His

Asp Trp Leu Asn Gly

Leu Pro Ala Pro Ile

100

Arg Glu Pro Gln Val 115

Lys Asn Gln Val Ser 130

Asp Ile Ala Val Glu

150

Asp Thr Thr Pro Pro

165

Ser Asp Leu Thr Val

180

Ser Cys Ser Val Met

195

Ser Leu Ser Leu Ser 210

Gly Pro Gly Arg Cys

230

Asp Leu Gly Trp Ala

245

Thr Met Cys Ile Gly 260

His Ala Gln Ile Lys

275

Lys Glu Tyr Lys Cys

Lys Val Ser Asn Lys

Glu Lys Thr Ile Ser 105

Lys Ala Lys Gly Gln

110

Tyr Thr Leu Pro Pro

120

Leu Thr Cys Leu Val 135

Trp Glu Ser Asn Gly

155

Val Leu Asp Ser Asp

170

Asp Lys Ser Arg Trp 185

His Glu Ala Leu His

200

Pro Gly Ala Arg Asn 215

Cys Arg Leu His Thr

235

Asp Trp Val Leu Ser

250

Ala Cys Pro Ser Gln 265

Thr Ser Leu His Arg

280

Ser Arg Glu Glu Met

125

Lys Gly Phe Tyr Pro 140

Gln Pro Glu Asn Asn

160

Gly Ser Phe Phe Leu

175

Gln Gln Gly Asn Val

190

Asn His Tyr Thr Gln

205

Gly Asp His Cys Pro 220

Val Arg Ala Ser Leu

240

Pro Arg Glu Val Gln

255

Phe Arg Ala Ala Asn

270

Leu Lys Pro Asp Thr

285

- 199 046387

Val Pro Ala Pro Cys Cys Val Pro

290 295

Ala Ser Tyr Asn Pro Met Val Leu

300

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

305 310 315 320

Leu Ala Lys Asp Cys His Cys Ile

325 <210> 51 <211> 654 <212> DNA <213>

Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide <400> 51 gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac120 cctgaggt ca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag180 ccgcgggagg agcagtacaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc300 cccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtacacc360 ctgcccccat cccggaagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa420 ggcttctatc ccagcgacat cgccgtggag tgggagagca atggg cagcc ggagaacaac480 tacaagacca cgcctcccgt gctgaagtcc gacggctcct tcttcctcta tagcaagctc540 accgtggaca agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccgggtaa atga654 <210> 52 <211> 112 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=description of artificial sequence: synthetic polypeptide <400> 52

Ala Arg Asp Gly Asp His Cys Pro Leu Gly Pro Gly Arg Cys Cys Arg

5 10 15

Leu His Thr Val Arg Ala Ser Leu Glu Asp Leu Gly Trp Ala Asp Trp 20 25 30

- 200 046387

Val Leu Ser Pro Arg Glu Val Gln

40

Val Thr Met Cys Ile Gly Ala Cys 45

Pro Ser Gln Phe Arg Ala Ala Asn

55

Met His Ala Gln Ile Lys Thr Ser 60

Leu His Arg Leu Lys Pro Asp Thr 65 70

Val Pro Ala Pro Cys Cys Val Pro

80

Ala Ser Tyr Asn Pro Met Val Leu 85

Ile Gln Lys Thr Asp Thr Gly Val

95

Ser Leu Gln Thr Tyr Asp Asp Leu

100

Leu Ala Lys Asp Cys His Cys Ile

105 110 <210> 53 <211> 984 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide <400> 53

gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 180 ccgcgggagg agcagtacaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 ccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtacacc 360 ctgcccccat cccggggaga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tggggagagca atggggcagcc ggagaacaac 480 tacgacacca cgcctcccgt gctggactcc gacggctcct tcttcctcta tagcgacctc 540 accgtggac agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccgggtgc gcgcgacgga 660 gaccactgtc cgctcgggcc cggggcgttgc tgccgtctgc acacggtccg cgcgtcgctg 720 gaagacctgg gctggggccga ttgggtgctg tcgccacggg aggtgcaagt gaccatgtgc 780 atcggcgcgt gcccgagcca gttccggggcg gcaaacatgc acgcgcagat caagacgagc 840 ctgcaccgcc tgaagcccga cacggtgcca gcgccctgct gcgtgcccgc cagctacaat 900

- 201 046387 cccatggtgc tcattcaaaa gaccgacacc ggggtgtcgc tccagaccta tgatgacttg 960 ttagccaaag actgccactg cata

984 <210> 54 <211> 328 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 54

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

5 1015

Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 2530

Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 4045

Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 5560

Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 7580

Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 9095

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

100 105110

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

115 120125

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

130 135140

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

145 150 155160

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

165 170175

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

180 185190

- 202 046387

Phe Ser Cys Ser Val Met His Glu Ala Leu His

195 200

Asn His Tyr Thr Gln

205

Lys Ser Leu Ser Leu Ser Pro Gly Ala Arg Asp Gly Asp His Cys Pro

210 215 220

Leu Gly Pro Gly Arg Cys Cys Arg Leu His Thr Val Arg Ala Ser Leu

225 230 235 240

Glu Asp Leu Gly Trp Ala Asp Trp Val

245

Leu Ser Pro Arg Glu Val Gln

250 255

Val Thr Met Cys Ile Gly Ala Cys Pro Ser Gln Phe Arg Ala Ala Asn

260 265 270

Met His Ala Gln Ile Lys Thr Ser Leu His Arg Leu Lys Pro Asp Thr

275 280 285

Val Pro Ala Pro Cys Cys Val Pro Ala Ser Tyr Asn Pro Met Val Leu

290 295 300

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

305 310 315 320

Leu Ala Lys Asp Cys His Cys Ile

325 <210> 55 <211> 109 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 55

Gly Asp His Cys Pro Leu Gly Pro Gly Arg Cys Cys Arg Leu His Thr

5 1015

Val Arg Ala Ser Leu Glu Asp Leu Gly Trp Ala Asp Trp Val LeuSer

2530

Pro Arg Glu Val Gln Val Thr Met Cys Ile Gly Ala Cys Pro Ser Gln 35 4045

Phe Arg Ala Ala Asn Met His Ala Gln Ile Lys Thr Ser Leu His Arg

5560

- 203 046387

Leu Lys Pro Asp Thr Val Pro Ala 65 70

Pro Cys Cys

Val Pro Ala Ser Tyr

Asn Pro Met Val

Thr Tyr Asp Asp

100

Leu Ile Gln Lys Thr Asp Thr Gly Val Ser Leu Gln

90 95

Leu Leu Ala Lys Asp Cys His Cys Ile

105 <210> 56 <211> 975 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide <400> 56

gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 180 ccgcgggagg agcagtacaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 ccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtacacc 360 ctgcccccat cccggggaga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tggggagagca atggggcagcc ggagaacaac 480 tacgacacca cgcctcccgt gctggactcc gacggctcct tcttcctcta tagcgacctc 540 accgtggac agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccggggtgg agaccactgt 660 ccgctcgggc ccgggcgttg ctgccgtctg cacacggtcc gcgcgtcgct ggaagacctg 720 ggctgggccg attgggtgct gtcgccacgg gaggtgcaag tgaccatgtg catcggcgcg 780 tgcccgagcc agttccggggc ggcaaacatg cacgcgcaga tcaagacgag cctgcaccgc 840 ctgaagcccg acacggtgcc agcgccctgc tgcgtgcccg ccagctacaa tcccatggtg 900 ctcattcaaa agaccgacac cggggtgtcg ctccagacct atgatgactt gttagccaaa 960 gactgccact gcata 975

<210> 57 <211> 325 <212> PRT <213> Artificial sequence

- 204 046387 <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 57

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

5 1015

Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 2530

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

4045

Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 5560

Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 7580

Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 9095

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

100 105110

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

115 120125

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

130 135140

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

145 150 155160

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

165 170175

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

180 185190

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

195 200205

Lys Ser Leu Ser Leu Ser Pro Gly Gly Asp His Cys Pro Leu Gly Pro

210 215220

- 205 046387

Gly 225

Arg

Cys

Cys

Arg

Leu

230

His

Thr

Val

Arg

Ala

235

Ser

Leu

Glu

Asp

Leu

240

Gly

Trp

Ala

Asp

Trp

245

Val

Leu

Ser

Pro

Arg 250

Glu

Val

Gln

Val

Thr

255

Met

Cys

Ile

Gly

Ala

260

Cys

Pro

Ser

Gln

Phe

265

Arg

Ala

Ala

Asn

Met

270

His

Ala

Gln

Ile

Lys 275

Thr

Ser

Leu

His

Arg 280

Leu

Lys

Pro

Asp

Thr

285

Val

Pro

Ala

Pro

Cys 290

Cys

Val

Pro

Ala

Ser

295

Tyr

Asn

Pro

Met

Val

300

Leu

Ile

Gln

Lys

Thr

305

Asp

Thr

Gly

Val

Ser

310

Leu

Gln

Thr

Tyr

Asp

315

Asp

Leu

Leu

Ala

Lys 320

Asp Cys His Cys Ile

325 <210> 58 <211> 4 <212> PRT <213>

Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic peptide <400> 58

Gly Gly Gly Gly <210> 59 <211> 996 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=description of artificial sequence: synthetic polynucleotide

<400> 59 gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 180 ccgcgggagg agcagtacaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300

- 206 046387

ccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtacacc 360 ctgcccccat cccggggaga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tggggagagca atggggcagcc ggagaacaac 480 tacgacacca cgcctcccgt gctggactcc gacggctcct tcttcctcta tagcgacctc 540 accgtggac agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccggggtgg aggtggtgga 660 gcgcgcgacg gagaccactg tccgctcggg cccggggcgtt gctgccgtct gcacacggtc 720 cgcgcgtcgc tggaagacct gggctgggcc gattgggtgc tgtcgccacg ggaggtgcaa 780 gtgaccatgt gcatcggcgc gtgcccgagc cagttccgggg cggcaaacat gcacgcgcag 840 atcaagacga gcctgcaccg cctgaagccc gacacggtgc cagcgccctg ctgcgtgccc 900 gccagctaca atcccatggt gctcattcaa aagaccgaca ccggggtgtc gctccagacc 960 tatgatgact tgttagccaa agactgccac tgcata 996

<210> 60 <211> 332 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 60

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

5 1015

Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 2530

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

4045

Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 5560

Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 7580

Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 9095

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

100 105110

- 207 046387

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

115 120 125

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

130 135 140

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

145 150 155

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

165 170 175

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

180 185 190

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

195 200 205

Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Gly Ala Arg Asp

210 215 220

Asp His Cys Pro Leu Gly Pro Gly Arg Cys Cys Arg Leu His Thr

225 230 235

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

245 250 255

Arg Glu Val Gln Val Thr Met Cys Ile Gly Ala Cys Pro Ser Gln

260 265 270

Arg Ala Ala Asn Met His Ala Gln Ile Lys Thr Ser Leu His Arg

275 280 285

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

290 295 300

Pro Met Val Leu Ile Gln Lys Thr Asp Thr Gly Val Ser Leu Gln

305 310 315

Met

Pro

Asn 160

Leu

Val

Gln

Gly

Val 240

Pro

Phe

Leu

Asn

Thr 320

Tyr Asp Asp Leu Leu Ala Lys Asp Cys His Cys Ile

325 330 <210> 61 <211> 5 <212> PRT <213> Artificial sequence

- 208 046387 <220> <221> source <223> /note=''description of artificial sequence: synthetic peptide <400> 61 Gly Gly Gly Gly Ser 1 5 <210> 62 <211> 1002 <212> DNA <213> Artificial sequence <220> <221> source <223> /note=''description of artificial sequence: synthetic polynucleotide

<400> 62 gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 180 ccgcgggagg agcagtacaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 ccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtacacc 360 ctgcccccat cccggggaga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tggggagagca atggggcagcc ggagaacaac 480 tacgacacca cgcctcccgt gctggactcc gacggctcct tcttcctcta tagcgacctc 540 accgtggac agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccggggtgg aggtggtgga 660 tccgcgcgca acggagacca ctgtccgctc gggcccggggc gttgctgccg tctgcacacg 720 gtccgcgcgt cgctggaaga cctggggctgg gccgattggg tgctgtcgcc acgggaggtg 780 caagtgacca tgtgcatcgg cgcgtgcccg agccagttcc gggcggcaaa catgcacgcg 840 cagatcaaga cgagcctgca ccgcctgaag cccgacacgg tgccagcgcc ctgctgcgtg 900 cccgccagct acaatcccat ggtgctcatt caaaagaccg acaccggggt gtcgctccag 960 acctatgatg acttgttagc caaagactgc cactgcatat ga 1002

<210> 63 <211> 333 <212> PRT <213> Artificial sequence <220>

<221> source

- 209 046387 <223>

/note=’’description of artificial sequence synthetic polypeptide <400> 63

Ala Pro Glu Leu 1

Leu Gly Gly Pro 5

Ser Val Phe Leu

Phe Pro Pro Lys 15

Pro Lys Asp Thr

Leu Met Ile Ser

Arg Thr Pro Glu 25

Val Thr Cys Val 30

Val Val Asp Val

Ser His Glu Asp 40

Pro Glu Val Lys

Phe Asn Trp Tyr 45

Val Asp Gly Val 50

Glu Val His Asn

Ala Lys Thr Lys 60

Pro Arg Glu Glu

Gln Tyr Asn Ser 65

Thr Tyr Arg Val 70

Val Ser Val Leu

Thr Val Leu His

Gln Asp Trp Leu

Asn Gly Lys Glu 85

Tyr Lys Cys Lys 90

Val Ser Asn Lys

Ala Leu Pro Ala

100

Pro Ile Glu Lys

Thr Ile Ser Lys 105

Ala Lys Gly Gln 110

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

115 120125

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

130 135140

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

145 150 155160

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

165 170175

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

180 185190

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

195 200205

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

210 215220

Gly Asp His Cys Pro Leu Gly Pro Gly Arg Cys Cys Arg Leu His Thr

225 230 235240

- 210 046387

Val Arg Ala Ser Leu Glu Asp Leu

245

Gly Trp Ala Asp Trp Val Leu Ser

250 255

Pro Arg Glu Val Gln Val Thr Met

260

Cys Ile Gly Ala Cys Pro Ser Gln

265 270

Phe Arg Ala Ala Asn Met His Ala

275 280

Gln Ile Lys Thr Ser Leu His Arg

285

Leu Lys Pro Asp Thr Val Pro Ala

290 295

Pro Cys Cys Val Pro Ala Ser Tyr

300

Asn Pro Met Val Leu Ile Gln Lys

305 310

Thr Asp Thr Gly Val Ser Leu Gln

315 320

Thr Tyr Asp Asp Leu Leu Ala Lys

325

Asp Cys His Cys Ile 330 <210> 64 <211> 10 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic peptide <400> 64

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser

5 10 <210> 65 <211> 1014 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=description of artificial sequence: synthetic polynucleotide <400> 65

gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 180 ccgcgggagg agcagtacaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 ccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtacacc 360

- 211 046387

ctgcccccat cccggggaga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tggggagagca atggggcagcc ggagaacaac 480 tacgacacca cgcctcccgt gctggactcc gacggctcct tcttcctcta tagcgacctc 540 accgtggac agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccggggtgg aggtggtgga 660 tccggagaggcg gtggaagcgc gcgcaacgga gaccactgtc cgctcgggcc cggggcgttgc 720 tgccgtctgc acacggtccg cgcgtcgctg gaagacctgg gctggggccga ttgggtgctg 780 tcgccacggg aggtgcaagt gaccatgtgc atcggcgcgt gccccgagcca gttccggggcg 840 gcaaacatgc acgcgcagat caagacgagc ctgcaccgcc tgaagcccga cacggtgcca 900 gcgccctgct gcgtgcccgc cagctacaat cccatggtgc tcattcaaaa gaccgacacc 960 ggggtgtcgc tccagaccta tgatgacttg ttagccaaag actgccactg cata 1014

<210> 66 <211> 338 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 66

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

5 1015

Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 2530

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

4045

Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 5560

Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 7580

Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 9095

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

100 105110

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

- 212 046387

115 120125

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

130 135140

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

145 150 155160

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

165 170175

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

180 185190

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

195 200205

Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly

210 215220

Gly Ser Ala Arg Asn Gly Asp His Cys Pro Leu Gly Pro Gly Arg Cys

225 230 235240

Cys Arg Leu His Thr Val Arg Ala Ser Leu Glu Asp Leu Gly Trp Ala

245 250255

Asp Trp Val Leu Ser Pro Arg Glu Val Gln Val Thr Met Cys Ile Gly

260 265270

Ala Cys Pro Ser Gln Phe Arg Ala Ala Asn Met His Ala Gln Ile Lys

275 280285

Thr Ser Leu His Arg Leu Lys Pro Asp Thr Val Pro Ala Pro Cys Cys

290 295300

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

305 310 315320

Gly Val Ser Leu Gln Thr Tyr Asp Asp Leu Leu Ala Lys Asp Cys His

325 330335

Cys Ile <210> 67 <211> 1014 <212> DNA <213> Artificial sequence

- 213 046387 <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide

<400> 67 gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 180 ccgcgggagg agcagtacaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 ccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtacacc 360 ctgcccccat cccggggaga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tggggagagca atggggcagcc ggagaacaac 480 tacgacacca cgcctcccgt gctggactcc gacggctcct tcttcctcta tagcgacctc 540 accgtggac agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccggggtgg aggtggtgga 660 tccggagaggcg gtggaagcgc gcgcgacgga gaccactgtc cgctcgggcc cggggcgttgc 720 tgccgtctgc acacggtccg cgcgtcgctg gaagacctgg gctggggccga ttgggtgctg 780 tcgccacggg aggtgcaagt gaccatgtgc atcggcgcgt gcccgagcca gttccggggcg 840 gcaaacatgc acgcgcagat caagacgagc ctgcaccgcc tgaagcccga cacggtgcca 900 gcgccctgct gcgtgcccgc cagctacaat cccatggtgc tcattcaaaa gaccgacacc 960 ggggtgtcgc tccagaccta tgatgacttg ttagccaaag actgccactg cata 1014

<210> 68 <211> 338 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=description of artificial sequence: synthetic polypeptide <400> 68

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

5 1015

Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 2530

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

4045

- 214 046387

Val

Gln 65

Gln

Ala

Pro

Thr

Ser 145

Tyr

Tyr

Phe

Lys

Gly 225

Cys

Asp

Ala

Thr

Asp Gly Val Glu Val 50

Tyr Asn Ser Thr Tyr

Asp Trp Leu Asn Gly

Leu Pro Ala Pro Ile

100

Arg Glu Pro Gln Val 115

Lys Asn Gln Val Ser 130

Asp Ile Ala Val Glu

150

Asp Thr Thr Pro Pro

165

Ser Asp Leu Thr Val

180

Ser Cys Ser Val Met

195

Ser Leu Ser Leu Ser 210

Ser Ala Arg Asp Gly

230

Arg Leu His Thr Val

245

Trp Val Leu Ser Pro

260

Cys Pro Ser Gln Phe

275

Ser Leu His Arg Leu

His Asn Ala Lys Thr 55

Lys Pro Arg Glu Glu 60

Arg Val Val Ser Val 75

Leu Thr Val Leu His

Lys Glu Tyr Lys Cys

Lys Val Ser Asn Lys

Glu Lys Thr Ile Ser 105

Tyr Thr Leu Pro Pro 120

Leu Thr Cys Leu Val 135

Trp Glu Ser Asn Gly

155

Val Leu Asp Ser Asp

170

Asp Lys Ser Arg Trp 185

His Glu Ala Leu His

200

Pro Gly Gly Gly Gly 215

Asp His Cys Pro Leu

235

Arg Ala Ser Leu Glu

250

Arg Glu Val Gln Val

265

Arg Ala Ala Asn Met 280

Lys Pro Asp Thr Val

Lys Ala Lys Gly Gln

110

Ser Arg Glu Glu Met

125

Lys Gly Phe Tyr Pro 140

Gln Pro Glu Asn Asn

160

Gly Ser Phe Phe Leu

175

Gln Gln Gly Asn Val

190

Asn His Tyr Thr Gln

205

Gly Ser Gly Gly Gly 220

Gly Pro Gly Arg Cys

240

Asp Leu Gly Trp Ala

255

Thr Met Cys Ile Gly 270

His Ala Gln Ile Lys

285

Pro Ala Pro Cys Cys

- 215 046387

290 295300

Val Pro Ala Ser Tyr Asn Pro Met Val Leu Ile Gln Lys Thr AspThr

305 310 315320

Gly Val Ser Leu Gln Thr Tyr Asp Asp Leu Leu Ala Lys Asp CysHis

325 330335

Cys Ile <210> 69 <211> 5 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic peptide <400> 69

Gly Gly Gly Gly Pro

5 <210> 70 <211> 999 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=description of artificial sequence: synthetic polynucleotide <400> 70

gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 180 ccgcgggagg agcagtacaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 ccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtacacc 360 ctgcccccat cccggggaga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tggggagagca atggggcagcc ggagaacaac 480 tacgacacca cgcctcccgt gctggactcc gacggctcct tcttcctcta tagcgacctc 540 accgtggac agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccggggtgg aggtggtgga 660

- 216 046387

cccgcgcgca acggagacca ctgtccgctc gggcccggggc gttgctgccg tctgcacacg 720 gtccgcgcgt cgctggaaga cctggggctgg gccgattggg tgctgtcgcc acgggaggtg 780 caagtgacca tgtgcatcgg cgcgtgcccg agccagttcc gggcggcaaa catgcacgcg 840 cagatcaaga cgagcctgca ccgcctgaag cccgacacgg tgccagcgcc ctgctgcgtg 900 cccgccagct acaatcccat ggtgctcatt caaaagaccg acaccggggt gtcgctccag 960 acctatgatg acttgttagc caaagactgc cactgcata 999

<210> 71 <211> 333 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 71

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

5 1015

Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 2530

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

4045

Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 5560

Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 7580

Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 9095

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

100 105110

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

115 120125

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

130 135140

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

145 150 155160

- 217 046387

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

165 170175

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

180 185190

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

195 200205

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

210 215220

Gly Asp His Cys Pro Leu Gly Pro Gly Arg Cys Cys Arg Leu His Thr

225 230 235240

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

245 250255

Pro Arg Glu Val Gln Val Thr Met Cys Ile Gly Ala Cys Pro Ser Gln

260 265270

Phe Arg Ala Ala Asn Met His Ala Gln Ile Lys Thr Ser Leu His Arg

275 280285

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

290 295300

Asn Pro Met Val Leu Ile Gln Lys Thr Asp Thr Gly Val Ser Leu Gln

305 310 315320

Thr Tyr Asp Asp

Leu Leu Ala Lys Asp Cys His Cys Ile

325330 <210> 72 <211> 10 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic peptide <400> 72

Gly Gly Gly Gly Pro Gly Gly Gly Gly Pro

5 10 <210> 73 <211> 1017 <212> DNA

- 218 046387 <213> Artificial sequence <220>

<221> source <223> /note=description of artificial sequence: synthetic polynucleotide”

<400> 73 gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 180 ccgcgggagg agcagtacaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 ccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtacacc 360 ctgcccccat cccggggaga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tggggagagca atggggcagcc ggagaacaac 480 tacgacacca cgcctcccgt gctggactcc gacggctcct tcttcctcta tagcgacctc 540 accgtggac agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccggggtgg aggtggtgga 660 cctggaggcg gtggaccagc gcgcaacgga gaccactgtc cgctcgggcc cggggcgttgc 720 tgccgtctgc acacggtccg cgcgtcgctg gaagacctgg gctggggccga ttgggtgctg 780 tcgccacggg aggtgcaagt gaccatgtgc atcggcgcgt gcccgagcca gttccggggcg 840 gcaaacatgc acgcgcagat caagacgagc ctgcaccgcc tgaagcccga cacggtgcca 900 gcgccctgct gcgtgcccgc cagctacaat cccatggtgc tcattcaaaa gaccgacacc 960 ggggtgtcgc tccagaccta tgatgacttg ttagccaaag actgccactg catatga 1017

<210> 74 <211> 338 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=description of artificial sequence: synthetic polypeptide” <400> 74

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

5 1015

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

2530

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

- 219 046387

40 45

Val

Gln 65

Gln

Ala

Pro

Thr

Ser 145

Tyr

Tyr

Phe

Lys

Gly 225

Cys

Asp

Ala

Asp Gly Val Glu Val 50

His Asn Ala Lys Thr 55

Lys Pro Arg Glu Glu 60

Tyr Asn Ser Thr Tyr

Arg Val Val Ser Val 75

Leu Thr Val Leu His

Asp Trp Leu Asn Gly

Leu Pro Ala Pro Ile

100

Arg Glu Pro Gln Val 115

Lys Asn Gln Val Ser 130

Asp Ile Ala Val Glu

150

Asp Thr Thr Pro Pro

165

Ser Asp Leu Thr Val

180

Ser Cys Ser Val Met

195

Ser Leu Ser Leu Ser 210

Pro Ala Arg Asn Gly

230

Arg Leu His Thr Val

245

Trp Val Leu Ser Pro 260

Cys Pro Ser Gln Phe

275

Lys Glu Tyr Lys Cys

Lys Val Ser Asn Lys

Glu Lys Thr Ile Ser 105

Lys Ala Lys Gly Gln

110

Tyr Thr Leu Pro Pro

120

Leu Thr Cys Leu Val 135

Trp Glu Ser Asn Gly

155

Val Leu Asp Ser Asp

170

Asp Lys Ser Arg Trp 185

His Glu Ala Leu His

200

Pro Gly Gly Gly Gly 215

Asp His Cys Pro Leu

235

Arg Ala Ser Leu Glu

250

Arg Glu Val Gln Val 265

Arg Ala Ala Asn Met

280

Ser Arg Glu Glu Met

125

Lys Gly Phe Tyr Pro 140

Gln Pro Glu Asn Asn

160

Gly Ser Phe Phe Leu

175

Gln Gln Gly Asn Val

190

Asn His Tyr Thr Gln

205

Gly Pro Gly Gly Gly 220

Gly Pro Gly Arg Cys

240

Asp Leu Gly Trp Ala

255

Thr Met Cys Ile Gly 270

His Ala Gln Ile Lys

285

- 220 046387

Thr Ser Leu His Arg Leu Lys Pro

290 295

Asp Thr Val

Pro Ala Pro Cys Cys

300

Val

305

Pro

Ala

Ser

Tyr

Asn

310

Pro

Met

Val

Leu

Ile

315

Gln

Lys

Thr

Asp

Thr

320

Gly

Val

Ser

Leu

Gln

325

Thr

Tyr

Asp

Asp

Leu

330

Leu

Ala

Lys

Asp

Cys 335

His

Cys Ile <210> 75 <211> 5 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic peptide <400> 75

Gly Gly Gly Gly Gln

5 <210> 76 <211> 1002 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=description of artificial sequence: synthetic polynucleotide

<400> 76 gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 180 ccgcgggagg agcagtacaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 ccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtacacc 360 ctgcccccat cccggggaga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tggggagagca atggggcagcc ggagaacaac 480 tacgacacca cgcctcccgt gctggactcc gacggctcct tcttcctcta tagcgacctc 540 actgtggac agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccggggtgg aggtggtgga 660

- 221 046387

caggcgcgca acggagacca ctgtccgctc gggcccggggc gttgctgccg tctgcacacg 720 gtccgcgcgt cgctggaaga cctggggctgg gccgattggg tgctgtcgcc acgggaggtg 780 caagtgacca tgtgcatcgg cgcgtgcccg agccagttcc gggcggcaaa catgcacgcg 840 cagatcaaga cgagcctgca ccgcctgaag cccgacacgg tgccagcgcc ctgctgcgtg 900 cccgccagct acaatcccat ggtgctcatt caaaagaccg acaccggggt gtcgctccag 960 acctatgatg acttgttagc caaagactgc cactgcatat ga 1002

<210> 77 <211> 333 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 77

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

5 1015

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

2530

Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 4045

Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 5560

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

70 7580

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

9095

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

100 105110

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

115 120125

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

130 135140

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

145 150 155160

- 222 046387

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

165 170175

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

180 185190

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

195 200205

Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Gly Gln Ala Arg Asn

210 215220

Gly Asp His Cys Pro Leu Gly Pro Gly Arg Cys Cys Arg Leu His Thr

225 230 235240

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

245 250255

Pro Arg Glu Val Gln Val Thr Met Cys Ile Gly Ala Cys Pro Ser Gln

260 265270

Phe Arg Ala Ala Asn Met His Ala Gln Ile Lys Thr Ser Leu His Arg

275 280285

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

290 295300

Asn Pro Met Val Leu Ile Gln Lys Thr Asp Thr Gly Val Ser Leu Gln

305 310 315320

Thr Tyr Asp Asp

Leu Leu Ala Lys Asp Cys His Cys Ile

325330 <210> 78 <211> 10 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic peptide <400> 78

Gly Gly Gly Gly Gln Gly Gly Gly Gly Gln

5 10 <210> 79 <211> 1017

- 223 046387 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=description of artificial sequence: synthetic polynucleotide”

<400> 79 gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 180 ccgcgggagg agcagtacaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 ccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtacacc 360 ctgcccccat cccggggaga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tggggagagca atggggcagcc ggagaacaac 480 tacgacacca cgcctcccgt gctggactcc gacggctcct tcttcctcta tagcgacctc 540 accgtggac agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccggggtgg aggtggtgga 660 cagggaggcg gtggacagggc gcgcaacgga gaccactgtc cgctcgggcc cggggcgttgc 720 tgccgtctgc acacggtccg cgcgtcgctg gaagacctgg gctggggccga ttgggtgctg 780 tcgccacggg aggtgcaagt gaccatgtgc atcggcgcgt gcccgagcca gttccggggcg 840 gcaaacatgc acgcgcagat caagacgagc ctgcaccgcc tgaagcccga cacggtgcca 900 gcgccctgct gcgtgcccgc cagctacaat cccatggtgc tcattcaaaa gaccgacacc 960 ggggtgtcgc tccagaccta tgatgacttg ttagccaaag actgccactg catatga 1017

<210> 80 <211> 338 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=description of artificial sequence: synthetic polypeptide” <400> 80

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

5 1015

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

2530

- 224 046387

Val

Val

Gln 65

Gln

Ala

Pro

Thr

Ser 145

Tyr

Tyr

Phe

Lys

Gly 225

Cys

Asp

Ala

Val Asp Val Ser His 35

Asp Gly Val Glu Val 50

Tyr Asn Ser Thr Tyr

Asp Trp Leu Asn Gly

Leu Pro Ala Pro Ile

100

Arg Glu Pro Gln Val 115

Lys Asn Gln Val Ser 130

Asp Ile Ala Val Glu

150

Asp Thr Thr Pro Pro

165

Ser Asp Leu Thr Val

180

Ser Cys Ser Val Met

195

Ser Leu Ser Leu Ser 210

Gln Ala Arg Asn Gly

230

Arg Leu His Thr Val

245

Trp Val Leu Ser Pro 260

Cys Pro Ser Gln Phe

275

Glu Asp Pro Glu Val 40

His Asn Ala Lys Thr 55

Arg Val Val Ser Val 75

Lys Glu Tyr Lys Cys

Glu Lys Thr Ile Ser 105

Tyr Thr Leu Pro Pro 120

Leu Thr Cys Leu Val 135

Trp Glu Ser Asn Gly

155

Val Leu Asp Ser Asp

170

Asp Lys Ser Arg Trp 185

His Glu Ala Leu His

200

Pro Gly Gly Gly Gly 215

Asp His Cys Pro Leu

235

Arg Ala Ser Leu Glu

250

Arg Glu Val Gln Val 265

Arg Ala Ala Asn Met 280

Lys Phe Asn Trp Tyr 45

Lys Pro Arg Glu Glu 60

Leu Thr Val Leu His

Lys Val Ser Asn Lys

Lys Ala Lys Gly Gln

110

Ser Arg Glu Glu Met

125

Lys Gly Phe Tyr Pro 140

Gln Pro Glu Asn Asn

160

Gly Ser Phe Phe Leu

175

Gln Gln Gly Asn Val

190

Asn His Tyr Thr Gln

205

Gly Gln Gly Gly Gly 220

Gly Pro Gly Arg Cys

240

Asp Leu Gly Trp Ala

255

Thr Met Cys Ile Gly 270

His Ala Gln Ile Lys

285

- 225 046387

Thr Ser Leu His Arg Leu Lys Pro Asp Thr Val Pro Ala Pro Cys Cys

290 295300

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

305 310 315320

Gly Val Ser Leu Gln Thr Tyr Asp Asp Leu Leu Ala Lys Asp Cys His

325 330335

Cys Ile <210> 81 <211> 1014 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide <400> 81

gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 180 ccgcgggagg agcagtacaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 ccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtacacc 360 ctgcccccat cccggggaga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tggggagagca atggggcagcc ggagaacaac 480 tacgacacca cgcctcccgt gctggactcc gacggctcct tcttcctcta tagcgacctc 540 accgtggac agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccggggtgg aggtggtgga 660 cagggaggcg gtggacagggc gcgcgacgga gaccactgtc cgctcgggcc cggggcgttgc 720 tgccgtctgc acacggtccg cgcgtcgctg gaagacctgg gctggggccga ttgggtgctg 780 tcgccacggg aggtgcaagt gaccatgtgc atcggcgcgt gcccgagcca gttccggggcg 840 gcaaacatgc acgcgcagat caagacgagc ctgcaccgcc tgaagcccga cacggtgcca 900 gcgccctgct gcgtgcccgc cagctacaat cccatggtgc tcattcaaaa gaccgacacc 960 ggggtgtcgc tccagaccta tgatgacttg ttagccaaag actgccactg cata 1014

- 226 046387 <210> 82 <211> 338 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 82

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

5 1015

Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 2530

Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 4045

Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 5560

Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 7580

Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 9095

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

100 105110

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

115 120125

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

130 135140

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

145 150 155160

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

165 170175

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

180 185190

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

195 200205

- 227 046387

Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Gly Gln Gly Gly Gly

210 215220

Gly Gln Ala Arg Asp Gly Asp His Cys Pro Leu Gly Pro Gly Arg Cys

225 230 235240

Cys Arg Leu His Thr Val Arg Ala Ser Leu Glu Asp Leu Gly Trp Ala

245 250255

Asp Trp Val Leu Ser Pro Arg Glu Val Gln Val Thr Met Cys Ile Gly

260 265270

Ala Cys Pro Ser Gln Phe Arg Ala Ala Asn Met His Ala Gln Ile Lys

275 280285

Thr Ser Leu His Arg Leu Lys Pro Asp Thr Val Pro Ala Pro Cys Cys

290 295300

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

305 310 315320

Gly Val Ser Leu Gln Thr Tyr Asp Asp Leu Leu Ala Lys Asp Cys His

325 330335

Cys Ile <210> 83 <211> 1005 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide <400> 83

gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 180 ccgcgggagg agcagtacaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 ccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtacacc 360 ctgcccccat cccggggaga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tggggagagca atggggcagcc ggagaacaac 480

- 228 046387

tacgacacca cgcctcccgt gctggactcc gacggctcct tcttcctcta tagcgacctc 540 accgtggac agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccggggtgg aggtggtgga 660 cagggaggcg gtggacaggg agaccactgt ccgctcgggc ccgggcgttg ctgccgtctg 720 cacacggtcc gcgcgtcgct ggaagacctg ggctgggccg attgggtgct gtcgccacgg 780 gaggtgcaag tgaccatgtg catcggcgcg tgcccgagcc agttccggggc ggcaaacatg 840 cacgcgcaga tcaagacgag cctgcaccgc ctgaagcccg acacggtgcc agcgccctgc 900 tgcgtgcccg ccagctacaa tcccatggtg ctcattcaaa agaccgacac cggggtgtcg 960 ctccagacct atgatgactt gttagccaaa gactgccact gcata 1005

<210> 84 <211> 335 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 84

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

5 1015

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

2530

Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 4045

Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 5560

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

70 7580

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

9095

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

100 105110

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

115 120125

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

- 229 046387

130 135140

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

145 150 155160

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

165 170175

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

180 185190

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

195 200205

Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Gly Gln Gly Gly Gly

210 215220

Gly Gln Gly Asp His Cys Pro Leu Gly Pro Gly Arg Cys Cys Arg Leu

225 230 235240

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

245 250255

Leu Ser Pro Arg Glu Val Gln Val Thr Met Cys Ile Gly Ala Cys Pro

260 265270

Ser Gln Phe Arg Ala Ala Asn Met His Ala Gln Ile Lys Thr Ser Leu

275 280285

His Arg Leu Lys Pro Asp Thr Val Pro Ala Pro Cys Cys Val Pro Ala

290 295300

Ser Tyr Asn Pro Met Val Leu Ile Gln Lys Thr Asp Thr Gly Val Ser

305 310 315320

Leu Gln Thr Tyr Asp Asp Leu Leu Ala Lys Asp Cys His Cys Ile

325 330335 <210> 85 <211> 216 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 85

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

- 230 046387

5 1015

Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 2530

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

4045

Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 5560

Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 7580

Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 9095

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

100 105110

Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Lys Glu Met

115 120125

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

130 135140

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

145 150 155160

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

165 170175

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

180 185190

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

195 200205

Lys Ser Leu Ser Leu Ser Pro Gly

210215 <210> 86 <211> 217 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic

- 231 046387 polypeptide” <400> 86 Ala Pro Glu Leu Leu 1 5

Gly Gly Pro Ser Val

Phe Leu Phe Pro Pro

Pro Lys Asp Thr Leu

Met Ile Ser Arg Thr 25

Pro Glu Val Thr Cys

Val Val Asp Val Ser 35

His Glu Asp Pro Glu 40

Val Lys Phe Asn Trp 45

Val Asp Gly Val Glu 50

Val His Asn Ala Lys 55

Thr Lys Pro Arg Glu 60

Gln Tyr Asn Ser Thr 65

Tyr Arg Val Val Ser 70

Val Leu Thr Val Leu 75

Gln Asp Trp Leu Asn

Gly Lys Glu Tyr Lys

Cys Lys Val Ser Asn 95

Ala Leu Pro Ala Pro

100

Ile Glu Lys Thr Ile

105

Ser Lys Ala Lys Gly

110

Pro Arg Glu Pro Gln 115

Val Cys Thr Leu Pro

120

Pro Ser Arg Glu Glu 125

Thr Lys Asn Gln Val

130

Ser Leu Thr Cys Leu 135

Val Lys Gly Phe Tyr

140

Ser Asp Ile Ala Val 145

Glu Trp Glu Ser Asn 150

Gly Gln Pro Glu Asn 155

Tyr Asp Thr Thr Pro

165

Pro Val Leu Asp Ser

170

Asp Gly Ser Phe Phe

175

Tyr Ser Asp Leu Thr

180

Val Asp Lys Ser Arg

185

Trp Gln Gln Gly Asn

190

Phe Ser Cys Ser Val 195

Met His Glu Ala Leu

200

His Asn His Tyr Thr 205

Lys

Val

Tyr

Glu

His 80

Lys

Gln

Met

Pro

Asn 160

Leu

Val

Gln

Lys Ser Leu Ser Leu 210

Ser Pro Gly Lys

215 <210> 87 <211> 984 <212> DNA <213> Artificial sequence

- 232 046387 <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide <400> 87

gccccagagc tgcttggtgg accatccgtg ttcctgtttc ctccaaagcc gaaggacacc 60 ctgatgatct caagaactcc ggaagtgact tgcgtcgtcg tggacgtgtc acatgaggat 120 ccagaggtca agttcaattg gtatgtggac ggagtggaag tgcataacgc caagaccaaa 180 ccccgcgaag aacagtacaa tagcacctac cgcgtggtga gcgtccttac tgtgctccac 240 caggactggc ttaatgggaa ggaatacaag tgtaaggtgt ccaacaaggc cctccccgct 300 cccatcgaaa agaccatctc aaaggcaaag gggcaaccaa gggaacctca agtgtacacc 360 ctgcctccgt gcaggaagga gatgaccaag aaccaggtca gcctgacttg tctcgtgaag 420 ggcttctatc ccagcgatat tgctgtggaa tggggagtcaa atggccagcc cgagaataac 480 tacaaaacta ccccacccgt gctgaaatct gatgggtcct tcttccttta ctccaagctg 540 accgtggac agagccgctg gcaacaaggc aatgtcttta gctgctcagt gatgcatgag 600 gctctccata atcactacac tcagaagtca ctgtccctgt cacctggcgc gcgcgacgga 660 gaccactgtc cgctcgggcc cggggcgttgc tgccgtctgc acacggtccg cgcgtcgctg 720 gaagacctgg gctggggccga ttgggtgctg tcgccacggg aggtgcaagt gaccatgtgc 780 atcggcgcgt gcccgagcca gttccggggcg gcaaacatgc acgcgcagat caagacgagc 840 ctgcaccgcc tgaagcccga cacggtgcca gcgccctgct gcgtgcccgc cagctacaat 900 cccatggtgc tcattcaaaa gaccgacacc ggggtgtcgc tccagaccta tgatgacttg 960 ttagccaaag actgccactg cata 984

<210> 88 <211> 328 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=description of artificial sequence: synthetic polypeptide <400> 88

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

5 1015

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

2530

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

4045

- 233 046387

Val

Gln 65

Gln

Ala

Pro

Thr

Ser 145

Tyr

Tyr

Phe

Lys

Leu 225

Glu

Val

Met

Val

Asp Gly Val Glu Val 50

Tyr Asn Ser Thr Tyr

Asp Trp Leu Asn Gly

Leu Pro Ala Pro Ile

100

Arg Glu Pro Gln Val 115

Lys Asn Gln Val Ser 130

Asp Ile Ala Val Glu

150

Lys Thr Thr Pro Pro

165

Ser Lys Leu Thr Val

180

Ser Cys Ser Val Met

195

Ser Leu Ser Leu Ser 210

Gly Pro Gly Arg Cys

230

Asp Leu Gly Trp Ala

245

Thr Met Cys Ile Gly 260

His Ala Gln Ile Lys

275

His Asn Ala Lys Thr 55

Lys Pro Arg Glu Glu 60

Arg Val Val Ser Val 75

Leu Thr Val Leu His

Lys Glu Tyr Lys Cys

Lys Val Ser Asn Lys

Glu Lys Thr Ile Ser 105

Tyr Thr Leu Pro Pro 120

Leu Thr Cys Leu Val 135

Trp Glu Ser Asn Gly

155

Val Leu Lys Ser Asp

170

Asp Lys Ser Arg Trp 185

His Glu Ala Leu His

200

Pro Gly Ala Arg Asp 215

Cys Arg Leu His Thr

235

Asp Trp Val Leu Ser

250

Ala Cys Pro Ser Gln

265

Thr Ser Leu His Arg

280

Lys Ala Lys Gly Gln

110

Cys Arg Lys Glu Met

125

Lys Gly Phe Tyr Pro 140

Gln Pro Glu Asn Asn

160

Gly Ser Phe Phe Leu

175

Gln Gln Gly Asn Val

190

Asn His Tyr Thr Gln

205

Gly Asp His Cys Pro 220

Val Arg Ala Ser Leu

240

Pro Arg Glu Val Gln

255

Phe Arg Ala Ala Asn

270

Leu Lys Pro Asp Thr

285

Pro Ala Pro Cys Cys

Val Pro Ala Ser Tyr

Asn Pro Met Val Leu

- 234 046387

290

295

300

Ile

305

Gln Lys

Thr Asp

Thr

310

Gly Val Ser Leu Gln Thr Tyr Asp Asp Leu

315

320

Leu

Ala Lys

Asp Cys

325

His

Cys Ile <210> 89 <211> 651 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide

<400> 89 gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 180 ccgcgggagg agcagtacaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 ccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtgcacc 360 ctgcccccat cccggggaga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tggggagagca atggggcagcc ggagaacaac 480 tacgacacca cgcctcccgt gctggactcc gacggctcct tcttcctcta tagcgacctc 540 accgtggac agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccgggtaa a 651

<210> 90 <211> 217 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=description of artificial sequence: synthetic polypeptide <400> 90

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

5 10 15

Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 25 30

- 235 046387

Val Val Asp Val Ser His Glu Asp

40

Pro Glu Val

Lys Phe Asn Trp Tyr 45

Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 55 60

Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 75 80

Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 90 95

Ala Leu Pro Ala Pro

100

Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln

105 110

Pro Arg Glu Pro Gln Val

Tyr

115

Thr Leu Pro Pro Cys Arg Lys Glu Met

120 125

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

130 135140

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

145 150 155160

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

165 170175

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

180 185190

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

195 200205

Lys Ser Leu Ser Leu Ser Pro Gly Lys

210215 <210> 91 <211> 216 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 91

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

5 10 15

- 236 046387

Pro

Lys

Asp

Thr

Leu

Met

Ile

Ser

Arg 25

Thr

Pro

Glu

Val

Thr

Cys

Val

Val

Val

Asp 35

Val

Ser

His

Glu

Asp 40

Pro

Glu

Val

Lys

Phe 45

Asn

Trp

Tyr

Val

Asp 50

Gly

Val

Glu

Val

His 55

Asn

Ala

Lys

Thr

Lys 60

Pro

Arg

Glu

Glu

Gln 65

Tyr

Asn

Ser

Thr

Tyr 70

Arg

Val

Val

Ser

Val 75

Leu

Thr

Val

Leu

His 80

Gln

Asp

Trp

Leu

Asn 85

Gly

Lys

Glu

Tyr

Lys 90

Cys

Lys

Val

Ser

Asn 95

Lys

Ala

Leu

Pro

Ala

100

Pro

Ile

Glu

Lys

Thr

105

Ile

Ser

Lys

Ala

Lys 110

Gly

Gln

Pro

Arg

Glu

115

Pro

Gln

Val

Cys

Thr

120

Leu

Pro

Pro

Ser

Arg 125

Glu

Glu

Met

Thr

Lys

130

Asn

Gln

Val

Ser

Leu

135

Thr

Cys

Leu

Val

Lys

140

Gly

Phe

Tyr

Pro

Ser

145

Asp

Ile

Ala

Val

Glu

150

Trp

Glu

Ser

Asn

Gly 155

Gln

Pro

Glu

Asn

Asn

160

Tyr

Asp

Thr

Thr

Pro

165

Pro

Val

Leu

Asp

Ser

170

Asp

Gly

Ser

Phe

Phe

175

Leu

Tyr

Ser

Asp

Leu

180

Thr

Val

Asp

Lys

Ser

185

Arg

Trp

Gln

Gln

Gly 190

Asn

Val

Phe

Ser

Cys 195

Ser

Val

Met

His

Glu

200

Ala

Leu

His

Asn

His

205

Tyr

Thr

Gln

Lys Ser Leu Ser Leu Ser Pro Gly

210 215 <210> 92 <211> 984 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide

- 237 046387

<400> 92 gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 180 ccgcgggagg agcagtacaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 ccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtgcacc 360 ctgcccccat cccggggaga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tggggagagca atggggcagcc ggagaacaac 480 tacgacacca cgcctcccgt gctggactcc gacggctcct tcttcctcta tagcgacctc 540 accgtggac agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccgggtgc gcgcaacgga 660 gaccactgtc cgctcgggcc cggggcgttgc tgccgtctgc acacggtccg cgcgtcgctg 720 gaagacctgg gctggggccga ttgggtgctg tcgccacggg aggtgcaagt gaccatgtgc 780 atcggcgcgt gccccgagcca gttccggggcg gcaaacatgc acgcgcagat caagacgagc 840 ctgcaccgcc tgaagcccga cacggtgcca gcgccctgct gcgtgcccgc cagctacaat 900 cccatggtgc tcattcaaaa gaccgacacc ggggtgtcgc tccagaccta tgatgacttg 960 ttagccaaag actgccactg cata 984

<210> 93 <211> 328 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 93

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

5 1015

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

2530

Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 4045

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

5560

- 238 046387

Gln 65

Gln

Ala

Pro

Thr

Ser 145

Tyr

Tyr

Phe

Lys

Leu 225

Glu

Val

Met

Val

Ile 305

Tyr Asn Ser Thr Tyr

Asp Trp Leu Asn Gly

Leu Pro Ala Pro Ile

100

Arg Glu Pro Gln Val 115

Lys Asn Gln Val Ser 130

Asp Ile Ala Val Glu

150

Asp Thr Thr Pro Pro

165

Ser Asp Leu Thr Val

180

Ser Cys Ser Val Met

195

Ser Leu Ser Leu Ser 210

Gly Pro Gly Arg Cys

230

Asp Leu Gly Trp Ala

245

Thr Met Cys Ile Gly 260

His Ala Gln Ile Lys

275

Pro Ala Pro Cys Cys 290

Gln Lys Thr Asp Thr

310

Arg Val Val Ser Val 75

Lys Glu Tyr Lys Cys

Glu Lys Thr Ile Ser 105

Cys Thr Leu Pro Pro

120

Leu Thr Cys Leu Val 135

Trp Glu Ser Asn Gly

155

Val Leu Asp Ser Asp

170

Asp Lys Ser Arg Trp 185

His Glu Ala Leu His

200

Pro Gly Ala Arg Asn 215

Cys Arg Leu His Thr

235

Asp Trp Val Leu Ser

250

Ala Cys Pro Ser Gln 265

Thr Ser Leu His Arg

280

Val Pro Ala Ser Tyr 295

Gly Val Ser Leu Gln

315

Leu Thr Val Leu His

Lys Val Ser Asn Lys

Lys Ala Lys Gly Gln

110

Ser Arg Glu Glu Met

125

Lys Gly Phe Tyr Pro 140

Gln Pro Glu Asn Asn

160

Gly Ser Phe Phe Leu

175

Gln Gln Gly Asn Val

190

Asn His Tyr Thr Gln

205

Gly Asp His Cys Pro 220

Val Arg Ala Ser Leu

240

Pro Arg Glu Val Gln

255

Phe Arg Ala Ala Asn

270

Leu Lys Pro Asp Thr

285

Asn Pro Met Val Leu 300

Thr Tyr Asp Asp Leu

320

- 239 046387

Leu Ala Lys Asp Cys His Cys Ile

325 <210> 94 <211> 651 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide

<400> 94 gccccagagc tgcttggtgg accatccgtg ttcctgtttc ctccaaagcc gaaggacacc 60 ctgatgatct caagaactcc ggaagtgact tgcgtcgtcg tggacgtgtc acatgaggat 120 ccagaggtca agttcaattg gtatgtggac ggagtggaag tgcataacgc caagaccaaa 180 ccccgcgaag aacagtacaa tagcacctac cgcgtggtga gcgtccttac tgtgctccac 240 caggactggc ttaatgggaa ggaatacaag tgtaaggtgt ccaacaaggc cctccccgct 300 cccatcgaaa agaccatctc aaaggcaaag gggcaaccaa gggaacctca agtgtacacc 360 ctgcctccgt gcaggaagga gatgaccaag aaccaggtca gcctgacttg tctcgtgaag 420 ggcttctatc ccagcgatat tgctgtggaa tggggagtcaa atggccagcc cgagaataac 480 tacaaaacta ccccacccgt gctgaaatct gatgggtcct tcttccttta ctccaagctg 540 accgtggac agagccgctg gcaacaaggc aatgtcttta gctgctcagt gatgcatgag 600 gctctccata atcactacac tcagaagtca ctgtccctgt ctccgggtaa a 651

<210> 95 <211> 984 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=description of artificial sequence: synthetic polynucleotide

<400> 95 gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 180 ccgcgggagg agcagtacaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 ccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtgcacc 360 ctgcccccat cccggggaga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 420

- 240 046387

ggcttctatc ccagcgacat cgccgtggag tggggagagca atggggcagcc ggagaacaac 480 tacgacacca cgcctcccgt gctggactcc gacggctcct tcttcctcta tagcgacctc 540 accgtggac agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccgggtgc gcgcgacgga 660 gaccactgtc cgctcgggcc cggggcgttgc tgccgtctgc acacggtccg cgcgtcgctg 720 gaagacctgg gctggggccga ttgggtgctg tcgccacggg aggtgcaagt gaccatgtgc 780 atcggcgcgt gcccgagcca gttccggggcg gcaaacatgc acgcgcagat caagacgagc 840 ctgcaccgcc tgaagcccga cacggtgcca gcgccctgct gcgtgcccgc cagctacaat 900 cccatggtgc tcattcaaaa gaccgacacc ggggtgtcgc tccagaccta tgatgacttg 960 ttagccaaag actgccactg cata 984

<210> 96 <211> 328 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 96

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

5 1015

Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 2530

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

4045

Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 5560

Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 7580

Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 9095

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

100 105110

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

115 120125

- 241 046387

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

130 135140

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

145 150 155160

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

165 170175

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

180 185190

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

195 200205

Lys Ser Leu Ser Leu Ser Pro Gly Ala Arg Asp Gly Asp His Cys Pro

210 215220

Leu Gly Pro Gly Arg Cys Cys Arg Leu His Thr Val Arg Ala Ser Leu

225 230 235240

Glu Asp Leu Gly Trp Ala Asp Trp Val Leu Ser Pro Arg Glu Val Gln

245 250255

Val Thr Met Cys Ile Gly Ala Cys Pro Ser Gln Phe Arg Ala Ala Asn

260 265270

Met His Ala Gln Ile Lys Thr Ser Leu His Arg Leu Lys Pro Asp Thr

275 280285

Val Pro Ala Pro Cys Cys Val Pro Ala Ser Tyr Asn Pro Met Val Leu

290 295300

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

305 310 315320

Leu Ala Lys Asp Cys His Cys Ile

325 <210> 97 <211> 975 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide

- 242 046387

<400> 97 gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 180 ccgcgggagg agcagtacaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 ccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtgcacc 360 ctgcccccat cccggggaga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tggggagagca atggggcagcc ggagaacaac 480 tacgacacca cgcctcccgt gctggactcc gacggctcct tcttcctcta tagcgacctc 540 accgtggac agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccggggtgg agaccactgt 660 ccgctcgggc ccgggcgttg ctgccgtctg cacacggtcc gcgcgtcgct ggaagacctg 720 ggctgggccg attgggtgct gtcgccacgg gaggtgcaag tgaccatgtg catcggcgcg 780 tgcccgagcc agttccggggc ggcaaacatg cacgcgcaga tcaagacgag cctgcaccgc 840 ctgaagcccg acacggtgcc agcgccctgc tgcgtgcccg ccagctacaa tcccatggtg 900 ctcattcaaa agaccgacac cggggtgtcg ctccagacct atgatgactt gttagccaaa 960 gactgccact gcata 975

<210> 98 <211> 325 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 98

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

5 1015

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

2530

Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 4045

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

5560

- 243 046387

Gln 65

Gln

Ala

Pro

Thr

Ser 145

Tyr

Tyr

Phe

Lys

Gly 225

Gly

Cys

Gln

Pro

Thr 305

Tyr Asn Ser Thr Tyr

Asp Trp Leu Asn Gly

Leu Pro Ala Pro Ile

100

Arg Glu Pro Gln Val 115

Lys Asn Gln Val Ser 130

Asp Ile Ala Val Glu

150

Asp Thr Thr Pro Pro

165

Ser Asp Leu Thr Val

180

Ser Cys Ser Val Met

195

Ser Leu Ser Leu Ser 210

Arg Cys Cys Arg Leu

230

Trp Ala Asp Trp Val

245

Ile Gly Ala Cys Pro

260

Ile Lys Thr Ser Leu

275

Cys Cys Val Pro Ala 290

Asp Thr Gly Val Ser

310

Arg Val Val Ser Val 75

Lys Glu Tyr Lys Cys

Glu Lys Thr Ile Ser 105

Cys Thr Leu Pro Pro

120

Leu Thr Cys Leu Val 135

Trp Glu Ser Asn Gly

155

Val Leu Asp Ser Asp

170

Asp Lys Ser Arg Trp 185

His Glu Ala Leu His

200

Pro Gly Gly Asp His 215

His Thr Val Arg Ala

235

Leu Ser Pro Arg Glu

250

Ser Gln Phe Arg Ala

265

His Arg Leu Lys Pro

280

Ser Tyr Asn Pro Met 295

Leu Gln Thr Tyr Asp

315

Leu Thr Val Leu His

Lys Val Ser Asn Lys

Lys Ala Lys Gly Gln

110

Ser Arg Glu Glu Met

125

Lys Gly Phe Tyr Pro 140

Gln Pro Glu Asn Asn

160

Gly Ser Phe Phe Leu

175

Gln Gln Gly Asn Val

190

Asn His Tyr Thr Gln

205

Cys Pro Leu Gly Pro 220

Ser Leu Glu Asp Leu

240

Val Gln Val Thr Met

255

Ala Asn Met His Ala

270

Asp Thr Val Pro Ala

285

Val Leu Ile Gln Lys 300

Asp Leu Leu Ala Lys

320

- 244 046387

Asp Cys His Cys Ile 325 <210> 99 <211> 996 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide <400> 99 gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac120 cctgaggt ca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag180 ccgcgggagg agcagtacaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc300 cccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtgcacc360 ctgcccccat cccgggagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa420 ggcttctatc ccagcgacat cgccgtggag tgggagagca atgg gcagcc ggagaacaac480 tacgacacca cgcctcccgt gctggactcc gacggctcct tcttcctcta tagcgacctc540 accgtggaca agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccggggt gg tggaggtggt660 gcgcgcgacg gagaccactg tccgctcggg cccgggcgtt gctgccgtct gcacacggtc720 cgcgcgtcgc tggaagacct gggctgggcc gattgggtgc tgtcgccacg ggaggtgcaa780 gtgaccatgt gcatcggcgc gtgcccgagc cagttccggg cggcaaacat gcacgcgcag840 atcaagacga gcctgcaccg cctgaagccc gacacggtgc cagcgccctg ctgcgtgccc900 gccagctaca atcccatggt gctcattcaa aagaccgaca ccggggtgtc gctccag acc960 tatgatgact tgttagccaa agactgccac tgcata996 <210> 100 <211> 332 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=description of artificial sequence: synthetic polypeptide <400> 100

- 245 046387

Ala 1

Pro

Val

Val

Gln 65

Gln

Ala

Pro

Thr

Ser 145

Tyr

Tyr

Phe

Lys

Asp 225

Arg

Pro Glu Leu Leu Gly 5

Lys Asp Thr Leu Met 20

Val Asp Val Ser His 35

Asp Gly Val Glu Val 50

Tyr Asn Ser Thr Tyr

Asp Trp Leu Asn Gly

Leu Pro Ala Pro Ile

100

Arg Glu Pro Gln Val 115

Lys Asn Gln Val Ser 130

Asp Ile Ala Val Glu

150

Asp Thr Thr Pro Pro

165

Ser Asp Leu Thr Val

180

Ser Cys Ser Val Met

195

Ser Leu Ser Leu Ser 210

His Cys Pro Leu Gly

230

Ala Ser Leu Glu Asp

245

Gly Pro Ser Val Phe

Leu Phe Pro Pro Lys 15

Ile Ser Arg Thr Pro 25

Glu Val Thr Cys Val 30

Glu Asp Pro Glu Val 40

His Asn Ala Lys Thr 55

Arg Val Val Ser Val 75

Lys Glu Tyr Lys Cys 90

Glu Lys Thr Ile Ser 105

Cys Thr Leu Pro Pro

120

Leu Thr Cys Leu Val 135

Trp Glu Ser Asn Gly

155

Val Leu Asp Ser Asp

170

Asp Lys Ser Arg Trp 185

His Glu Ala Leu His

200

Pro Gly Gly Gly Gly 215

Pro Gly Arg Cys Cys

235

Leu Gly Trp Ala Asp

250

Lys Phe Asn Trp Tyr 45

Lys Pro Arg Glu Glu 60

Leu Thr Val Leu His

Lys Val Ser Asn Lys

Lys Ala Lys Gly Gln

110

Ser Arg Glu Glu Met

125

Lys Gly Phe Tyr Pro 140

Gln Pro Glu Asn Asn

160

Gly Ser Phe Phe Leu

175

Gln Gln Gly Asn Val

190

Asn His Tyr Thr Gln

205

Gly Ala Arg Asp Gly 220

Arg Leu His Thr Val

240

Trp Val Leu Ser Pro

255

- 246 046387

Arg Glu Val Gln Val Thr Met Cys

260

Ile Gly Ala Cys Pro Ser Gln Phe

265 270

Arg Ala Ala Asn Met His Ala Gln

275 280

Ile Lys Thr Ser Leu His Arg Leu

285

Lys Pro Asp Thr Val Pro Ala Pro

290 295

Cys Cys Val Pro Ala Ser Tyr Asn

300

Pro Met Val Leu Ile Gln Lys Thr

305 310

Asp Thr Gly Val Ser Leu Gln Thr

315 320

Tyr Asp Asp Leu Leu Ala Lys Asp

325

Cys His Cys Ile 330 <210> 101 <211> 1014 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide

<400> 101 gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 180 ccgcgggagg agcagtacaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 ccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtgcacc 360 ctgcccccat cccggggaga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tggggagagca atggggcagcc ggagaacaac 480 tacgacacca cgcctcccgt gctggactcc gacggctcct tcttcctcta tagcgacctc 540 accgtggac agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccggggtgg aggtggtgga 660 tccggagaggcg gtggaagcgc gcgcgacgga gaccactgtc cgctcgggcc cggggcgttgc 720 tgccgtctgc acacggtccg cgcgtcgctg gaagacctgg gctggggccga ttgggtgctg 780 tcgccacggg aggtgcaagt gaccatgtgc atcggcgcgt gcccgagcca gttccggggcg 840 gcaaacatgc acgcgcagat caagacgagc ctgcaccgcc tgaagcccga cacggtgcca 900 gcgccctgct gcgtgcccgc cagctacaat cccatggtgc tcattcaaaa gaccgacacc 960

- 247 046387 ggggtgtcgc tccagaccta tgatgacttg ttagccaaag actgccactg cata

1014 <210> 102 <211> 338 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 102

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

5 1015

Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 2530

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

4045

Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 5560

Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 7580

Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 9095

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

100 105110

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

115 120125

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

130 135140

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

145 150 155160

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

165 170175

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

180 185190

- 248 046387

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

195 200205

Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly

210 215220

Gly Ser Ala Arg Asp Gly Asp His Cys Pro Leu Gly Pro Gly Arg Cys

225 230 235240

Cys Arg Leu His Thr Val Arg Ala Ser Leu Glu Asp Leu Gly Trp Ala

245 250255

Asp Trp Val Leu Ser Pro Arg Glu Val Gln Val Thr Met Cys Ile Gly

260 265270

Ala Cys Pro Ser Gln Phe Arg Ala Ala Asn Met His Ala Gln Ile Lys

275 280285

Thr Ser Leu His Arg Leu Lys Pro Asp Thr Val Pro Ala Pro Cys Cys

290 295300

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

305 310 315320

Gly Val Ser Leu Gln Thr Tyr Asp Asp Leu Leu Ala Lys Asp Cys His

325 330335

Cys Ile <210> 103 <211> 1014 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide <400> 103

gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 180 ccgcgggagg agcagtacaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 ccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtgcacc 360

- 249 046387

ctgcccccat cccggggaga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tggggagagca atggggcagcc ggagaacaac 480 tacgacacca cgcctcccgt gctggactcc gacggctcct tcttcctcta tagcgacctc 540 accgtggac agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccggggtgg aggtggtgga 660 cagggaggcg gtggacagggc gcgcgacgga gaccactgtc cgctcgggcc cggggcgttgc 720 tgccgtctgc acacggtccg cgcgtcgctg gaagacctgg gctggggccga ttgggtgctg 780 tcgccacggg aggtgcaagt gaccatgtgc atcggcgcgt gcccgagcca gttccggggcg 840 gcaaacatgc acgcgcagat caagacgagc ctgcaccgcc tgaagcccga cacggtgcca 900 gcgccctgct gcgtgcccgc cagctacaat cccatggtgc tcattcaaaa gaccgacacc 960 ggggtgtcgc tccagaccta tgatgacttg ttagccaaag actgccactg cata 1014

<210> 104 <211> 338 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 104

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

5 1015

Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 2530

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

4045

Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 5560

Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 7580

Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 9095

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

100 105110

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

- 250 046387

115

120

125

Thr Lys Asn Gln Val

130

Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr

135 140

Ser Asp Ile Ala Val 145

Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 150 155

Tyr Asp Thr Thr Pro

165

Pro Val Leu Asp Ser Asp Gly Ser Phe Phe

170 175

Tyr Ser Asp Leu Thr

180

Val Asp Lys Ser Arg Trp Gln Gln Gly Asn

185 190

Phe Ser Cys Ser Val 195

Met His Glu Ala Leu His Asn His Tyr Thr

200 205

Lys Ser Leu Ser Leu 210

Ser Pro Gly Gly Gly Gly Gly Gln Gly Gly

215 220

Gly Gln Ala Arg Asp 225

Gly Asp His Cys Pro Leu Gly Pro Gly Arg

230 235

Cys Arg Leu His Thr

245

Val Arg Ala Ser Leu Glu Asp Leu Gly Trp

250 255

Asp Trp Val Leu Ser

260

Pro Arg Glu Val Gln Val Thr Met Cys Ile

265 270

Ala Cys Pro Ser Gln 275

Phe Arg Ala Ala Asn Met His Ala Gln Ile

280 285

Thr Ser Leu His Arg

290

Leu Lys Pro Asp Thr Val Pro Ala Pro Cys

295 300

Val Pro Ala Ser Tyr 305

Asn Pro Met Val Leu Ile Gln Lys Thr Asp 310 315

Gly Val Ser Leu Gln

325

Thr Tyr Asp Asp Leu Leu Ala Lys Asp Cys

330 335

Pro

Asn 160

Leu

Val

Gln

Gly

Cys 240

Ala

Gly

Lys

Cys

Thr 320

His

Cys Ile <210> 105 <211> 217 <212> PRT <213> Artificial sequence

- 251 046387 <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 105

Ala Pro Glu Leu 1

Leu Gly Gly Pro 5

Ser Val Phe Leu

Phe Pro Pro Lys 15

Pro Lys Asp Thr

Leu Met Ile Ser

Arg Thr Pro Glu 25

Val Thr Cys Val 30

Val Val Asp Val

Ser His Glu Asp 40

Pro Glu Val Lys

Phe Asn Trp Tyr 45

Val Asp Gly Val

Glu Val His Asn

Ala Lys Thr Lys 60

Pro Arg Glu Glu

Gln Tyr Asn Ser 65

Thr Tyr Arg Val 70

Val Ser Val Leu

Thr Val Leu His

Gln Asp Trp Leu

Asn Gly Lys Glu 85

Tyr Lys Cys Lys 90

Val Ser Asn Lys

Ala Leu Pro Ala

100

Pro Ile Glu Lys

Thr Ile Ser Lys 105

Ala Lys Gly Gln 110

Pro Arg Glu Pro

115

Gln Val Tyr Thr

120

Cys Pro Pro Ser

Arg Lys Glu Met 125

Thr Lys Asn Gln

130

Val Ser Leu Thr

135

Cys Leu Val Lys

140

Gly Phe Tyr Pro

Ser Asp Ile Ala 145

Val Glu Trp Glu

150

Ser Asn Gly Gln

155

Pro Glu Asn Asn

160

Tyr Lys Thr Thr

Pro Pro Val Leu 165

Lys Ser Asp Gly

170

Ser Phe Phe Leu

175

Tyr Ser Lys Leu

180

Thr Val Asp Lys

Ser Arg Trp Gln 185

Gln Gly Asn Val

190

Phe Ser Cys Ser

195

Val Met His Glu

200

Ala Leu His Asn

His Tyr Thr Gln 205

Lys Ser Leu Ser Leu Ser Pro Gly

210 215

Lys

- 252 046387 <210> 106 <211> 216 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 106

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

5 1015

Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 2530

Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 4045

Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 5560

Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 7580

Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 9095

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

100 105110

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

115 120125

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

130 135140

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

145 150 155160

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

165 170175

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

180 185190

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

195 200205

- 253 046387

Lys Ser Leu Ser Leu Ser Pro Gly

210

215 <210> 107 <211> 1014 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide

<400> 107 gcgccggaac tgctggggcgg cccgagcgtg tttctgtttc cgccgaaacc gaaagatacc 60 ctgatgatta gccgcacccc ggaagtgacc tgcgtggtgg tggatgtgag ccatgaagat 120 ccggaagtga aatttaactg gtatgtggat ggcgtggaag tgcataacgc gaaaaccaaa 180 ccgcgcgaag aacagtataa cagcacctat cgcgtggtga gcgtgctgac cgtgctgcat 240 caggattggc tgaacggcaa agaatataaa tgcaaagtga gcaacaaagc gctgccggcg 300 ccgattgaaa aaaccattag caaagcgaaa ggccagccgc gcgaaccgca ggtgtatacc 360 tgcccgccga gccgcgaaga aatgaccaaa aaccaggtga gcctgacctg cctggtgaaa 420 ggcttttatc cgagcgatat tgcggtggaa tgggaaagca acggccagcc ggaaaacaac 480 tatgatacca ccccgccggt gctggatagc gatggcagct tttttctgta tagcgatctg 540 accgtggata aaagccgctg gcagcagggc aacgtgttta gctgcagcgt gatgcatgaa 600 gcgctgcata accattatac ccagaaaagc ctgagcctga gcccggggcgg cggcggcggc 660 agcggcggcg gcggcagcgc gcgcaacggc gatcattgcc cgctgggccc gggccgctgc 720 tgccgcctgc ataccgtgcg cgcgagcctg gaagatctgg gctggggcgga ttgggtgctg 780 agcccgcgcg aagtgcaggt gaccatgtgc attggcgcgt gcccgagcca gtttcgcgcg 840 gcgaacatgc atgcgcagat taaaaccagc ctgcatcgcc tgaaaccgga taccgtgccg 900 gcgccgtgct gcgtgccggc gagctataac ccgatggtgc tgattcagaa aaccgatacc 960 ggcgtgagcc tgcagaccta tgatgatctg ctggcgaaag attgccatg catt 1014

<210> 108 <211> 338 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=description of artificial sequence: synthetic polypeptide <400> 108

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

5 10 15

- 254 046387

Pro

Val

Val

Gln 65

Gln

Ala

Pro

Thr

Ser 145

Tyr

Tyr

Phe

Lys

Gly 225

Cys

Asp

Lys Asp Thr Leu Met

Ile Ser Arg Thr Pro 25

Glu Val Thr Cys Val 30

Val Asp Val Ser His 35

Asp Gly Val Glu Val 50

Tyr Asn Ser Thr Tyr

Asp Trp Leu Asn Gly

Leu Pro Ala Pro Ile

100

Arg Glu Pro Gln Val 115

Lys Asn Gln Val Ser 130

Asp Ile Ala Val Glu

150

Asp Thr Thr Pro Pro

165

Ser Asp Leu Thr Val

180

Ser Cys Ser Val Met

195

Ser Leu Ser Leu Ser 210

Ser Ala Arg Asn Gly

230

Arg Leu His Thr Val

245

Glu Asp Pro Glu Val 40

His Asn Ala Lys Thr 55

Arg Val Val Ser Val

Lys Glu Tyr Lys Cys

Glu Lys Thr Ile Ser 105

Tyr Thr Cys Pro Pro

120

Leu Thr Cys Leu Val 135

Trp Glu Ser Asn Gly

155

Val Leu Asp Ser Asp

170

Asp Lys Ser Arg Trp 185

His Glu Ala Leu His

200

Pro Gly Gly Gly Gly 215

Asp His Cys Pro Leu

235

Arg Ala Ser Leu Glu

250

Lys Phe Asn Trp Tyr 45

Lys Pro Arg Glu Glu 60

Leu Thr Val Leu His

Lys Val Ser Asn Lys

Lys Ala Lys Gly Gln

110

Ser Arg Glu Glu Met

125

Lys Gly Phe Tyr Pro 140

Gln Pro Glu Asn Asn

160

Gly Ser Phe Phe Leu

175

Gln Gln Gly Asn Val

190

Asn His Tyr Thr Gln

205

Gly Ser Gly Gly Gly 220

Gly Pro Gly Arg Cys

240

Asp Leu Gly Trp Ala

255

Trp Val Leu Ser Pro

Arg Glu Val Gln Val

Thr Met Cys Ile Gly

- 255 046387

260 265270

Ala Cys Pro Ser Gln Phe Arg Ala Ala Asn Met His Ala Gln Ile Lys

275 280285

Thr Ser Leu His Arg Leu Lys Pro Asp Thr Val Pro Ala Pro Cys Cys

290 295300

Val Pro Ala Ser Tyr Asn Pro Met Val Leu Ile Gln Lys Thr AspThr

305 310 315320

Gly Val Ser Leu Gln Thr Tyr Asp Asp Leu Leu Ala Lys Asp CysHis

325 330335

Cys Ile <210> 109 <211> 651 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide

<400> 109 gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 180 ccgcgggagg agcagtacaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 ccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtacacc 360 tgtcccccat cccggggaga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tggggagagca atggggcagcc ggagaacaac 480 tacgacacca cgcctcccgt gctggactcc gacggctcct tcttcctcta tagcgacctc 540 accgtggac agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccgggtaa a 651

<210> 110 <211> 585 <212> PRT <213> Artificial sequence <220>

- 256 046387 <221> source <223> /note=’’description of the artificial sequence: synthetic polypeptide <400> 110

Asp Ala His Lys Ser Glu Val Ala His Arg Phe Lys Asp Leu Gly Glu

5 1015

Glu Asn Phe Lys Ala Leu Val Leu Ile Ala Phe Ala Gln Tyr LeuGln

2530

Gln Cys Pro Phe Glu Asp His Val Lys Leu Val Asn Glu Val Thr Glu 35 4045

Phe Ala Lys Thr Cys Val Ala Asp Glu Ser Ala Glu Asn Cys Asp Lys 50 5560

Ser Leu His Thr Leu Phe Gly Asp Lys Leu Cys Thr Val Ala Thr Leu

70 7580

Arg Glu Thr Tyr Gly Glu Met Ala Asp Cys Cys Ala Lys Gln Glu Pro 85 9095

Glu Arg Asn Glu Cys Phe Leu Gln His Lys Asp Asp Asn Pro Asn Leu

100 105110

Pro Arg Leu Val Arg Pro Glu Val Asp Val Met Cys Thr Ala Phe His

115 120125

Asp Asn Glu Glu Thr Phe Leu Lys Lys Tyr Leu Tyr Glu Ile Ala Arg

130 135140

Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu Leu Phe Phe Ala Lys Arg

145 150 155160

Tyr Lys Ala Ala Phe Thr Glu Cys Cys Gln Ala Ala Asp Lys Ala Ala

165 170175

Cys Leu Leu Pro Lys Leu Asp Glu Leu Arg Asp Glu Gly Lys Ala Ser

180 185190

Ser Ala Lys Gln Arg Leu Lys Cys Ala Ser Leu Gln Lys Phe Gly Glu

195 200205

Arg Ala Phe Lys Ala Trp Ala Val Ala Arg Leu Ser Gln Arg Phe Pro

210 215220

Lys Ala Glu Phe Ala Glu Val Ser Lys Leu Val Thr Asp Leu Thr Lys

225 230 235240

- 257 046387

Val His Thr Glu Cys Cys His Gly Asp Leu Leu Glu Cys Ala Asp

245 250 255

Arg Ala Asp Leu Ala Lys Tyr Ile Cys Glu Asn Gln Asp Ser Ile

260 265 270

Ser Lys Leu Lys Glu Cys Cys Glu Lys Pro Leu Leu Glu Lys Ser

275 280 285

Cys Ile Ala Glu Val Glu Asn Asp Glu Met Pro Ala Asp Leu Pro

290 295 300

Leu Ala Ala Asp Phe Val Glu Ser Lys Asp Val Cys Lys Asn Tyr

305 310 315

Glu Ala Lys Asp Val Phe Leu Gly Met Phe Leu Tyr Glu Tyr Ala

325 330 335

Arg His Pro Asp Tyr Ser Val Val Leu Leu Leu Arg Leu Ala Lys

340 345 350

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

355 360 365

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

370 375 380

Gln Asn Leu Ile Lys Gln Asn Cys Glu Leu Phe Glu Gln Leu Gly 385 390 395

Tyr Lys Phe Gln Asn Ala Leu Leu Val Arg Tyr Thr Lys Lys Val

405 410 415

Gln Val Ser Thr Pro Thr Leu Val Glu Val Ser Arg Asn Leu Gly

420 425 430

Val Gly Ser Lys Cys Cys Lys His Pro Glu Ala Lys Arg Met Pro

435 440 445

Ala Glu Asp Tyr Leu Ser Val Val Leu Asn Gln Leu Cys Val Leu

450 455 460

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

465 470 475

Leu Val Asn Arg Arg Pro Cys Phe Ser Ala Leu Glu Val Asp Glu

Asp

Ser

His

Ser

Ala 320

Arg

Thr

Glu

Pro

Glu 400

Pro

Lys

Cys

His

Ser 480

Thr

- 258 046387

485 490495

Tyr Val Pro Lys Glu Phe Asn Ala Glu Thr Phe Thr Phe His Ala Asp

500 505510

Ile Cys Thr Leu Ser Glu Lys Glu Arg Gln Ile Lys Lys Gln Thr Ala

515 520525

Leu Val Glu Leu Val Lys His Lys Pro Lys Ala Thr Lys Glu Gln Leu

530 535540

Lys Ala Val Met Asp Asp Phe Ala Ala Phe Val Glu Lys Cys Cys Lys

545 550 555560

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

565 570575

Ala Ala Ser Gln Ala Ala Leu Gly Leu

580585 <210> 111 <211> 2154 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide

<400> 111 gatgcacaca agagtgaggt tgctcatcga tttaaagatt tggggagaaga aaatttcaaa 60 gccttggtgt tgattgcctt tgctcagtat cttcagcagt gtccattga agatcatgta 120 aaattagtga atgaagtaac tgaatttgca aaaacatgtg ttgctgatga gtcagctgaa 180 aattgtgaca aatcacttca tacccttttt ggagacaaat tatgcacagt tgcaactctt 240 cgtgaaacct atggtgaaat ggctgactgc tgtgcaaaac aagaacctga gagaaatgaa 300 tgcttcttgc aacacaaaga tgacaaccca aacctcccc gattggtgag accagaggtt 360 gatgtgatgt gcactgcttt tcatgacaat gaagagacat ttttgaaaaa atacttatat 420 gaaattgcca gaagacatcc ttacttttat gccccggaac tccttttctt tgctaaaagg 480 tataaagctg cttttacaga atgttgccaa gctgctgata aagctgcctg cctgttgcca 540 aagctcgatg aacttcggga tgaagggaag gcttcgtctg ccaaacagag actcaagtgt 600 gccagtctcc aaaaatttgg agaaagagct ttcaaagcat gggcagtagc tcgcctgagc 660 cagagatttc ccaaagctga gtttgcagaa gtttccaagt tagtgacaga tcttaccaaa 720 gtccacacgg aatgctgcca tggagatctg cttgaatgtg ctgatgacag ggcggacctt 780

- 259 046387

gccaagtata tctgtgaaaa tcaagattcg atctccagta aactgaagga atgctgtgaa 840 aaacctctgt tggaaaaatc ccactgcatt gccgaagtgg aaaatgatga gatgcctgct 900 gacttgcctt cattagctgc tgattttgtt gaaagtaagg atgtttgcaa aaactatgct 960 gaggcaaagg atgtcttcct gggcatgttt ttgtatgaat atgcaagaag gcatcctgat 1020 tactctgtcg tgctgctgct gagacttgcc aagacatatg aaaccactct agagaagtgc 1080 tgtgccgctg cagatcctca tgaatgctat gccaaagtgt tcgatgaatt taaacctctt 1140 gtggaagagc ctcagaattt aatcaaacaa aattgtgagc tttttgagca gcttggagag 1200 takaaattcc agaatgcgct attagttcgt takaccaaga aagtacccca agtgtcaact 1260 ccaactcttg tagaggtctc aagaaaccta ggaaaagtgg gcagcaaatg ttgtaaacat 1320 cctgaagcaa aaagaatgcc ctgtgcagaa gactatctat ccgtggtcct gaaccagtta 1380 tgtgtgttgc atgagaaaac gccagtaagt gacagagtca ccaaatgctg cacagaatcc 1440 ttggtgaaca ggcgaccatg cttttcagct ctggaagtcg atgaaacata cgttcccaaa 1500 gagtttaatg ctgaaacatt caccttccat gcagatatat gcacactttc tgagaaggag 1560 agacaaatca agaaacaaac tgcacttgtt gagctcgtga aacacaagcc caaggcaaca 1620 aaagagcaac tgaaagctgt tatggatgat ttcgcagctt ttgtagagaa gtgctgcaag 1680 gctgacgata aggagacctg ctttgccgag gagggtaaaa aacttgttgc ggccagtcag 1740 gccgccttag gcttaggagg tggtggatcc ggagaggcggtg gaagcggagg tggtggatct 1800 ggagaggcggtg gaagcgcgcg caacggagac cactgtccgc tcgggcccgg gcgttgctgc 1860 cgtctgcaca cggtccgcgc gtcgctggaa gacctggggct gggccgattg ggtgctgtcg 1920 ccacgggagg tgcaagtgac catgtgcatc ggcgcgtgcc cgagccagtt ccggggcggca 1980 aacatgcacg cgcagatcaa gacgagcctg caccgcctga agcccgacac ggtgccagcg 2040 ccctgctgcg tgcccgccag ctacaatccc atggtgctca ttcaaaagac cgacaccgggg 2100 gtgtcgctcc agacctatga tgacttgtta gccaaagact gccactgcat atga 2154

<210> 112 <211> 717 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 112

Asp Ala His Lys Ser Glu Val Ala His Arg Phe Lys Asp Leu Gly Glu

5 10 15

- 260 046387

Glu Asn Phe Lys Ala Leu Val Leu 20

Ile Ala Phe Ala Gln Tyr Leu

thirty

Gln Cys Pro Phe Glu Asp His Val

40

Lys Leu Val Asn Glu Val Thr

Phe Ala Lys Thr Cys Val Ala Asp Glu Ser Ala Glu Asn Cys Asp 50 55 60

Ser Leu His Thr Leu Phe Gly Asp Lys Leu Cys Thr Val Ala Thr 65 70 75

Arg Glu Thr Tyr Gly Glu Met Ala Asp Cys Cys Ala Lys Gln Glu 85 90 95

Glu Arg Asn Glu Cys Phe Leu Gln His

100 105

Lys Asp Asp Asn Pro Asn

110

Pro Arg Leu Val Arg Pro Glu Val Asp Val Met Cys Thr Ala Phe

115 120 125

Asp Asn Glu Glu

130

Thr Phe Leu Lys Lys Tyr Leu Tyr Glu Ile Ala

135 140

Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu Leu Phe Phe Ala Lys

145 150 155

Tyr

Lys Ala Ala

Phe Thr Glu Cys Cys Gln Ala Ala Asp Lys Ala

165 170 175

Cys Leu Leu Pro Lys Leu Asp Glu Leu Arg Asp Glu Gly Lys Ala

180 185 190

Ser Ala Lys Gln Arg Leu Lys Cys Ala Ser Leu Gln Lys Phe Gly

195 200 205

Arg Ala Phe Lys Ala Trp Ala Val Ala Arg Leu Ser Gln Arg Phe

210 215 220

Lys Ala Glu Phe Ala Glu Val Ser Lys Leu Val Thr Asp Leu Thr

225 230 235

Val His Thr Glu Cys Cys His Gly Asp Leu Leu Glu Cys Ala Asp

245 250 255

Arg Ala Asp Leu Ala Lys Tyr Ile Cys Glu Asn Gln Asp Ser Ile

260 265 270

Gln

Glu

Lys

Leu 80

Pro

Leu

His

Arg

Arg 160

Ala

Ser

Glu

Pro

Lys 240

Asp

Ser

- 261 046387

Ser Lys

Leu Lys Glu Cys Cys Glu

275 280

Lys Pro Leu Leu Glu Lys Ser

285

Cys Ile Ala Glu Val Glu Asn Asp Glu Met Pro Ala Asp Leu Pro

290 295 300

Leu Ala Ala Asp Phe Val Glu Ser Lys Asp Val Cys Lys Asn Tyr 305 310 315

Glu Ala Lys Asp Val Phe Leu Gly Met Phe Leu Tyr Glu Tyr Ala

325 330 335

Arg His Pro Asp Tyr Ser Val Val Leu Leu Leu Arg Leu Ala Lys

340 345 350

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

355 360 365

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

370 375 380

Gln Asn Leu Ile Lys Gln Asn Cys Glu Leu Phe Glu Gln Leu Gly

385 390 395

Tyr Lys Phe Gln Asn Ala Leu Leu Val Arg Tyr Thr Lys Lys Val

405 410 415

Gln Val Ser Thr Pro Thr Leu Val Glu Val Ser Arg Asn Leu Gly

420 425 430

Val Gly Ser Lys Cys Cys Lys His Pro Glu Ala Lys Arg Met Pro

435 440 445

Ala Glu Asp Tyr Leu Ser Val Val Leu Asn Gln Leu Cys Val Leu

450 455 460

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

465 470 475

Leu Val Asn Arg Arg Pro Cys Phe Ser Ala Leu Glu Val Asp Glu

485 490 495

Tyr Val Pro Lys Glu Phe Asn Ala Glu Thr Phe Thr Phe His Ala

500 505 510

Ile Cys Thr Leu Ser Glu Lys Glu Arg Gln Ile Lys Lys Gln Thr

515 520 525

His

Ser

Ala 320

Arg

Thr

Glu

Pro

Glu 400

Pro

Lys

Cys

His

Ser 480

Thr

Asp

Ala

- 262 046387

Leu Val Glu Leu Val Lys His Lys Pro Lys Ala Thr Lys Glu Gln Leu

530 535540

Lys Ala Val Met Asp Asp Phe Ala Ala Phe Val Glu Lys Cys Cys Lys

545 550 555560

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

565 570575

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

580 585590

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Arg Asn

595 600605

Gly Asp His Cys Pro Leu Gly Pro Gly Arg Cys Cys Arg Leu His Thr

610 615620

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

625 630 635640

Pro Arg Glu Val Gln Val Thr Met Cys Ile Gly Ala Cys Pro Ser Gln

645 650655

Phe Arg Ala Ala Asn Met His Ala Gln Ile Lys Thr Ser Leu His Arg

660 665670

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

675 680685

Asn Pro Met Val Leu Ile Gln Lys Thr Asp Thr Gly Val Ser Leu Gln

690 695700

Thr Tyr Asp Asp Leu Leu Ala Lys Asp Cys His Cys Ile

705 710715 <210> 113 <211> 9 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic peptide <400> 113

Gly Ser Pro Ala Pro Ala Pro Gly Ser

5

- 263 046387 <210> 114 <211> 2121 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide <400> 114 gatgcacaca agagtgaggt tgctcatcga tttaaagatt tgggagaaga aaatttcaaa60 gccttggtgt tgattgcctt tgctcagtat cttcagcagt gtccatttga agatcatgta120 a aattagtga atgaagtaac tgaatttgca aaaacatgtg ttgctgatga gtcagctgaa180 aattgtgaca aatcacttca tacccttttt ggagacaaat tatgcacagt tgcaactctt240 cgtgaaacct atggtgaaat ggctgactgc tgtgcaaaac aagaacctga gagaaatgaa300 tgcttcttgc aacacaaaga tgacaaccca aacctccccc gattggtgag accagaggtt360 gatgtgatgt gcactgcttt tcatgacaat gaagagacat ttttgaaaaa atacttatat420 gaaattgcca gaagacatcc ttacttttat gccccggaac tcctt ttctt tgctaaaagg480 tataaagctg cttttacaga atgttgccaa gctgctgata aagctgcctg cctgttgcca540 aagctcgatg aacttcggga tgaagggaag gcttcgtctg ccaaacagag actcaagtgt600 gccagtctcc aaaaatttgg agaaagagct ttcaaagcat gggcagtagc tcgcctgagc660 cagagatttc ccaaagctga gtttgcagaa gtttccaagt tagtgacaga tcttaccaaa720 gtccacacgg aatgctgcca tggagatctg cttgaatgtg ctgatgacag ggcggacctt780 gccaagtata tctgtgaaaa tcaagattcg atctccagta aactgaagga atgctgtgaa840 aaacctctgt tggaaaaatc ccactgcatt gccgaagtgg aaaatgatga gatgcctgct900 gacttgcctt cattagctgc tgattttgtt gaaagtaagg atgtttgcaa aaactatgct 960 gaggcaaagg atgtcttcct gggcatgttt ttgtatgaat atgcaagaag gcatcctgat1020 tactctgtcg tgctgctgct gagacttgcc aagacatatg aaaccactct agagaagtgc1080 tgtgccgctg cagatcctca tgaatgctat gccaaagtgt tcgatgaatt taaacct ctt1140 gtggaagagc ctcagaattt aatcaaacaa aattgtgagc tttttgagca gcttggagag1200 tacaaattcc agaatgcgct attagttcgt tacaccaaga aagtacccca agtgtcaact1260 ccaactcttg tagaggtctc aagaaaccta ggaaaagtgg gcagcaaatg ttgtaaacat1320 cctgaagcaa aaagaatgcc ctgtgcagaa gactatctat ccgtggtcct gaaccagtta1380 tgtgtgttgc atgagaaaac gccagtaagt gacagagtca ccaaatgctg cacagaatcc1440 ttggtgaaca ggcgaccatg cttttcagct ctggaagtcg atgaaacata cgttcccaaa1500

- 264 046387

gagtttaatg ctgaaacatt caccttccat gcagatatat gcacactttc tgagaaggag 1560 agacaaatca agaaacaaac tgcacttgtt gagctcgtga aacacaagcc caaggcaaca 1620 aaagagcaac tgaaagctgt tatggatgat ttcgcagctt ttgtagagaa gtgctgcaag 1680 gctgacgata aggagacctg ctttgccgag gagggtaaaa aacttgttgc ggccagtcag 1740 gccgccttag gcttaggatc cccagctcca gctccaggaa gcgcgcgcaa cggagaccac 1800 tgtccgctcg ggcccggggcg ttgctgccgt ctgcacacgg tccgcgcgtc gctggaagac 1860 ctggggctggg ccgattgggt gctgtcgcca cgggaggtgc aagtgaccat gtgcatcggc 1920 gcgtgcccga gccagttccg ggcggcaaac atgcacgcgc agatcaagac gagcctgcac 1980 cgcctgaagc ccgacacggt gccagcgccc tgctgcgtgc ccgccagcta caatcccatg 2040 gtgctcattc aaaagaccga caccggggtg tcgctccaga cctatgatga cttgttagcc 2100 aaagactgcc actgcatatg a 2121

<210> 115 <211> 706 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 115

Asp Ala His Lys Ser Glu Val Ala His Arg Phe Lys Asp Leu Gly Glu

5 1015

Glu Asn Phe Lys Ala Leu Val Leu Ile Ala Phe Ala Gln Tyr Leu Gln 20 2530

Gln Cys Pro Phe Glu Asp His Val Lys Leu Val Asn Glu Val Thr Glu 35 4045

Phe Ala Lys Thr Cys Val Ala Asp Glu Ser Ala Glu Asn Cys Asp Lys 50 5560

Ser Leu His Thr Leu Phe Gly Asp Lys Leu Cys Thr Val Ala Thr Leu

70 7580

Arg Glu Thr Tyr Gly Glu Met Ala Asp Cys Cys Ala Lys Gln Glu Pro 85 9095

Glu Arg Asn Glu Cys Phe Leu Gln His Lys Asp Asp Asn Pro Asn Leu

100 105110

Pro Arg Leu Val Arg Pro Glu Val Asp Val Met Cys Thr Ala Phe His

- 265 046387

115 120

125

Asp Asn Glu Glu Thr Phe Leu Lys Lys

130 135

Arg His Pro Tyr Phe Tyr Ala Pro Glu 145 150

Tyr Lys Ala Ala Phe Thr Glu Cys Cys

165

Cys Leu Leu Pro Lys Leu Asp Glu Leu

180 185

Ser Ala Lys Gln Arg Leu Lys Cys Ala

195 200

Arg Ala Phe Lys Ala Trp Ala Val Ala

210 215

Lys Ala Glu Phe Ala Glu Val Ser Lys

225 230

Val His Thr Glu Cys Cys His Gly Asp

245

Arg Ala Asp Leu Ala Lys Tyr Ile Cys

260 265

Ser Lys Leu Lys Glu Cys Cys Glu Lys

275 280

Cys Ile Ala Glu Val Glu Asn Asp Glu

290 295

Leu Ala Ala Asp Phe Val Glu Ser Lys

305 310

Glu Ala Lys Asp Val Phe Leu Gly Met

325

Arg His Pro Asp Tyr Ser Val Val Leu

340 345

Tyr Glu Thr Thr Leu Glu Lys Cys Cys

355 360

Leu Tyr Glu Ile Ala Arg

140

Leu Phe Phe Ala Lys Arg

155 160

Ala Ala Asp Lys Ala Ala

175

Asp Glu Gly Lys Ala Ser

190

Leu Gln Lys Phe Gly Glu

205

Leu Ser Gln Arg Phe Pro

220

Val Thr Asp Leu Thr Lys

235 240

Leu Glu Cys Ala Asp Asp

255

Asn Gln Asp Ser Ile Ser

270

Leu Leu Glu Lys Ser His

285

Pro Ala Asp Leu Pro Ser

300

Val Cys Lys Asn Tyr Ala

315 320

Leu Tyr Glu Tyr Ala Arg

335

Leu Arg Leu Ala Lys Thr

350

Ala Ala Asp Pro His Glu

365

- 266 046387

Cys ^T U ^G Ala Lys Val Phe Asp Glu Phe

370 375

Gln Asn Leu Ile Lys Gln Asn Cys Glu 385 390

Tyr Lys Phe Gln Asn Ala Leu Leu Val 405

Gln Val Ser Thr Pro Thr Leu Val Glu

420 425

Val Gly Ser Lys Cys Cys Lys His Pro

435 440

Ala Glu Asp Tyr Leu Ser Val Val Leu

450 455

Glu Lys Thr Pro Val Ser Asp Arg Val 465 470

Leu Val Asn Arg Arg Pro Cys Phe Ser 485

Tyr Val Pro Lys Glu Phe Asn Ala Glu

500 505

Ile Cys Thr Leu Ser Glu Lys Glu Arg

515 520

Leu Val Glu Leu Val Lys His Lys Pro

530 535

Lys Ala Val Met Asp Asp Phe Ala Ala 545 550

Ala Asp Asp Lys Glu Thr Cys Phe Ala 565

Ala Ala Ser Gln Ala Ala Leu Gly Leu

580 585

Gly Ser Ala Arg Asn Gly Asp His Cys

595 600

Cys Arg Leu His Thr Val Arg Ala Ser

610 615

Pro Leu Val Glu Glu Pro

380

Phe Glu Gln Leu Gly Glu

395 400

Tyr Thr Lys Lys Val Pro

415

Ser Arg Asn Leu Gly Lys

430

Ala Lys Arg Met Pro Cys 445

Gln Leu Cys Val Leu His

460

Lys Cys Cys Thr Glu Ser

475 480

Leu Glu Val Asp Glu Thr

495

Phe Thr Phe His Ala Asp

510

Ile Lys Lys Gln Thr Ala

525

Ala Thr Lys Glu Gln Leu 540

Val Glu Lys Cys Cys Lys

555 560

Glu Gly Lys Lys Leu Val

575

Ser Pro Ala Pro Ala Pro

590

Leu Gly Pro Gly Arg Cys

605

Glu Asp Leu Gly Trp Ala 620

- 267 046387

Asp Trp Val Leu Ser Pro Arg Glu Val Gln Val Thr Met Cys Ile Gly

625 630 635640

Ala Cys Pro Ser Gln Phe Arg Ala Ala Asn Met His Ala Gln Ile Lys

645 650655

Thr Ser Leu His Arg Leu Lys Pro Asp Thr Val Pro Ala Pro Cys Cys

660 665670

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

675 680685

Gly Val Ser Leu Gln Thr Tyr Asp Asp Leu Leu Ala Lys Asp Cys His

690 695700

Cys Ile 705 <210> 116 <211> 14 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic peptide <400> 116

Gly Ser Pro Ala Pro Ala Pro Pro Ala Pro Ala Pro Gly Ser

5 10 <210> 117 <211> 2136 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=description of artificial sequence: synthetic polynucleotide <400> 117

gatgcacaca agagtgaggt tgctcatcga tttaaagatt tggggagaaga aaatttcaaa 60 gccttggtgt tgattgcctt tgctcagtat cttcagcagt gtccattga agatcatgta 120 aaattagtga atgaagtaac tgaatttgca aaaacatgtg ttgctgatga gtcagctgaa 180 aattgtgaca aatcacttca tacccttttt ggagacaaat tatgcacagt tgcaactctt 240 cgtgaaacct atggtgaaat ggctgactgc tgtgcaaaac aagaacctga gagaaatgaa 300 tgcttcttgc aacacaaaga tgacaaccca aacctccccc gattggtgag accagaggtt 360

- 268 046387 gatgtgatgt gcactgcttt tcatgacaat gaagagacat ttttgaaaaa atacttatat 420 gaaattgcca gaagacatcc ttacttttat gccccggaac tccttttctt tgctaaaagg 480 tataaagctg ctttttacaga atgttgccaa gctgctga ta aagctgcctg cctgttgcca 540 aagctcgatg aacttcggga tgaagggaag gcttcgtctg ccaaacagag actcaagtgt 600 gccagtctcc aaaaatttgg agaaagagct ttcaaagcat gggcagtagc tcgcctgagc 660 cagagatttc ccaaagctga gtttgcagaa gtttccaagt tagtgacaga tcttaccaaa 720 gtccacacgg aatgctgcca tggagatctg cttgaatgtg ctgatgacag ggcggacctt 780 gccaagtata tctgtgaaaa tcaagattcg atctccagta aactgaagga atgctgtgaa 840 aaacctctgt tggaaaaatc ccactgcatt gccgaagtgg aaaatgatga gatgcctgct 900 gacttgcctt cattagctgc tgattttgtt gaaagtaagg at gtttgcaa aaactatgct 960 gaggcaaagg atgtcttcct gggcatgttt ttgtatgaat atgcaagaag gcatcctgat 1020 tactctgtcg tgctgctgct gagacttgcc aagacatatg aaaccactct agagaagtgc 1080 tgtgccgctg cagatcctca tgaatgctat gcca aagtgt tcgatgaatt taaacctctt 1140 gtggaagagc ctcagaattt aatcaaacaa aattgtgagc tttttgagca gcttggagag 1200 tacaaattcc agaatgcgct attagttcgt tacaccaaga aagtacccca agtgtcaact 1260 ccaactcttg tagaggtctc aagaaaccta ggaaaagtgg gcagcaaatg ttgtaaacat 1320 cctgaagcaa aaagaatgcc ctgtgcagaa gactatctat ccgtggtcct gaaccagtta 1380 tgtgtgttgc atgagaaaac gccagtaagt gacagagtca ccaaatgctg cacagaatcc 1440 ttggtgaaca ggcgaccatg cttttcagct ctggaagtcg atgaaacata cgttcccaaa 1500 gagtttaatg ctgaaacatt caccttccat gcaga tatat gcacactttc tgagaaggag 1560 agacaaatca agaaacaaac tgcacttgtt gagctcgtga aacacaagcc caaggcaaca 1620 aaagagcaac tgaaagctgt tatggatgat ttcgcagctt ttgtagagaa gtgctgcaag 1680 gctgacgata aggagacctg ctttgccgag gagggtaaaa aacttgttgc ggccagtcag 1740 gccgccttag gcttaggatc cccagctcca gctccacccg cacctgcccc tgga agcgcg 1800 cgcaacggag accactgtcc gctcgggccc gggcgttgct gccgtctgca cacggtccgc 1860 gcgtcgctgg aagacctggg ctgggccgat tgggtgctgt cgccacggga ggtgcaagtg 1920 accatgtgca tcggcgcgtg cccgagccag ttccgggcgg caaacatgca cgcgcagatc 1980 aagacgagcc tgcaccgcct gaagcccgac acggtgccag cgccctgctg cgtgcccgcc 2040 agctacaatc ccatggtgct cattcaaaag accgacaccg gggtgtcgct ccagacctat 2100 gatgacttgt tagccaaaga ctgccactgc atatga 2136 <210> 118 <211> 711

- 269 046387 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 118

Asp Ala His Lys Ser Glu Val Ala His Arg Phe Lys Asp Leu Gly Glu

5 1015

Glu Asn Phe Lys Ala Leu Val Leu Ile Ala Phe Ala Gln Tyr LeuGln

2530

Gln Cys Pro Phe Glu Asp His Val Lys Leu Val Asn Glu Val Thr Glu

4045

Phe Ala Lys

Thr Cys Val Ala Asp Glu Ser Ala Glu Asn Cys Asp Lys 5560

Ser Leu His Thr Leu Phe Gly Asp 65 70

Lys Leu Cys Thr Val Ala Thr Leu

80

Arg Glu Thr Tyr Gly Glu Met Ala 85

Asp Cys Cys Ala Lys Gln Glu Pro

95

Glu Arg Asn Glu Cys Phe Leu Gln

100

His Lys Asp Asp Asn Pro Asn Leu

105 110

Pro Arg Leu Val Arg Pro Glu Val

115 120

Asp Val Met Cys Thr Ala Phe His

125

Asp Asn Glu Glu Thr Phe Leu Lys Lys Tyr Leu Tyr Glu Ile Ala Arg

130 135140

Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu Leu Phe Phe Ala Lys Arg

145 150 155160

Tyr Lys Ala Ala Phe Thr Glu Cys Cys Gln Ala Ala Asp Lys Ala Ala

165 170175

Cys Leu Leu Pro Lys Leu Asp Glu Leu Arg Asp Glu Gly Lys Ala Ser

180 185190

Ser Ala Lys Gln Arg Leu Lys Cys Ala

195200

Ser Leu Gln Lys Phe Gly Glu

205

Arg Ala Phe Lys Ala Trp Ala Val Ala Arg Leu

210215

Ser Gln Arg Phe Pro

220

- 270 046387

Lys 225

Ala

Glu

Phe

Ala

Glu

230

Val

Ser

Lys

Leu

Val

235

Thr

Asp

Leu

Thr

Lys 240

Val

His

Thr

Glu

Cys 245

Cys

His

Gly

Asp

Leu 250

Leu

Glu

Cys

Ala

Asp 255

Asp

Arg Ala Asp Leu Ala Lys Tyr Ile Cys Glu Asn Gln Asp Ser Ile Ser

260 265270

Ser Lys Leu Lys Glu Cys Cys Glu Lys Pro Leu Leu Glu Lys Ser His

275 280285

Cys Ile Ala Glu Val Glu Asn Asp Glu Met Pro Ala Asp Leu Pro Ser

290 295300

Leu Ala Ala Asp Phe Val Glu Ser Lys Asp Val Cys Lys Asn Tyr Ala

305 310 315320

Glu Ala Lys Asp Val Phe Leu Gly Met Phe Leu Tyr Glu Tyr Ala Arg

325 330335

Arg His Pro Asp Tyr Ser Val Val Leu Leu Leu Arg Leu Ala Lys Thr

340 345350

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

355 360365

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

370 375380

Gln Asn Leu Ile Lys Gln Asn Cys Glu Leu Phe Glu Gln Leu Gly Glu

385 390 395400

Tyr Lys Phe Gln Asn Ala Leu Leu Val Arg Tyr Thr Lys Lys Val Pro

405 410415

Gln Val Ser Thr Pro Thr Leu Val Glu Val Ser Arg Asn Leu Gly Lys

420 425430

Val Gly Ser Lys Cys Cys Lys His Pro Glu Ala Lys Arg Met Pro Cys

435 440445

Ala Glu Asp Tyr Leu Ser Val Val Leu Asn Gln Leu Cys Val Leu His

450 455460

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

- 271 046387

465 470 475

Leu Val Asn Arg Arg Pro Cys Phe 485

Ser Ala Leu Glu Val Asp Glu

490 495

Tyr Val Pro Lys

500

Glu Phe Asn Ala Glu Thr Phe Thr Phe His Ala

505 510

Ile Cys Thr Leu

515

Ser Glu Lys Glu Arg Gln Ile Lys Lys Gln Thr

520 525

Leu Val Glu Leu Val

530

Lys His Lys Pro Lys Ala Thr Lys Glu Gln

535 540

Lys Ala Val Met Asp Asp Phe Ala Ala Phe Val Glu Lys Cys Cys

545 550 555

Ala Asp Asp Lys

Glu Thr Cys Phe Ala Glu Glu Gly Lys Lys Leu

565 570 575

Ala Ala

Ser Gln Ala Ala Leu Gly Leu Gly Ser Pro Ala Pro Ala

580 585 590

Pro Ala Pro Ala Pro Gly Ser Ala Arg Asn Gly Asp His Cys Pro

595 600 605

Gly Pro Gly Arg Cys Cys Arg Leu His

610 615

Thr Val Arg Ala Ser Leu

620

Asp Leu Gly Trp Ala Asp Trp Val Leu Ser Pro Arg Glu Val Gln

625 630 635

Thr Met Cys Ile Gly Ala Cys Pro Ser Gln Phe Arg Ala Ala Asn

645 650 655

His Ala Gln Ile Lys Thr Ser Leu His Arg Leu Lys Pro Asp Thr

660 665 670

Pro Ala Pro Cys Cys Val Pro Ala Ser Tyr Asn Pro Met Val Leu

675 680 685

Gln Lys Thr Asp Thr Gly Val

690 695

Ser Leu Gln Thr Tyr Asp Asp Leu

700

480

Thr

Asp

Ala

Leu

Lys 560

Val

Pro

Leu

Glu

Val 640

Met

Val

Ile

Leu

Ala Lys Asp Cys His Cys Ile

705 710

- 272 046387 <210> 119 <211> 11 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic peptide <400> 119

Gly Ser Ala Ala Gln Ala Ala Gln Gln Gly Ser

5 10 <210> 120 <211> 2127 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide

<400> 120 gatgcacaca agagtgaggt tgctcatcga tttaaagatt tggggagaaga aaatttcaaa 60 gccttggtgt tgattgcctt tgctcagtat cttcagcagt gtccattga agatcatgta 120 aaattagtga atgaagtaac tgaatttgca aaaacatgtg ttgctgatga gtcagctgaa 180 aattgtgaca aatcacttca tacccttttt ggagacaaat tatgcacagt tgcaactctt 240 cgtgaaacct atggtgaaat ggctgactgc tgtgcaaaac aagaacctga gagaaatgaa 300 tgcttcttgc aacacaaaga tgacaaccca aacctcccc gattggtgag accagaggtt 360 gatgtgatgt gcactgcttt tcatgacaat gaagagacat ttttgaaaaa atacttatat 420 gaaattgcca gaagacatcc ttacttttat gccccggaac tccttttctt tgctaaaagg 480 tataaagctg cttttacaga atgttgccaa gctgctgata aagctgcctg cctgttgcca 540 aagctcgatg aacttcggga tgaagggaag gcttcgtctg ccaaacagag actcaagtgt 600 gccagtctcc aaaaatttgg agaaagagct ttcaaagcat gggcagtagc tcgcctgagc 660 cagagatttc ccaaagctga gtttgcagaa gtttccaagt tagtgacaga tcttaccaaa 720 gtccacacgg aatgctgcca tggagatctg cttgaatgtg ctgatgacag ggcggacctt 780 gccaagtata tctgtgaaaa tcaagattcg atctccagta aactgaagga atgctgtgaa 840 aaacctctgt tggaaaaatc ccactgcatt gccgaagtgg aaaatgatga gatgcctgct 900 gacttgcctt cattagctgc tgattttgtt gaaagtaagg atgtttgcaa aaactatgct 960 gaggcaaagg atgtcttcct gggcatgttt ttgtatgaat atgcaagaag gcatcctgat 1020 tactctgtcg tgctgctgct gagacttgcc aagacatatg aaaccactct agagaagtgc 1080 tgtgccgctg cagatcctca tgaatgctat gccaaagtgt tcgatgaatt taaacctctt 1140

- 273 046387

gtggaagagc ctcagaattt aatcaaacaa aattgtgagc tttttgagca gcttggagag 1200 takaaattcc agaatgcgct attagttcgt takaccaaga aagtacccca agtgtcaact 1260 ccaactcttg tagaggtctc aagaaaccta ggaaaagtgg gcagcaaatg ttgtaaacat 1320 cctgaagcaa aaagaatgcc ctgtgcagaa gactatctat ccgtggtcct gaaccagtta 1380 tgtgtgttgc atgagaaaac gccagtaagt gacagagtca ccaaatgctg cacagaatcc 1440 ttggtgaaca ggcgaccatg cttttcagct ctggaagtcg atgaaacata cgttcccaaa 1500 gagtttaatg ctgaaacatt caccttccat gcagatatat gcacactttc tgagaaggag 1560 agacaaatca agaaacaaac tgcacttgtt gagctcgtga aacacaagcc caaggcaaca 1620 aaagagcaac tgaaagctgt tatggatgat ttcgcagctt ttgtagagaa gtgctgcaag 1680 gctgacgata aggagacctg ctttgccgag gagggtaaaa aacttgttgc ggccagtcag 1740 gccgccttag gcttaggatc cgccgctcag gctgcacagc aaggaagcgc gcgcaacgga 1800 gaccactgtc cgctcgggcc cggggcgttgc tgccgtctgc acacggtccg cgcgtcgctg 1860 gaagacctgg gctggggccga ttgggtgctg tcgccacggg aggtgcaagt gaccatgtgc 1920 atcggcgcgt gcccgagcca gttccggggcg gcaaacatgc acgcgcagat caagacgagc 1980 ctgcaccgcc tgaagcccga cacggtgcca gcgccctgct gcgtgcccgc cagctacaat 2040 cccatggtgc tcattcaaaa gaccgacacc ggggtgtcgc tccagaccta tgatgacttg 2100 ttagccaaag actgccactg catatga 2127

<210> 121 <211> 708 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 121

Asp Ala His Lys Ser Glu Val Ala His Arg Phe Lys Asp Leu Gly Glu

5 1015

Glu Asn Phe Lys Ala Leu Val Leu Ile Ala Phe Ala Gln Tyr LeuGln

2530

Gln Cys Pro Phe Glu Asp His Val Lys Leu Val Asn Glu Val Thr Glu 35 4045

Phe Ala Lys Thr Cys Val Ala Asp Glu Ser Ala Glu Asn Cys Asp Lys

5560

- 274 046387

Ser Leu His Thr Leu Phe Gly Asp Lys 65 70

Arg Glu Thr Tyr Gly Glu Met Ala Asp 85

Glu Arg Asn Glu Cys Phe Leu Gln His

100 105

Pro Arg Leu Val Arg Pro Glu Val Asp

115 120

Asp Asn Glu Glu Thr Phe Leu Lys Lys

130 135

Arg His Pro Tyr Phe Tyr Ala Pro Glu 145 150

Tyr Lys Ala Ala Phe Thr Glu Cys Cys

165

Cys Leu Leu Pro Lys Leu Asp Glu Leu

180 185

Ser Ala Lys Gln Arg Leu Lys Cys Ala

195 200

Arg Ala Phe Lys Ala Trp Ala Val Ala

210 215

Lys Ala Glu Phe Ala Glu Val Ser Lys 225 230

Val His Thr Glu Cys Cys His Gly Asp

245

Arg Ala Asp Leu Ala Lys Tyr Ile Cys

260 265

Ser Lys Leu Lys Glu Cys Cys Glu Lys

275 280

Cys Ile Ala Glu Val Glu Asn Asp Glu

290 295

Leu Ala Ala Asp Phe Val Glu Ser Lys

305 310

Cys Thr Val Ala Thr Leu 75 80

Cys Ala Lys Gln Glu Pro 95

Asp Asp Asn Pro Asn Leu

110

Met Cys Thr Ala Phe His

125

Leu Tyr Glu Ile Ala Arg 140

Leu Phe Phe Ala Lys Arg

155 160

Ala Ala Asp Lys Ala Ala

175

Asp Glu Gly Lys Ala Ser

190

Leu Gln Lys Phe Gly Glu

205

Leu Ser Gln Arg Phe Pro

220

Val Thr Asp Leu Thr Lys

235 240

Leu Glu Cys Ala Asp Asp

255

Asn Gln Asp Ser Ile Ser

270

Leu Leu Glu Lys Ser His

285

Pro Ala Asp Leu Pro Ser

300

Val Cys Lys Asn Tyr Ala

315 320

- 275 046387

Glu Ala Lys Asp Val Phe Leu Gly Met Phe Leu Tyr Glu Tyr Ala Arg

325 330335

Arg His Pro Asp Tyr Ser Val Val Leu Leu Leu Arg Leu Ala Lys Thr

340 345350

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

355 360365

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

370 375380

Gln Asn Leu Ile Lys Gln Asn Cys Glu Leu Phe Glu Gln Leu Gly Glu

385 390 395400

Tyr Lys Phe Gln Asn Ala Leu Leu Val Arg Tyr Thr Lys Lys Val Pro

405 410415

Gln Val Ser Thr Pro Thr Leu Val Glu Val Ser Arg Asn Leu Gly Lys

420 425430

Val Gly Ser Lys Cys Cys Lys His Pro Glu Ala Lys Arg Met Pro Cys

435 440445

Ala Glu Asp Tyr Leu Ser Val Val Leu Asn Gln Leu Cys Val Leu His

450 455460

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

465 470 475480

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

485 490495

Tyr Val Pro Lys Glu Phe Asn Ala Glu Thr Phe Thr Phe His Ala Asp

500 505510

Ile Cys Thr Leu Ser Glu Lys Glu Arg Gln Ile Lys Lys Gln Thr Ala

515 520525

Leu Val Glu Leu Val Lys His Lys Pro Lys Ala Thr Lys Glu Gln Leu

530 535540

Lys Ala Val Met Asp Asp Phe Ala Ala Phe Val Glu Lys Cys Cys Lys

545 550 555560

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

565 570575

- 276 046387

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

580 585590

Gln Gln Gly Ser Ala Arg Asn Gly Asp His Cys Pro Leu Gly Pro Gly

595 600605

Arg Cys Cys Arg Leu His Thr Val Arg Ala Ser Leu Glu Asp Leu Gly

610 615620

Trp Ala Asp Trp Val Leu Ser Pro Arg Glu Val Gln Val Thr Met Cys

625 630 635640

Ile Gly Ala Cys Pro Ser Gln Phe Arg Ala Ala Asn Met His Ala Gln

645 650655

Ile Lys Thr Ser Leu His Arg Leu Lys Pro Asp Thr Val Pro Ala Pro

660 66567 0

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

675 680685

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

690 695700

Cys His Cys Ile 705 <210> 122 <211> 18 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic peptide <400> 122

Gly Ser Ala Ala Gln Ala Ala Gln Gln Ala Ala Gln Ala Ala Gln Gln

5 10 15

Gly Ser <210> 123 <211> 2148 <212> DNA <213> Artificial sequence <220>

- 277 046387 <221> source <223> /note=''description of artificial sequence: synthetic polynucleotide <400> 123 gatgcacaca agagtgaggt tgctcatcga tttaaagatt tgggagaaga aaatttcaaa60 gccttggtgt tgattgcctt tgctcagtat cttcagcagt gtccatt tga agatcatgta120 aaattagtga atgaagtaac tgaatttgca aaaacatgtg ttgctgatga gtcagctgaa180 aattgtgaca aatcacttca tacccttttt ggagacaaat tatgcacagt tgcaactctt240 cgtgaaacct atggtgaaat ggctgactgc tgtgcaaaac aagaacctga gagaaatgaa300 tgcttcttgc aacacaaaga tgacaaccca aacctccccc gattggtgag accagaggtt360 gatgtgatgt gcactgcttt tcatgacaat gaagagacat ttttgaaaaa atacttatat420 gaaattgcca gaagacatcc ttacttttat gccccggaac tccttttctt tgctaaaagg480 tataaagctg cttttacaga atgttgccaa gctgctgata aagctgcctg cctgttgcca540 aagctcgatg aacttcggga tgaagggaag gcttcgtctg ccaaacagag actcaagtgt600 gccagt ctcc aaaaatttgg agaaagagct ttcaaagcat gggcagtagc tcgcctgagc660 cagagatttc ccaaagctga gtttcagaa gtttccaagt tagtgacaga tcttaccaaa720 gtccacacgg aatgctgcca tggagatctg cttgaatgtg ctgatgacag ggcggacctt780 gccaagtata tctgtgaaaa tcaagattcg atctccagta aactgaagga atgctgtgaa840 aaacctctgt tggaaaaatc ccactgcatt gccgaagtgg aaaatgatga gatgcctgct900 gacttgcctt cattagctgc tgattt tgtt gaaagtaagg atgtttgcaa aaactatgct960 gaggcaaagg atgtcttcct gggcatgttt ttgtatgaat atgcaagaag gcatcctgat1020 tactctgtcg tgctgctgct gagacttgcc aagacatatg aaaccactct agagaagtgc1080 tgtgccgctg cagatcct ca tgaatgctat gccaaagtgt tcgatgaatt taaacctctt1140 gtggaagagc ctcagaattt aatcaaacaa aattgtgagc tttttgagca gcttggagag1200 tacaaattcc agaatgcgct attagttcgt tacaccaaga aagtacccca agtgtcaact1260 ccaactcttg tagaggtctc aagaaaccta ggaaaagtgg gcagcaaatg ttgtaaacat1320 cctgaagcaa aaagaatgcc ctgtgcagaa gactatctat ccgtggtcct gaaccagtta1380 tgtgtgttgc atgagaaaac gccagtaagt gacagagtca ccaaatgctg cacagaatcc1440 ttggtgaaca ggcgaccatg cttttcagct ctggaagtcg atgaaacata cgttcccaaa1500 gagtttaatg ctgaaacatt caccttccat gcagatatat gcacactttc tgagaaggag1560 agacaaatca agaaacaaac tgcacttgt t gagctcgtga aacacaagcc caaggcaaca1620 aaagagcaac tgaaagctgt tatggatgat ttcgcagctt ttgtagagaa gtgctgcaag1680 gctgacgata aggagacctg ctttgccgag gagggtaaaa aacttgttgc ggccagtcag1740

- 278 046387

gccgccttag gcttaggatc cgccgctcag gctgcacagc aagcagccca agcagctcag 1800 cagggaagcg cgcgcaacgg agaccactgt ccgctcgggc ccgggcgttg ctgccgtctg 1860 cacacggtcc gcgcgtcgct ggaagacctg ggctgggccg attgggtgct gtcgccacgg 1920 gaggtgcaag tgaccatgtg catcggcgcg tgcccgagcc agttccggggc ggcaaacatg 1980 cacgcgcaga tcaagacgag cctgcaccgc ctgaagcccg acacggtgcc agcgccctgc 2040 tgcgtgcccg ccagctacaa tcccatggtg ctcattcaaa agaccgacac cggggtgtcg 2100 ctccagacct atgatgactt gttagccaaa gactgccact gcatatga 2148

<210> 124 <211> 715 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 124

Asp Ala His Lys Ser Glu Val Ala His Arg Phe Lys Asp Leu Gly Glu

5 1015

Glu Asn Phe Lys Ala Leu Val Leu Ile Ala Phe Ala Gln Tyr Leu Gln 20 2530

Gln Cys Pro Phe Glu Asp His Val Lys Leu Val Asn Glu Val Thr Glu 35 4045

Phe Ala Lys Thr Cys Val Ala Asp Glu Ser Ala Glu Asn Cys Asp Lys 50 5560

Ser Leu His Thr Leu Phe Gly Asp Lys Leu Cys Thr Val Ala Thr Leu

70 7580

Arg Glu Thr Tyr Gly Glu Met Ala Asp Cys Cys Ala Lys Gln Glu Pro 85 9095

Glu Arg Asn Glu Cys Phe Leu Gln His Lys Asp Asp Asn Pro Asn Leu

100 105110

Pro Arg Leu Val Arg Pro Glu Val Asp Val Met Cys Thr Ala Phe His

115 120125

Asp Asn Glu Glu Thr Phe Leu Lys Lys Tyr Leu Tyr Glu Ile Ala Arg

130 135140

Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu Leu Phe Phe Ala Lys Arg

- 279 046387

145 150 155160

Tyr Lys Ala Ala Phe Thr Glu Cys Cys Gln Ala Ala Asp Lys Ala Ala

165 170175

Cys Leu Leu Pro Lys Leu Asp Glu Leu Arg Asp Glu Gly Lys Ala Ser

180 185190

Ser Ala Lys Gln Arg Leu Lys Cys Ala Ser Leu Gln Lys Phe Gly Glu

195 200205

Arg Ala Phe Lys Ala Trp Ala Val Ala Arg Leu Ser Gln Arg Phe Pro

210 215220

Lys Ala Glu Phe Ala Glu Val Ser Lys Leu Val Thr Asp Leu Thr Lys

225 230 235240

Val His Thr Glu Cys Cys His Gly Asp Leu Leu Glu Cys Ala Asp Asp

245 250255

Arg Ala Asp Leu Ala Lys Tyr Ile Cys Glu Asn Gln Asp Ser Ile Ser

260 265270

Ser Lys Leu Lys Glu Cys Cys Glu Lys Pro Leu Leu Glu Lys Ser His

275 280285

Cys Ile Ala Glu Val Glu Asn Asp Glu Met Pro Ala Asp Leu Pro Ser

290 295300

Leu Ala Ala Asp Phe Val Glu Ser Lys Asp Val Cys Lys Asn Tyr Ala

305 310 315320

Glu Ala Lys Asp Val Phe Leu Gly Met Phe Leu Tyr Glu Tyr Ala Arg

325 330335

Arg His Pro Asp Tyr Ser Val Val Leu Leu Leu Arg Leu Ala Lys Thr

340 345350

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

355 360365

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

370 375380

Gln Asn Leu Ile Lys Gln Asn Cys Glu Leu Phe Glu Gln Leu Gly Glu

385 390 395400

- 280 046387

Tyr Lys Phe Gln Asn Ala Leu Leu Val 405

Gln Val Ser Thr Pro Thr Leu Val Glu

420 425

Val Gly Ser Lys Cys Cys Lys His Pro

435 440

Ala Glu Asp Tyr Leu Ser Val Val Leu

450 455

Glu Lys Thr Pro Val Ser Asp Arg Val 465 470

Leu Val Asn Arg Arg Pro Cys Phe Ser 485

Tyr Val Pro Lys Glu Phe Asn Ala Glu

500 505

Ile Cys Thr Leu Ser Glu Lys Glu Arg

515 520

Leu Val Glu Leu Val Lys His Lys Pro

530 535

Lys Ala Val Met Asp Asp Phe Ala Ala

545 550

Ala Asp Asp Lys Glu Thr Cys Phe Ala 565

Ala Ala Ser Gln Ala Ala Leu Gly Leu

580 585

Gln Gln Ala Ala Gln Ala Ala Gln Gln

595 600

His Cys Pro Leu Gly Pro Gly Arg Cys

610 615

Ala Ser Leu Glu Asp Leu Gly Trp Ala

625 630

Glu Val Gln Val Thr Met Cys Ile Gly 645

Tyr Thr Lys Lys Val Pro

415

Ser Arg Asn Leu Gly Lys

430

Ala Lys Arg Met Pro Cys 445

Gln Leu Cys Val Leu His

460

Lys Cys Cys Thr Glu Ser

475 480

Leu Glu Val Asp Glu Thr

495

Phe Thr Phe His Ala Asp

510

Ile Lys Lys Gln Thr Ala

525

Ala Thr Lys Glu Gln Leu 540

Val Glu Lys Cys Cys Lys

555 560

Glu Gly Lys Lys Leu Val

575

Ser Ala Ala Gln Ala Ala

590

Ser Ala Arg Asn Gly Asp

605

Arg Leu His Thr Val Arg

620

Trp Val Leu Ser Pro Arg

635 640

Cys Pro Ser Gln Phe Arg

655

- 281 046387

Ala Ala Asn Met

660

His Ala Gln Ile

Lys Thr Ser Leu 665

His Arg Leu Lys 670

Pro Asp Thr Val

675

Pro Ala Pro Cys

680

Cys Val Pro Ala

Ser Tyr Asn Pro 685

Met Val Leu Ile

690

Gln Lys Thr Asp

695

Thr Gly Val Ser

700

Leu Gln Thr Tyr

Asp Asp Leu Leu 705

Ala Lys Asp Cys 710

His Cys Ile 715 <210> 125 <211> 22 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic peptide <400> 125

Gly Gly Asn Ala Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala

5 10 15

Ala Ala Lys Ala Gly Gly <210> 126 <211> 2175 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide <400> 126

gatgcacaca agagtgaggt tgctcatcga tttaaagatt tggggagaaga aaatttcaaa 60 gccttggtgt tgattgcctt tgctcagtat cttcagcagt gtccattga agatcatgta 120 aaattagtga atgaagtaac tgaatttgca aaaacatgtg ttgctgatga gtcagctgaa 180 aattgtgaca aatcacttca tacccttttt ggagacaaat tatgcacagt tgcaactctt 240 cgtgaaacct atggtgaaat ggctgactgc tgtgcaaaac aagaacctga gagaaatgaa 300 tgcttcttgc aacacaaaga tgacaaccca aacctccccc gattggtgag accagaggtt 360 gatgtgatgt gcactgcttt tcatgacaat gaagagacat ttttgaaaaa atacttatat 420 gaaattgcca gaagacatcc ttacttttat gccccggaac tccttttctt tgctaaaagg 480

- 282 046387 tataaagctg cttttacaga atgttgccaa gctgctgata aagctgcctg cctgttgcca540 aagctcgatg aacttcggga tgaagggaag gcttcgtctg ccaaacagag actcaagtgt600 gccagtctcc aaaaatttgg agaaagagct ttcaaagcat ggg cagtagc tcgcctgagc660 cagagatttc ccaaagctga gtttgcagaa gtttccaagt tagtgacaga tcttaccaaa720 gtccacacgg aatgctgcca tggagatctg cttgaatgtg ctgatgacag ggcggacctt780 gccaagtata tctgtgaaaa tcaagattcg atctccagta aact gaagga atgctgtgaa840 aaacctctgt tggaaaaatc ccactgcatt gccgaagtgg aaaatgatga gatgcctgct900 gacttgcctt cattagctgc tgattttgtt gaaagtaagg atgtttgcaa aaactatgct960 gaggcaaagg atgtcttcct gggcatgttt ttgtatgaat atgcaagaag gcatcctgat1020 tactctgtcg tgctgctgct gagacttgcc aagacatatg aaaccactct agagaagtgc1080 tgtgccgctg cagatcctca tgaatgctat gccaaagtgt tcgat gaatt taaacctctt1140 gtggaagagc ctcagaattt aatcaaacaa aattgtgagc tttttgagca gcttggagag1200 tacaaattcc agaatgcgct attagttcgt tacaccaaga aagtacccca agtgtcaact1260 ccaactcttg tagaggtctc aagaaaccta ggaaaagtgg gca gcaaatg ttgtaaacat1320 cctgaagcaa aaagaatgcc ctgtgcagaa gactatctat ccgtggtcct gaaccagtta1380 tgtgtgttgc atgagaaaac gccagtaagt gacagagtca ccaaatgctg cacagaatcc1440 ttggtgaaca ggcgaccatg cttttcagct ctggaagtcg atgaaacata cgttcccaaa1500 gagtttaatg ctgaaacatt caccttccat gcagatatat gcacactttc tgagaaggag1560 agacaaatca agaaacaaac tgcacttgtt gagctcgtga aacacaagcc caaggcaaca16 20 aaagagcaac tgaaagctgt tatggatgat ttcgcagctt ttgtagagaa gtgctgcaag1680 gctgacgata aggagacctg ctttgccgag gagggtaaaa aacttgttgc ggccagtcag1740 gccgccttag gcttaggagg caacgccgag gctgccgcta aggaagccgc tg ccaaggag1800 gccgcagcaa aagaggctgc agctaaggcc ggaggagcgc gcaacggaga ccactgtccg1860 ctcgggcccg ggcgttgctg ccgtctgcac acggtccgcg cgtcgctgga agacctgggc1920 tgggccgatt gggtgctgtc gccacgggag gtgcaagtga ccatgtgcat cggcgcgtgc1980 ccgagccagt tccgggcggc aaacatgcac gcgcagatca agacgagcct gcaccgcctg2040 aagcccgaca cggtgccagc gccctgctgc gtgcccgcca gctacaatcc catggtgctc2100 attcaaaaga ccga caccgg ggtgtcgctc cagacctatg atgacttgtt agccaaagac 2160 tgccactgca tatga2175 <210> 127 <211> 724 <212> PRT <213> Artificial sequence

- 283 046387 <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 127

Asp Ala His Lys Ser Glu Val Ala His Arg Phe Lys Asp Leu Gly Glu

5 1015

Glu Asn Phe Lys Ala Leu Val Leu Ile Ala Phe Ala Gln Tyr Leu Gln 20 2530

Gln Cys Pro Phe Glu Asp His Val Lys Leu Val Asn Glu Val Thr Glu 35 4045

Phe Ala Lys Thr Cys Val Ala Asp Glu Ser Ala Glu Asn Cys Asp Lys 50 5560

Ser Leu His Thr Leu Phe Gly Asp Lys Leu Cys Thr Val Ala Thr Leu

70 7580

Arg Glu Thr Tyr Gly Glu Met Ala Asp Cys Cys Ala Lys Gln Glu Pro 85 9095

Glu Arg Asn Glu Cys Phe Leu Gln His Lys Asp Asp Asn Pro Asn Leu

100 105110

Pro Arg Leu Val Arg Pro Glu Val Asp Val Met Cys Thr Ala Phe His

115 120125

Asp Asn Glu Glu Thr Phe Leu Lys Lys Tyr Leu Tyr Glu Ile Ala Arg

130 135140

Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu Leu Phe Phe Ala Lys Arg

145 150 155160

Tyr Lys Ala Ala Phe Thr Glu Cys Cys Gln Ala Ala Asp Lys Ala Ala

165 170175

Cys Leu Leu Pro Lys Leu Asp Glu Leu Arg Asp Glu Gly Lys Ala Ser

180 185190

Ser Ala Lys Gln Arg Leu Lys Cys Ala Ser Leu Gln Lys Phe Gly Glu

195 200205

Arg Ala Phe Lys Ala Trp Ala Val Ala Arg Leu Ser Gln Arg Phe Pro

210 215220

- 284 046387

Lys Ala Glu Phe Ala Glu Val Ser Lys Leu Val Thr Asp Leu Thr

225 230 235

Val His Thr Glu Cys Cys His Gly Asp Leu Leu Glu Cys Ala Asp

245 250 255

Arg Ala Asp Leu Ala Lys Tyr Ile Cys Glu Asn Gln Asp Ser Ile

260 265 270

Ser Lys Leu Lys Glu Cys Cys Glu Lys Pro Leu Leu Glu Lys Ser

275 280 285

Cys Ile Ala Glu Val Glu Asn Asp Glu Met Pro Ala Asp Leu Pro

290 295 300

Leu Ala Ala Asp Phe Val Glu Ser Lys Asp Val Cys Lys Asn Tyr

305 310 315

Glu Ala Lys Asp Val Phe Leu Gly Met Phe Leu Tyr Glu Tyr Ala

325 330 335

Arg His Pro Asp Tyr Ser Val Val Leu Leu Leu Arg Leu Ala Lys

340 345 350

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

355 360 365

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

370 375 380

Gln Asn Leu Ile Lys Gln Asn Cys Glu Leu Phe Glu Gln Leu Gly

385 390 395

Tyr Lys Phe Gln Asn Ala Leu Leu Val Arg Tyr Thr Lys Lys Val

405 410 415

Gln Val Ser Thr Pro Thr Leu Val Glu Val Ser Arg Asn Leu Gly

420 425 430

Val Gly Ser Lys Cys Cys Lys His Pro Glu Ala Lys Arg Met Pro

435 440 445

Ala Glu Asp Tyr Leu Ser Val Val Leu Asn Gln Leu Cys Val Leu

450 455 460

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

465 470 475

Lys 240

Asp

Ser

His

Ser

Ala 320

Arg

Thr

Glu

Pro

Glu 400

Pro

Lys

Cys

His

Ser 480

- 285 046387

Leu Val Asn Arg Arg Pro Cys Phe 485

Ser Ala Leu Glu Val Asp Glu

490 495

Tyr Val Pro Lys Glu Phe Asn Ala Glu Thr Phe Thr Phe His Ala

500 505 510

Ile Cys Thr Leu Ser Glu Lys Glu Arg Gln Ile Lys Lys Gln Thr

515 520 525

Leu Val Glu Leu Val Lys His Lys Pro Lys Ala Thr Lys Glu Gln

530 535 540

Lys Ala Val Met Asp Asp Phe Ala Ala Phe Val Glu Lys Cys Cys

545 550 555

Ala Asp Asp Lys Glu Thr Cys Phe Ala Glu Glu Gly Lys Lys Leu

565 570 575

Ala Ala Ser Gln Ala Ala Leu Gly Leu Gly Gly Asn Ala Glu Ala

580 585 590

Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala

595 600 605

Lys Ala Gly Gly Ala Arg Asn Gly Asp His Cys Pro Leu Gly Pro

610 615 620

Arg Cys Cys Arg Leu His Thr Val Arg Ala Ser Leu Glu Asp Leu

625 630 635

Trp Ala Asp Trp Val Leu Ser Pro Arg Glu Val Gln Val Thr Met

645 650 655

Ile Gly Ala Cys Pro Ser Gln Phe Arg Ala Ala Asn Met His Ala

660 665 670

Ile Lys Thr Ser Leu His Arg Leu Lys Pro Asp Thr Val Pro Ala

675 680 685

Cys Cys Val Pro Ala Ser Tyr Asn Pro Met Val Leu Ile Gln Lys

690 695 700

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

705 710 715

Thr

Asp

Ala

Leu

Lys 560

Val

Ala

Ala

Gly

Gly 640

Cys

Gln

Pro

Thr

Asp 720

Cys His Cys Ile

- 286 046387 <210> 128 <211> 30 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 128

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

5 10 15

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 20 25 30 <210> 129 <211> 2184 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=description of artificial sequence: synthetic polynucleotide

<400> 129 gatgcacaca agagtgaggt tgctcatcga tttaaagatt tggggagaaga aaatttcaaa 60 gccttggtgt tgattgcctt tgctcagtat cttcagcagt gtccattga agatcatgta 120 aaattagtga atgaagtaac tgaatttgca aaaacatgtg ttgctgatga gtcagctgaa 180 aattgtgaca aatcacttca tacccttttt ggagacaaat tatgcacagt tgcaactctt 240 cgtgaaacct atggtgaaat ggctgactgc tgtgcaaaac aagaacctga gagaaatgaa 300 tgcttcttgc aacacaaaga tgacaaccca aacctccccc gattggtgag accagaggtt 360 gatgtgatgt gcactgcttt tcatgacaat gaagagacat ttttgaaaaa atacttatat 420 gaaattgcca gaagacatcc ttacttttat gccccggaac tccttttctt tgctaaaagg 480 tataaagctg cttttacaga atgttgccaa gctgctgata aagctgcctg cctgttgcca 540 aagctcgatg aacttcggga tgaagggaag gcttcgtctg ccaaacagag actcaagtgt 600 gccagtctcc aaaaatttgg agaaagagct ttcaaagcat gggcagtagc tcgcctgagc 660 cagagatttc ccaaagctga gtttgcagaa gtttccaagt tagtgacaga tcttaccaaa 720 gtccacacgg aatgctgcca tggagatctg cttgaatgtg ctgatgacag ggcggacctt 780 gccaagtata tctgtgaaaa tcaagattcg atctccagta aactgaagga atgctgtgaa 840 aaacctctgt tggaaaaatc ccactgcatt gccgaagtgg aaaatgatga gatgcctgct 900 gacttgcctt cattagctgc tgattttgtt gaaagtaagg atgtttgcaa aaactatgct 960

- 287 046387

gaggcaaagg atgtcttcct gggcatgttt ttgtatgaat atgcaagaag gcatcctgat 1020 tactctgtcg tgctgctgct gagacttgcc aagacatatg aaaccactct agagaagtgc 1080 tgtgccgctg cagatcctca tgaatgctat gccaaagtgt tcgatgaatt taaacctctt 1140 gtggaagagc ctcagaattt aatcaaacaa aattgtgagc tttttgagca gcttggagag 1200 takaaattcc agaatgcgct attagttcgt takaccaaga aagtacccca agtgtcaact 1260 ccaactcttg tagaggtctc aagaaaccta ggaaaagtgg gcagcaaatg ttgtaaacat 1320 cctgaagcaa aaagaatgcc ctgtgcagaa gactatctat ccgtggtcct gaaccagtta 1380 tgtgtgttgc atgagaaaac gccagtaagt gacagagtca ccaaatgctg cacagaatcc 1440 ttggtgaaca ggcgaccatg cttttcagct ctggaagtcg atgaaacata cgttcccaaa 1500 gagtttaatg ctgaaacatt caccttccat gcagatatat gcacactttc tgagaaggag 1560 agacaaatca agaaacaaac tgcacttgtt gagctcgtga aacacaagcc caaggcaaca 1620 aaagagcaac tgaaagctgt tatggatgat ttcgcagctt ttgtagagaa gtgctgcaag 1680 gctgacgata aggagacctg ctttgccgag gagggtaaaa aacttgttgc ggccagtcag 1740 gccgccttag gcttaggagg tggtggctct ggagaggcggtg gaagcggagg cggtggatcc 1800 ggagaggcggtg gaagcggagg tggtggatct ggagaggcggtg gaagcgcgcg caacggagac 1860 cactgtccgc tcgggcccgg gcgttgctgc cgtctgcaca cggtccgcgc gtcgctggaa 1920 gacctggggct gggccgattg ggtgctgtcg ccacgggagg tgcaagtgac catgtgcatc 1980 ggcgcgtgcc cgagccagtt ccggggcggca aacatgcacg cgcagatcaa gacgagcctg 2040 caccgcctga agcccgacac ggtgccagcg ccctgctgcg tgcccgccag ctacaatccc 2100 atggtgctca ttcaaaagac cgacaccggg gtgtcgctcc agacctatga tgacttgtta 2160 gccaaagact gccactgcat atga 2184

<210> 130 <211> 777 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 130

Asp Ala His Lys Ser Glu Val Ala His Arg Phe Lys Asp Leu Gly Glu

5 10 15

Glu Asn Phe Lys Ala Leu Val Leu Ile Ala Phe Ala Gln Tyr Leu Gln 20 25 30

- 288 046387

Gln

Phe

Gly 65

Leu

Thr

Asp

Thr

Glu 145

Asn

Phe

Ala

Lys

Ala 225

Ala

Gly

Phe

Cys Pro Phe Glu Asp 35

Ala Asp Ala His Lys 50

Glu Glu Asn Phe Lys

Gln Gln Cys Pro Phe 85

Glu Phe Ala Lys Thr

100

Lys Ser Leu His Thr 115

Leu Arg Glu Thr Tyr 130

Pro Glu Arg Asn Glu

150

Leu Pro Arg Leu Val

165

His Asp Asn Glu Glu 180

Arg Arg His Pro Tyr 195

Arg Tyr Lys Ala Ala 210

Ala Cys Leu Leu Pro

230

Ser Ser Ala Lys Gln

245

Glu Arg Ala Phe Lys 260

Pro Lys Ala Glu Phe

275

His Val Lys Leu Val 40

Ser Glu Val Ala His 55

Ala Leu Val Leu Ile

Glu Asp His Val Lys

Cys Val Ala Asp Glu 105

Leu Phe Gly Asp Lys

120

Gly Glu Met Ala Asp 135

Cys Phe Leu Gln His

155

Arg Pro Glu Val Asp

170

Thr Phe Leu Lys Lys 185

Phe Tyr Ala Pro Glu

200

Phe Thr Glu Cys Cys 215

Lys Leu Asp Glu Leu

235

Arg Leu Lys Cys Ala

250

Ala Trp Ala Val Ala 265

Ala Glu Val Ser Lys 280

Asn Glu Val Thr Glu 45

Arg Phe Lys Asp Leu 60

Ala Phe Ala Gln Tyr

Leu Val Asn Glu Val

Ser Ala Glu Asn Cys

110

Leu Cys Thr Val Ala

125

Cys Cys Ala Lys Gln 140

Lys Asp Asp Asn Pro

160

Val Met Cys Thr Ala

175

Tyr Leu Tyr Glu Ile 190

Leu Leu Phe Phe Ala

205

Gln Ala Ala Asp Lys 220

Arg Asp Glu Gly Lys

240

Ser Leu Gln Lys Phe

255

Arg Leu Ser Gln Arg

270

Leu Val Thr Asp Leu

285

- 289 046387

Thr Lys Val His Thr

290

Glu Cys Cys His Gly 295

Asp Leu Leu Glu Cys 300

Asp Asp Arg Ala Asp 305

Leu Ala Lys Tyr Ile 310

Cys Glu Asn Gln Asp 315

Ile Ser Ser Lys Leu

325

Lys Glu Cys Cys Glu

330

Lys Pro Leu Leu Glu

335

Ser His Cys Ile Ala

340

Glu Val Glu Asn Asp

345

Glu Met Pro Ala Asp

350

Pro Ser Leu Ala Ala

355

Asp Phe Val Glu Ser 360

Lys Asp Val Cys Lys

365

Tyr Ala Glu Ala Lys

370

Asp Val Phe Leu Gly 375

Met Phe Leu Tyr Glu 380

Ala Arg Arg His Pro 385

Asp Tyr Ser Val Val 390

Leu Leu Leu Arg Leu 395

Lys Thr Tyr Glu Thr

405

Thr Leu Glu Lys Cys

410

Cys Ala Ala Ala Asp

415

His Glu Cys Tyr Ala

420

Lys Val Phe Asp Glu

425

Phe Lys Pro Leu Val

430

Glu Pro Gln Asn Leu

435

Ile Lys Gln Asn Cys

440

Glu Leu Phe Glu Gln

445

Gly Glu Tyr Lys Phe 450

Gln Asn Ala Leu Leu

455

Val Arg Tyr Thr Lys

460

Val Pro Gln Val Ser 465

Thr Pro Thr Leu Val 470

Glu Val Ser Arg Asn 475

Gly Lys Val Gly Ser

485

Lys Cys Cys Lys His

490

Pro Glu Ala Lys Arg

495

Pro Cys Ala Glu Asp

500

Tyr Leu Ser Val Val

505

Leu Asn Gln Leu Cys

510

Leu His Glu Lys Thr 515

Pro Val Ser Asp Arg 520

Val Thr Lys Cys Cys 525

Glu Ser Leu Val Asn

530

Arg Arg Pro Cys Phe 535

Ser Ala Leu Glu Val

540

Ala

Ser 320

Lys

Leu

Asn

Tyr

Ala 400

Pro

Glu

Leu

Lys

Leu 480

Met

Val

Thr

Asp

- 290 046387

Glu Thr Tyr 545

Val Pro Lys Glu Phe Asn Ala Glu

550 555

Thr Phe Thr Phe His

560

Ala Asp Ile

Cys Thr Leu Ser Glu Lys Glu Arg Gln Ile Lys Lys Gln

565 570 575

Thr Ala Leu

Val Glu Leu Val Lys His Lys Pro Lys Ala Thr Lys Glu

580 585 590

Gln Leu Lys

595

Ala Val Met Asp Asp Phe Ala Ala Phe Val Glu Lys Cys

600 605

Cys Lys Ala

610

Asp Asp Lys Glu Thr Cys Phe Ala Glu Glu Gly Lys Lys

615 620

Leu Val Ala 625

Ala

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

630 635 640

Gly Gly Gly

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

645 650 655

Gly Gly Gly

Ser Gly Gly Gly Gly Ser Ala Arg Asn Gly Asp His Cys

660 665 670

Pro Leu Gly

675

Pro Gly Arg Cys Cys Arg Leu His Thr Val Arg Ala Ser

680 685

Leu Glu Asp

690

Leu Gly Trp Ala Asp Trp Val Leu Ser Pro Arg Glu Val

695 700

Gln Val Thr 705

Met Cys

Ile Gly Ala Cys Pro Ser Gln Phe Arg Ala Ala

710 715 720

Asn Met His

Ala Gln Ile Lys Thr Ser Leu His Arg Leu Lys Pro Asp

725 730 735

Thr Val Pro

Ala Pro Cys Cys Val Pro Ala

740 745

Ser Tyr Asn Pro Met Val

750

Leu Ile Gln

755

Lys

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

760 765

Leu Leu Ala

770

Lys Asp Cys His Cys Ile 775 <210> 131

- 291 046387 <211> 217 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 131

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

5 1015

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

2530

Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 4045

Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 5560

Gln Tyr Gly Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val LeuHis

70 7580

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

9095

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

100 105110

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

115 120125

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

130 135140

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

145 150 155160

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

165 170175

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

180 185190

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

195 200205

Lys Ser Leu Ser Leu Ser Pro Gly Lys

- 292 046387

210

215 <210> 132 <211> 216 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 132

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

5 1015

Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 2530

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

4045

Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 5560

Gln Tyr Gly Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 7580

Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 9095

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

100 105110

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

115 120125

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

130 135140

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

145 150 155160

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

165 170175

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

180 185190

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

- 293 046387

195

200

205

Lys Ser Leu Ser Leu Ser Pro Gly

210

215 <210> 133 <211> 975 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide <400> 133 gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac120 cctgagg tca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag180 ccgcgggagg agcagtacgg gagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc300 cccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtacacc360 ctgcccccat cccgggagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa420 ggcttctatc ccagcgacat cgccgtggag tgggagagca atggg cagcc ggagaacaac480 tacgacacca cgcctcccgt gctggactcc gacggctcct tcttcctcta tagcgacctc540 accgtggaca agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccgggtgg agaccactgt660 ccgctcgggc ccgggcgttg ctgccgtctg cacacggtcc gcgcgtcgct ggaagacctg720 ggctgggccg attgggtgct gtcgccacgg gaggtgcaag tgaccatgtg catcggcgcg780 tgcccgagcc agttccgggc ggcaaacatg cacgcgcaga tcaagacgag cctgcaccgc840 ctgaagcccg acacggtgcc agcgccctgc tgcgtgcccg ccagctacaa tcccatggtg900 ctcattcaaa agaccgacac cggggtgtcg ctccagacct atgatgactt gttagccaaa960 gactgccact gcata975 <210> 134 <211> 325 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=description of artificial sequence: synthetic polypeptide

- 294 046387 <400> 134

Ala Pro Glu Leu Leu 1 5

Gly Gly Pro Ser Val

Phe Leu Phe Pro Pro

Pro Lys Asp Thr Leu

Met Ile Ser Arg Thr 25

Pro Glu Val Thr Cys 30

Val Val Asp Val Ser 35

His Glu Asp Pro Glu 40

Val Lys Phe Asn Trp 45

Val Asp Gly Val Glu 50

Val His Asn Ala Lys 55

Thr Lys Pro Arg Glu 60

Gln Tyr Gly Ser Thr 65

Tyr Arg Val Val Ser 70

Val Leu Thr Val Leu 75

Gln Asp Trp Leu Asn

Gly Lys Glu Tyr Lys

Cys Lys Val Ser Asn 95

Ala Leu Pro Ala Pro

100

Ile Glu Lys Thr Ile

105

Ser Lys Ala Lys Gly

110

Pro Arg Glu Pro Gln 115

Val Tyr Thr Leu Pro

120

Pro Ser Arg Glu Glu 125

Thr Lys Asn Gln Val

130

Ser Leu Thr Cys Leu

135

Val Lys Gly Phe Tyr

140

Ser Asp Ile Ala Val 145

Glu Trp Glu Ser Asn 150

Gly Gln Pro Glu Asn 155

Tyr Asp Thr Thr Pro

165

Pro Val Leu Asp Ser

170

Asp Gly Ser Phe Phe

175

Tyr Ser Asp Leu Thr

180

Val Asp Lys Ser Arg

185

Trp Gln Gln Gly Asn

190

Phe Ser Cys Ser Val 195

Met His Glu Ala Leu

200

His Asn His Tyr Thr

205

Lys Ser Leu Ser Leu 210

Ser Pro Gly Gly Asp

215

His Cys Pro Leu Gly

220

Gly Arg Cys Cys Arg 225

Leu His Thr Val Arg 230

Ala Ser Leu Glu Asp 235

Gly Trp Ala Asp Trp

245

Val Leu Ser Pro Arg

250

Glu Val Gln Val Thr

255

Lys

Val

Tyr

Glu

His 80

Lys

Gln

Met

Pro

Asn 160

Leu

Val

Gln

Pro

Leu 240

Met

- 295 046387

Cys Ile Gly Ala Cys Pro Ser Gln Phe Arg Ala Ala Asn Met His Ala 260 265270

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

275 280285

Pro Cys Cys Val Pro Ala Ser Tyr Asn Pro Met Val Leu Ile Gln Lys

290 295300

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

305 310 315320

Asp Cys His Cys Ile 325 <210> 135 <211> 654 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide

<400> 135 gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 180 ccgcgggagg agcagtacgg gagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 ccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtacacc 360 ctgcccccat cccggaagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tggggagagca atggggcagcc ggagaacaac 480 tacaagacca cgcctcccgt gctgaagtcc gacggctcct tcttcctcta tagcaagctc 540 accgtggac agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccgggtaa atga 654

<210> 136 <211> 984 <212> DNA <213> Artificial sequence <220>

<221> source

- 296 046387 <223> /note=’’description of an artificial sequence: synthetic polynucleotide

<400> 136 gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 180 ccgcgggagg agcagtacgg gagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 ccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtacacc 360 ctgcccccat cccggggaga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tggggagagca atggggcagcc ggagaacaac 480 tacgacacca cgcctcccgt gctggactcc gacggctcct tcttcctcta tagcgacctc 540 accgtggac agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccgggtgc gcgcgacgga 660 gaccactgtc cgctcgggcc cggggcgttgc tgccgtctgc acacggtccg cgcgtcgctg 720 gaagacctgg gctggggccga ttgggtgctg tcgccacggg aggtgcaagt gaccatgtgc 780 atcggcgcgt gcccgagcca gttccggggcg gcaaacatgc acgcgcagat caagacgagc 840 ctgcaccgcc tgaagcccga cacggtgcca gcgccctgct gcgtgcccgc cagctacaat 900 cccatggtgc tcattcaaaa gaccgacacc ggggtgtcgc tccagaccta tgatgacttg 960 ttagccaaag actgccactg cata 984

<210> 137 <211> 328 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=description of artificial sequence: synthetic polypeptide <400> 137

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

5 1015

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

2530

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

4045

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

- 297 046387

55 60

Gln 65

Gln

Ala

Pro

Thr

Ser 145

Tyr

Tyr

Phe

Lys

Leu 225

Glu

Val

Met

Val

Tyr Gly Ser Thr Tyr

Arg Val Val Ser Val 75

Leu Thr Val Leu His

Asp Trp Leu Asn Gly

Leu Pro Ala Pro Ile

100

Arg Glu Pro Gln Val 115

Lys Asn Gln Val Ser 130

Asp Ile Ala Val Glu

150

Asp Thr Thr Pro Pro

165

Ser Asp Leu Thr Val

180

Ser Cys Ser Val Met

195

Ser Leu Ser Leu Ser 210

Gly Pro Gly Arg Cys

230

Asp Leu Gly Trp Ala

245

Thr Met Cys Ile Gly 260

His Ala Gln Ile Lys

275

Pro Ala Pro Cys Cys 290

Lys Glu Tyr Lys Cys

Lys Val Ser Asn Lys

Glu Lys Thr Ile Ser 105

Tyr Thr Leu Pro Pro 120

Leu Thr Cys Leu Val 135

Trp Glu Ser Asn Gly

155

Val Leu Asp Ser Asp

170

Asp Lys Ser Arg Trp 185

His Glu Ala Leu His

200

Pro Gly Ala Arg Asp 215

Cys Arg Leu His Thr

235

Asp Trp Val Leu Ser

250

Ala Cys Pro Ser Gln 265

Thr Ser Leu His Arg

280

Val Pro Ala Ser Tyr 295

Lys Ala Lys Gly Gln

110

Ser Arg Glu Glu Met

125

Lys Gly Phe Tyr Pro 140

Gln Pro Glu Asn Asn

160

Gly Ser Phe Phe Leu

175

Gln Gln Gly Asn Val

190

Asn His Tyr Thr Gln

205

Gly Asp His Cys Pro 220

Val Arg Ala Ser Leu

240

Pro Arg Glu Val Gln

255

Phe Arg Ala Ala Asn

270

Leu Lys Pro Asp Thr

285

Asn Pro Met Val Leu 300

- 298 046387

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

305 310 315 320

Leu Ala Lys Asp Cys His Cys Ile

325 <210> 138 <211> 996 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide

<400> 138 gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 180 ccgcgggagg agcagtacgg gagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 ccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtacacc 360 ctgcccccat cccggggaga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tggggagagca atggggcagcc ggagaacaac 480 tacgacacca cgcctcccgt gctggactcc gacggctcct tcttcctcta tagcgacctc 540 accgtggac agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccggggtgg aggtggtgga 660 gcgcgcgacg gagaccactg tccgctcggg cccggggcgtt gctgccgtct gcacacggtc 720 cgcgcgtcgc tggaagacct gggctgggcc gattgggtgc tgtcgccacg ggaggtgcaa 780 gtgaccatgt gcatcggcgc gtgcccgagc cagttccgggg cggcaaacat gcacgcgcag 840 atcaagacga gcctgcaccg cctgaagccc gacacggtgc cagcgccctg ctgcgtgccc 900 gccagctaca atcccatggt gctcattcaa aagaccgaca ccggggtgtc gctccagacc 960 tatgatgact tgttagccaa agactgccac tgcata 996

<210> 139 <211> 332 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=description of artificial sequence: synthetic polypeptide

- 299 046387 <400> 139 Ala Pro Glu 1

Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro

10 15

Pro Lys Asp

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

25 30

Val Val Asp

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

45

Val Asp Gly

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 55 60

Gln Tyr Gly 65

Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 70 75

Gln Asp Trp

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

90 95

Ala Leu Pro

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

100 105 110

Pro Arg Glu

115

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

120 125

Thr Lys Asn

130

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

135 140

Ser Asp Ile 145

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

150 155

Tyr Asp Thr

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

165 170 175

Tyr Ser Asp

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

180 185 190

Phe Ser Cys

195

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

200 205

Lys Ser Leu

210

Ser Leu Ser Pro Gly Gly Gly Gly Gly Ala Arg Asp

215 220

Asp His Cys 225

Pro Leu Gly Pro Gly Arg Cys Cys Arg Leu His Thr

230 235

Lys

Val

Tyr

Glu

His 80

Lys

Gln

Met

Pro

Asn 160

Leu

Val

Gln

Gly

Val 240

Pro

Arg Ala Ser

Leu Glu Asp Leu Gly Trp Ala Asp Trp Val Leu Ser

- 300 046387

245

250

255

Arg Glu Val Gln Val Thr Met Cys

260

Ile Gly Ala Cys Pro Ser Gln Phe

265 270

Arg Ala Ala Asn Met His Ala Gln

275 280

Ile Lys Thr Ser Leu His Arg Leu

285

Lys Pro Asp Thr Val Pro Ala Pro

290 295

Cys Cys Val Pro Ala Ser Tyr Asn

300

Pro Met Val Leu Ile Gln Lys Thr

305 310

Asp Thr Gly Val Ser Leu Gln Thr

315 320

Tyr Asp Asp Leu Leu Ala Lys Asp

325

Cys His Cys Ile 330 <210> 140 <211> 217 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 140

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

5 1015

Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 2530

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

4045

Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 5560

Gln Tyr Gly Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 7580

Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 9095

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

100 105110

Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Lys Glu Met

- 301 046387

Thr

Lys 130

115

Asn

Gln

Val

Ser

Leu

135

120

Thr

Cys

Leu

Val

Lys 140

125

Gly

Phe

Tyr

Pro

Ser

145

Asp

Ile

Ala

Val

Glu

150

Trp

Glu

Ser

Asn

Gly 155

Gln

Pro

Glu

Asn

Asn

160

Tyr

Lys

Thr

Thr

Pro

165

Pro

Val

Leu

Lys

Ser

170

Asp

Gly

Ser

Phe

Phe

175

Leu

Tyr

Ser

Lys

Leu

180

Thr

Val

Asp

Lys

Ser

185

Arg

Trp

Gln

Gln

Gly 190

Asn

Val

Phe

Ser

Cys 195

Ser

Val

Met

His

Glu

200

Ala

Leu

His

Asn

His

205

Tyr

Thr

Gln

Lys

Ser

210

Leu

Ser

Leu

Ser

Pro

215

Gly

Lys <210> 141 <211> 216 <212> PRT <213>

Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 141

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

5 1015

Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 2530

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

4045

Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 5560

Gln Tyr Gly Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 7580

Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 9095

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

- 302 046387

Pro

Arg

Glu

115

Thr

Lys 130

Asn

100

Pro

Gln

Gln

Val

Val

Ser

Cys

Leu

135

105

110

Thr

120

Leu

Pro

Pro

Ser

Arg 125

Glu

Glu

Met

Thr

Cys

Leu

Val

Lys 140

Gly

Phe

Tyr

Pro

Ser

145

Asp

Ile

Ala

Val

Glu

150

Trp

Glu

Ser

Asn

Gly 155

Gln

Pro

Glu

Asn

Asn

160

Tyr

Asp

Thr

Thr

Pro

165

Pro

Val

Leu

Asp

Ser

170

Asp

Gly

Ser

Phe

Phe

175

Leu

Tyr

Ser

Asp

Leu

180

Thr

Val

Asp

Lys

Ser

185

Arg

Trp

Gln

Gln

Gly 190

Asn

Val

Phe

Ser

Cys 195

Ser

Val

Met

His

Glu

200

Ala

Leu

His

Asn

His

205

Tyr

Thr

Gln

Lys Ser Leu Ser Leu Ser Pro Gly

210 215 <210> 142 <211> 975 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide

<400> 142 gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 180 ccgcgggagg agcagtacgg cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 ccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtgcacc 360 ctgcccccat cccggggaga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tggggagagca atggggcagcc ggagaacaac 480 tacgacacca cgcctcccgt gctggactcc gacggctcct tcttcctcta tagcgacctc 540 accgtggac agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccggggtgg agaccactgt 660

- 303 046387

ccgctcgggc ccgggcgttg ctgccgtctg cacacggtcc gcgcgtcgct ggaagacctg 720 ggctgggccg attgggtgct gtcgccacgg gaggtgcaag tgaccatgtg catcggcgcg 780 tgcccgagcc agttccggggc ggcaaacatg cacgcgcaga tcaagacgag cctgcaccgc 840 ctgaagcccg acacggtgcc agcgccctgc tgcgtgcccg ccagctacaa tcccatggtg 900 ctcattcaaa agaccgacac cggggtgtcg ctccagacct atgatgactt gttagccaaa 960 gactgccact gcata 975

<210> 143 <211> 325 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 143

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

5 1015

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

2530

Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 4045

Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 5560

Gln Tyr Gly Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val LeuHis

70 7580

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

9095

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

100 105110

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

115 120125

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

130 135140

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

145 150 155160

- 304 046387

Tyr

Asp

Thr

Thr

Pro

165

Pro

Val

Leu

Asp

Ser

170

Asp

Gly

Ser

Phe

Phe

175

Leu

Tyr

Ser

Asp

Leu

180

Thr

Val

Asp

Lys

Ser

185

Arg

Trp

Gln

Gln

Gly 190

Asn

Val

Phe

Ser

Cys 195

Ser

Val

Met

His

Glu

200

Ala

Leu

His

Asn

His

205

Tyr

Thr

Gln

Lys

Ser Leu Ser Leu Ser Pro Gly Gly Asp His 210 215

Cys Pro Leu Gly Pro

220

Gly Arg Cys Cys Arg Leu His Thr Val Arg Ala Ser Leu Glu Asp Leu

225 230 235240

Gly Trp Ala Asp Trp Val Leu Ser Pro Arg Glu Val Gln Val Thr Met

245 250255

Cys Ile Gly Ala Cys Pro Ser Gln Phe Arg Ala Ala Asn Met His Ala

260 265270

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

275 280285

Pro Cys Cys Val Pro Ala Ser Tyr Asn Pro Met Val Leu Ile Gln Lys

290 295300

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

305 310 315320

Asp Cys His Cys Ile

325 <210> 144 <211> 651 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide <400> 144 gccccagagc tgcttggtgg accatccgtg ttcctgtttc ctccaaagcc gaaggacacc60 ctgatgatct caagaactcc ggaagtgact tgcgtcgtcg tggacgtgtc acatgaggat120 ccagaggtca agttcaattg gtatgtggac ggagtggaag tgcataacgc caagaccaaa180

- 305 046387

ccccgcgaag aacagtacgg gagcacctac cgcgtggtga gcgtccttac tgtgctccac 240 caggactggc ttaatgggaa ggaatacaag tgtaaggtgt ccaacaaggc cctccccgct 300 cccatcgaaa agaccatctc aaaggcaaag gggcaaccaa gggaacctca agtgtacacc 360 ctgcctccgt gcaggaagga gatgaccaag aaccaggtca gcctgacttg tctcgtgaag 420 ggcttctatc ccagcgatat tgctgtggaa tggggagtcaa atggccagcc cgagaataac 480 tacaaaacta ccccacccgt gctgaaatct gatgggtcct tcttccttta ctccaagctg 540 accgtggac agagccgctg gcaacaaggc aatgtcttta gctgctcagt gatgcatgag 600 gctctccata atcactacac tcagaagtca ctgtccctgt ctccgggtaa a 651

<210> 145 <211> 984 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide <400> 145

gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 180 ccgcgggagg agcagtacgg gagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 ccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtgcacc 360 ctgcccccat cccggggaga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tggggagagca atggggcagcc ggagaacaac 480 tacgacacca cgcctcccgt gctggactcc gacggctcct tcttcctcta tagcgacctc 540 accgtggac agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccgggtgc gcgcgacgga 660 gaccactgtc cgctcgggcc cggggcgttgc tgccgtctgc acacggtccg cgcgtcgctg 720 gaagacctgg gctggggccga ttgggtgctg tcgccacggg aggtgcaagt gaccatgtgc 780 atcggcgcgt gcccgagcca gttccggggcg gcaaacatgc acgcgcagat caagacgagc 840 ctgcaccgcc tgaagcccga cacggtgcca gcgccctgct gcgtgcccgc cagctacaat 900 cccatggtgc tcattcaaaa gaccgacacc ggggtgtcgc tccagaccta tgatgacttg 960 ttagccaaag actgccactg cata 984

- 306 046387 <210> 146 <211> 328 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 146

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

5 1015

Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 2530

Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 4045

Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 5560

Gln Tyr Gly Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 7580

Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 9095

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

100 105110

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

115 120125

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

130 135140

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

145 150 155160

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

165 170175

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

180 185190

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

195 200205

- 307 046387

Lys

Ser Leu Ser Leu Ser Pro Gly Ala Arg Asp

210 215

Gly Asp His Cys Pro

220

Leu Gly Pro Gly Arg Cys Cys Arg Leu His 225 230

Thr Val Arg Ala Ser Leu

235 240

Glu Asp Leu Gly Trp Ala Asp Trp Val

245

Leu Ser Pro Arg Glu Val Gln

250 255

Val Thr Met Cys

260

Ile Gly Ala Cys

Pro Ser Gln Phe 265

Arg Ala Ala Asn 270

Met His Ala Gln

275

Ile Lys Thr Ser

280

Leu His Arg Leu

Lys Pro Asp Thr 285

Val Pro Ala Pro

290

Ile Gln Lys Thr 305

Cys Cys Val Pro 295

Asp Thr Gly Val 310

Ala Ser Tyr Asn

300

Pro Met Val Leu

Ser Leu Gln Thr

315

Tyr Asp Asp Leu

320

Leu Ala Lys Asp Cys His Cys Ile

325 <210> 147 <211> 217 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 147

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

5 1015

Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 2530

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

4045

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

5560

Gln Tyr Gly Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 7580

- 308 046387

Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 9095

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

100 105110

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

115 120125

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

130 135140

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

145 150 155160

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

165 170175

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

180 185190

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

195 200205

Lys Ser Leu Ser Leu Ser Pro Gly Lys

210215 <210> 148 <211> 216 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 148

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

5 1015

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

2530

Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 4045

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

5560

- 309 046387

Gln Tyr Gly Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 7580

Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 9095

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

100 105110

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

115 120125

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

130 135140

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

145 150 155160

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

165 170175

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

180 185190

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

195 200205

Lys Ser Leu Ser Leu Ser Pro Gly

210215 <210> 149 <211> 984 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide <400> 149

gcgccggaac tgctggggcgg cccgagcgtg tttctgtttc cgccgaaacc gaaagatacc 60 ctgatgatta gccgcacccc ggaagtgacc tgcgtggtgg tggatgtgag ccatgaagat 120 ccggaagtga aatttaactg gtatgtggat ggcgtggaag tgcataacgc gaaaaccaaa 180 ccgcgcgaag aacagtatgg cagcacctat cgcgtggtga gcgtgctgac cgtgctgcat 240 caggattggc tgaacggcaa agaatataaa tgcaaagtga gcaacaaagc gctgccggcg 300 ccgattgaaa aaaccattag caaagcgaaa ggccagccgc gcgaaccgca ggtgtatacc 360

- 310 046387

tgcccgccga gccgcaaaga aatgaccaaa aaccaggtga gcctgacctg cctggtgaaa 420 ggcttttatc cgagcgatat tgcggtggaa tgggaaagca acggccagcc ggaaaacaac 480 tataaaacca ccccgccggt gctgaaaagc gatggcagct tttttctgta tagcaaactg 540 accgtggata aaagccgctg gcagcagggc aacgtgttta gctgcagcgt gatgcatgaa 600 gcgctgcata accattatac ccagaaaagc ctgagcctga gcccgggcgc gcgcaacggc 660 gatcattgcc cgctgggccc gggccgctgc tgccgcctgc ataccgtgcg cgcgagcctg 720 gaagatctgg gctggggcgga ttgggtgctg agcccgcgcg aagtgcaggt gaccatgtgc 780 attggcgcgt gcccgagcca gtttcgcgcg gcgaacatgc atgcgcagat taaaaccagc 840 ctgcatcgcc tgaaaccgga taccgtgccg gcgccgtgct gcgtgccggc gagctataac 900 ccgatggtgc tgattcagaa aaccgatacc ggcgtgagcc tgcagaccta tgatgatctg 960 ctggcgaaag attgccatg catt 984

<210> 150 <211> 328 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 150

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

5 1015

Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 2530

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

4045

Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 5560

Gln Tyr Gly Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 7580

Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 9095

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

100 105110

Pro Arg Glu Pro Gln Val Tyr Thr Cys Pro Pro Ser Arg Lys Glu Met

- 311 046387

115 120125

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

130 135140

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

145 150 155160

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

165 170175

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

180 185190

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

195 200205

Lys Ser Leu Ser Leu Ser Pro Gly Ala Arg Asn Gly Asp His Cys Pro

210 215220

Leu Gly Pro Gly Arg Cys Cys Arg Leu His Thr Val Arg Ala Ser Leu

225 230 235240

Glu Asp Leu Gly Trp Ala Asp Trp Val Leu Ser Pro Arg Glu Val Gln

245 250255

Val Thr Met Cys Ile Gly Ala Cys Pro Ser Gln Phe Arg Ala Ala Asn

260 265270

Met His Ala Gln Ile Lys Thr Ser Leu His Arg Leu Lys Pro Asp Thr

275 280285

Val Pro Ala Pro Cys Cys Val Pro Ala Ser Tyr Asn Pro Met Val Leu

290 295300

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

305 310 315320

Leu Ala Lys Asp Cys His Cys Ile

325 <210> 151 <211> 651 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic

- 312 046387 polynucleotide

<400> 151 gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 180 ccgcgggagg agcagtacgg gagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 ccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtacacc 360 tgtcccccat cccggggaga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tggggagagca atggggcagcc ggagaacaac 480 tacgacacca cgcctcccgt gctggactcc gacggctcct tcttcctcta tagcgacctc 540 accgtggac agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccgggtaa a 651

<210> 152 <211> 984 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=description of artificial sequence: synthetic polynucleotide <400> 152

gcgccggaac tgctggggcgg cccgagcgtg tttctgtttc cgccgaaacc gaaagatacc 60 ctgatgatta gccgcacccc ggaagtgacc tgcgtggtgg tggatgtgag ccatgaagat 120 ccggaagtga aatttaactg gtatgtggat ggcgtggaag tgcataacgc gaaaaccaaa 180 ccgcgcgaag aacagtatgg cagcacctat cgcgtggtga gcgtgctgac cgtgctgcat 240 caggattggc tgaacggcaa agaatataaa tgcaaagtga gcaacaaagc gctgccggcg 300 ccgattgaaa aaaccattag caaagcgaaa ggccagccgc gcgaaccgca ggtgtatacc 360 tgcccgccga gccgcaaaga aatgaccaaa aaccaggtga gcctgacctg cctggtgaaa 420 ggcttttatc cgagcgatat tgcggtggaa tgggaaagca acggccagcc ggaaaacaac 480 tataaaacca ccccgccggt gctgaaaagc gatggcagct tttttctgta tagcaaactg 540 accgtggata aaagccgctg gcagcagggc aacgtgttta gctgcagcgt gatgcatgaa 600 gcgctgcata accattatac ccagaaaagc ctgagcctga gcccgggcgc gcgcgatggc 660 gatcattgcc cgctgggccc gggccgctgc tgccgcctgc ataccgtgcg cgcgagcctg 720 gaagatctgg gctggggcgga ttgggtgctg agcccgcgcg aagtgcaggt gaccatgtgc 780

- 313 046387

attggcgcgt gcccgagcca gtttcgcgcg gcgaacatgc atgcgcagat taaaaccagc 840 ctgcatcgcc tgaaaccgga taccgtgccg gcgccgtgct gcgtgccggc gagctataac 900 ccgatggtgc tgattcagaa aaccgatacc ggcgtgagcc tgcagaccta tgatgatctg 960 ctggcgaaag attgccatg catt 984

<210> 153 <211> 328 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 153

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

5 1015

Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 2530

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

4045

Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 5560

Gln Tyr Gly Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 7580

Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 9095

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

100 105110

Pro Arg Glu Pro Gln Val Tyr Thr Cys Pro Pro Ser Arg Lys Glu Met

115 120125

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

130 135140

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

145 150 155160

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

165 170175

- 314 046387

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

180 185190

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

195 200205

Lys Ser Leu Ser Leu Ser Pro Gly Ala Arg Asp Gly Asp His Cys Pro

210 215220

Leu Gly Pro Gly Arg Cys Cys Arg Leu His Thr Val Arg Ala Ser Leu

225 230 235240

Glu Asp Leu Gly Trp Ala Asp Trp Val Leu Ser Pro Arg Glu Val Gln

245 250255

Val Thr Met Cys Ile Gly Ala Cys Pro Ser Gln Phe Arg Ala Ala Asn

260 265270

Met His Ala Gln Ile Lys Thr Ser Leu His Arg Leu Lys Pro Asp Thr

275 280285

Val Pro Ala Pro Cys Cys Val Pro Ala Ser Tyr Asn Pro Met Val Leu

290 295300

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

305 310 315320

Leu Ala Lys Asp Cys His Cys Ile

325 <210> 154 <211> 210 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 154

Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu MetIle

5 1015

Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser HisGlu

2530

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

4045

- 315 046387

Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 50 5560

Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 65 70 7580

Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 85 9095

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

100 105110

Thr Leu Pro Pro

115

Ser Arg Lys Glu Met Thr Lys Asn Gln Val Ser Leu

120125

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

130 135140

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

145 150 155160

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

165 170175

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

180 185190

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

195 200205

Gly Lys

210 <210> 155 <211> 209 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 155

Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu MetIle

5 1015

Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser HisGlu

2530

- 316 046387

Asp Pro Glu Val Lys Phe Asn Trp

40

Tyr Val Asp Gly Val Glu Val His 45

Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 50 55 60

Val Val Ser Val

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys

75 80

Glu Tyr Lys Cys

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 85 90 95

Lys

Thr

Ile

Ser

100

Lys

Ala

Lys

Gly

Gln

105

Pro

Arg

Glu

Pro

Gln

110

Val

Tyr

Thr Leu Pro Pro

115

Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu

120125

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

130 135140

Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Asp Thr Thr Pro Pro Val

145 150 155160

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

165 170175

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

180 185190

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

195 200205

Gly <210> 156 <211> 954 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide <400> 156 ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 60 gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 12 0

- 317 046387

tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcggggaga gcagtacaac 180 agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 240 gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 300 aaagccaaag ggcagccccg agaaccacag gtgtacacc tgcccccatc ccggggagg 360 atgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 420 gccgtggagt ggggagagcaa tggggcagccg gagaacaact acgacaccac gcctcccgtg 480 ctggactccg acggctcctt cttcctctat agcgacctca ccgtggacaa gagcaggtgg 540 cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 600 cagaagagcc tctccctgtc tccggggtgga gaccactgtc cgctcgggcc cggggcgttgc 660 tgccgtctgc acacggtccg cgcgtcgctg gaagacctgg gctggggccga ttgggtgctg 720 tcgccacggg aggtgcaagt gaccatgtgc atcggcgcgt gcccgagcca gttccggggcg 780 gcaaacatgc acgcgcagat caagacgagc ctgcaccgcc tgaagcccga cacggtgcca 840 gcgccctgct gcgtgcccgc cagctacaat cccatggtgc tcattcaaaa gaccgacacc 900 ggggtgtcgc tccagaccta tgatgacttg ttagccaaag actgccactg cata 954

<210> 157 <211> 318 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 157

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

5 1015

Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 20 2530

Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 35 4045

Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 50 5560

Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 65 70 7580

Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 85 9095

- 318 046387

Lys Thr Ile Ser Lys

100

Ala Lys Gly Gln Pro

105

Arg Glu Pro Gln Val

110

Thr Leu Pro Pro Ser

115

Arg Glu Glu Met Thr 120

Lys Asn Gln Val Ser

125

Thr Cys Leu Val Lys

130

Gly Phe Tyr Pro Ser 135

Asp Ile Ala Val Glu

140

Glu Ser Asn Gly Gln 145

Pro Glu Asn Asn Tyr 150

Asp Thr Thr Pro Pro 155

Leu Asp Ser Asp Gly

165

Ser Phe Phe Leu Tyr

170

Ser Asp Leu Thr Val

175

Lys Ser Arg Trp Gln

180

Gln Gly Asn Val Phe

185

Ser Cys Ser Val Met

190

Glu Ala Leu His Asn

195

His Tyr Thr Gln Lys

200

Ser Leu Ser Leu Ser

205

Gly Gly Asp His Cys 210

Pro Leu Gly Pro Gly 215

Arg Cys Cys Arg Leu 220

Thr Val Arg Ala Ser 225

Leu Glu Asp Leu Gly 230

Trp Ala Asp Trp Val 235

Ser Pro Arg Glu Val

245

Gln Val Thr Met Cys

250

Ile Gly Ala Cys Pro

255

Gln Phe Arg Ala Ala

260

Asn Met His Ala Gln

265

Ile Lys Thr Ser Leu

270

Arg Leu Lys Pro Asp 275

Thr Val Pro Ala Pro

280

Cys Cys Val Pro Ala 285

Tyr Asn Pro Met Val 290

Leu Ile Gln Lys Thr

295

Asp Thr Gly Val Ser 300

Tyr

Leu

Trp

Val 160

Asp

His

Pro

His

Leu 240

Ser

His

Ser

Leu

Gln Thr Tyr Asp Asp 305

Leu Leu Ala Lys Asp 310

Cys His Cys Ile 315 <210>

<211>

<212>

<213>

158

633

DNA

Artificial sequence

- 319 046387 <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide <400> 158 ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct60 gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg120 t acgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacaac180 agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag240 gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc300 aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccggaaggag360 atgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc420 gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg480 ctgaagtccg acggctcctt cttcctctat agcaagctca ccgtggacaa gagcaggtgg540 cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg600 cagaagagcc tctccctgtc tccgggtaaa tga633 <210> 159 <211> 963 <212> DNA <213 > Artificial sequence <220>

<221> source <223> /note=description of artificial sequence: synthetic polynucleotide

<400> 159 ccgtcagtct tcctcttccc cccaaaaccc aaggacacc tcatgatctc ccggacccct 60 gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 120 tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcggggaga gcagtacaac 180 agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 240 gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 300 aaagccaaag ggcagccccg agaaccacag gtgtacacc tgcccccatc ccggggagg 360 atgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 420 gccgtggagt ggggagagcaa tggggcagccg gagaacaact acgacaccac gcctcccgtg 480 ctggactccg acggctcctt cttcctctat agcgacctca ccgtggacaa gagcaggtgg 540 cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 600 cagaagagcc tctccctgtc tccgggtgcg cgcgacggag accactgtcc gctcgggccc 660 gggcgttgct gccgtctgca cacggtccgc gcgtcgctgg aagacctggg ctggggccgat 720

- 320 046387

tgggtgctgt cgccacggga ggtgcaagtg accatgtgca tcggcgcgtg cccgagccag 780 ttccggggcgg caaacatgca cgcgcagatc aagacgagcc tgcaccgcct gaagcccgac 840 acggtgccag cgccctgctg cgtgcccgcc agctacaatc ccatggtgct cattcaaaag 900 accgacaccg gggtgtcgct ccagacctat gatgacttgt tagccaaaga ctgccactgc 960 ata 963

<210> 160 <211> 321 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 160

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

5 1015

Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 20 2530

Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 35 4045

Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 50 5560

Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 65 70 7580

Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 85 9095

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

100 105110

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

115 120125

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

130 135140

Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Asp Thr Thr Pro Pro Val

145 150 155160

- 321 046387

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

165 170175

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

180 185190

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

195 200205

Gly Ala Arg Asp Gly Asp His Cys Pro Leu Gly Pro Gly Arg Cys Cys

210 215220

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

225 230 235240

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

245 250255

Cys Pro Ser Gln Phe Arg Ala Ala Asn Met His Ala Gln Ile Lys Thr

260 265270

Ser Leu His Arg Leu Lys Pro Asp Thr Val Pro Ala Pro Cys Cys Val

275 280285

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

290 295300

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

305 310 315320

Ile <210> 161 <211> 210 <212> PRT <213>

Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 161

Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu MetIle

5 1015

Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser HisGlu

2530

- 322 046387

Asp Pro Glu Val Lys Phe Asn Trp

40

Tyr Val Asp Gly Val Glu Val His 45

Asn Ala Lys Thr

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 55 60

Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 65 70 75 80

Glu Tyr Lys Cys

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 85 90 95

Lys

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

100 105 110

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

115 120 125

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

130 135 140

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

145 150 155 160

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

165 170 175

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

180 185 190

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

195 200 205

Gly Lys

210 <210> 162 <211> 209 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 162

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

5 10 15

- 323 046387

Ser Arg Thr Pro Glu Val Thr Cys 20

Val Val Val Asp Val Ser His Glu 25 30

Asp Pro Glu Val

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

45

His

Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 50 5560

Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 65 70 7580

Glu Tyr Lys Cys

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro 8590

Ile Glu 95

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

100 105110

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

115 120125

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

130 135140

Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Asp Thr Thr Pro Pro Val

145 150 155160

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

165 170175

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

180 185190

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

195 200205

Gly <210> 163 <211> 954 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide <400> 163

- 324 046387

ccgtcagtct tcctcttccc cccaaaaccc aaggacacc tcatgatctc ccggacccct 60 gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 120 tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcggggaga gcagtacaac 180 agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 240 gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 300 aaagccaaag ggcagccccg agaaccacag gtgtgcaccc tgcccccatc ccggggagg 360 atgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 420 gccgtggagt ggggagagcaa tggggcagccg gagaacaact acgacaccac gcctcccgtg 480 ctggactccg acggctcctt cttcctctat agcgacctca ccgtggacaa gagcaggtgg 540 cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 600 cagaagagcc tctccctgtc tccggggtgga gaccactgtc cgctcgggcc cggggcgttgc 660 tgccgtctgc acacggtccg cgcgtcgctg gaagacctgg gctggggccga ttgggtgctg 720 tcgccacggg aggtgcaagt gaccatgtgc atcggcgcgt gcccgagcca gttccggggcg 780 gcaaacatgc acgcgcagat caagacgagc ctgcaccgcc tgaagcccga cacggtgcca 840 gcgccctgct gcgtgcccgc cagctacaat cccatggtgc tcattcaaaa gaccgacacc 900 ggggtgtcgc tccagaccta tgatgacttg ttagccaaag actgccactg cata 954

<210> 164 <211> 318 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 164

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

5 1015

Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 20 2530

Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 35 4045

Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 50 5560

Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 65 70 7580

- 325 046387

Glu Tyr Lys Cys Lys

Val Ser Asn Lys Ala

Leu Pro Ala Pro Ile

Lys Thr Ile Ser Lys

100

Ala Lys Gly Gln Pro

105

Arg Glu Pro Gln Val

110

Thr Leu Pro Pro Ser

115

Arg Glu Glu Met Thr 120

Lys Asn Gln Val Ser

125

Thr Cys Leu Val Lys

130

Gly Phe Tyr Pro Ser 135

Asp Ile Ala Val Glu

140

Glu Ser Asn Gly Gln 145

Pro Glu Asn Asn Tyr 150

Asp Thr Thr Pro Pro 155

Leu Asp Ser Asp Gly

165

Ser Phe Phe Leu Tyr

170

Ser Asp Leu Thr Val

175

Lys Ser Arg Trp Gln

180

Gln Gly Asn Val Phe

185

Ser Cys Ser Val Met

190

Glu Ala Leu His Asn

195

His Tyr Thr Gln Lys

200

Ser Leu Ser Leu Ser

205

Gly Gly Asp His Cys

210

Pro Leu Gly Pro Gly 215

Arg Cys Cys Arg Leu 220

Thr Val Arg Ala Ser 225

Leu Glu Asp Leu Gly 230

Trp Ala Asp Trp Val 235

Ser Pro Arg Glu Val

245

Gln Val Thr Met Cys

250

Ile Gly Ala Cys Pro

255

Gln Phe Arg Ala Ala

260

Asn Met His Ala Gln

265

Ile Lys Thr Ser Leu

270

Arg Leu Lys Pro Asp

275

Thr Val Pro Ala Pro

280

Cys Cys Val Pro Ala

285

Tyr Asn Pro Met Val 290

Leu Ile Gln Lys Thr

295

Asp Thr Gly Val Ser 300

Glu

Cys

Leu

Trp

Val 160

Asp

His

Pro

His

Leu 240

Ser

His

Ser

Leu

Gln Thr Tyr Asp Asp 305

Leu Leu Ala Lys Asp 310

Cys His Cys Ile 315 <210> 165 <211> 630

- 326 046387 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=description of artificial sequence: synthetic polynucleotide” <400> 165

ccatccgtgt tcctgtttcc tccaaagccg aaggacacc tgatgatctc aagaactccg 60 gaagtgactt gcgtcgtcgt ggacgtgtca catgaggatc cagaggtcaa gttcaattgg 120 tatgtggacg gagtggaagt gcataacgcc aagaccaaac cccgcgaaga acagtacaat 180 agcacctacc gcgtggtgag cgtccttact gtgctccacc aggactggct taatgggaag 240 gaatacaagt gtaaggtgtc caacaaggcc ctccccgctc ccatcgaaaa gaccatctca 300 aaggcaaagg ggcaaccaag ggaacctcaa gtgtacacc tgcctccgtg caggaaggag 360 atgaccaaga accaggtcag cctgacttgt ctcgtgaagg gcttctatcc cagcgatatt 420 gctgtggaat ggggagtcaaa tggccagccc gagaataact acaaaactac cccacccgtg 480 ctgaaatctg atgggtcctt cttcctttac tccaagctga ccgtggacaa gagccgctgg 540 caacaaggca atgtctttag ctgctcagtg atgcatgagg ctctccataa tcactacact 600 cagaagtcac tgtccctgtc tccggggtaaa 630

<210> 166 <211> 963 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=description of artificial sequence: synthetic polynucleotide” <400> 166

ccgtcagtct tcctcttccc cccaaaaccc aaggacacc tcatgatctc ccggacccct 60 gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 120 tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcggggaga gcagtacaac 180 agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 240 gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 300 aaagccaaag ggcagccccg agaaccacag gtgtgcaccc tgcccccatc ccggggagg 360 atgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 420 gccgtggagt ggggagagcaa tggggcagccg gagaacaact acgacaccac gcctcccgtg 480 ctggactccg acggctcctt cttcctctat agcgacctca ccgtggacaa gagcaggtgg 540 cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 600

- 327 046387 cagaagagcc tctccctgtc tccgggtgcg cgcgacggag accactgtcc gctcgggccc660 gggcgttgct gccgtctgca cacggtccgc gcgtcgctgg aagacctggg ctgggccgat720 tgggtgctgt cgccacggga ggtgcaagtg ac catgtgca tcggcgcgtg cccgagccag780 ttccgggcgg caaacatgca cgcgcagatc aagacgagcc tgcaccgcct gaagcccgac840 acggtgccag cgccctgctg cgtgcccgcc agctacaatc ccatggtgct cattcaaaag900 accgacaccg gggtgtcgct ccagacctat gatgacttgt tagccaaaga ctgccactgc960 ata963 <210> 167 <211> 321 <212 > PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 167

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

5 1015

Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 20 2530

Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 35 4045

Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 50 5560

Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 65 70 7580

Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 85 9095

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

100 105110

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

115 120125

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

130 135140

Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Asp Thr Thr Pro Pro Val

- 328 046387

145 150 155160

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

165 170175

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

180 185190

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

195 200205

Gly Ala Arg Asp Gly Asp His Cys Pro Leu Gly Pro Gly Arg Cys Cys

210 215220

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

225 230 235240

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

245 250255

Cys Pro Ser Gln Phe Arg Ala Ala Asn Met His Ala Gln Ile Lys Thr

260 265270

Ser Leu His Arg Leu Lys Pro Asp Thr Val Pro Ala Pro Cys Cys Val

275 280285

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

290 295300

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

305 310 315320

Ile <210> 168 <211> 227 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 168

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

5 10 15

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

- 329 046387

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

40 45

Ser His

Glu Asp Pro Glu Val

Lys

Phe Asn Trp Tyr Val Asp Gly Val Glu Val 55 60

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr 65 70 7580

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 9095

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

100 105110

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

115 120125

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

130 135140

Ser

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

145 150 155160

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

165 170175

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

180 185190

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

195 200205

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

210 215220

Pro Gly Lys

225 <210> 169 <211> 226 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic

- 330 046387 polypeptide” <400> 169

Asp Lys Thr His Thr 1 5

Cys Pro Pro Cys Pro

Ala Pro Glu Leu Leu

Gly Pro Ser Val Phe

Leu Phe Pro Pro Lys

Pro Lys Asp Thr Leu

Ile Ser Arg Thr Pro 35

Glu Val Thr Cys Val 40

Val Val Asp Val Ser 45

Glu Asp Pro Glu Val 50

Lys Phe Asn Trp Tyr 55

Val Asp Gly Val Glu 60

His Asn Ala Lys Thr 65

Lys Pro Arg Glu Glu 70

Gln Tyr Gly Ser Thr 75

Arg Val Val Ser Val 85

Leu Thr Val Leu His

Gln Asp Trp Leu Asn

Lys Glu Tyr Lys Cys

100

Lys Val Ser Asn Lys

105

Ala Leu Pro Ala Pro

110

Glu Lys Thr Ile Ser 115

Lys Ala Lys Gly Gln

120

Pro Arg Glu Pro Gln

125

Tyr Thr Leu Pro Pro

130

Ser Arg Glu Glu Met

135

Thr Lys Asn Gln Val 140

Leu Thr Cys Leu Val 145

Lys Gly Phe Tyr Pro 150

Ser Asp Ile Ala Val 155

Trp Glu Ser Asn Gly

165

Gln Pro Glu Asn Asn

170

Tyr Asp Thr Thr Pro

175

Val Leu Asp Ser Asp

180

Gly Ser Phe Phe Leu

185

Tyr Ser Asp Leu Thr

190

Asp Lys Ser Arg Trp 195

Gln Gln Gly Asn Val 200

Phe Ser Cys Ser Val 205

His Glu Ala Leu His

210

Asn His Tyr Thr Gln 215

Lys Ser Leu Ser Leu 220

Gly

Met

His

Val

Tyr 80

Gly

Ile

Val

Ser

Glu 160

Pro

Val

Met

Ser

Pro Gly 225

- 331 046387 <210> 170 <211> 1005 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide

<400> 170 gacaaaactc acacatgccc accgtgccca gcacctgaac tcctgggggg accgtcagtc 60 ttcctcttcc ccccaaaacc caaggacacc ctcatgatct cccggacccc tgaggtcaca 120 tgcgtggtgg tggacgtgag ccacgaagac cctgaggtca agttcaactg gtacgtggac 180 ggcgtggagg tgcataatgc caagacaaag ccgcgggagg agcagtacgg cagcacgtac 240 cgtgtggtca gcgtcctcac cgtcctgcac caggactggc tgaatggcaa ggagtacaag 300 tgcaaggtct ccaacaaagc cctcccagcc ccatcgaga aaaccatctc caaagccaaa 360 gggcagcccc gagaaccaca ggtgtacacc ctgcccccat cccggggaga gatgaccaag 420 aaccaggtca gcctgacctg cctggtcaaa ggcttctatc ccagcgacat cgccgtggag 480 tggggagagca atggggcagcc ggagaacaac tacgacacca cgcctcccgt gctggactcc 540 gacggctcct tcttcctcta tagcgacctc accgtggac agagcaggtg gcagcagggg 600 aacgtcttct catgctccgt gatgcatgag gctctgcaca accactacac gcagaagagc 660 ctctccctgt ctccggggtgg agaccactgt ccgctcgggc ccgggcgttg ctgccgtctg 720 cacacggtcc gcgcgtcgct ggaagacctg ggctgggccg attgggtgct gtcgccacgg 780 gaggtgcaag tgaccatgtg catcggcgcg tgcccgagcc agttccggggc ggcaaacatg 840 cacgcgcaga tcaagacgag cctgcaccgc ctgaagcccg acacggtgcc agcgccctgc 900 tgcgtgcccg ccagctacaa tcccatggtg ctcattcaaa agaccgacac cggggtgtcg 960 ctccagacct atgatgactt gttagccaaa gactgccact gcata 1005

<210> 171 <211> 335 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=description of artificial sequence: synthetic polypeptide <400> 171

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

5 10 15

Gly Pro Ser Val Phe Leu Phe Pro Pro

25

Lys Pro Lys Asp Thr Leu Met

- 332 046387

Ile Ser Arg Thr Pro 35

Glu Val Thr Cys Val 40

Val Val Asp Val Ser 45

Glu Asp Pro Glu Val 50

Lys Phe Asn Trp Tyr 55

Val Asp Gly Val Glu 60

His Asn Ala Lys Thr 65

Lys Pro Arg Glu Glu 70

Gln Tyr Gly Ser Thr 75

Arg Val Val Ser Val 85

Leu Thr Val Leu His

Gln Asp Trp Leu Asn

Lys Glu Tyr Lys Cys

100

Lys Val Ser Asn Lys

105

Ala Leu Pro Ala Pro

110

Glu Lys Thr Ile Ser 115

Lys Ala Lys Gly Gln

120

Pro Arg Glu Pro Gln 125

Tyr Thr Leu Pro Pro

130

Ser Arg Glu Glu Met

135

Thr Lys Asn Gln Val 140

Leu Thr Cys Leu Val 145

Lys Gly Phe Tyr Pro 150

Ser Asp Ile Ala Val 155

Trp Glu Ser Asn Gly

165

Gln Pro Glu Asn Asn

170

Tyr Asp Thr Thr Pro

175

Val Leu Asp Ser Asp

180

Gly Ser Phe Phe Leu

185

Tyr Ser Asp Leu Thr

190

Asp Lys Ser Arg Trp 195

Gln Gln Gly Asn Val 200

Phe Ser Cys Ser Val 205

His Glu Ala Leu His

210

Asn His Tyr Thr Gln 215

Lys Ser Leu Ser Leu 220

Pro Gly Gly Asp His 225

Cys Pro Leu Gly Pro 230

Gly Arg Cys Cys Arg 235

His Thr Val Arg Ala

245

Ser Leu Glu Asp Leu

250

Gly Trp Ala Asp Trp

255

Leu Ser Pro Arg Glu

260

Val Gln Val Thr Met

265

Cys Ile Gly Ala Cys

270

Ser Gln Phe Arg Ala

Ala Asn Met His Ala

Gln Ile Lys Thr Ser

His

Val

Tyr 80

Gly

Ile

Val

Ser

Glu 160

Pro

Val

Met

Ser

Leu 240

Val

Pro

Leu

- 333 046387

275

280

285

His Arg Leu Lys

290

Pro Asp Thr Val Pro Ala Pro Cys Cys Val Pro Ala

295300

Ser Tyr Asn Pro Met Val Leu Ile Gln Lys Thr Asp Thr Gly Val

305 310315

Ser

320

Leu Gln Thr Tyr Asp Asp Leu Leu Ala Lys Asp Cys His Cys

325330

Ile

335 <210> 172 <211> 681 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide <400> 172

gacaaaactc acacatgccc accgtgccca gcacctgaac tcctgggggg accgtcagtc 60 ttcctcttcc ccccaaaacc caaggacacc ctcatgatct cccggacccc tgaggtcaca 120 tgcgtggtgg tggacgtgag ccacgaagac cctgaggtca agttcaactg gtacgtggac 180 ggcgtggagg tgcataatgc caagacaaag ccgcgggagg agcagtacgg cagcacgtac 240 cgtgtggtca gcgtcctcac cgtcctgcac caggactggc tgaatggcaa ggagtacaag 300 tgcaaggtct ccaacaaagc cctcccagcc ccatcgaga aaaccatctc caaagccaaa 360 gggcagcccc gagaaccaca ggtgtacacc ctgcccccat cccggaagga gatgaccaag 420 aaccaggtca gcctgacctg cctggtcaaa ggcttctatc ccagcgacat cgccgtggag 480 tggggagagca atggggcagcc ggagaacaac tacaagacca cgcctcccgt gctgaagtcc 540 gacggctcct tcttcctcta tagcaagctc accgtggac agagcaggtg gcagcagggg 600 aacgtcttct catgctccgt gatgcatgag gctctgcaca accactacac gcagaagagc 660 ctctccctgt ctccgggtaa a 681

<210> 173 <211> 1014 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=description of artificial sequence: synthetic polynucleotide <400> 173 gacaaaactc acacatgccc accgtgccca gcacctgaac tcctgggggg accgtcagtc 60

- 334 046387

ttcctcttcc ccccaaaacc caaggacacc ctcatgatct cccggacccc tgaggtcaca 120 tgcgtggtgg tggacgtgag ccacgaagac cctgaggtca agttcaactg gtacgtggac 180 ggcgtggagg tgcataatgc caagacaaag ccgcgggagg agcagtacgg cagcacgtac 240 cgtgtggtca gcgtcctcac cgtcctgcac caggactggc tgaatggcaa ggagtacaag 300 tgcaaggtct ccaacaaagc cctcccagcc ccatcgaga aaaccatctc caaagccaaa 360 gggcagcccc gagaaccaca ggtgtacacc ctgcccccat cccggggaga gatgaccaag 420 aaccaggtca gcctgacctg cctggtcaaa ggcttctatc ccagcgacat cgccgtggag 480 tggggagagca atggggcagcc ggagaacaac tacgacacca cgcctcccgt gctggactcc 540 gacggctcct tcttcctcta tagcgacctc accgtggac agagcaggtg gcagcagggg 600 aacgtcttct catgctccgt gatgcatgag gctctgcaca accactacac gcagaagagc 660 ctctccctgt ctccgggtgc gcgcgacgga gaccactgtc cgctcgggcc cggggcgttgc 720 tgccgtctgc acacggtccg cgcgtcgctg gaagacctgg gctggggccga ttgggtgctg 780 tcgccacggg aggtgcaagt gaccatgtgc atcggcgcgt gcccgagcca gttccggggcg 840 gcaaacatgc acgcgcagat caagacgagc ctgcaccgcc tgaagcccga cacggtgcca 900 gcgccctgct gcgtgcccgc cagctacaat cccatggtgc tcattcaaaa gaccgacacc 960 ggggtgtcgc tccagaccta tgatgacttg ttagccaaag actgccactg cata 1014

<210> 174 <211> 338 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 174

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

5 1015

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

2530

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 4045

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 5560

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

70 7580

- 335 046387

Arg Val Val Ser Val 85

Leu Thr Val Leu His

Gln Asp Trp Leu Asn

Lys Glu Tyr Lys Cys

100

Lys Val Ser Asn Lys

105

Ala Leu Pro Ala Pro

110

Glu Lys Thr Ile Ser 115

Lys Ala Lys Gly Gln

120

Pro Arg Glu Pro Gln 125

Tyr Thr Leu Pro Pro

130

Ser Arg Glu Glu Met

135

Thr Lys Asn Gln Val

140

Leu Thr Cys Leu Val 145

Lys Gly Phe Tyr Pro 150

Ser Asp Ile Ala Val 155

Trp Glu Ser Asn Gly

165

Gln Pro Glu Asn Asn

170

Tyr Asp Thr Thr Pro

175

Val Leu Asp Ser Asp

180

Gly Ser Phe Phe Leu

185

Tyr Ser Asp Leu Thr

190

Asp Lys Ser Arg Trp 195

Gln Gln Gly Asn Val 200

Phe Ser Cys Ser Val 205

His Glu Ala Leu His

210

Asn His Tyr Thr Gln 215

Lys Ser Leu Ser Leu 220

Pro Gly Ala Arg Asp 225

Gly Asp His Cys Pro 230

Leu Gly Pro Gly Arg 235

Cys Arg Leu His Thr

245

Val Arg Ala Ser Leu

250

Glu Asp Leu Gly Trp

255

Asp Trp Val Leu Ser

260

Pro Arg Glu Val Gln

265

Val Thr Met Cys Ile

270

Ala Cys Pro Ser Gln 275

Phe Arg Ala Ala Asn 280

Met His Ala Gln Ile

285

Thr Ser Leu His Arg

290

Leu Lys Pro Asp Thr

295

Val Pro Ala Pro Cys

300

Val Pro Ala Ser Tyr 305

Asn Pro Met Val Leu 310

Ile Gln Lys Thr Asp 315

Gly Val Ser Leu Gln

Thr Tyr Asp Asp Leu

Leu Ala Lys Asp Cys

Gly

Ile

Val

Ser

Glu 160

Pro

Val

Met

Ser

Cys 240

Ala

Gly

Lys

Cys

Thr 320

His

- 336 046387

335

325

Cys Ile

330 <210> 175 <211> 210 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 175

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

5 1015

Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 20 2530

Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 35 4045

Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr Arg 50 5560

Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 65 70 7580

Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 85 9095

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

100 105110

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

115 120125

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

130 135140

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

145 150 155160

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

165 170175

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

- 337 046387

180

185

190

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

195 200 205

Gly Lys

210 <210> 176 <211> 209 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 176

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

5 1015

Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 20 2530

Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 35 4045

Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr Arg 50 5560

Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 65 70 7580

Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 85 9095

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

100 105110

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

115 120125

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

130 135140

Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Asp Thr Thr Pro Pro Val

145 150 155160

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

- 338 046387

175

165

170

Lys Ser Arg Trp Gln Gln Gly Asn Val

180 185

Phe Ser Cys Ser Val Met His

190

Glu Ala Leu His Asn His

Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

195

200

205

Gly <210> 177 <211> 954 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide

<400> 177 ccgtcagtct tcctcttccc cccaaaaccc aaggacacc tcatgatctc ccggacccct 60 gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 120 tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcggggaga gcagtacgggg 180 agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 240 gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 300 aaagccaaag ggcagccccg agaaccacag gtgtacacc tgcccccatc ccggggagg 360 atgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 420 gccgtggagt ggggagagcaa tggggcagccg gagaacaact acgacaccac gcctcccgtg 480 ctggactccg acggctcctt cttcctctat agcgacctca ccgtggacaa gagcaggtgg 540 cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 600 cagaagagcc tctccctgtc tccggggtgga gaccactgtc cgctcgggcc cggggcgttgc 660 tgccgtctgc acacggtccg cgcgtcgctg gaagacctgg gctggggccga ttgggtgctg 720 tcgccacggg aggtgcaagt gaccatgtgc atcggcgcgt gcccgagcca gttccggggcg 780 gcaaacatgc acgcgcagat caagacgagc ctgcaccgcc tgaagcccga cacggtgcca 840 gcgccctgct gcgtgcccgc cagctacaat cccatggtgc tcattcaaaa gaccgacacc 900 ggggtgtcgc tccagaccta tgatgacttg ttagccaaag actgccactg cata 954

<210> 178 <211> 318 <212> PRT <213> Artificial sequence

- 339 046387 <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 178

Pro Ser Val Phe 1

Leu Phe Pro Pro 5

Lys Pro Lys Asp 10

Thr Leu Met Ile

Ser Arg Thr Pro

Glu Val Thr Cys

Val Val Val Asp 25

Val Ser His Glu 30

Asp Pro Glu Val 35

Lys Phe Asn Trp 40

Tyr Val Asp Gly

Val Glu Val His 45

Asn Ala Lys Thr 50

Lys Pro Arg Glu 55

Glu Gln Tyr Gly

Ser Thr Tyr Arg

Val Val Ser Val 65

Leu Thr Val Leu

His Gln Asp Trp 75

Leu Asn Gly Lys 80

Glu Tyr Lys Cys

Lys Val Ser Asn 85

Lys Ala Leu Pro 90

Ala Pro Ile Glu

Lys Thr Ile Ser

100

Lys Ala Lys Gly

Gln Pro Arg Glu 105

Pro Gln Val Tyr 110

Thr Leu Pro Pro

115

Ser Arg Glu Glu

120

Met Thr Lys Asn

Gln Val Ser Leu 125

Thr Cys Leu Val

130

Lys Gly Phe Tyr

135

Pro Ser Asp Ile

140

Ala Val Glu Trp

Glu Ser Asn Gly 145

Gln Pro Glu Asn

150

Asn Tyr Asp Thr

155

Thr Pro Pro Val

160

Leu Asp Ser Asp

Gly Ser Phe Phe 165

Leu Tyr Ser Asp 170

Leu Thr Val Asp

175

Lys Ser Arg Trp

180

Gln Gln Gly Asn

Val Phe Ser Cys 185

Ser Val Met His

190

Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 195 200 205

Gly Gly Asp His Cys Pro Leu Gly Pro Gly Arg Cys Cys Arg Leu His

210 215 220

- 340 046387

Thr

225

Val

Arg

Ala

Ser

Leu

230

Glu

Asp

Leu

Gly

Trp

235

Ala

Asp

Trp

Val

Leu

240

Ser

Pro

Arg

Glu

Val

245

Gln

Val

Thr

Met

Cys 250

Ile

Gly

Ala

Cys

Pro

255

Ser

Gln

Phe

Arg

Ala

260

Ala

Asn

Met

His

Ala

265

Gln

Ile

Lys

Thr

Ser

270

Leu

His

Arg

Leu

Lys 275

Pro

Asp

Thr

Val

Pro

280

Ala

Pro

Cys

Cys

Val

285

Pro

Ala

Ser

Tyr

Asn

290

Pro

Met

Val

Leu

Ile

295

Gln

Lys

Thr

Asp

Thr

300

Gly

Val

Ser

Leu

Gln

305

Thr

Tyr

Asp

Asp

Leu

310

Leu

Ala

Lys

Asp

Cys 315

His

Cys

Ile <210> 179 <211> 633 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide <400> 179 ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct60 gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg120 t acgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacggg180 agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag240 gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc300 aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccggaaggag360 atgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc420 gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg480 ctgaagtccg acggctcctt cttcctctat agcaagctca ccgtggacaa gagcaggtgg540 cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg600 cagaagagcc tctccctgtc tccgggtaaa tga633 <210> 180 <211> 963 <212> DNA <213 > Artificial sequence

- 341 046387 <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide <400> 180 ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 60 gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 12 0 tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacggg 180 agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 240 gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 300 aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggaggag 360 atgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 420 gcc gtggagt ggggagagcaa tgggcagccg gagaacaact acgacaccac gcctcccgtg 480 ctggactccg acggctcctt cttcctctat agcgacctca ccgtggacaa gagcaggtgg 540 cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 60 0 cagaagagcc tctccctgtc tccgggtgcg cgcgacggag accactgtcc gctcgggccc 660 gggcgttgct gccgtctgca cacggtccgc gcgtcgctgg aagacctggg ctgggccgat 720 tgggtgctgt cgccacggga ggtgcaagtg accatgtgca tcggcgcgtg cccgagccag 780 ttccgggcgg caaacatgca cgcgcagatc aagacgagcc tgcaccgcct gaagc ccgac 840 acggtgccag cgccctgctg cgtgcccgcc agctacaatc ccatggtgct cattcaaaag 900 accgacaccg gggtgtcgct ccagacctat gatgacttgt tagccaaaga ctgccactgc 960 ata 963 <210> 181 <211> 321 <212> PRT < 213 > Artificial sequence <220>

<221> source <223> /note=description of artificial sequence: synthetic polypeptide <400> 181

Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu MetIle

5 1015

Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser HisGlu

2530

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

4045

- 342 046387

Asn Ala Lys Thr Lys 50

Pro Arg Glu Glu Gln 55

Tyr Gly Ser Thr Tyr 60

Val Val Ser Val Leu 65

Thr Val Leu His Gln 70

Asp Trp Leu Asn Gly 75

Glu Tyr Lys Cys Lys 85

Val Ser Asn Lys Ala

Leu Pro Ala Pro Ile

Lys Thr Ile Ser Lys

100

Ala Lys Gly Gln Pro

105

Arg Glu Pro Gln Val

110

Thr Leu Pro Pro Ser

115

Arg Glu Glu Met Thr 120

Lys Asn Gln Val Ser

125

Thr Cys Leu Val Lys

130

Gly Phe Tyr Pro Ser 135

Asp Ile Ala Val Glu

140

Glu Ser Asn Gly Gln 145

Pro Glu Asn Asn Tyr 150

Asp Thr Thr Pro Pro 155

Leu Asp Ser Asp Gly

165

Ser Phe Phe Leu Tyr

170

Ser Asp Leu Thr Val

175

Lys Ser Arg Trp Gln

180

Gln Gly Asn Val Phe

185

Ser Cys Ser Val Met

190

Glu Ala Leu His Asn

195

His Tyr Thr Gln Lys

200

Ser Leu Ser Leu Ser

205

Gly Ala Arg Asp Gly

210

Asp His Cys Pro Leu 215

Gly Pro Gly Arg Cys 220

Arg Leu His Thr Val 225

Arg Ala Ser Leu Glu 230

Asp Leu Gly Trp Ala 235

Trp Val Leu Ser Pro

245

Arg Glu Val Gln Val

250

Thr Met Cys Ile Gly

255

Cys Pro Ser Gln Phe

260

Arg Ala Ala Asn Met

265

His Ala Gln Ile Lys

270

Ser Leu His Arg Leu

275

Lys Pro Asp Thr Val 280

Pro Ala Pro Cys Cys 285

Pro Ala Ser Tyr Asn 290

Pro Met Val Leu Ile

295

Gln Lys Thr Asp Thr

300

Arg

Lys 80

Glu

Tyr

Leu

Trp

Val 160

Asp

His

Pro

Cys

Asp 240

Ala

Thr

Val

Gly

- 343 046387

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

305 310 315 320

Ile <210> 182 <211> 210 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 182

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

5 1015

Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 20 2530

Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 35 4045

Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr Arg 50 5560

Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 65 70 7580

Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 85 9095

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

100 105110

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

115 120125

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

130 135140

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

145 150 155160

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

165 170175

- 344 046387

Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser

180 185

Cys Ser Val Met His

190

Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser

195 200

Leu Ser Leu Ser Pro

205

Gly Lys

210 <210> 183 <211> 209 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 183

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

5 10 15

Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 20 25 30

Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 35 40 45

Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr Arg 50 55 60

Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 65 70 75 80

Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 85 90 95

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

100 105 110

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

115 120 125

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

130 135 140

Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Asp Thr Thr Pro Pro Val

145 150 155 160

- 345 046387

Leu

Asp

Ser

Asp

Gly 165

Ser

Phe

Phe

Leu

Tyr 170

Ser

Asp

Leu

Thr

Val

175

Asp

Lys

Ser

Arg

Trp 180

Gln

Gln

Gly

Asn

Val

185

Phe

Ser

Cys

Ser

Val

190

Met

His

Glu

Ala

Leu

195

His

Asn

His

Tyr

Thr

200

Gln

Lys

Ser

Leu

Ser

205

Leu

Ser

Pro

Gly <210> 184 <211> 954 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide

<400> 184 ccgtcagtct tcctcttccc cccaaaaccc aaggacacc tcatgatctc ccggacccct 60 gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 120 tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcggggaga gcagtacggc 180 agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 240 gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 300 aaagccaaag ggcagccccg agaaccacag gtgtgcaccc tgcccccatc ccggggagg 360 atgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 420 gccgtggagt ggggagagcaa tggggcagccg gagaacaact acgacaccac gcctcccgtg 480 ctggactccg acggctcctt cttcctctat agcgacctca ccgtggacaa gagcaggtgg 540 cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 600 cagaagagcc tctccctgtc tccggggtgga gaccactgtc cgctcgggcc cggggcgttgc 660 tgccgtctgc acacggtccg cgcgtcgctg gaagacctgg gctggggccga ttgggtgctg 720 tcgccacggg aggtgcaagt gaccatgtgc atcggcgcgt gcccgagcca gttccggggcg 780 gcaaacatgc acgcgcagat caagacgagc ctgcaccgcc tgaagcccga cacggtgcca 840 gcgccctgct gcgtgcccgc cagctacaat cccatggtgc tcattcaaaa gaccgacacc 900 ggggtgtcgc tccagaccta tgatgacttg ttagccaaag actgccactg cata 954

<210> 185

- 346 046387 <211> 318 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 185

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

5 10 15

Ser Arg Thr Pro Glu Val

Thr Cys Val Val Val Asp Val Ser His Glu

thirty

Asp Pro Glu Val

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 40 45

Asn Ala Lys Thr Lys Pro Arg Glu

55

Glu Gln Tyr Gly Ser Thr Tyr Arg 60

Val Val Ser Val Leu Thr Val Leu

70

His Gln Asp Trp Leu Asn Gly Lys

80

Glu Tyr Lys Cys Lys Val Ser Asn 85

Lys Ala Leu Pro Ala Pro Ile Glu

95

Lys Thr Ile Ser Lys Ala Lys Gly

100

Gln Pro Arg Glu Pro Gln Val Cys

105 110

Thr Leu Pro Pro Ser Arg Glu Glu

115 120

Met Thr Lys Asn Gln Val Ser Leu

125

Thr Cys Leu Val Lys Gly Phe Tyr

130 135

Pro Ser Asp Ile Ala Val Glu Trp

140

Glu Ser Asn Gly Gln Pro Glu Asn

145 150

Asn Tyr Asp Thr Thr Pro Pro Val

155 160

Leu Asp Ser Asp Gly Ser Phe Phe

165

Leu Tyr Ser Asp Leu Thr Val Asp

170 175

Lys Ser Arg Trp Gln Gln Gly Asn

180

Val Phe Ser Cys Ser Val Met His

185 190

Glu Ala Leu His Asn His Tyr Thr

195 200

Gln Lys Ser Leu Ser Leu Ser Pro

205

Gly Gly Asp His Cys Pro Leu Gly

Pro Gly Arg Cys Cys Arg Leu His

- 347 046387

210

215

220

Thr

225

Val

Arg

Ala

Ser

Leu

230

Glu

Asp

Leu

Gly

Trp 235

Ala

Asp

Trp

Val

Leu

240

Ser

Pro

Arg

Glu

Val

245

Gln

Val

Thr

Met

Cys 250

Ile

Gly

Ala

Cys

Pro

255

Ser

Gln

Phe

Arg

Ala

260

Ala

Asn

Met

His

Ala

265

Gln

Ile

Lys

Thr

Ser

270

Leu

His

Arg

Leu

Lys 275

Pro

Asp

Thr

Val

Pro

280

Ala

Pro

Cys

Cys

Val

285

Pro

Ala

Ser

Tyr

Asn

290

Pro

Met

Val

Leu

Ile

295

Gln

Lys

Thr

Asp

Thr

300

Gly

Val

Ser

Leu

Gln

305

Thr

Tyr

Asp

Asp

Leu

310

Leu

Ala

Lys

Asp

Cys 315

His

Cys

Ile <210> 186 <211> 630 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide

<400> 186 ccatccgtgt tcctgtttcc tccaaagccg aaggacacc tgatgatctc aagaactccg 60 gaagtgactt gcgtcgtcgt ggacgtgtca catgaggatc cagaggtcaa gttcaattgg 120 tatgtggacg gagtggaagt gcataacgcc aagaccaaac cccgcgaaga acagtacgggg 180 agcacctacc gcgtggtgag cgtccttact gtgctccacc aggactggct taatgggaag 240 gaatacaagt gtaaggtgtc caacaaggcc ctccccgctc ccatcgaaaa gaccatctca 300 aaggcaaagg ggcaaccaag ggaacctcaa gtgtacacc tgcctccgtg caggaaggag 360 atgaccaaga accaggtcag cctgacttgt ctcgtgaagg gcttctatcc cagcgatatt 420 gctgtggaat ggggagtcaaa tggccagccc gagaataact acaaaactac cccacccgtg 480 ctgaaatctg atgggtcctt cttcctttac tccaagctga ccgtggacaa gagccgctgg 540 caacaaggca atgtctttag ctgctcagtg atgcatgagg ctctccataa tcactacact 600 cagaagtcac tgtccctgtc tccggggtaaa 630

<210> 187 <211> 963

- 348 046387 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=description of artificial sequence: synthetic polynucleotide” <400> 187 ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 60 gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 120 tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacggg 180 agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 240 gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 300 aaagccaaag ggcagccccg agaaccacag gtgtgcaccc tgcccccatc ccgggaggag 360 atgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 420 gccgtggagt ggggagagcaa tgggcagccg gagaacaact acgacaccac gcctcccgtg 480 ctggactccg acggctcctt cttcctctat agcgacctca ccgtggacaa gagcaggtgg 540 cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 600 cagaagag cc tctccctgtc tccgggtgcg cgcgacggag accactgtcc gctcgggccc 660 gggcgttgct gccgtctgca cacggtccgc gcgtcgctgg aagacctggg ctgggccgat 720 tgggtgctgt cgccacggga ggtgcaagtg accatgtgca tcggcgcgtg cccgagccag 780 ttccgggcgg caaacatgca cgcgcagatc aagacgagcc tgcaccgcct gaagcccgac 840 acggtgccag cgccctgctg cgtgcccgcc agctacaatc ccatggtgct cattcaaaag 900 accgacaccg gggtgtcgct ccagacctat gatgacttgt tagccaaaga ctgccactgc 960 ata 963 <210> 188 <211> 321 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=description of artificial sequence: synthetic polypeptide” <400> 188

Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu MetIle

5 1015

Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser HisGlu

2530

- 349 046387

Asp Pro Glu Val Lys 35

Phe Asn Trp Tyr Val 40

Asp Gly Val Glu Val 45

Asn Ala Lys Thr Lys 50

Pro Arg Glu Glu Gln 55

Tyr Gly Ser Thr Tyr 60

Val Val Ser Val Leu 65

Thr Val Leu His Gln 70

Asp Trp Leu Asn Gly 75

Glu Tyr Lys Cys Lys 85

Val Ser Asn Lys Ala

Leu Pro Ala Pro Ile

Lys Thr Ile Ser Lys

100

Ala Lys Gly Gln Pro

105

Arg Glu Pro Gln Val

110

Thr Leu Pro Pro Ser

115

Arg Glu Glu Met Thr 120

Lys Asn Gln Val Ser

125

Thr Cys Leu Val Lys

130

Gly Phe Tyr Pro Ser

135

Asp Ile Ala Val Glu

140

Glu Ser Asn Gly Gln 145

Pro Glu Asn Asn Tyr 150

Asp Thr Thr Pro Pro 155

Leu Asp Ser Asp Gly

165

Ser Phe Phe Leu Tyr

170

Ser Asp Leu Thr Val

175

Lys Ser Arg Trp Gln

180

Gln Gly Asn Val Phe

185

Ser Cys Ser Val Met

190

Glu Ala Leu His Asn

195

His Tyr Thr Gln Lys 200

Ser Leu Ser Leu Ser

205

Gly Ala Arg Asp Gly

210

Asp His Cys Pro Leu

215

Gly Pro Gly Arg Cys

220

Arg Leu His Thr Val 225

Arg Ala Ser Leu Glu 230

Asp Leu Gly Trp Ala 235

Trp Val Leu Ser Pro

245

Arg Glu Val Gln Val

250

Thr Met Cys Ile Gly

255

Cys Pro Ser Gln Phe

260

Arg Ala Ala Asn Met

265

His Ala Gln Ile Lys

270

Ser Leu His Arg Leu

275

Lys Pro Asp Thr Val

280

Pro Ala Pro Cys Cys 285

His

Arg

Lys 80

Glu

Cys

Leu

Trp

Val 160

Asp

His

Pro

Cys

Asp 240

Ala

Thr

Val

- 350 046387

Pro Ala Ser Tyr Asn Pro Met Val

290 295

Leu Ile Gln

Lys Thr Asp Thr Gly 300

Val Ser Leu Gln Thr 305

Tyr Asp Asp Leu Leu Ala Lys Asp Cys His Cys

310 315 320

Ile <210> 189 <211> 113 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 189

Met Ala Arg Asn Gly Asp His Cys Pro Leu Gly Pro Gly Arg Cys Cys

5 10 15

Arg Leu His Thr Val Arg Ala Ser Leu Glu Asp Leu Gly Trp Ala Asp 20 25 30

Trp Val Leu Ser Pro Arg Glu Val Gln Val Thr Met Cys Ile Gly Ala 35 40 45

Cys Pro Ser Gln Phe Arg Ala Ala Asn Met His Ala Gln Ile Lys Thr 50 55 60

Ser Leu His Arg Leu Lys Pro Asp Thr Val Pro Ala Pro Cys Cys Val 65 70 75 80

Pro Ala Ser Tyr Asn Pro Met Val Leu Ile Gln Lys Thr Asp Thr Gly 85 90 95

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

100 105 110

Ile <210> 190 <211> 342 <212> DNA <213> Artificial <220>

<221> source sequence

- 351 046387 <223> /note=’’description of artificial sequence: synthetic polynucleotide

<400> 190 atggcgcgca acggggacca ctgtccgctc gggcccggggc gttgctgccg tctgcacacg 60 gtccgcgcgt cgctggaaga cctggggctgg gccgattggg tgctgtcgcc acgggaggtg 120 caagtgacca tgtgcatcgg cgcgtgcccg agccagttcc gggcggcaaa catgcacgcg 180 cagatcaaga cgagcctgca ccgcctgaag cccgacacgg tgccagcgcc ctgctgcgtg 240 cccgccagct acaatcccat ggtgctcatt caaaagaccg acaccggggt gtcgctccag 300 acctatgatg acttgttagc caaagactgc cactgcatat aa 342

<210> 191 <211> 210 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=description of artificial sequence: synthetic polypeptide <400> 191

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

5 1015

Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 20 2530

Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 35 4045

Asn Cys Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr Arg 50 5560

Val Val Ser Val Cys Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 65 70 7580

Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 85 9095

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

100 105110

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

115 120125

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

130 135140

- 352 046387

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

145 150 155160

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

165 170175

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

180 185190

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

195 200205

Gly Lys

210 <210> 192 <211> 209 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 192

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

5 1015

Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 20 2530

Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 35 4045

Asn Cys Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr Arg 50 5560

Val Val Ser Val Cys Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 65 70 7580

Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 85 9095

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

100 105110

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

115 120125

- 353 046387

Thr

Cys 130

Leu

Val

Lys

Gly

Phe

135

Tyr

Pro

Ser

Asp

Ile

140

Ala

Val

Glu

Trp

Glu

145

Ser

Asn

Gly

Gln

Pro

150

Glu

Asn

Asn

Tyr

Asp

155

Thr

Thr

Pro

Pro

Val

160

Leu

Asp

Ser

Asp

Gly 165

Ser

Phe

Phe

Leu

Tyr

170

Ser

Asp

Leu

Thr

Val

175

Asp

Lys

Ser

Arg

Trp 180

Gln

Gln

Gly

Asn

Val

185

Phe

Ser

Cys

Ser

Val

190

Met

His

Glu

Ala

Leu

195

His

Asn

His

Tyr

Thr

200

Gln

Lys

Ser

Leu

Ser

205

Leu

Ser

Pro

Gly <210> 193 <211> 954 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide

<400> 193 ccgtcagtct tcctcttccc cccaaaaccc aaggacacc tcatgatctc ccggacccct 60 gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 120 tacgtggacg gcgtggaggt gcataattgc aagacaaagc cgcggggaga gcagtacggc 180 agcacgtacc gtgtggtcag cgtctgcacc gtcctgcacc aggactggct gaatggcaag 240 gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 300 aaagccaaag ggcagccccg agaaccacag gtgtacacc tgcccccatc ccggggagg 360 atgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 420 gccgtggagt ggggagagcaa tggggcagccg gagaacaact acgacaccac gcctcccgtg 480 ctggactccg acggctcctt cttcctctat agcgacctca ccgtggacaa gagcaggtgg 540 cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 600 cagaagagcc tctccctgtc tccggggtgga gaccactgtc cgctcgggcc cggggcgttgc 660 tgccgtctgc acacggtccg cgcgtcgctg gaagacctgg gctggggccga ttgggtgctg 720 tcgccacggg aggtgcaagt gaccatgtgc atcggcgcgt gcccgagcca gttccggggcg 780 gcaaacatgc acgcgcagat caagacgagc ctgcaccgcc tgaagcccga cacggtgcca 840

- 354 046387 gcgccctgct gcgtgcccgc cagctacaat cccatggtgc tcattcaaaa gaccgacacc 900 ggggtgtcgc tccagaccta tgatgacttg ttagccaaag actgccactg cata 954 <210> 194 <211> 318 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 194

Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu MetIle

5 1015

Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser HisGlu

2530

Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 35 4045

Asn Cys Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr Arg 50 5560

Val Val Ser Val Cys Thr Val Leu His Gln Asp Trp Leu Asn GlyLys

70 7580

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

9095

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

100 105110

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

115 120125

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

130 135140

Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Asp Thr Thr Pro ProVal

145 150 155160

Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Asp Leu Thr ValAsp

165 170175

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

180 185190

- 355 046387

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

195 200205

Gly Gly Asp His Cys Pro Leu Gly Pro Gly Arg Cys Cys Arg Leu His

210 215220

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

225 230 235240

Ser Pro Arg Glu Val Gln Val Thr Met Cys Ile Gly Ala Cys Pro Ser

245 250255

Gln Phe Arg Ala Ala Asn Met His Ala Gln Ile Lys Thr Ser Leu His

260 265270

Arg Leu Lys Pro Asp Thr Val Pro Ala Pro Cys Cys Val Pro Ala Ser

275 280285

Tyr Asn Pro Met Val Leu Ile Gln Lys Thr Asp Thr Gly Val Ser Leu

290 295300

Gln Thr Tyr Asp Asp Leu Leu Ala Lys Asp Cys His Cys Ile

305 310315 <210> 195 <211> 630 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide <400> 195

ccgtcagtct tcctcttccc cccaaaaccc aaggacacc tcatgatctc ccggacccct 60 gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 120 tacgtggacg gcgtggaggt gcataattgc aagacaaagc cgcggggaga gcagtacggc 180 agcacgtacc gtgtggtcag cgtctgcacc gtcctgcacc aggactggct gaatggcaag 240 gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 300 aaagccaaag ggcagccccg agaaccacag gtgtacacc tgcccccatc ccggaaggag 360 atgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 420 gccgtggagt ggggagagcaa tggggcagccg gagaacaact acaagaccac gcctcccgtg 480 ctgaagtccg acggctcctt cttcctctat agcaagctca ccgtggacaa gagcaggtgg 540

- 356 046387 cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 600 cagaagagcc tctccctgtc tccgggtaaa

630 <210> 196 <211> 963 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide <400> 196 ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct60 gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg120 t acgtggacg gcgtggaggt gcataattgc aagacaaagc cgcgggagga gcagtacggc180 agcacgtacc gtgtggtcag cgtctgcacc gtcctgcacc aggactggct gaatggcaag240 gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc300 aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggaggag360 atgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc420 gccgtggagt gggagagcaa tgggcagccg gagaacaact acgacaccac g cctcccgtg480 ctggactccg acggctcctt cttcctctat agcgacctca ccgtggacaa gagcaggtgg540 cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg600 cagaagagcc tctccctgtc tccgggtgcg cgcgacggag accactg tcc gctcgggccc660 gggcgttgct gccgtctgca cacggtccgc gcgtcgctgg aagacctggg ctgggccgat720 tgggtgctgt cgccacggga ggtgcaagtg accatgtgca tcggcgcgtg cccgagccag780 ttccgggcgg caaacatgca cgcgcagatc aagacgagcc tgcaccgcct gaagcccgac840 acggtgccag cgccctgctg cgtgcccgcc agctacaatc ccatggtgct cattcaaaag900 accgacaccg gggtgtcgct ccagacctat gatgacttgt tagccaaaga ctgccactg c960 ata963 <210> 197 <211> 321 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=description of artificial sequence: synthetic polypeptide <400> 197

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

- 357 046387

Ser Arg Thr Pro Glu

Val Thr Cys Val Val

Val Asp Val Ser His

Asp Pro Glu Val Lys 35

Phe Asn Trp Tyr Val 40

Asp Gly Val Glu Val 45

Asn Cys Lys Thr Lys 50

Pro Arg Glu Glu Gln 55

Tyr Gly Ser Thr Tyr 60

Val Val Ser Val Cys 65

Thr Val Leu His Gln 70

Asp Trp Leu Asn Gly 75

Glu Tyr Lys Cys Lys 85

Val Ser Asn Lys Ala

Leu Pro Ala Pro Ile

Lys Thr Ile Ser Lys

100

Ala Lys Gly Gln Pro

105

Arg Glu Pro Gln Val

110

Thr Leu Pro Pro Ser

115

Arg Glu Glu Met Thr 120

Lys Asn Gln Val Ser

125

Thr Cys Leu Val Lys

130

Gly Phe Tyr Pro Ser 135

Asp Ile Ala Val Glu

140

Glu Ser Asn Gly Gln 145

Pro Glu Asn Asn Tyr 150

Asp Thr Thr Pro Pro 155

Leu Asp Ser Asp Gly

165

Ser Phe Phe Leu Tyr

170

Ser Asp Leu Thr Val

175

Lys Ser Arg Trp Gln

180

Gln Gly Asn Val Phe

185

Ser Cys Ser Val Met

190

Glu Ala Leu His Asn

195

His Tyr Thr Gln Lys 200

Ser Leu Ser Leu Ser

205

Gly Ala Arg Asp Gly

210

Asp His Cys Pro Leu 215

Gly Pro Gly Arg Cys 220

Arg Leu His Thr Val 225

Arg Ala Ser Leu Glu 230

Asp Leu Gly Trp Ala 235

Trp Val Leu Ser Pro

245

Arg Glu Val Gln Val

250

Thr Met Cys Ile Gly

255

Glu

His

Arg

Lys 80

Glu

Tyr

Leu

Trp

Val 160

Asp

His

Pro

Cys

Asp 240

Ala

- 358 046387

Cys Pro Ser Gln Phe Arg Ala Ala Asn Met His Ala Gln Ile Lys Thr

260 265270

Ser Leu His Arg Leu Lys Pro Asp Thr Val Pro Ala Pro Cys Cys Val

275 280285

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

290 295300

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

305 310 315320

Ile <210> 198 <211> 210 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 198

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

5 1015

Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 20 2530

Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 35 4045

Asn Cys Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr Arg 50 5560

Val Val Ser Val Cys Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 65 70 7580

Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 85 9095

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

100 105110

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

115 120125

- 359 046387

Thr Cys Leu Val Lys Gly Phe Tyr

130 135

Pro Ser Asp Ile Ala Val Glu Trp

140

Glu Ser Asn Gly Gln Pro Glu Asn

145 150

Asn Tyr Lys Thr Thr Pro Pro Val

155 160

Leu Lys Ser Asp Gly Ser Phe Phe

165

Leu Tyr Ser Lys Leu Thr Val Asp

170 175

Lys Ser Arg Trp Gln Gln Gly Asn

180

Val Phe Ser Cys Ser Val Met His

185 190

Glu Ala Leu His Asn His Tyr Thr

195 200

Gln Lys Ser Leu Ser Leu Ser Pro

205

Gly Lys

210 <210> 199 <211> 209 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 199

Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu MetIle

5 1015

Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser HisGlu

2530

Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 35 4045

Asn Cys Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr Arg 50 5560

Val Val Ser Val Cys Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 65 70 7580

Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 85 9095

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

100 105110

- 360 046387

Thr

Leu

Pro

115

Pro

Ser

Arg

Glu

Glu

120

Met

Thr

Lys

Asn

Gln

125

Val

Ser

Leu

Thr

Cys 130

Leu

Val

Lys

Gly

Phe

135

Tyr

Pro

Ser

Asp

Ile

140

Ala

Val

Glu

Trp

Glu

145

Ser

Asn

Gly

Gln

Pro

150

Glu

Asn

Asn

Tyr

Asp

155

Thr

Thr

Pro

Pro

Val

160

Leu

Asp

Ser

Asp

Gly 165

Ser

Phe

Phe

Leu

Tyr 170

Ser

Asp

Leu

Thr

Val

175

Asp

Lys

Ser

Arg

Trp 180

Gln

Gln

Gly

Asn

Val

185

Phe

Ser

Cys

Ser

Val

190

Met

His

Glu

Ala

Leu

195

His

Asn

His

Tyr

Thr

200

Gln

Lys

Ser

Leu

Ser

205

Leu

Ser

Pro

Gly <210> 200 <211> 954 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide <400> 200

ccgtcagtct tcctcttccc cccaaaaccc aaggacacc tcatgatctc ccggacccct 60 gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 120 tacgtggacg gcgtggaggt gcataattgc aagacaaagc cgcggggaga gcagtacggc 180 agcacgtacc gtgtggtcag cgtctgcacc gtcctgcacc aggactggct gaatggcaag 240 gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 300 aaagccaaag ggcagccccg agaaccacag gtgtgcaccc tgcccccatc ccggggagg 360 atgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 420 gccgtggagt ggggagagcaa tggggcagccg gagaacaact acgacaccac gcctcccgtg 480 ctggactccg acggctcctt cttcctctat agcgacctca ccgtggacaa gagcaggtgg 540 cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 600 cagaagagcc tctccctgtc tccggggtgga gaccactgtc cgctcgggcc cggggcgttgc 660 tgccgtctgc acacggtccg cgcgtcgctg gaagacctgg gctggggccga ttgggtgctg 720

- 361 046387

tcgccacggg aggtgcaagt gaccatgtgc atcggcgcgt gcccgagcca gttccggggcg 780 gcaaacatgc acgcgcagat caagacgagc ctgcaccgcc tgaagcccga cacggtgcca 840 gcgccctgct gcgtgcccgc cagctacaat cccatggtgc tcattcaaaa gaccgacacc 900 ggggtgtcgc tccagaccta tgatgacttg ttagccaaag actgccactg cata 954

<210> 201 <211> 318 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 201

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

5 1015

Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 20 2530

Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 35 4045

Asn Cys Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr Arg 50 5560

Val Val Ser Val Cys Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 65 70 7580

Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 85 9095

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

100 105110

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

115 120125

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

130 135140

Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Asp Thr Thr Pro Pro Val

145 150 155160

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

165 170175

- 362 046387

Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser

180185

Cys Ser Val Met His

190

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

195 200205

Gly Gly Asp His Cys Pro Leu Gly Pro Gly Arg Cys Cys Arg Leu His

210 215220

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

225 230 235240

Ser Pro Arg Glu Val Gln Val Thr Met Cys Ile Gly Ala Cys Pro Ser

245 250255

Gln Phe Arg Ala Ala Asn Met His Ala Gln Ile Lys Thr Ser Leu His

260 265270

Arg Leu Lys Pro Asp Thr Val Pro Ala Pro Cys Cys Val Pro Ala Ser

275 280285

Tyr Asn Pro Met Val Leu Ile Gln Lys Thr Asp Thr Gly Val Ser Leu

290 295300

Gln Thr Tyr Asp Asp Leu Leu Ala Lys Asp Cys His Cys Ile

305 310315 <210> 202 <211> 630 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide

<400> 202 ccgtcagtct tcctcttccc cccaaaaccc aaggacacc tcatgatctc ccggacccct 60 gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 120 tacgtggacg gcgtggaggt gcataattgc aagacaaagc cgcggggaga gcagtacggc 180 agcacgtacc gtgtggtcag cgtctgcacc gtcctgcacc aggactggct gaatggcaag 240 gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 300 aaagccaaag ggcagccccg agaaccacag gtgtacacc tgcccccatg ccggaaggag 360 atgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 420 gccgtggagt ggggagagcaa tggggcagccg gagaacaact acaagaccac gcctcccgtg 480

- 363 046387

ctgaagtccg acggctcctt cttcctctat agcaagctca ccgtggacaa gagcaggtgg 540 cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 600 cagaagagcc tctccctgtc tccggggtaaa 630

<210> 203 <211> 963 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide <400> 203 ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct60 gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg120 t acgtggacg gcgtggaggt gcataattgc aagacaaagc cgcgggagga gcagtacggc180 agcacgtacc gtgtggtcag cgtctgcacc gtcctgcacc aggactggct gaatggcaag240 gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc300 aaagccaaag ggcagccccg agaaccacag gtgtgcaccc tgcccccatc ccgggaggag360 atgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc420 gccgtggagt gggagagcaa tgggcagccg gagaacaact acgacaccac gcctcccgtg480 ctggactccg acggctcctt cttcctctat agcgacctca ccgtggacaa gagcaggtgg540 cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg600 cagaagagcc tctccctgtc tccgggtgcg cgcgacggag accact gtcc gctcgggccc660 gggcgttgct gccgtctgca cacggtccgc gcgtcgctgg aagacctggg ctgggccgat720 tgggtgctgt cgccacggga ggtgcaagtg accatgtgca tcggcgcgtg cccgagccag780 ttccgggcgg caaacatgca cgcgcagatc aagacgagcc tgcaccgcct gaagcccgac840 acggtgccag cgccctgctg cgtgcccgcc agctacaatc ccatggtgct cattcaaaag900 accgacaccg gggtgtcgct ccagacctat gatgacttgt tagccaaaga ctgccactg c960 ata963 <210> 204 <211> 321 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=description of artificial sequence: synthetic polypeptide

- 364 046387 <400> 204

Pro Ser Val Phe Leu

5

Phe Pro Pro Lys Pro

Lys Asp Thr Leu Met

Ser Arg Thr Pro Glu

Val Thr Cys Val Val

Val Asp Val Ser His

Asp Pro Glu Val Lys 35

Phe Asn Trp Tyr Val 40

Asp Gly Val Glu Val 45

Asn Cys Lys Thr Lys 50

Pro Arg Glu Glu Gln 55

Tyr Gly Ser Thr Tyr 60

Val Val Ser Val Cys 65

Thr Val Leu His Gln 70

Asp Trp Leu Asn Gly 75

Glu Tyr Lys Cys Lys 85

Val Ser Asn Lys Ala

Leu Pro Ala Pro Ile

Lys Thr Ile Ser Lys

100

Ala Lys Gly Gln Pro

105

Arg Glu Pro Gln Val

110

Thr Leu Pro Pro Ser

115

Arg Glu Glu Met Thr 120

Lys Asn Gln Val Ser

125

Thr Cys Leu Val Lys

130

Gly Phe Tyr Pro Ser

135

Asp Ile Ala Val Glu

140

Glu Ser Asn Gly Gln 145

Pro Glu Asn Asn Tyr 150

Asp Thr Thr Pro Pro 155

Leu Asp Ser Asp Gly

165

Ser Phe Phe Leu Tyr

170

Ser Asp Leu Thr Val

175

Lys Ser Arg Trp Gln

180

Gln Gly Asn Val Phe

185

Ser Cys Ser Val Met

190

Glu Ala Leu His Asn

195

His Tyr Thr Gln Lys 200

Ser Leu Ser Leu Ser

205

Gly Ala Arg Asp Gly

210

Asp His Cys Pro Leu

215

Gly Pro Gly Arg Cys

220

Arg Leu His Thr Val 225

Arg Ala Ser Leu Glu 230

Asp Leu Gly Trp Ala 235

Ile

Glu

His

Arg

Lys 80

Glu

Cys

Leu

Trp

Val 160

Asp

His

Pro

Cys

Asp 240

Ala

Trp Val Leu Ser Pro

Arg Glu Val Gln Val

Thr Met Cys Ile Gly

- 365 046387

245 250255

Cys Pro Ser Gln Phe Arg Ala Ala Asn Met His Ala Gln Ile Lys Thr

260 265270

Ser Leu His Arg Leu Lys Pro Asp Thr Val Pro Ala Pro Cys Cys Val

275 280285

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

290 295300

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

305 310 315320

Ile <210> 205 <211> 212 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 205

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

5 1015

Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 20 2530

His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 35 4045

Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 50 5560

Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 65 70 7580

Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro 85 9095

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

100 105110

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

- 366 046387

Ser

Leu

130

115

Thr

Cys

Leu

Val

Lys

135

120

Gly

Phe

Tyr

Pro

Ser

140

125

Asp

Ile

Ala

Val

Glu

145

Trp

Glu

Ser

Asn

Gly 150

Gln

Pro

Glu

Asn

Asn

155

Tyr

Lys

Thr

Thr

Pro

160

Pro

Val

Leu

Lys

Ser

165

Asp

Gly

Ser

Phe

Phe

170

Leu

Tyr

Ser

Lys

Leu

175

Thr

Val

Asp

Lys

Ser

180

Arg

Trp

Gln

Gln

Gly 185

Asn

Val

Phe

Ser

Cys 190

Ser

Val

Met

His

Glu

195

Ala

Leu

His

Asn

His

200

Tyr

Thr

Gln

Lys

Ser

205

Leu

Ser

Leu

Ser

Pro

210

Gly

Lys <210> 206 <211> 211 <212> PRT <213>

Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 206

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

5 1015

Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 20 2530

His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 35 4045

Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 50 5560

Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 65 70 7580

Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro 85 9095

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

- 367 046387

Val

100

Tyr Thr Leu Pro Pro

115

105

110

Ser Arg Glu Glu Met Thr Lys Asn Gln Val

120 125

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

130 135140

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

145 150 155160

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

165 170175

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

180 185190

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

195 200205

Ser Pro Gly

210 <210> 207 <211> 960 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide

<400> 207 ggtggcccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg 60 acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 120 aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggagaggagcag 180 tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 240 ggcaagggagt acaagtgcaa ggtctccaac aaagccctcc cagcccccat cgagaaaacc 300 atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc cccacccgg 360 gaggagatga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatcccagc 420 gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacga caccacgcct 480 cccgtgctgg actccgacgg ctccttcttc ctctatagcg acctcaccgt ggacaagagc 540 aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 600 tacacgcaga agagcctctc cctgtctccg ggtggagacc actgtccgct cgggcccggg 660

- 368 046387

cgttgctgcc gtctgcacac ggtccgcgcg tcgctggaag acctggggctg ggccgattgg 720 gtgctgtcgc caggggggt gcaagtgacc atgtgcatcg gcgcgtgccc gagccagttc 780 cggggcggcaa acatgcacgc gcagatcaag acgagcctgc accgcctgaa gccccgacacg 840 gtgccagcgc cctgctgcgt gcccgccagc tacaatccca tggtgctcat tcaaaagacc 900 gacaccgggg tgtcgctcca gacctatgat gacttgttag ccaaagactg ccactgcata 960

<210> 208 <211> 320 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 208

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

5 1015

Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 20 2530

His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 35 4045

Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 50 5560

Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 65 70 7580

Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro 85 9095

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

100 105110

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

115 120125

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

130 135140

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

145 150 155160

- 369 046387

Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu

165170

Tyr Ser Asp Leu Thr

175

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

180 185190

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

195 200205

Ser Pro Gly Gly Asp His Cys Pro Leu Gly Pro Gly Arg Cys Cys Arg

210 215220

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

225 230 235240

Val Leu Ser Pro Arg Glu Val Gln Val Thr Met Cys Ile Gly Ala Cys

245 250255

Pro Ser Gln Phe Arg Ala Ala Asn Met His Ala Gln Ile Lys Thr Ser

260 265270

Leu His Arg Leu Lys Pro Asp Thr Val Pro Ala Pro Cys Cys Val Pro

275 280285

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

290 295300

Ser Leu Gln Thr Tyr Asp Asp Leu Leu Ala Lys Asp Cys His Cys Ile

305 310 315320 <210> 209 <211> 636 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide <400> 209

ggtggcccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg 60 acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 120 aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggagaggagcag 180 tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 240 ggcaagggagt acaagtgcaa ggtctccaac aaagccctcc cagcccccat cgagaaaacc 300 atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc cccacccgg 360

- 370 046387

aaggagatga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatcccagc 420 gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct 480 cccgtgctga agtccgacgg ctccttcttc ctctatagca agctcaccgt ggacaagagc 540 aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 600 tacacgcaga agagcctctc cctgtctccg ggtaaa 636

<210> 210 <211> 969 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide <400> 210 ggtggcccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg60 acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc120 aactgg tacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag180 tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat240 ggcaaggagt acaagtgcaa ggtctccaac aaagccctcc cagcccccat cgagaaaacc300 atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc cccatcccgg360 gaggagatga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatcccagc420 gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacga caccacgcct480 cccgtgctgg actccgacgg ctccttcttc ctctatagcg acctcaccgt ggacaagagc540 aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac600 tacacgcaga agagcctctc cctgtctccg ggtgcgcgcg ggagacca ctgtccgctc660 gggcccggggc gttgctgccg tctgcacacg gtccgcgcgt cgctggaaga cctgggctgg720 gccgattggg tgctgtcgcc acgggaggtg caagtgacca tgtgcatcgg cgcgtgcccg780 agccagttcc gggcggcaaa catgcacgcg cagatcaaga cgagcctgca ccgcctgaag840 cccgacacgg tgccagcgcc ctgctgcgtg cccgccagct acaatcccat ggtgctcatt900 caaaagaccg acaccggggt gtcgctccag acctatgatg acttgttagc caaagactgc9 60 cactgcata969 <210> 211 <211> 323 <212> PRT <213> Artificial sequence <220>

- 371 046387 <221> source <223> /note=’’description of the artificial sequence: synthetic polypeptide <400> 211

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

5 1015

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

2530

His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 35 4045

Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 50 5560

Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 65 70 7580

Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro 85 9095

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

100 105110

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

115 120125

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

130 135140

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

145 150 155160

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

165 170175

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

180 185190

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

195 200205

Ser Pro Gly Ala Arg Asp Gly Asp His Cys Pro Leu Gly Pro Gly Arg

210 215220

Cys Cys Arg Leu His Thr Val Arg Ala Ser Leu Glu Asp Leu Gly Trp

225 230 235240

- 372 046387

Ala Asp Trp Val Leu Ser Pro Arg Glu Val Gln Val Thr Met Cys Ile

245 250255

Gly Ala Cys Pro Ser Gln Phe Arg Ala Ala Asn Met His Ala Gln Ile

260 265270

Lys Thr Ser Leu His Arg Leu Lys Pro Asp Thr Val Pro Ala Pro Cys

275 280285

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

290 295300

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

305 310 315320

His Cys Ile <210> 212 <211> 212 <212> PRT <213>

Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 212

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

5 1015

Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 20 2530

His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 35 4045

Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 50 5560

Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 65 70 7580

Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro 85 9095

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

100 105110

- 373 046387

Val Tyr Thr Leu Pro Pro Cys Arg Lys Glu Met Thr Lys Asn Gln Val

115 120125

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

130 135140

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

145 150 155160

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

165 170175

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

180 185190

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

195 200205

Ser Pro Gly Lys

210 <210> 213 <211> 211 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 213

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

5 1015

Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 20 2530

His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 35 4045

Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 50 5560

Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 65 70 7580

Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro 85 9095

- 374 046387

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

100 105110

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

115 120125

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

130 135140

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

145 150 155160

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

165 170175

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

180 185190

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

195 200205

Ser Pro Gly

210 <210> 214 <211> 960 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide <400> 214

ggtggcccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg 60 acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 120 aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggagaggagcag 180 tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 240 ggcaagggagt acaagtgcaa ggtctccaac aaagccctcc cagcccccat cgagaaaacc 300 atctccaaag ccaaagggca gccccgagaa ccacaggtgt gcaccctgcc cccacccgg 360 gaggagatga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatcccagc 420 gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacga caccacgcct 480 cccgtgctgg actccgacgg ctccttcttc ctctatagcg acctcaccgt ggacaagagc 540

- 375 046387

aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 600 tacacgcaga agagcctctc cctgtctccg ggtggagacc actgtccgct cgggcccggg 660 cgttgctgcc gtctgcacac ggtccgcgcg tcgctggaag acctggggctg ggccgattgg 720 gtgctgtcgc caggggggt gcaagtgacc atgtgcatcg gcgcgtgccc gagccagttc 780 cggggcggcaa acatgcacgc gcagatcaag acgagcctgc accgcctgaa gccccgacacg 840 gtgccagcgc cctgctgcgt gcccgccagc tacaatccca tggtgctcat tcaaaagacc 900 gacaccgggg tgtcgctcca gacctatgat gacttgttag ccaaagactg ccactgcata 960

<210> 215 <211> 320 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 215

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

5 1015

Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 20 2530

His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 35 4045

Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 50 5560

Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 65 70 7580

Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro 85 9095

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

100 105110

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

115 120125

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

130 135140

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

- 376 046387

145 150 155160

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

165 170175

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

180 185190

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

195 200205

Ser Pro Gly Gly Asp His Cys Pro Leu Gly Pro Gly Arg Cys Cys Arg

210 215220

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

225 230 235240

Val Leu Ser Pro Arg Glu Val Gln Val Thr Met Cys Ile Gly Ala Cys

245 250255

Pro Ser Gln Phe Arg Ala Ala Asn Met His Ala Gln Ile Lys Thr Ser

260 265270

Leu His Arg Leu Lys Pro Asp Thr Val Pro Ala Pro Cys Cys Val Pro

275 280285

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

290 295300

Ser Leu Gln Thr Tyr Asp Asp Leu Leu Ala Lys Asp Cys His Cys Ile

305 310 315320 <210> 216 <211> 636 <212> DNA <213>

Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide <400> 216 ggtggcccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg60 acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc120 aactgg tacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag180 tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat240 ggcaaggagt acaagtgcaa ggtctccaac aaagccctcc cagcccccat cgagaaaacc300

- 377 046387

atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc cccatgccgg 360 aaggagatga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatcccagc 420 gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct 480 cccgtgctga agtccgacgg ctccttcttc ctctatagca agctcaccgt ggacaagagc 540 aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 600 tacacgcaga agagcctctc cctgtctccg ggtaaa 636

<210> 217 <211> 969 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide

<400> 217 ggtggcccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg 60 acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 120 aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggagaggagcag 180 tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 240 ggcaagggagt acaagtgcaa ggtctccaac aaagccctcc cagcccccat cgagaaaacc 300 atctccaaag ccaaagggca gccccgagaa ccacaggtgt gcaccctgcc cccacccgg 360 gaggagatga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatcccagc 420 gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacga caccacgcct 480 cccgtgctgg actccgacgg ctccttcttc ctctatagcg acctcaccgt ggacaagagc 540 aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 600 tacacgcaga agagcctctc cctgtctccg ggtgcgcgcg acggagacca ctgtccgctc 660 gggcccggggc gttgctgccg tctgcacacg gtccgcgcgt cgctggaaga cctggggctgg 720 gccgattggg tgctgtcgcc acgggaggtg caagtgacca tgtgcatcgg cgcgtgcccg 780 agccagttcc gggcggcaaa catgcacgcg cagatcaaga cgagcctgca ccgcctgaag 840 cccgacacgg tgccagcgcc ctgctgcgtg cccgccagct acaatcccat ggtgctcatt 900 caaaagaccg acaccggggt gtcgctccag acctatgatg acttgttagc caaagactgc 960 cactgcata 969

<210> 218 <211> 323 <212> PRT

- 378 046387 <213> Artificial sequence <220>

<221> source <223> /note=description of artificial sequence: synthetic polypeptide” <400> 218

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

5 1015

Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 20 2530

His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 35 4045

Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 50 5560

Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 65 70 7580

Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro 85 9095

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

100 105110

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

115 120125

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

130 135140

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

145 150 155160

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

165 170175

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

180 185190

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

195 200205

Ser Pro Gly Ala Arg Asp Gly Asp His Cys Pro Leu Gly Pro Gly Arg

210 215220

- 379 046387

Cys Cys Arg Leu His Thr Val Arg Ala Ser Leu Glu Asp Leu Gly Trp

225 230 235240

Ala Asp Trp Val Leu Ser Pro Arg Glu Val Gln Val Thr Met Cys Ile

245 250255

Gly Ala Cys Pro Ser Gln Phe Arg Ala Ala Asn Met His Ala Gln Ile

260 265270

Lys Thr Ser Leu His Arg Leu Lys Pro Asp Thr Val Pro Ala Pro Cys

275 280285

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

290 295300

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

305 310 315320

His Cys Ile <210> 219 <211> 211 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 219

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

5 1015

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

2530

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 35 4045

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 50 5560

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu AsnGly

70 7580

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

9095

- 380 046387

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

100 105110

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

115 120125

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

130 135140

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

145 150 155160

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

165 170175

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

180 185190

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

195 200205

Pro Gly Lys

210 <210> 220 <211> 210 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 220

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

5 1015

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 20 2530

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 35 4045

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 50 5560

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 65 70 7580

- 381 046387

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala 8590

Leu Pro Ala Pro Ile

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

100 105110

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

115 120125

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

130 135140

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

145 150 155160

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

165 170175

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

180 185190

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

195 200205

Pro Gly

210 <210> 221 <211> 957 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide

<400> 221 ggcccgtcag tcttcctctt ccccccaaaa cccaaggaca ccctcatgat ctcccggacc 60 cctgaggtca catgcgtggt ggtggacgtg agccacgaag accctgaggt caagttcaac 120 tggtacgtgg acggcgtgga ggtgcataat gccaagacaa agccgcggga ggagcagtac 180 aacagcacgt accgtgtggt cagcgtcctc accgtcctgc accaggactg gctgaatggc 240 aaggagtaca agtgcaaggt ctccaacaaa gccctcccag ccccatcga gaaaaccatc 300 tccaaagcca aagggcagcc ccgagaacca caggtgtaca ccctgccccc atcccggggag 360 gagatgacca agaaccaggt cagcctgacc tgcctggtca aaggcttcta tccagcgac 420 atcgccgtgg agggggagag caatggggcag ccggagaaca actacgacac cacgcctccc 480

- 382 046387

gtgctggact ccgacggctc cttcttcctc tatagcgacc tcaccgtgga caagagcagg 540 tggcagcagg ggaacgtctt ctcatgctcc gtgatgcatg aggctctgca caaccactac 600 acgcagaaga gcctctccct gtctccggggt ggagaaccact gtccgctcgg gccgggcgt 660 tgctgccgtc tgcacacggt ccgcgcgtcg ctggaagacc tgggctgggc cgattgggtg 720 ctgtcgccac gggaggtgca agtgaccatg tgcatcggcg cgtgcccgag ccagttccgg 780 gcggcaaaca tgcacgcgca gatcaagacg agcctgcacc gcctgaagcc cgacacggtg 840 ccagcgccct gctgcgtgcc cgccagctac aatcccatgg tgctcattca aaagaccgac 900 accggggtgt cgctccagac ctatgatgac ttgttagcca aagactgcca ctgcata 957

<210> 222 <211> 319 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 222

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

5 1015

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 20 2530

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 35 4045

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 50 5560

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 65 70 7580

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 85 9095

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

100 105110

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

115 120125

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

130 135140

- 383 046387

Trp Glu Ser Asn Gly Gln Pro Glu

145 150

Asn Asn Tyr Asp Thr Thr Pro Pro

155 160

Val

Leu

Asp

Ser

Asp 165

Gly

Ser

Phe

Phe

Leu

170

Tyr

Ser

Asp

Leu

Thr

175

Val

Asp

Lys

Ser

Arg 180

Trp

Gln

Gln

Gly

Asn

185

Val

Phe

Ser

Cys

Ser

190

Val

Met

His

Glu

Ala

195

Leu

His

Asn

His

Tyr

200

Thr

Gln

Lys

Ser

Leu

205

Ser

Leu

Ser

Pro Gly Gly Asp His

Cys

210

Pro Leu Gly Pro Gly Arg Cys Cys Arg Leu

215 220

His Thr Val Arg Ala

225

Ser Leu Glu Asp Leu Gly Trp Ala Asp Trp Val

230 235 240

Leu Ser Pro Arg Glu Val Gln Val Thr Met Cys

245 250

Ile Gly Ala Cys Pro

255

Ser Gln Phe Arg Ala Ala Asn Met His Ala Gln

260 265

Ile Lys Thr Ser Leu

270

His Arg Leu Lys Pro Asp Thr Val

275 280

Pro Ala Pro Cys Cys Val Pro Ala

285

Ser Tyr Asn Pro Met Val

290

Leu Ile Gln Lys Thr Asp Thr Gly Val

295 300

Ser

Leu Gln Thr Tyr Asp Asp Leu Leu Ala Lys Asp Cys His Cys Ile

305 310 315 <210> 223 <211> 633 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide <400> 223

ggcccgtcag tcttcctctt ccccccaaaa cccaaggaca ccctcatgat ctcccggacc 60 cctgaggtca catgcgtggt ggtggacgtg agccacgaag accctgaggt caagttcaac 120 tggtacgtgg acggcgtgga ggtgcataat gccaagacaa agccgcggga ggagcagtac 180

- 384 046387

aacagcacgt accgtgtggt cagcgtcctc accgtcctgc accaggactg gctgaatggc 240 aaggagtaca agtgcaaggt ctccaacaaa gccctcccag ccccatcga gaaaaccatc 300 tccaaagcca aagggcagcc ccgagaacca caggtgtaca ccctgccccc atcccggaag 360 gagatgacca agaaccaggt cagcctgacc tgcctggtca aaggcttcta tccagcgac 420 atcgccgtgg agggggagag caatggggcag ccggagaaca actacaagac cacgcctccc 480 gtgctgaagt ccgacggctc cttcttcctc tatagcaagc tcaccgtgga caagagcagg 540 tggcagcagg ggaacgtctt ctcatgctcc gtgatgcatg aggctctgca caaccactac 600 acgcagaaga gcctctccct gtctccggggt aaa 633

<210> 224 <211> 1032 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide

<400> 224 atggacatga gggtgcccgc tcagctcctg gggctcctgc tgctgtggct gagaggtgcg 60 cgctgtggcc cgtcagtctt cctcttcccc ccaaaaccca aggacaccct catgatctcc 120 cggacccctg aggtcacatg cgtggtggtg gacgtgagcc acgaagaaccc tgaggtcaag 180 ttcaactggt acgtggacgg cgtggaggtg cataatgcca agacaaagcc gcgggaggag 240 cagtacaaca gcacgtaccg tgtggtcagc gtcctcaccg tcctgcacca ggactggctg 300 aatggcaagg agtacaagtg caaggtctcc aacaaagccc tccagcccc catcgagaaa 360 accatctcca aagccaaagg gcagccccga gaaccacagg tgtacaccct gcccccatcc 420 cgggaggaga tgaccaagaa ccaggtcagc ctgacctgcc tggtcaaagg cttctatccc 480 agcgacatcg ccgtggagtg ggagagcaat gggcagccgg agaacaacta cgacaccacg 540 cctcccgtgc tggactccga cggctccttc ttcctctata gcgacctcac cgtggacaag 600 agcaggtggc agcaggggaa cgtcttctca tgctccgtga tgcatgaggc tctgcacaac 660 cactacacgc agaagagcct ctccctgtct ccgggtgcgc gcgacggaga ccactgtccg 720 ctcgggcccg ggcgttgctg ccgtctgcac acggtccgcg cgtcgctgga agacctggggc 780 tggggccgatt gggtgctgtc gccacggggag gtgcaagtga ccatgtgcat cggcgcgtgc 840 ccgagccagt tccggggcggc aaacatgcac gcgcagatca agacgagcct gcaccgcctg 900 aagcccgaca cggtgccagc gccctgctgc gtgcccgcca gctacaatcc catggtgctc 960 attcaaaaga ccgacaccgg ggtgtcgctc cagacctatg atgacttgtt agccaaagac 1020 tgccactgca ta 1032

- 385 046387 <210> 225 <211> 322 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: polypeptide <400> 225

Gly Pro Ser Val Phe Leu Phe Pro 1 5

Pro Lys Pro Lys Asp Thr Leu Met

15

Ile Ser Arg Thr Pro Glu Val Thr

Cys Val Val Val Asp Val Ser His 25 30

Glu Asp Pro Glu Val Lys Phe Asn

40

Trp Tyr Val Asp Gly Val Glu Val 45

His Asn Ala Lys Thr Lys Pro Arg

55

Glu Glu Gln Tyr Asn Ser Thr Tyr 60

Arg Val Val Ser Val Leu Thr Val 65 70

Leu His Gln Asp Trp Leu Asn Gly

80

Lys Glu Tyr Lys Cys Lys Val Ser 85

Asn Lys Ala Leu Pro Ala Pro Ile

95

Glu Lys Thr Ile Ser Lys Ala Lys

100

Gly Gln Pro Arg Glu Pro Gln Val

105 110

Tyr Thr Leu Pro Pro Ser Arg Glu

115 120

Glu Met Thr Lys Asn Gln Val Ser

125

Leu Thr Cys Leu Val Lys Gly Phe

130 135

Tyr Pro Ser Asp Ile Ala Val Glu

140

Trp Glu Ser Asn Gly Gln Pro Glu

145 150

Asn Asn Tyr Asp Thr Thr Pro Pro

155 160

Val Leu Asp Ser Asp Gly Ser Phe

165

Phe Leu Tyr Ser Asp Leu Thr Val

170 175

Asp Lys Ser Arg Trp Gln Gln Gly

180

Asn Val Phe Ser Cys Ser Val Met

185 190

His Glu Ala Leu His Asn His Tyr

195 200

Thr Gln Lys Ser Leu Ser Leu Ser

205

- 386 046387

Pro Gly Ala Arg Asp Gly Asp His Cys Pro Leu Gly Pro Gly Arg Cys

210 215220

Cys Arg Leu His Thr Val Arg Ala Ser Leu Glu Asp Leu Gly Trp Ala

225 230 235240

Asp Trp Val Leu Ser Pro Arg Glu Val Gln Val Thr Met Cys Ile Gly

245 250255

Ala Cys Pro Ser Gln Phe Arg Ala Ala Asn Met His Ala Gln Ile Lys

260 265270

Thr Ser Leu His Arg Leu Lys Pro Asp Thr Val Pro Ala Pro Cys Cys

275 280285

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

290 295300

Gly Val Ser Leu Gln Thr Tyr Asp Asp Leu Leu Ala Lys Asp Cys His

305 310 315320

Cys Ile <210> 226 <211> 211 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 226

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

5 1015

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 20 2530

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 35 4045

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 50 5560

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 65 70 7580

- 387 046387

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala 85 90

Leu Pro Ala Pro Ile

Glu Lys Thr Ile

Ser

100

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

105 110

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

115 120125

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

130 135140

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

145 150 155160

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

165 170175

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

180 185190

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

195 200205

Pro Gly Lys

210 <210> 227 <211> 210 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 227

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

5 1015

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

2530

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 35 4045

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

5560

- 388 046387

Arg 65

Val

Val

Ser

Val

Leu 70

Thr

Val

Leu

His

Gln 75

Asp

Trp

Leu

Asn

Gly 80

Lys

Glu

Tyr

Lys

Cys 85

Lys

Val

Ser

Asn

Lys 90

Ala

Leu

Pro

Ala

Pro 95

Ile

Glu

Lys

Thr

Ile

100

Ser

Lys

Ala

Lys

Gly 105

Gln

Pro

Arg

Glu

Pro

110

Gln

Val

Cys

Thr

Leu

115

Pro

Pro

Ser

Arg

Glu

120

Glu

Met

Thr

Lys

Asn

125

Gln

Val

Ser

Leu

Thr

130

Cys

Leu

Val

Lys

Gly 135

Phe

Tyr

Pro

Ser

Asp 140

Ile

Ala

Val

Glu

Trp 145

Glu

Ser

Asn

Gly

Gln

150

Pro

Glu

Asn

Asn

Tyr 155

Asp

Thr

Thr

Pro

Pro

160

Val

Leu

Asp

Ser

Asp 165

Gly

Ser

Phe

Phe

Leu

170

Tyr

Ser

Asp

Leu

Thr

175

Val

Asp

Lys

Ser

Arg 180

Trp

Gln

Gln

Gly

Asn

185

Val

Phe

Ser

Cys

Ser

190

Val

Met

His

Glu

Ala

195

Leu

His

Asn

His

Tyr 200

Thr

Gln

Lys

Ser

Leu

205

Ser

Leu

Ser

Pro Gly

210 <210> 228 <211> 1023 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide <400> 228

atggacatga gggtgcccgc tcagctcctg gggctcctgc tgctgtggct gagaggtgcg 60 cgctgtggcc cgtcagtctt cctcttcccc ccaaaaccca aggacaccct catgatctcc 120 cggacccctg aggtcacatg cgtggtggtg gacgtgagcc acgaagaaccc tgaggtcaag 180 ttcaactggt acgtggacgg cgtggaggtg cataatgcca agacaaagcc gcgggaggag 240 cagtacaaca gcacgtaccg tgtggtcagc gtcctcaccg tcctgcacca ggactggctg 300

- 389 046387

aatggcaagg agtacaagtg caaggtctcc aacaaagccc tccagcccc catcgagaaa 360 accatctcca aagccaaagg gcagccccga gaaccacagg tgtgcaccct gcccccatcc 420 cgggaggaga tgaccaagaa ccaggtcagc ctgacctgcc tggtcaaagg cttctatccc 480 agcgacatcg ccgtggagtg ggagagcaat gggcagccgg agaacaacta cgacaccacg 540 cctcccgtgc tggactccga cggctccttc ttcctctata gcgacctcac cgtggacaag 600 agcaggtggc agcaggggaa cgtcttctca tgctccgtga tgcatgaggc tctgcacaac 660 cactacacgc agaagagcct ctccctgtct ccggggtggag accactgtcc gctcgggccc 720 gggcgttgct gccgtctgca cacggtccgc gcgtcgctgg aagacctggg ctggggccgat 780 tgggtgctgt cgccacggga ggtgcaagtg accatgtgca tcggcgcgtg cccgagccag 840 ttccggggcgg caaacatgca cgcgcagatc aagacgagcc tgcaccgcct gaagcccgac 900 acggtgccag cgccctgctg cgtgcccgcc agctacaatc ccatggtgct cattcaaaag 960 accgacaccg ata gggtgtcgct ccagacctat gatgacttgt tagccaaaga ctgccactgc 1020 1023

<210> 229 <211> 319 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 229

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

5 1015

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 20 2530

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 35 4045

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 50 5560

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 65 70 7580

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 85 9095

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

- 390 046387

100 105110

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

115 120125

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

130 135140

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

145 150 155160

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

165 170175

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

180 185190

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

195 200205

Pro Gly Gly Asp His Cys Pro Leu Gly Pro Gly Arg Cys Cys Arg Leu

210 215220

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

225 230 235240

Leu Ser Pro Arg Glu Val Gln Val Thr Met Cys Ile Gly Ala Cys Pro

245 250255

Ser Gln Phe Arg Ala Ala Asn Met His Ala Gln Ile Lys Thr Ser Leu

260 265270

His Arg Leu Lys Pro Asp Thr Val Pro Ala Pro Cys Cys Val Pro Ala

275 280285

Ser Tyr Asn Pro Met Val Leu Ile Gln Lys Thr Asp Thr Gly Val Ser

290 295300

Leu Gln Thr Tyr Asp Asp Leu Leu Ala Lys Asp Cys His Cys Ile

305 310315 <210> 230 <211> 633 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic

- 391 046387 polynucleotide

<400> 230 ggcccgtcag tcttcctctt ccccccaaaa cccaaggaca ccctcatgat ctcccggacc 60 cctgaggtca catgcgtggt ggtggacgtg agccacgaag accctgaggt caagttcaac 120 tggtacgtgg acggcgtgga ggtgcataat gccaagacaa agccgcggga ggagcagtac 180 aacagcacgt accgtgtggt cagcgtcctc accgtcctgc accaggactg gctgaatggc 240 aaggagtaca agtgcaaggt ctccaacaaa gccctcccag ccccatcga gaaaaccatc 300 tccaaagcca aagggcagcc ccgagaacca caggtgtaca ccctgccccc atgccggaag 360 gagatgacca agaaccaggt cagcctgacc tgcctggtca aaggcttcta tccagcgac 420 atcgccgtgg agggggagag caatggggcag ccggagaaca actacaagac cacgcctccc 480 gtgctgaagt ccgacggctc cttcttcctc tatagcaagc tcaccgtgga caagagcagg 540 tggcagcagg ggaacgtctt ctcatgctcc gtgatgcatg aggctctgca caaccactac 600 acgcagaaga gcctctccct gtctccggggt aaa 633

<210> 231 <211> 966 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=description of artificial sequence: synthetic polynucleotide <400> 231

ggcccgtcag tcttcctctt ccccccaaaa cccaaggaca ccctcatgat ctcccggacc 60 cctgaggtca catgcgtggt ggtggacgtg agccacgaag accctgaggt caagttcaac 120 tggtacgtgg acggcgtgga ggtgcataat gccaagacaa agccgcggga ggagcagtac 180 aacagcacgt accgtgtggt cagcgtcctc accgtcctgc accaggactg gctgaatggc 240 aaggagtaca agtgcaaggt ctccaacaaa gccctcccag ccccatcga gaaaaccatc 300 tccaaagcca aagggcagcc ccgagaacca caggtgtgca ccctgccccc atcccggggag 360 gagatgacca agaaccaggt cagcctgacc tgcctggtca aaggcttcta tccagcgac 420 atcgccgtgg agggggagag caatggggcag ccggagaaca actacgacac cacgcctccc 480 gtgctggact ccgacggctc cttcttcctc tatagcgacc tcaccgtgga caagagcagg 540 tggcagcagg ggaacgtctt ctcatgctcc gtgatgcatg aggctctgca caaccactac 600 acgcagaaga gcctctccct gtctccggggt gcgcgcgacg gagaccactg tccgctcggg 660 cccggggcgtt gctgccgtct gcacacggtc cgcgcgtcgc tggaagacct gggctgggcc 720 gattgggtgc tgtcgccacg ggaggtgcaa gtgaccatgt gcatcggcgc gtgcccgagc 780

- 392 046387

cagttccgggg cggcaaacat gcacgcgcag atcaagacga gcctgcaccg cctgaagccc 840 gacacggtgc cagcgccctg ctgcgtgccc gccagctaca atcccatggt gctcattcaa 900 aagaccgaca ccggggtgtc gctccagacc tatgatgact tgttagccaa agactgccac 960 tgcata 966

<210> 232 <211> 322 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 232

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

5 1015

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 20 2530

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 35 4045

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 50 5560

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 65 70 7580

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 85 9095

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

100 105110

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

115 120125

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

130 135140

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

145 150 155160

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

165 170175

- 393 046387

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

180 185190

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

195 200205

Pro Gly Ala Arg Asp Gly Asp His Cys Pro Leu Gly Pro Gly Arg Cys

210 215220

Cys Arg Leu His Thr Val Arg Ala Ser Leu Glu Asp Leu Gly Trp Ala

225 230 235240

Asp Trp Val Leu Ser Pro Arg Glu Val Gln Val Thr Met Cys Ile Gly

245 250255

Ala Cys Pro Ser Gln Phe Arg Ala Ala Asn Met His Ala Gln Ile Lys

260 265270

Thr Ser Leu His Arg Leu Lys Pro Asp Thr Val Pro Ala Pro Cys Cys

275 280285

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

290 295300

Gly Val Ser Leu Gln Thr Tyr Asp Asp Leu Leu Ala Lys Asp Cys His

305 310 315320

Cys Ile <210> 233 <211> 216 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 233

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

5 1015

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

2530

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

4045

- 394 046387

Val Asp Gly Val Glu Val His Asn Ala Lys Thr

55

Lys Pro Arg Glu Glu

Gln 65

Tyr

Gly

Ser

Thr

Tyr 70

Arg

Val

Val

Ser

Val 75

Leu

Thr

Val

Leu

His 80

Gln

Asp

Trp

Leu

Asn 85

Gly

Lys

Glu

Tyr

Lys 90

Cys

Lys

Val

Ser

Asn 95

Lys

Ala

Leu

Pro

Ala

100

Pro

Ile

Glu

Lys

Thr

105

Ile

Ser

Lys

Ala

Lys 110

Gly

Gln

Pro

Arg

Glu

115

Pro

Gln

Val

Thr

Thr

120

Leu

Pro

Pro

Ser

Arg 125

Glu

Glu

Met

Thr

Lys 130

Asn

Gln

Val

Ser

Leu

135

Thr

Cys

Leu

Val

Lys 140

Gly

Phe

Tyr

Pro

Ser

145

Asp

Ile

Ala

Val

Glu

150

Trp

Glu

Ser

Asn

Gly 155

Gln

Pro

Glu

Asn

Asn

160

Tyr

Asp

Thr

Thr

Pro

165

Pro

Val

Leu

Asp

Ser

170

Asp

Gly

Ser

Phe

Phe

175

Leu

Tyr

Ser

Asp

Leu

180

Thr

Val

Asp

Lys

Ser

185

Arg

Trp

Gln

Gln

Gly 190

Asn

Val

Phe

Ser

Cys

195

Ser

Val

Met

His

Glu

200

Ala

Leu

His

Asn

His

205

Tyr

Thr

Gln

Lys Ser Leu Ser Leu Ser Pro Gly

210 215 <210> 234 <211> 984 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide <400> 234

gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 180 ccgcgggagg agcagtacgg cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 240

- 395 046387

caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 ccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgaccacc 360 ctgcccccat cccggggaga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tggggagagca atggggcagcc ggagaacaac 480 tacgacacca cgcctcccgt gctggactcc gacggctcct tcttcctcta tagcgacctc 540 accgtggac agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccgggtgc gcgcaacgga 660 gaccactgtc cgctcgggcc cggggcgttgc tgccgtctgc acacggtccg cgcgtcgctg 720 gaagacctgg gctggggccga ttgggtgctg tcgccacggg aggtgcaagt gaccatgtgc 780 atcggcgcgt gccccgagcca gttccggggcg gcaaacatgc acgcgcagat caagacgagc 840 ctgcaccgcc tgaagcccga cacggtgcca gcgccctgct gcgtgcccgc cagctacaat 900 cccatggtgc tcattcaaaa gaccgacacc ggggtgtcgc tccagaccta tgatgacttg 960 ttagccaaag actgccactg cata 984

<210> 235 <211> 328 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 235

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

5 1015

Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 2530

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

4045

Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 5560

Gln Tyr Gly Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 7580

Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 9095

- 396 046387

Ala Leu Pro Ala Pro Ile Glu Lys Thr

100 105

Pro Arg Glu Pro Gln Val Thr Thr Leu

115 120

Thr Lys Asn Gln Val Ser Leu Thr Cys

130 135

Ser Asp Ile Ala Val Glu Trp Glu Ser

145 150

Tyr Asp Thr Thr Pro Pro Val Leu Asp

165

Tyr Ser Asp Leu Thr Val Asp Lys Ser

180 185

Phe Ser Cys Ser Val Met His Glu Ala

195 200

Lys Ser Leu Ser Leu Ser Pro Gly Ala

210 215

Leu Gly Pro Gly Arg Cys Cys Arg Leu

225 230

Glu Asp Leu Gly Trp Ala Asp Trp Val

245

Val Thr Met Cys Ile Gly Ala Cys Pro

260 265

Met His Ala Gln Ile Lys Thr Ser Leu

275 280

Val Pro Ala Pro Cys Cys Val Pro Ala

290 295

Ile Gln Lys Thr Asp Thr Gly Val Ser

305 310

Ser Lys Ala Lys Gly Gln

110

Pro Ser Arg Glu Glu Met

125

Val Lys Gly Phe Tyr Pro

140

Gly Gln Pro Glu Asn Asn

155 160

Asp Gly Ser Phe Phe Leu

175

Trp Gln Gln Gly Asn Val

190

His Asn His Tyr Thr Gln

205

Asn Gly Asp His Cys Pro

220

Thr Val Arg Ala Ser Leu

235 240

Ser Pro Arg Glu Val Gln

255

Gln Phe Arg Ala Ala Asn

270

Arg Leu Lys Pro Asp Thr

285

Tyr Asn Pro Met Val Leu

300

Gln Thr Tyr Asp Asp Leu

315 320

Leu Ala Lys Asp Cys His Cys Ile

325 <210> 236 <211> 216 <212> PRT

- 397 046387 <213> Artificial sequence <220>

<221> source <223> /note=description of artificial sequence: synthetic polypeptide” <400> 236

Ala Pro Glu Leu 1

Leu Gly Gly Pro 5

Ser Val Phe Leu

Phe Pro Pro Lys 15

Pro Lys Asp Thr

Leu Met Ile Ser

Arg Thr Pro Glu 25

Val Thr Cys Val 30

Val Val Asp Val

Ser His Glu Asp 40

Pro Glu Val Lys

Phe Asn Trp Tyr 45

Val Asp Gly Val 50

Glu Val His Asn

Ala Lys Thr Lys 60

Pro Arg Glu Glu

Gln Tyr Gly Ser 65

Thr Tyr Arg Val 70

Val Ser Val Leu

Thr Val Leu His

Gln Asp Trp Leu

Asn Gly Lys Glu 85

Tyr Lys Cys Lys 90

Val Ser Asn Lys

Ala Leu Pro Ala

100

Pro Ile Glu Lys

Thr Ile Ser Lys 105

Ala Lys Gly Gln 110

Pro Arg Glu Pro

115

Gln Val Thr Thr

120

Leu Pro Pro Ser

Arg Glu Glu Met 125

Thr Lys Asn Gln 130

Val Ser Leu Thr

135

Cys Leu Val Lys

140

Gly Phe Tyr Pro

Ser Asp Ile Ala 145

Val Glu Trp Glu

150

Ser Asn Gly Gln

155

Pro Glu Asn Asn

160

Tyr Asp Thr Thr

Pro Pro Val Leu 165

Asp Ser Asp Gly 170

Ser Phe Phe Leu

175

Tyr Ser Asp Leu

180

Thr Val Asp Lys

Ser Arg Trp Gln 185

Gln Gly Asn Val

190

Phe Ser Cys Ser

195

Val Met His Glu

200

Ala Leu His Asn

His Tyr Thr Gln 205

Lys Ser Leu Ser Leu Ser Pro Gly

210 215

- 398 046387 <210> 237 <211> 1044 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide <400> 237

gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 180 ccgcgggagg agcagtacgg cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 ccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgaccacc 360 ctgcccccat cccggggaga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tggggagagca atggggcagcc ggagaacaac 480 tacgacacca cgcctcccgt gctggactcc gacggctcct tcttcctcta tagcgacctc 540 accgtggac agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccggggtgg aggtggtgga 660 tccggagaggcg gtggaagcgg aggtggtgga tctggaggcg gtggaagcgc gcgcaacgga 720 gaccactgtc cgctcgggcc cggggcgttgc tgccgtctgc acacggtccg cgcgtcgctg 780 gaagacctgg gctggggccga ttgggtgctg tcgccacggg aggtgcaagt gaccatgtgc 840 atcggcgcgt gcccgagcca gttccggggcg gcaaacatgc acgcgcagat caagacgagc 900 ctgcaccgcc tgaagcccga cacggtgcca gcgccctgct gcgtgcccgc cagctacaat 960 cccatggtgc tcattcaaaa gaccgacacc ggggtgtcgc tccagaccta tgatgacttg 1020 ttagccaaag actgccactg cata 1044

<210> 238 <211> 348 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=description of artificial sequence: synthetic polypeptide <400> 238

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

5 10 15

- 399 046387

Pro

Val

Val

Gln 65

Gln

Ala

Pro

Thr

Ser 145

Tyr

Tyr

Phe

Lys

Gly 225

Asp

Arg

Lys Asp Thr Leu Met

Ile Ser Arg Thr Pro 25

Glu Val Thr Cys Val 30

Val Asp Val Ser His 35

Asp Gly Val Glu Val 50

Tyr Gly Ser Thr Tyr

Asp Trp Leu Asn Gly

Leu Pro Ala Pro Ile

100

Arg Glu Pro Gln Val 115

Lys Asn Gln Val Ser 130

Asp Ile Ala Val Glu

150

Asp Thr Thr Pro Pro

165

Ser Asp Leu Thr Val

180

Ser Cys Ser Val Met

195

Ser Leu Ser Leu Ser 210

Ser Gly Gly Gly Gly

230

His Cys Pro Leu Gly

245

Ala Ser Leu Glu Asp 260

Glu Asp Pro Glu Val 40

His Asn Ala Lys Thr 55

Arg Val Val Ser Val 75

Lys Glu Tyr Lys Cys

Glu Lys Thr Ile Ser 105

Thr Thr Leu Pro Pro

120

Leu Thr Cys Leu Val 135

Trp Glu Ser Asn Gly

155

Val Leu Asp Ser Asp

170

Asp Lys Ser Arg Trp 185

His Glu Ala Leu His

200

Pro Gly Gly Gly Gly 215

Ser Gly Gly Gly Gly

235

Pro Gly Arg Cys Cys

250

Leu Gly Trp Ala Asp 265

Lys Phe Asn Trp Tyr 45

Lys Pro Arg Glu Glu 60

Leu Thr Val Leu His

Lys Val Ser Asn Lys

Lys Ala Lys Gly Gln

110

Ser Arg Glu Glu Met

125

Lys Gly Phe Tyr Pro 140

Gln Pro Glu Asn Asn

160

Gly Ser Phe Phe Leu

175

Gln Gln Gly Asn Val

190

Asn His Tyr Thr Gln

205

Gly Ser Gly Gly Gly 220

Ser Ala Arg Asn Gly

240

Arg Leu His Thr Val

255

Trp Val Leu Ser Pro 270

- 400 046387

Arg

Glu

Val

275

Gln

Val

Thr

Met

Cys 280

Ile

Gly

Ala

Cys

Pro

285

Ser

Gln

Phe

Arg

Ala

290

Ala

Asn

Met

His

Ala

295

Gln

Ile

Lys

Thr

Ser

300

Leu

His

Arg

Leu

Lys

305

Pro

Asp

Thr

Val

Pro

310

Ala

Pro

Cys

Cys

Val

315

Pro

Ala

Ser

Tyr

Asn

320

Pro

Met

Val

Leu

Ile

325

Gln

Lys

Thr

Asp

Thr

330

Gly

Val

Ser

Leu

Gln

335

Thr

Tyr

Asp

Asp

Leu

340

Leu

Ala

Lys

Asp

Cys 345

His

Cys

Ile <210> 239 <211> 996 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide <400> 239

gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 180 ccgcgggagg agcagtacgg cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 ccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgaccacc 360 ctgcccccat cccggggaga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tggggagagca atggggcagcc ggagaacaac 480 tacgacacca cgcctcccgt gctggactcc gacggctcct tcttcctcta tagcgacctc 540 accgtggac agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccggggtgg aggtggtgga 660 gcgcgcaacg gagaccactg tccgctcggg cccggggcgtt gctgccgtct gcacacggtc 720 cgcgcgtcgc tggaagacct gggctgggcc gattgggtgc tgtcgccacg ggaggtgcaa 780 gtgaccatgt gcatcggcgc gtgcccgagc cagttccgggg cggcaaacat gcacgcgcag 840 atcaagacga gcctgcaccg cctgaagccc gacacggtgc cagcgccctg ctgcgtgccc 900

- 401 046387 gccagctaca atcccatggt gctcattcaa aagaccgaca ccggggtgtc gctccagacc 960 tatgatgact tgttagccaa agactgccac tgcata

996 <210> 240 <211> 332 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 240

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

5 1015

Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 2530

Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 4045

Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 5560

Gln Tyr Gly Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 7580

Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 9095

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

100 105110

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

115 120125

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

130 135140

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

145 150 155160

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

165 170175

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

180 185190

- 402 046387

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

195 200205

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

210 215220

Asp His Cys Pro Leu Gly Pro Gly Arg Cys Cys Arg Leu His Thr Val

225 230 235240

Arg Ala Ser Leu Glu Asp Leu Gly Trp Ala Asp Trp Val Leu Ser Pro

245 250255

Arg Glu Val Gln Val Thr Met Cys Ile Gly Ala Cys Pro Ser Gln Phe

260 265270

Arg Ala Ala Asn Met His Ala Gln Ile Lys Thr Ser Leu His Arg Leu

275 280285

Lys Pro Asp Thr Val Pro Ala Pro Cys Cys Val Pro Ala Ser Tyr Asn

290 295300

Pro Met Val Leu Ile Gln Lys Thr Asp Thr Gly Val Ser Leu Gln Thr

305 310 315320

Tyr Asp Asp Leu Leu Ala Lys Asp Cys His Cys Ile

325330 <210> 241 <211> 2145 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide

<400> 241 gatgcacaca agagtgaggt tgctcatcga tttaaagatt tggggagaaga aaatttcaaa 60 gccttggtgt tgattgcctt tgctcagtat cttcagcagt gtccattga agatcatgta 120 aaattagtga atgaagtaac tgaatttgca aaaacatgtg ttgctgatga gtcagctgaa 180 aattgtgaca aatcacttca tacccttttt ggagacaaat tatgcacagt tgcaactctt 240 cgtgaaacct atggtgaaat ggctgactgc tgtgcaaaac aagaacctga gagaaatgaa 300 tgcttcttgc aacacaaaga tgacaaccca aacctccccc gattggtgag accagaggtt 360 gatgtgatgt gcactgcttt tcatgacaat gaagagacat ttttgaaaaa atacttatat 420 gaaattgcca gaagacatcc ttacttttat gccccggaac tccttttctt tgctaaaagg 480

- 403 046387 tataaagctg cttttacaga atgttgccaa gctgctgata aagctgcctg cctgttgcca540 aagctcgatg aacttcggga tgaagggaag gcttcgtctg ccaaacagag actcaagtgt600 gccagtctcc aaaaatttgg agaaagagct ttcaaagcat ggg cagtagc tcgcctgagc660 cagagatttc ccaaagctga gtttgcagaa gtttccaagt tagtgacaga tcttaccaaa720 gtccacacgg aatgctgcca tggagatctg cttgaatgtg ctgatgacag ggcggacctt780 gccaagtata tctgtgaaaa tcaagattcg atctccagta aact gaagga atgctgtgaa840 aaacctctgt tggaaaaatc ccactgcatt gccgaagtgg aaaatgatga gatgcctgct900 gacttgcctt cattagctgc tgattttgtt gaaagtaagg atgtttgcaa aaactatgct960 gaggcaaagg atgtcttcct gggcatgttt ttgtatgaat atgcaagaag gcatcctgat1020 tactctgtcg tgctgctgct gagacttgcc aagacatatg aaaccactct agagaagtgc1080 tgtgccgctg cagatcctca tgaatgctat gccaaagtgt tcgat gaatt taaacctctt1140 gtggaagagc ctcagaattt aatcaaacaa aattgtgagc tttttgagca gcttggagag1200 tacaaattcc agaatgcgct attagttcgt tacaccaaga aagtacccca agtgtcaact1260 ccaactcttg tagaggtctc aagaaaccta ggaaaagtgg gca gcaaatg ttgtaaacat1320 cctgaagcaa aaagaatgcc ctgtgcagaa gactatctat ccgtggtcct gaaccagtta1380 tgtgtgttgc atgagaaaac gccagtaagt gacagagtca ccaaatgctg cacagaatcc1440 ttggtgaaca ggcgaccatg cttttcagct ctggaagtcg atgaaacata cgttcccaaa1500 gagtttaatg ctgaaacatt caccttccat gcagatatat gcacactttc tgagaaggag1560 agacaaatca agaaacaaac tgcacttgtt gagctcgtga aacacaagcc caaggcaaca16 19 gcagctcag1800 cagggaagcg cgcgcgacgg agaccactgt ccgctcgggc ccgggcgttg ctgccgtctg1860 cacacggtcc gcgcgtcgct ggaagacctg ggctgggccg attgggtgct gtcgccacgg1920 gaggtgcaag tgaccatgtg catcggcgc g tgcccgagcc agttccgggc ggcaaacatg1980 cacgcgcaga tcaagacgag cctgcaccgc ctgaagcccg acacggtgcc agcgccctgc2040 tgcgtgcccg ccagctacaa tcccatggtg ctcattcaaa agaccgacac cggggtgtcg2100 ctccagacct atgatgactt gttagccaaa gactgccact gcata2145 <210> 242 <211> 715 <212> PRT <213> Artificial sequence

- 404 046387 <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 242

Asp Ala His Lys Ser Glu Val Ala His Arg Phe Lys Asp Leu Gly Glu

5 10 15

Glu Asn Phe Lys

Ala Leu Val Leu

Ile Ala Phe Ala 25

Gln Tyr Leu Gln 30

Gln Cys Pro Phe 35

Glu Asp His Val 40

Lys Leu Val Asn

Glu Val Thr Glu 45

Phe Ala Lys Thr 50

Cys Val Ala Asp 55

Glu Ser Ala Glu

Asn Cys Asp Lys

Ser Leu His Thr 65

Leu Phe Gly Asp 70

Lys Leu Cys Thr 75

Val Ala Thr Leu

Arg Glu Thr Tyr Gly Glu Met Ala Asp Cys Cys Ala Lys Gln Glu Pro 85 9095

Glu Arg Asn Glu Cys Phe Leu Gln His Lys Asp Asp Asn Pro Asn Leu

100 105110

Pro Arg Leu Val Arg Pro Glu Val Asp Val Met Cys Thr Ala Phe His

115 120125

Asp Asn Glu Glu Thr Phe Leu Lys Lys Tyr Leu Tyr Glu Ile Ala Arg

130 135140

Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu Leu Phe Phe Ala Lys Arg

145 150 155160

Tyr Lys Ala Ala Phe Thr Glu Cys Cys Gln Ala Ala Asp Lys Ala Ala

165 170175

Cys Leu Leu Pro Lys Leu Asp Glu Leu Arg Asp Glu Gly Lys Ala Ser

180 185190

Ser Ala Lys Gln Arg Leu Lys Cys Ala Ser Leu Gln Lys Phe Gly Glu

195 200205

Arg Ala Phe Lys Ala Trp Ala Val Ala Arg Leu Ser Gln Arg Phe Pro

210 215220

Lys Ala Glu Phe Ala Glu Val Ser Lys Leu Val Thr Asp Leu Thr Lys

- 405 046387

225 230 235240

Val His Thr Glu Cys Cys His Gly Asp Leu Leu Glu Cys Ala Asp Asp

245 250255

Arg Ala Asp Leu Ala Lys Tyr Ile Cys Glu Asn Gln Asp Ser Ile Ser

260 265270

Ser Lys Leu Lys Glu Cys Cys Glu Lys Pro Leu Leu Glu Lys Ser His

275 280285

Cys Ile Ala Glu Val Glu Asn Asp Glu Met Pro Ala Asp Leu Pro Ser

290 295300

Leu Ala Ala Asp Phe Val Glu Ser Lys Asp Val Cys Lys Asn Tyr Ala

305 310 315320

Glu Ala Lys Asp Val Phe Leu Gly Met Phe Leu Tyr Glu Tyr Ala Arg

325 330335

Arg His Pro Asp Tyr Ser Val Val Leu Leu Leu Arg Leu Ala Lys Thr

340 345350

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

355 360365

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

370 375380

Gln Asn Leu Ile Lys Gln Asn Cys Glu Leu Phe Glu Gln Leu Gly Glu

385 390 395400

Tyr Lys Phe Gln Asn Ala Leu Leu Val Arg Tyr Thr Lys Lys Val Pro

405 410415

Gln Val Ser Thr Pro Thr Leu Val Glu Val Ser Arg Asn Leu Gly Lys

420 425430

Val Gly Ser Lys Cys Cys Lys His Pro Glu Ala Lys Arg Met Pro Cys

435 440445

Ala Glu Asp Tyr Leu Ser Val Val Leu Asn Gln Leu Cys Val Leu His

450 455460

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

465 470 475480

- 406 046387

Leu Val Asn Arg Arg Pro Cys Phe Ser 485

Tyr Val Pro Lys Glu Phe Asn Ala Glu

500 505

Ile Cys Thr Leu Ser Glu Lys Glu Arg

515 520

Leu Val Glu Leu Val Lys His Lys Pro

530 535

Lys Ala Val Met Asp Asp Phe Ala Ala

545 550

Ala Asp Asp Lys Glu Thr Cys Phe Ala 565

Ala Ala Ser Gln Ala Ala Leu Gly Leu

580 585

Gln Gln Ala Ala Gln Ala Ala Gln Gln

595 600

His Cys Pro Leu Gly Pro Gly Arg Cys

610 615

Ala Ser Leu Glu Asp Leu Gly Trp Ala

625 630

Glu Val Gln Val Thr Met Cys Ile Gly 645

Ala Ala Asn Met His Ala Gln Ile Lys

660 665

Pro Asp Thr Val Pro Ala Pro Cys Cys

675 680

Met Val Leu Ile Gln Lys Thr Asp Thr

690 695

Asp Asp Leu Leu Ala Lys Asp Cys His 705 710

Leu Glu Val Asp Glu Thr

495

Phe Thr Phe His Ala Asp

510

Ile Lys Lys Gln Thr Ala

525

Ala Thr Lys Glu Gln Leu 540

Val Glu Lys Cys Cys Lys

555 560

Glu Gly Lys Lys Leu Val

575

Ser Ala Ala Gln Ala Ala

590

Ser Ala Arg Asp Gly Asp

605

Arg Leu His Thr Val Arg 620

Trp Val Leu Ser Pro Arg

635 640

Cys Pro Ser Gln Phe Arg

655

Ser Leu His Arg Leu Lys

670

Pro Ala Ser Tyr Asn Pro

685

Val Ser Leu Gln Thr Tyr 700

Ile

715 <210> 243 <211> 339 <212> PRT

- 407 046387 <213> Artificial sequence <220>

<221> source <223> /note=description of artificial sequence: synthetic polypeptide” <400> 243

Met Glu Trp Ser Trp Val Phe Leu Phe Phe Leu Ser Val Thr Thr Gly

5 1015

Val His Ser Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 20 2530

Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 35 4045

Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 50 5560

Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 65 70 7580

Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 85 9095

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

100 105110

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

115 120125

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

130 135140

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

145 150 155160

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

165 170175

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

180 185190

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

195 200205

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

210 215220

- 408 046387

Leu Ser Leu Ser Pro Gly Gly Asp His Cys Pro Leu Gly Pro Gly Arg

225 230 235240

Cys Cys Arg Leu His Thr Val Arg Ala Ser Leu Glu Asp Leu Gly Trp

245 250255

Ala Asp Trp Val Leu Ser Pro Arg Glu Val Gln Val Thr Met Cys Ile

260 265270

Gly Ala Cys Pro Ser Gln Phe Arg Ala Ala Asn Met His Ala Gln Ile

275 280285

Lys Thr Ser Leu His Arg Leu Lys Pro Asp Thr Val Pro Ala Pro Cys

290 295300

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

305 310 315320

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

325 330335

His Cys Ile <210> 244 <211> 1017 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide

<400> 244 atggaatgga gctgggtctt tctcttcttc ctgtcagtaa cgactggtgt ccactccggt 60 ggcccgtcag tcttcctctt ccccccaaaa cccaaggaca ccctcatgat ctcccggacc 120 cctgaggtca catgcgtggt ggtggacgtg agccacgaag accctgaggt caagttcaac 180 tggtacgtgg acggcgtgga ggtgcataat gccaagacaa agccgcggga ggagcagtac 240 aacagcacgt accgtgtggt cagcgtcctc accgtcctgc accaggactg gctgaatggc 300 aaggagtaca agtgcaaggt ctccaacaaa gccctcccag ccccatcga gaaaaccatc 360 tccaaagcca aagggcagcc ccgagaacca caggtgtaca ccctgccccc atcccggggag 420 gagatgacca agaaccaggt cagcctgacc tgcctggtca aaggcttcta tccagcgac 480 atcgccgtgg agggggagag caatggggcag ccggagaaca actacgacac cacgcctccc 540 gtgctggact ccgacggctc cttcttcctc tatagcgacc tcaccgtgga caagagcagg 600

- 409 046387

tggcagcagg ggaacgtctt ctcatgctcc gtgatgcatg aggctctgca caaccactac 660 acgcagaaga gcctctccct gtctccggggt ggagaaccact gtccgctcgg gccgggcgt 720 tgctgccgtc tgcacacggt ccgcgcgtcg ctggaagacc tgggctgggc cgattgggtg 780 ctgtcgccac gggaggtgca agtgaccatg tgcatcggcg cgtgcccgag ccagttccgg 840 gcggcaaaca tgcacgcgca gatcaagacg agcctgcacc gcctgaagcc cgacacggtg 900 ccagcgccct gctgcgtgcc cgccagctac aatcccatgg tgctcattca aaagaccgac 960 accggggtgt cgctccagac ctatgatgac ttgttagcca aagactgcca ctgcata 1017

<210> 245 <211> 231 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 245

Met Glu Trp Ser Trp Val Phe Leu Phe Phe Leu Ser Val Thr Thr Gly

5 1015

Val His Ser Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 20 2530

Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 35 4045

Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 50 5560

Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 65 70 7580

Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 85 9095

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

100 105110

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

115 120125

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

130 135140

- 410 046387

Asn

145

Gln

Val

Ser

Leu

Thr

150

Cys

Leu

Val

Lys

Gly 155

Phe

Tyr

Pro

Ser

Asp 160

Ile

Ala

Val

Glu

Trp 165

Glu

Ser

Asn

Gly

Gln

170

Pro

Glu

Asn

Asn

Tyr

175

Lys

Thr

Thr

Pro

Pro

180

Val

Leu

Lys

Ser

Asp 185

Gly

Ser

Phe

Phe

Leu

190

Tyr

Ser

Lys

Leu

Thr

195

Val

Asp

Lys

Ser

Arg 200

Trp

Gln

Gln

Gly

Asn

205

Val

Phe

Ser

Cys

Ser

210

Val

Met

His

Glu

Ala

215

Leu

His

Asn

His

Tyr 220

Thr

Gln

Lys

Ser

Leu

225

Ser

Leu

Ser

Pro

Gly 230

Lys <210> 246 <211> 693 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide

<400> 246 atggaatgga gctgggtctt tctcttcttc ctgtcagtaa cgactggtgt ccactccggt 60 ggcccgtcag tcttcctctt ccccccaaaa cccaaggaca ccctcatgat ctcccggacc 120 cctgaggtca catgcgtggt ggtggacgtg agccacgaag accctgaggt caagttcaac 180 tggtacgtgg acggcgtgga ggtgcataat gccaagacaa agccgcggga ggagcagtac 240 aacagcacgt accgtgtggt cagcgtcctc accgtcctgc accaggactg gctgaatggc 300 aaggagtaca agtgcaaggt ctccaacaaa gccctcccag ccccatcga gaaaaccatc 360 tccaaagcca aagggcagcc ccgagaacca caggtgtaca ccctgccccc atcccggaag 420 gagatgacca agaaccaggt cagcctgacc tgcctggtca aaggcttcta tccagcgac 480 atcgccgtgg agggggagag caatggggcag ccggagaaca actacaagac cacgcctccc 540 gtgctgaagt ccgacggctc cttcttcctc tatagcaagc tcaccgtgga caagagcagg 600 tggcagcagg ggaacgtctt ctcatgctcc gtgatgcatg aggctctgca caaccactac 660 acgcagaaga gcctctccct gtctccggggt aaa 693

<210> 247 <211> 342 <212> PRT

- 411 046387 <213> Artificial sequence <220>

<221> source <223> /note=description of artificial sequence: synthetic polypeptide” <400> 247

Met Glu Trp Ser Trp Val Phe Leu Phe Phe Leu Ser Val Thr Thr Gly

5 1015

Val His Ser Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 20 2530

Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 35 4045

Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 50 5560

Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 65 70 7580

Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 85 9095

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

100 105110

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

115 120125

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

130 135140

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

145 150 155160

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

165 170175

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

180 185190

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

195 200205

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

210 215220

- 412 046387

Leu Ser Leu Ser Pro Gly Ala Arg Asp Gly Asp His Cys Pro Leu Gly

225 230 235240

Pro Gly Arg Cys Cys Arg Leu His Thr Val Arg Ala Ser Leu Glu Asp

245 250255

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

260 265270

Met Cys Ile Gly Ala Cys Pro Ser Gln Phe Arg Ala Ala Asn Met His

275 280285

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

290 295300

Ala Pro Cys Cys Val Pro Ala Ser Tyr Asn Pro Met Val Leu Ile Gln

305 310 315320

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

325 330335

Lys Asp Cys His Cys Ile

340 <210> 248 <211> 1026 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide

<400> 248 atggaatgga gctgggtctt tctcttcttc ctgtcagtaa cgactggtgt ccactccggt 60 ggcccgtcag tcttcctctt ccccccaaaa cccaaggaca ccctcatgat ctcccggacc 120 cctgaggtca catgcgtggt ggtggacgtg agccacgaag accctgaggt caagttcaac 180 tggtacgtgg acggcgtgga ggtgcataat gccaagacaa agccgcggga ggagcagtac 240 aacagcacgt accgtgtggt cagcgtcctc accgtcctgc accaggactg gctgaatggc 300 aaggagtaca agtgcaaggt ctccaacaaa gccctcccag ccccatcga gaaaaccatc 360 tccaaagcca aagggcagcc ccgagaacca caggtgtaca ccctgccccc atcccggggag 420 gagatgacca agaaccaggt cagcctgacc tgcctggtca aaggcttcta tccagcgac 480 atcgccgtgg agggggagag caatggggcag ccggagaaca actacgacac cacgcctccc 540 gtgctggact ccgacggctc cttcttcctc tatagcgacc tcaccgtgga caagagcagg 600

- 413 046387

tggcagcagg ggaacgtctt ctcatgctcc gtgatgcatg aggctctgca caaccactac 660 acgcagaaga gcctctccct gtctccggggt gcgcgcgacg gagaccactg tccgctcggg 720 cccggggcgtt gctgccgtct gcacacggtc cgcgcgtcgc tggaagacct gggctgggcc 780 gattgggtgc tgtcgccacg ggaggtgcaa gtgaccatgt gcatcggcgc gtgcccgagc 840 cagttccgggg cggcaaacat gcacgcgcag atcaagacga gcctgcaccg cctgaagccc 900 gacacggtgc cagcgccctg ctgcgtgccc gccagctaca atcccatggt gctcattcaa 960 aagaccgaca ccggggtgtc gctccagacc tatgatgact tgttagccaa agactgccac 1020 tgcata 1026

<210> 249 <211> 339 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 249

Met Glu Trp Ser Trp Val Phe Leu Phe Phe Leu Ser Val Thr Thr Gly

5 1015

Val His Ser Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 20 2530

Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 35 4045

Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 50 5560

Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 65 70 7580

Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 85 9095

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

100 105110

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

115 120125

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

130 135140

- 414 046387

Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly

145 150 155

Phe Tyr Pro Ser Asp

160

Ile Ala Val Glu

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Asp

165 170 175

Thr Thr Pro Pro Val

180

Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser

185 190

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

195 200 205

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

210 215 220

Leu Ser Leu Ser Pro Gly Gly Asp His Cys Pro Leu Gly Pro Gly Arg

225 230 235 240

Cys Cys Arg Leu His Thr Val Arg Ala Ser Leu Glu Asp Leu Gly Trp

245 250 255

Ala Asp Trp Val Leu Ser Pro Arg Glu Val Gln Val Thr Met Cys Ile

260 265 270

Gly Ala Cys Pro Ser Gln Phe Arg Ala Ala Asn Met His Ala Gln Ile

275 280 285

Lys Thr Ser Leu His Arg Leu Lys Pro Asp Thr Val Pro Ala Pro Cys

290 295 300

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

305 310 315 320

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

325 330 335

His Cys Ile <210> 250 <211> 1017 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide

- 415 046387

<400> 250 atggaatgga gctgggtctt tctcttcttc ctgtcagtaa cgactggtgt ccactccggt 60 ggcccgtcag tcttcctctt ccccccaaaa cccaaggaca ccctcatgat ctcccggacc 120 cctgaggtca catgcgtggt ggtggacgtg agccacgaag accctgaggt caagttcaac 180 tggtacgtgg acggcgtgga ggtgcataat gccaagacaa agccgcggga ggagcagtac 240 aacagcacgt accgtgtggt cagcgtcctc accgtcctgc accaggactg gctgaatggc 300 aaggagtaca agtgcaaggt ctccaacaaa gccctcccag ccccatcga gaaaaccatc 360 tccaaagcca aagggcagcc ccgagaacca caggtgtgca ccctgccccc atcccggggag 420 gagatgacca agaaccaggt cagcctgacc tgcctggtca aaggcttcta tccagcgac 480 atcgccgtgg agggggagag caatggggcag ccggagaaca actacgacac cacgcctccc 540 gtgctggact ccgacggctc cttcttcctc tatagcgacc tcaccgtgga caagagcagg 600 tggcagcagg ggaacgtctt ctcatgctcc gtgatgcatg aggctctgca caaccactac 660 acgcagaaga gcctctccct gtctccggggt ggagaaccact gtccgctcgg gccgggcgt 720 tgctgccgtc tgcacacggt ccgcgcgtcg ctggaagacc tgggctgggc cgattgggtg 780 ctgtcgccac gggaggtgca agtgaccatg tgcatcggcg cgtgcccgag ccagttccgg 840 gcggcaaaca tgcacgcgca gatcaagacg agcctgcacc gcctgaagcc cgacacggtg 900 ccagcgccct gctgcgtgcc cgccagctac aatcccatgg tgctcattca aaagaccgac 960 accggggtgt cgctccagac ctatgatgac ttgttagcca aagactgcca ctgcata 1017

<210> 251 <211> 231 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 251

Met Glu Trp Ser Trp Val Phe Leu Phe Phe Leu Ser Val Thr Thr Gly

5 1015

Val His Ser Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys ProLys

2530

Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 35 4045

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

5560

- 416 046387

Gly Val Glu Val His Asn Ala Lys 65 70

Thr Lys Pro Arg Glu Glu Gln Tyr

80

Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 85 9095

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

100 105110

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

115 120125

Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Lys Glu Met Thr Lys

130 135140

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

145 150 155160

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

165 170175

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

180 185190

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

195 200205

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

210 215220

Leu Ser Leu Ser Pro Gly Lys

225230 <210> 252 <211> 693 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide <400> 252 atggaatgga gctgggtctt tctcttcttc ctgtcagtaa cgactggtgt ccactccggt60 ggcccgtcag tcttcctctt ccccccaaaa cccaaggaca ccctcatgat ctcccggacc120 cctgaggtca catgcgtggt ggtggacgtg agccacgaag accctgaggt caagttcaac180 tggtacgtgg acggcgtgga ggtgcataat gccaagacaa agccgcggga ggagcagtac240

- 417 046387

aacagcacgt accgtgtggt cagcgtcctc accgtcctgc accaggactg gctgaatggc 300 aaggagtaca agtgcaaggt ctccaacaaa gccctcccag ccccatcga gaaaaccatc 360 tccaaagcca aagggcagcc ccgagaacca caggtgtaca ccctgccccc atgccggaag 420 gagatgacca agaaccaggt cagcctgacc tgcctggtca aaggcttcta tccagcgac 480 atcgccgtgg agggggagag caatggggcag ccggagaaca actacaagac cacgcctccc 540 gtgctgaagt ccgacggctc cttcttcctc tatagcaagc tcaccgtgga caagagcagg 600 tggcagcagg ggaacgtctt ctcatgctcc gtgatgcatg aggctctgca caaccactac 660 acgcagaaga gcctctccct gtctccggggt aaa 693

<210> 253 <211> 342 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 253

Met Glu Trp Ser Trp Val Phe Leu Phe Phe Leu Ser Val Thr Thr Gly

5 1015

Val His Ser Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 20 2530

Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 35 4045

Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 50 5560

Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 65 70 7580

Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 85 9095

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

100 105110

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

115 120125

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

130 135140

- 418 046387

Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly

145 150 155

Phe Tyr Pro Ser Asp

160

Ile Ala Val Glu

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Asp

165 170 175

Thr Thr Pro Pro Val

180

Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser

185 190

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

195 200 205

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

210 215 220

Leu Ser Leu Ser Pro Gly Ala Arg Asp Gly Asp His Cys Pro Leu Gly

225 230 235 240

Pro Gly Arg Cys Cys Arg Leu His Thr Val Arg Ala Ser Leu Glu Asp

245 250 255

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

260 265 270

Met Cys Ile Gly Ala Cys Pro Ser Gln Phe Arg Ala Ala Asn Met His

275 280 285

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

290 295 300

Ala Pro Cys Cys Val Pro Ala Ser Tyr Asn Pro Met Val Leu Ile Gln

305 310 315 320

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

325 330 335

Lys Asp Cys His Cys Ile

340 <210> 254 <211> 1026 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide

- 419 046387 <400> 254 atggaatgga gctgggtctt tctcttcttc ctgtcagtaa cgactggtgt ccactccggt60 ggcccgtcag tcttcctctt ccccccaaaa cccaaggaca ccctcatgat ctcccggacc120 cctgaggtca catgcgtggt ggtggac gtg agccacgaag accctgaggt caagttcaac180 tggtacgtgg acggcgtgga ggtgcataat gccaagacaa agccgcggga ggagcagtac240 aacagcacgt accgtgtggt cagcgtcctc accgtcctgc accaggactg gctgaatggc300 aaggagtaca agtgcaagg t ctccaacaaa gccctcccag cccccatcga gaaaaccatc360 tccaaagcca aagggcagcc ccgagaacca caggtgtgca ccctgccccc atcccgggag420 gagatgacca agaaccaggt cagcctgacc tgcctggtca aaggcttcta tcccagcgac480 atcgccgtgg agtggggagag caatgggcag ccggagaaca actacgacac cacgcctccc540 gtgctggact ccgacggctc cttcttcctc tatagcgacc tcaccgtgga caagagcagg600 tggcagca gg ggaacgtctt ctcatgctcc gtgatgcatg aggctctgca caaccactac660 acgcagaaga gcctctccct gtctccgggt gcgcgcgacg gagaccactg tccgctcggg720 cccgggcgtt gctgccgtct gcacacggtc cgcgcgtcgc tggaagacct gggctgggcc780 gatt gggtgc tgtcgccacg ggaggtgcaa gtgaccatgt gcatcggcgc gtgcccgagc840 cagttccggg cggcaaacat gcacgcgcag atcaagacga gcctgcaccg cctgaagccc900 gacacggtgc cagcgccctg ctgcgtgccc gccagctaca atcccatggt gctcattcaa960 aagaccgaca ccggggtgtc gctccagacc tatgatgact tgttagccaa agactgccac1020 tgcata1026 <210> 255 <211> 341 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 255

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

5 1015

Leu Arg Gly Ala Arg Cys Gly Pro Ser Val Phe Leu Phe Pro Pro Lys 20 2530

Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 35 4045

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

- 420 046387

Val 65

Gln

Gln

Ala

Pro

Thr 145

Ser

Tyr

Tyr

Phe

Lys 225

Gly

Gly

Cys

Gln

Asp Gly Val Glu Val

His Asn Ala Lys Thr

Lys Pro Arg Glu Glu

Tyr Asn Ser Thr Tyr

Arg Val Val Ser Val

Leu Thr Val Leu His

Asp Trp Leu Asn Gly

100

Leu Pro Ala Pro Ile

115

Arg Glu Pro Gln Val 130

Lys Asn Gln Val Ser

150

Asp Ile Ala Val Glu

165

Asp Thr Thr Pro Pro 180

Ser Asp Leu Thr Val

195

Ser Cys Ser Val Met 210

Ser Leu Ser Leu Ser

230

Arg Cys Cys Arg Leu

245

Trp Ala Asp Trp Val 260

Ile Gly Ala Cys Pro

275

Ile Lys Thr Ser Leu 290

Lys Glu Tyr Lys Cys

105

Lys Val Ser Asn Lys

110

Glu Lys Thr Ile Ser 120

Tyr Thr Leu Pro Pro 135

Leu Thr Cys Leu Val

155

Trp Glu Ser Asn Gly

170

Val Leu Asp Ser Asp

185

Asp Lys Ser Arg Trp

200

His Glu Ala Leu His 215

Pro Gly Gly Asp His

235

His Thr Val Arg Ala

250

Leu Ser Pro Arg Glu

265

Ser Gln Phe Arg Ala

280

His Arg Leu Lys Pro 295

Lys Ala Lys Gly Gln

125

Ser Arg Glu Glu Met 140

Lys Gly Phe Tyr Pro

160

Gln Pro Glu Asn Asn

175

Gly Ser Phe Phe Leu

190

Gln Gln Gly Asn Val 205

Asn His Tyr Thr Gln 220

Cys Pro Leu Gly Pro

240

Ser Leu Glu Asp Leu

255

Val Gln Val Thr Met

270

Ala Asn Met His Ala

285

Asp Thr Val Pro Ala 300

- 421 046387

Pro Cys Cys Val

Pro Ala Ser Tyr Asn Pro Met Val Leu Ile Gln Lys

305

310 315 320

Thr Asp Thr Gly Val

325

Ser Leu Gln Thr Tyr Asp Asp Leu Leu Ala Lys

330 335

Asp Cys His Cys Ile

340 <210> 256 <211> 1023 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide

<400> 256 atggacatga gggtgcccgc tcagctcctg gggctcctgc tgctgtggct gagaggtgcg 60 cgctgtggcc cgtcagtctt cctcttcccc ccaaaaccca aggacaccct catgatctcc 120 cggacccctg aggtcacatg cgtggtggtg gacgtgagcc acgaagaaccc tgaggtcaag 180 ttcaactggt acgtggacgg cgtggaggtg cataatgcca agacaaagcc gcgggaggag 240 cagtacaaca gcacgtaccg tgtggtcagc gtcctcaccg tcctgcacca ggactggctg 300 aatggcaagg agtacaagtg caaggtctcc aacaaagccc tccagcccc catcgagaaa 360 accatctcca aagccaaagg gcagccccga gaaccacagg tgtacaccct gcccccatcc 420 cgggaggaga tgaccaagaa ccaggtcagc ctgacctgcc tggtcaaagg cttctatccc 480 agcgacatcg ccgtggagtg ggagagcaat gggcagccgg agaacaacta cgacaccacg 540 cctcccgtgc tggactccga cggctccttc ttcctctata gcgacctcac cgtggacaag 600 agcaggtggc agcaggggaa cgtcttctca tgctccgtga tgcatgaggc tctgcacaac 660 cactacacgc agaagagcct ctccctgtct ccggggtggag accactgtcc gctcgggccc 720 gggcgttgct gccgtctgca cacggtccgc gcgtcgctgg aagacctggg ctggggccgat 780 tgggtgctgt cgccacggga ggtgcaagtg accatgtgca tcggcgcgtg cccgagccag 840 ttccggggcgg caaacatgca cgcgcagatc aagacgagcc tgcaccgcct gaagcccgac 900 acggtgccag cgccctgctg cgtgcccgcc agctacaatc ccatggtgct cattcaaaag 960 accgacaccg gggtgtcgct ccagacctat gatgacttgt tagccaaaga ctgccactgc 1020 ata 1023

<210> 257 <211> 233 <212> PRT

- 422 046387 <213> Artificial sequence <220>

<221> source <223> /note=description of artificial sequence: synthetic polypeptide” <400> 257

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

5 1015

Leu Arg Gly Ala Arg Cys Gly Pro Ser Val Phe Leu Phe Pro ProLys

2530

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

4045

Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 50 5560

Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 65 70 7580

Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 85 9095

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

100 105110

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

115 120125

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

130 135140

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

145 150 155160

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

165 170175

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

180 185190

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

195 200205

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

210 215220

- 423 046387

Lys Ser Leu Ser Leu Ser Pro Gly Lys

225 230 <210> 258 <211> 699 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide

<400> 258 atggacatga gggtgcccgc tcagctcctg gggctcctgc tgctgtggct gagaggtgcg 60 cgctgtggcc cgtcagtctt cctcttcccc ccaaaaccca aggacaccct catgatctcc 120 cggacccctg aggtcacatg cgtggtggtg gacgtgagcc acgaagaaccc tgaggtcaag 180 ttcaactggt acgtggacgg cgtggaggtg cataatgcca agacaaagcc gcgggaggag 240 cagtacaaca gcacgtaccg tgtggtcagc gtcctcaccg tcctgcacca ggactggctg 300 aatggcaagg agtacaagtg caaggtctcc aacaaagccc tccagcccc catcgagaaa 360 accatctcca aagccaaagg gcagccccga gaaccacagg tgtacaccct gcccccatcc 420 cggaaggaga tgaccaagaa ccaggtcagc ctgacctgcc tggtcaaagg cttctatccc 480 agcgacatcg ccgtggagtg ggagagcaat gggcagccgg agaacaacta caagaccacg 540 cctcccgtgc tgaagtccga cggctccttc ttcctctata gcaagctcac cgtggacaag 600 agcaggtggc agcaggggaa cgtcttctca tgctccgtga tgcatgaggc tctgcacaac 660 cactacacgc agaagagcct ctccctgtct ccgggtaaa 699

<210> 259 <211> 344 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=description of artificial sequence: synthetic polypeptide <400> 259

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

5 1015

Leu Arg Gly Ala Arg Cys Gly Pro Ser Val Phe Leu Phe Pro Pro Lys 20 2530

Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 35 4045

- 424 046387

Val Val Asp Val Ser His Glu Asp Pro Glu Val

55

Lys Phe Asn Trp Tyr

Val Asp Gly Val

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

75 80

Gln Tyr Asn Ser Thr Tyr Arg Val Val 85

Ser Val Leu Thr Val Leu His

95

Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

100 105

Lys Val Ser Asn Lys

110

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

115 120 125

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

130 135 140

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

145 150 155 160

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

165 170 175

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

180 185 190

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

195 200 205

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

210 215 220

Lys Ser Leu Ser Leu Ser Pro Gly Ala Arg Asp Gly Asp His Cys Pro

225 230 235 240

Leu Gly Pro Gly Arg Cys Cys Arg Leu His Thr Val Arg Ala Ser Leu

245 250 255

Glu Asp Leu Gly Trp Ala Asp Trp Val Leu Ser Pro Arg Glu Val Gln

260 265 270

Val Thr Met Cys Ile Gly Ala Cys Pro Ser Gln Phe Arg Ala Ala Asn

275 280 285

Met His Ala Gln Ile Lys Thr Ser Leu His Arg Leu Lys Pro Asp Thr

290 295 300

- 425 046387

Val Pro Ala Pro Cys Cys Val Pro Ala 305 310

Ser Tyr Asn Pro Met Val Leu

315

320

Ile Gln Lys

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

325 330 335

Leu Ala Lys Asp Cys His Cys Ile

340 <210> 260 <211> 1032 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide

<400> 260 atggacatga gggtgcccgc tcagctcctg gggctcctgc tgctgtggct gagaggtgcg 60 cgctgtggcc cgtcagtctt cctcttcccc ccaaaaccca aggacaccct catgatctcc 120 cggacccctg aggtcacatg cgtggtggtg gacgtgagcc acgaagaaccc tgaggtcaag 180 ttcaactggt acgtggacgg cgtggaggtg cataatgcca agacaaagcc gcgggaggag 240 cagtacaaca gcacgtaccg tgtggtcagc gtcctcaccg tcctgcacca ggactggctg 300 aatggcaagg agtacaagtg caaggtctcc aacaaagccc tccagcccc catcgagaaa 360 accatctcca aagccaaagg gcagccccga gaaccacagg tgtacaccct gcccccatcc 420 cgggaggaga tgaccaagaa ccaggtcagc ctgacctgcc tggtcaaagg cttctatccc 480 agcgacatcg ccgtggagtg ggagagcaat gggcagccgg agaacaacta cgacaccacg 540 cctcccgtgc tggactccga cggctccttc ttcctctata gcgacctcac cgtggacaag 600 agcaggtggc agcaggggaa cgtcttctca tgctccgtga tgcatgaggc tctgcacaac 660 cactacacgc agaagagcct ctccctgtct ccgggtgcgc gcgacggaga ccactgtccg 720 ctcgggcccg ggcgttgctg ccgtctgcac acggtccgcg cgtcgctgga agacctggggc 780 tggggccgatt gggtgctgtc gccacggggag gtgcaagtga ccatgtgcat cggcgcgtgc 840 ccgagccagt tccggggcggc aaacatgcac gcgcagatca agacgagcct gcaccgcctg 900 aagcccgaca cggtgccagc gccctgctgc gtgcccgcca gctacaatcc catggtgctc 960 attcaaaaga ccgacaccgg ggtgtcgctc cagacctatg atgacttgtt agccaaagac 1020 tgccactgca ta 1032

<210> 261

- 426 046387 <211> 341 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 261

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

5 1015

Leu Arg Gly Ala Arg Cys Gly Pro Ser Val Phe Leu Phe Pro Pro Lys 20 2530

Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 35 4045

Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 50 5560

Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 65 70 7580

Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 85 9095

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

100 105110

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

115 120125

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

130 135140

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

145 150 155160

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

165 170175

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

180 185190

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

195 200205

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

- 427 046387

210

215

220

Lys Ser Leu Ser Leu Ser Pro Gly Gly Asp His Cys Pro Leu Gly Pro

225 230 235240

Gly Arg Cys Cys Arg Leu His Thr Val Arg Ala Ser Leu Glu Asp Leu

245 250255

Gly Trp Ala Asp Trp Val Leu Ser Pro Arg Glu Val Gln Val Thr Met

260 265270

Cys Ile Gly Ala Cys Pro Ser Gln Phe Arg Ala Ala Asn Met His Ala

275 280285

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

290 295300

Pro Cys Cys Val Pro Ala Ser Tyr Asn Pro Met Val Leu Ile Gln Lys

305 310 315320

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

325 330335

Asp Cys His Cys Ile

340 <210> 262 <211> 1023 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide

<400> 262 atggacatga gggtgcccgc tcagctcctg gggctcctgc tgctgtggct gagaggtgcg 60 cgctgtggcc cgtcagtctt cctcttcccc ccaaaaccca aggacaccct catgatctcc 120 cggacccctg aggtcacatg cgtggtggtg gacgtgagcc acgaagaaccc tgaggtcaag 180 ttcaactggt acgtggacgg cgtggaggtg cataatgcca agacaaagcc gcgggaggag 240 cagtacaaca gcacgtaccg tgtggtcagc gtcctcaccg tcctgcacca ggactggctg 300 aatggcaagg agtacaagtg caaggtctcc aacaaagccc tccagcccc catcgagaaa 360 accatctcca aagccaaagg gcagccccga gaaccacagg tgtgcaccct gcccccatcc 420 cgggaggaga tgaccaagaa ccaggtcagc ctgacctgcc tggtcaaagg cttctatccc 480 agcgacatcg ccgtggagtg ggagagcaat gggcagccgg agaacaacta cgacaccacg 540

- 428 046387

cctcccgtgc tggactccga cggctccttc ttcctctata gcgacctcac cgtggacaag 600 agcaggtggc agcaggggaa cgtcttctca tgctccgtga tgcatgaggc tctgcacaac 660 cactacacgc agaagagcct ctccctgtct ccggggtggag accactgtcc gctcgggccc 720 gggcgttgct gccgtctgca cacggtccgc gcgtcgctgg aagacctggg ctggggccgat 780 tgggtgctgt cgccacggga ggtgcaagtg accatgtgca tcggcgcgtg cccgagccag 840 ttccggggcgg caaacatgca cgcgcagatc aagacgagcc tgcaccgcct gaagcccgac 900 acggtgccag cgccctgctg cgtgcccgcc agctacaatc ccatggtgct cattcaaaag 960 accgacaccg ata gggtgtcgct ccagacctat gatgacttgt tagccaaaga ctgccactgc 1020 1023

<210> 263 <211> 233 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 263

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

5 1015

Leu Arg Gly Ala Arg Cys Gly Pro Ser Val Phe Leu Phe Pro Pro Lys 20 2530

Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 35 4045

Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 50 5560

Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 65 70 7580

Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 85 9095

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

100 105110

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

115 120125

- 429 046387

Pro

Arg 130

Glu

Pro

Gln

Val

Tyr 135

Thr

Leu

Pro

Pro

Cys 140

Arg

Lys

Glu

Met

Thr

145

Lys

Asn

Gln

Val

Ser

150

Leu

Thr

Cys

Leu

Val

155

Lys

Gly

Phe

Tyr

Pro

160

Ser

Asp

Ile

Ala

Val

165

Glu

Trp

Glu

Ser

Asn

170

Gly

Gln

Pro

Glu

Asn

175

Asn

Tyr

Lys

Thr

Thr

180

Pro

Pro

Val

Leu

Lys 185

Ser

Asp

Gly

Ser

Phe

190

Phe

Leu

Tyr

Ser

Lys 195

Leu

Thr

Val

Asp

Lys 200

Ser

Arg

Trp

Gln

Gln

205

Gly

Asn

Val

Phe

Ser

210

Cys

Ser

Val

Met

His

215

Glu

Ala

Leu

His

Asn

220

His

Tyr

Thr

Gln

Lys 225

Ser

Leu

Ser

Leu

Ser

230

Pro

Gly

Lys <210> 264 <211> 699 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide <400> 264

atggacatga gggtgcccgc tcagctcctg gggctcctgc tgctgtggct gagaggtgcg 60 cgctgtggcc cgtcagtctt cctcttcccc ccaaaaccca aggacaccct catgatctcc 120 cggacccctg aggtcacatg cgtggtggtg gacgtgagcc acgaagaaccc tgaggtcaag 180 ttcaactggt acgtggacgg cgtggaggtg cataatgcca agacaaagcc gcgggaggag 240 cagtacaaca gcacgtaccg tgtggtcagc gtcctcaccg tcctgcacca ggactggctg 300 aatggcaagg agtacaagtg caaggtctcc aacaaagccc tccagcccc catcgagaaa 360 accatctcca aagccaaagg gcagccccga gaaccacagg tgtacaccct gcccccatgc 420 cggaaggaga tgaccaagaa ccaggtcagc ctgacctgcc tggtcaaagg cttctatccc 480 agcgacatcg ccgtggagtg ggagagcaat gggcagccgg agaacaacta caagaccacg 540 cctcccgtgc tgaagtccga cggctccttc ttcctctata gcaagctcac cgtggacaag 600 agcaggtggc agcaggggaa cgtcttctca tgctccgtga tgcatgaggc tctgcacaac 660 cactacacgc agaagagcct ctccctgtct ccgggtaaa 699

- 430 046387 <210> 265 <211> 344 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 265

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

5 1015

Leu Arg Gly Ala Arg Cys Gly Pro Ser Val Phe Leu Phe Pro Pro Lys 20 2530

Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 35 4045

Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 50 5560

Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 65 70 7580

Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 85 9095

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

100 105110

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

115 120125

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

130 135140

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

145 150 155160

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

165 170175

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

180 185190

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

195 200205

- 431 046387

Phe Ser Cys Ser Val Met His Glu

210 215

Ala Leu His

Asn His Tyr Thr Gln

220

Lys Ser Leu Ser Leu Ser Pro Gly Ala Arg Asp Gly Asp His Cys Pro

225 230 235240

Leu Gly Pro Gly Arg Cys Cys Arg Leu His Thr Val Arg Ala Ser Leu

245 250255

Glu Asp Leu Gly Trp Ala Asp Trp Val Leu Ser Pro Arg Glu Val Gln

260 265270

Val Thr Met Cys Ile Gly Ala Cys Pro Ser Gln Phe Arg Ala Ala Asn

275 280285

Met His Ala Gln Ile Lys Thr Ser Leu His Arg Leu Lys Pro Asp Thr

290 295300

Val Pro Ala Pro Cys Cys Val Pro Ala Ser Tyr Asn Pro Met Val Leu

305 310 315320

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

325 330335

Leu Ala Lys Asp Cys His Cys Ile

340 <210> 266 <211> 1032 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide

<400> 266 atggacatga gggtgcccgc tcagctcctg gggctcctgc tgctgtggct gagaggtgcg 60 cgctgtggcc cgtcagtctt cctcttcccc ccaaaaccca aggacaccct catgatctcc 120 cggacccctg aggtcacatg cgtggtggtg gacgtgagcc acgaagaaccc tgaggtcaag 180 ttcaactggt acgtggacgg cgtggaggtg cataatgcca agacaaagcc gcgggaggag 240 cagtacaaca gcacgtaccg tgtggtcagc gtcctcaccg tcctgcacca ggactggctg 300 aatggcaagg agtacaagtg caaggtctcc aacaaagccc tccagcccc catcgagaaa 360 accatctcca aagccaaagg gcagccccga gaaccacagg tgtgcaccct gcccccatcc 420 cgggaggaga tgaccaagaa ccaggtcagc ctgacctgcc tggtcaaagg cttctatccc 480

- 432 046387

agcgacatcg ccgtggagtg ggagagcaat gggcagccgg agaacaacta cgacaccacg 540 cctcccgtgc tggactccga cggctccttc ttcctctata gcgacctcac cgtggacaag 600 agcaggtggc agcaggggaa cgtcttctca tgctccgtga tgcatgaggc tctgcacaac 660 cactacacgc agaagagcct ctccctgtct ccgggtgcgc gcgacggaga ccactgtccg 720 ctcgggcccg ggcgttgctg ccgtctgcac acggtccgcg cgtcgctgga agacctggggc 780 tggggccgatt gggtgctgtc gccacggggag gtgcaagtga ccatgtgcat cggcgcgtgc 840 ccgagccagt tccggggcggc aaacatgcac gcgcagatca agacgagcct gcaccgcctg 900 aagcccgaca cggtgccagc gccctgctgc gtgcccgcca gctacaatcc catggtgctc 960 attcaaaaga ccgacaccgg ggtgtcgctc cagacctatg atgacttgtt agccaaagac 1020 tgccactgca ta 1032

<210> 267 <211> 217 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 267

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

5 1015

Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 2530

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

4045

Val Asp Gly Val Glu Val His Asn Cys Lys Thr Lys Pro Arg Glu Glu 50 5560

Gln Tyr Gly Ser Thr Tyr Arg Val Val Ser Val Cys Thr Val Leu His 65 70 7580

Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 9095

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

100 105110

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

115 120125

- 433 046387

Thr

Lys 130

Asn

Gln

Val

Ser

Leu

135

Thr

Cys

Leu

Val

Lys 140

Gly

Phe

Tyr

Pro

Ser

145

Asp

Ile

Ala

Val

Glu

150

Trp

Glu

Ser

Asn

Gly 155

Gln

Pro

Glu

Asn

Asn

160

Tyr

Lys

Thr

Thr

Pro

165

Pro

Val

Leu

Lys

Ser

170

Asp

Gly

Ser

Phe

Phe

175

Leu

Tyr

Ser

Lys

Leu

180

Thr

Val

Asp

Lys

Ser

185

Arg

Trp

Gln

Gln

Gly 190

Asn

Val

Phe

Ser

Cys 195

Ser

Val

Met

His

Glu

200

Ala

Leu

His

Asn

His

205

Tyr

Thr

Gln

Lys Ser Leu Ser Leu Ser Pro Gly Lys

210 215 <210> 268 <211> 216 <212> PRT <213>

Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 268

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

5 1015

Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 2530

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

4045

Val Asp Gly Val Glu Val His Asn Cys Lys Thr Lys Pro Arg Glu Glu 50 5560

Gln Tyr Gly Ser Thr Tyr Arg Val Val Ser Val Cys Thr Val Leu His 65 70 7580

Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 9095

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

100 105110

- 434 046387

Pro

Arg

Glu

115

Pro

Gln

Val

Tyr

Thr

120

Leu

Pro

Pro

Ser

Arg 125

Glu

Glu

Met

Thr

Lys 130

Asn

Gln

Val

Ser

Leu

135

Thr

Cys

Leu

Val

Lys 140

Gly

Phe

Tyr

Pro

Ser

145

Asp

Ile

Ala

Val

Glu

150

Trp

Glu

Ser

Asn

Gly 155

Gln

Pro

Glu

Asn

Asn

160

Tyr

Asp

Thr

Thr

Pro

165

Pro

Val

Leu

Asp

Ser

170

Asp

Gly

Ser

Phe

Phe

175

Leu

Tyr

Ser

Asp

Leu

180

Thr

Val

Asp

Lys

Ser

185

Arg

Trp

Gln

Gln

Gly 190

Asn

Val

Phe

Ser

Cys 195

Ser

Val

Met

His

Glu

200

Ala

Leu

His

Asn

His

205

Tyr

Thr

Gln

Lys Ser Leu Ser Leu Ser Pro Gly

210 215 <210> 269 <211> 325 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 269

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

5 1015

Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 2530

Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 4045

Val Asp Gly Val Glu Val His Asn Cys Lys Thr Lys Pro Arg Glu Glu 50 5560

Gln Tyr Gly Ser Thr Tyr Arg Val Val Ser Val Cys Thr Val Leu His 65 70 7580

Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 9095

- 435 046387

Ala Leu Pro

Ala

100

Pro

Ile

Glu

Lys

Thr

105

Ile

Ser

Lys

Ala

Lys 110

Gly

Gln

Pro Arg Glu

115

Pro

Gln

Val

Tyr

Thr

120

Leu

Pro

Pro

Ser

Arg 125

Glu

Glu

Met

Thr Lys Asn

130

Gln

Val

Ser

Leu

135

Thr

Cys

Leu

Val

Lys 140

Gly

Phe

Tyr

Pro

Ser Asp Ile 145

Ala

Val

Glu

150

Trp

Glu

Ser

Asn

Gly 155

Gln

Pro

Glu

Asn

Asn

160

Tyr Asp Thr

Thr

Pro

165

Pro

Val

Leu

Asp

Ser

170

Asp

Gly

Ser

Phe

Phe

175

Leu

Tyr Ser Asp

Leu

180

Thr

Val

Asp

Lys

Ser

185

Arg

Trp

Gln

Gln

Gly 190

Asn

Val

Phe Ser Cys

195

Ser

Val

Met

His

Glu

200

Ala

Leu

His

Asn

His

205

Tyr

Thr

Gln

Lys Ser Leu

210

Ser

Leu

Ser

Pro

215

Gly

Gly

Asp

His

Cys 220

Pro

Leu

Gly

Pro

Gly Arg Cys 225

Cys

Arg

Leu

230

His

Thr

Val

Arg

Ala

235

Ser

Leu

Glu

Asp

Leu

240

Gly Trp Ala

Asp

Trp 245

Val

Leu

Ser

Pro

Arg 250

Glu

Val

Gln

Val

Thr

255

Met

Cys Ile Gly

Ala

260

Cys

Pro

Ser

Gln

Phe

265

Arg

Ala

Ala

Asn

Met

270

His

Ala

Gln Ile Lys

275

Thr

Ser

Leu

His

Arg 280

Leu

Lys

Pro

Asp

Thr

285

Val

Pro

Ala

Pro Cys Cys

290

Val

Pro

Ala

Ser

295

Tyr

Asn

Pro

Met

Val

300

Leu

Ile

Gln

Lys

Thr Asp Thr 305

Gly

Val

Ser

310

Leu

Gln

Thr

Tyr

Asp 315

Asp

Leu

Leu

Ala

Lys

320

Asp Cys His

Cys

Ile

325 <210> 270

- 436 046387 <211> 975 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide <400> 270

gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataattg caagacaaag 180 ccgcgggagg agcagtacgg cagcacgtac cgtgtggtca gcgtctgcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 ccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtacacc 360 ctgcccccat cccggggaga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tggggagagca atggggcagcc ggagaacaac 480 tacgacacca cgcctcccgt gctggactcc gacggctcct tcttcctcta tagcgacctc 540 accgtggac agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccggggtgg agaccactgt 660 ccgctcgggc ccgggcgttg ctgccgtctg cacacggtcc gcgcgtcgct ggaagacctg 720 ggctgggccg attgggtgct gtcgccacgg gaggtgcaag tgaccatgtg catcggcgcg 780 tgcccgagcc agttccggggc ggcaaacatg cacgcgcaga tcaagacgag cctgcaccgc 840 ctgaagcccg acacggtgcc agcgccctgc tgcgtgcccg ccagctacaa tcccatggtg 900 ctcattcaaa agaccgacac cggggtgtcg ctccagacct atgatgactt gttagccaaa 960 gactgccact gcata 975

<210> 271 <211> 651 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=description of artificial sequence: synthetic polynucleotide

<400> 271 gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataattg caagacaaag 180 ccgcgggagg agcagtacgg cagcacgtac cgtgtggtca gcgtctgcac cgtcctgcac 240

- 437 046387

caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 ccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtacacc 360 ctgcccccat cccggaagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tggggagagca atggggcagcc ggagaacaac 480 tacaagacca cgcctcccgt gctgaagtcc gacggctcct tcttcctcta tagcaagctc 540 accgtggac agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccgggtaa a 651

<210> 272 <211> 328 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 272

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

5 1015

Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 2530

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

4045

Val Asp Gly Val Glu Val His Asn Cys Lys Thr Lys Pro Arg Glu Glu 50 5560

Gln Tyr Gly Ser Thr Tyr Arg Val Val Ser Val Cys Thr Val Leu His 65 70 7580

Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 9095

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

100 105110

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

115 120125

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

130 135140

- 438 046387

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

145 150 155160

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

165 170175

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

180 185190

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

195 200205

Lys Ser Leu Ser Leu Ser Pro Gly Ala Arg Asp Gly Asp His Cys Pro

210 215220

Leu Gly Pro Gly Arg Cys Cys Arg Leu His Thr Val Arg Ala Ser Leu

225 230 235240

Glu Asp Leu Gly Trp Ala Asp Trp Val Leu Ser Pro Arg Glu Val Gln

245 250255

Val Thr Met Cys Ile Gly Ala Cys Pro Ser Gln Phe Arg Ala Ala Asn

260 265270

Met His Ala Gln Ile Lys Thr Ser Leu His Arg Leu Lys Pro Asp Thr

275 280285

Val Pro Ala Pro Cys Cys Val Pro Ala Ser Tyr Asn Pro Met Val Leu

290 295300

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

305 310 315320

Leu Ala Lys Asp Cys His Cys Ile

325 <210> 273 <211> 984 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide <400> 273 gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120

- 439 046387

cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataattg caagacaaag 180 ccgcgggagg agcagtacgg cagcacgtac cgtgtggtca gcgtctgcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 ccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtacacc 360 ctgcccccat cccggggaga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tggggagagca atggggcagcc ggagaacaac 480 tacgacacca cgcctcccgt gctggactcc gacggctcct tcttcctcta tagcgacctc 540 accgtggac agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccgggtgc gcgcgacgga 660 gaccactgtc cgctcgggcc cggggcgttgc tgccgtctgc acacggtccg cgcgtcgctg 720 gaagacctgg gctggggccga ttgggtgctg tcgccacggg aggtgcaagt gaccatgtgc 780 atcggcgcgt gcccgagcca gttccggggcg gcaaacatgc acgcgcagat caagacgagc 840 ctgcaccgcc tgaagcccga cacggtgcca gcgccctgct gcgtgcccgc cagctacaat 900 cccatggtgc tcattcaaaa gaccgacacc ggggtgtcgc tccagaccta tgatgacttg 960 ttagccaaag actgccactg cata 984

<210> 274 <211> 217 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 274

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

5 1015

Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 2530

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

4045

Val Asp Gly Val Glu Val His Asn Cys Lys Thr Lys Pro Arg Glu Glu 50 5560

Gln Tyr Gly Ser Thr Tyr Arg Val Val Ser Val Cys Thr Val Leu His 65 70 7580

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

- 440 046387

9095

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

100 105110

Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Lys Glu Met

115 120125

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

130 135140

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

145 150 155160

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

165 170175

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

180 185190

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

195 200205

Lys Ser Leu Ser Leu Ser Pro Gly Lys

210215 <210> 275 <211> 216 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 275

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

5 1015

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

2530

Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 4045

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

5560

Gln Tyr Gly Ser Thr Tyr Arg Val Val Ser Val Cys Thr Val Leu His

- 441 046387

70 7580

Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 9095

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

100 105110

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

115 120125

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

130 135140

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

145 150 155160

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

165 170175

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

180 185190

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

195 200205

Lys Ser Leu Ser Leu Ser Pro Gly

210215 <210> 276 <211> 325 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 276

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

5 1015

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

2530

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

4045

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

- 442 046387

55 60

Gln 65

Gln

Ala

Pro

Thr

Ser 145

Tyr

Tyr

Phe

Lys

Gly 225

Gly

Cys

Gln

Pro

Tyr Gly Ser Thr Tyr Arg Val Val 70

Ser Val Cys Thr Val Leu His

80

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 90 95

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

100 105 110

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

115 120 125

Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 130 135 140

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

150 155 160

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

165 170 175

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

180 185 190

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

195 200 205

Ser Leu Ser Leu Ser Pro Gly Gly Asp His Cys Pro Leu Gly Pro

210 215 220

Arg Cys Cys Arg Leu His Thr Val Arg Ala Ser Leu Glu Asp Leu

230 235 240

Trp Ala Asp Trp Val Leu Ser Pro Arg Glu Val Gln Val Thr Met

245 250 255

Ile Gly Ala Cys Pro Ser Gln Phe Arg Ala Ala Asn Met His Ala

260 265 270

Ile Lys Thr Ser Leu His Arg Leu Lys Pro Asp Thr Val Pro Ala

275 280 285

Cys Cys Val Pro Ala Ser Tyr Asn Pro Met Val Leu Ile Gln Lys 290 295 300

- 443 046387

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

305 310 315 320

Asp Cys His Cys Ile

325 <210> 277 <211> 975 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polynucleotide <400> 277

gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataattg caagacaaag 180 ccgcgggagg agcagtacgg cagcacgtac cgtgtggtca gcgtctgcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 ccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtgcacc 360 ctgcccccat cccggggaga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tggggagagca atggggcagcc ggagaacaac 480 tacgacacca cgcctcccgt gctggactcc gacggctcct tcttcctcta tagcgacctc 540 accgtggac agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccggggtgg agaccactgt 660 ccgctcgggc ccgggcgttg ctgccgtctg cacacggtcc gcgcgtcgct ggaagacctg 720 ggctgggccg attgggtgct gtcgccacgg gaggtgcaag tgaccatgtg catcggcgcg 780 tgcccgagcc agttccggggc ggcaaacatg cacgcgcaga tcaagacgag cctgcaccgc 840 ctgaagcccg acacggtgcc agcgccctgc tgcgtgcccg ccagctacaa tcccatggtg 900 ctcattcaaa agaccgacac cggggtgtcg ctccagacct atgatgactt gttagccaaa 960 gactgccact gcata 975

<210> 278 <211> 651 <212> DNA <213> Artificial sequence <220>

<221> source <223> /note=description of artificial sequence: synthetic polynucleotide

- 444 046387

<400> 278 gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataattg caagacaaag 180 ccgcgggagg agcagtacgg cagcacgtac cgtgtggtca gcgtctgcac cgtgctccac 240 caggactggc ttaatgggaa ggaatacaag tgtaaggtgt ccaacaaggc cctccccgct 300 cccatcgaaa agaccatctc aaaggcaaag gggcaaccaa gggaacctca agtgtacacc 360 ctgcctccgt gcaggaagga gatgaccaag aaccaggtca gcctgacttg tctcgtgaag 420 ggcttctatc ccagcgatat tgctgtggaa tggggagtcaa atggccagcc cgagaataac 480 tacaaaacta ccccacccgt gctgaaatct gatgggtcct tcttccttta ctccaagctg 540 accgtggac agagccgctg gcaacaaggc aatgtcttta gctgctcagt gatgcatgag 600 gctctccata atcactacac tcagaagtca ctgtccctgt ctccgggtaa a 651

<210> 279 <211> 328 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 279

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

5 1015

Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 2530

Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 4045

Val Asp Gly Val Glu Val His Asn Cys Lys Thr Lys Pro Arg Glu Glu 50 5560

Gln Tyr Gly Ser Thr Tyr Arg Val Val Ser Val Cys Thr Val Leu His 65 70 7580

Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 9095

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

100 105110

- 445 046387

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

115 120 125

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

130 135 140

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

145 150 155

Tyr Asp Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe

165 170 175

Tyr Ser Asp Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn

180 185 190

Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr

195 200 205

Lys Ser Leu Ser Leu Ser Pro Gly Ala Arg Asp Gly Asp His Cys

210 215 220

Leu Gly Pro Gly Arg Cys Cys Arg Leu His Thr Val Arg Ala Ser

225 230 235

Glu Asp Leu Gly Trp Ala Asp Trp Val Leu Ser Pro Arg Glu Val

245 250 255

Val Thr Met Cys Ile Gly Ala Cys Pro Ser Gln Phe Arg Ala Ala

260 265 270

Met His Ala Gln Ile Lys Thr Ser Leu His Arg Leu Lys Pro Asp

275 280 285

Val Pro Ala Pro Cys Cys Val Pro Ala Ser Tyr Asn Pro Met Val

290 295 300

Ile Gln Lys Thr Asp Thr Gly Val Ser Leu Gln Thr Tyr Asp Asp

305 310 315

Met

Pro

Asn 160

Leu

Val

Gln

Pro

Leu 240

Gln

Asn

Thr

Leu

Leu 320

Leu Ala Lys Asp Cys His Cys Ile

325 <210> 280 <211> 984 <212> DNA <213> Artificial sequence <220>

- 446 046387 <221> source <223> /note=''description of artificial sequence: synthetic polynucleotide <400> 280 gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataattg caagacaaag180 ccgcgggagg agcagtacgg cagcacgtac cgtgtggtca gcgtctgcac cgtcctgcac240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc300 cccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtgcacc360 ctgcccccat cccgggagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa420 ggcttctatc cca gcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac480 tacgacacca cgcctcccgt gctggactcc gacggctcct tcttcctcta tagcgacctc540 accgtggaca agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag600 gctctgcaca accactacac gcagaagagc ctctccctgt ctccgggtgc gcgcgacgga660 gaccactgtc cgctcgggcc cgggcgttgc tgccgtctgc acacggtccg cgcgtcgctg720 gaagacctgg gctgggccga ttgggtgctg tcgccacggg aggtgcaagt gaccatgtgc780 atcggcgcgt gcccgagcca gttccgggcg gcaaacatgc acgcgcagat caagacgagc840 ctgcaccgcc tgaagcccga cacggtgcca gcgccctgct gcgtgcccgc cagctacaat900 cccatggtgc tcattca aaa gaccgacacc ggggtgtcgc tccagaccta tgatgacttg960 ttagccaaag actgccactg cata984 <210> 281 <211> 216 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=description of artificial sequence: synthetic polypeptide <400> 281

Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys

5 1015

Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 2530

Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 4045

- 447 046387

Val Asp Gly Val Glu Val His Asn Ala Lys Thr

55

Lys Pro Arg Glu Glu

Gln 65

Tyr

Asn

Ser

Thr

Tyr 70

Arg

Val

Val

Ser

Val 75

Leu

Thr

Val

Leu

His 80

Gln

Asp

Trp

Leu

Asn 85

Gly

Lys

Glu

Tyr

Lys 90

Cys

Lys

Val

Ser

Asn 95

Lys

Ala

Leu

Pro

Ala

100

Pro

Ile

Glu

Lys

Thr

105

Ile

Ser

Lys

Ala

Lys 110

Gly

Gln

Pro

Arg

Glu

115

Pro

Gln

Val

Tyr

Thr

120

Leu

Pro

Pro

Ser

Arg 125

Asp

Glu

Leu

Thr

Lys 130

Asn

Gln

Val

Ser

Leu

135

Ser

Cys

Ala

Val

Lys 140

Gly

Phe

Tyr

Pro

Ser

145

Asp

Ile

Ala

Val

Glu

150

Trp

Glu

Ser

Asn

Gly 155

Gln

Pro

Glu

Asn

Asn

160

Tyr

Lys

Thr

Thr

Pro

165

Pro

Val

Leu

Asp

Ser

170

Asp

Gly

Ser

Phe

Phe

175

Leu

Val

Ser

Lys

Leu

180

Thr

Val

Asp

Lys

Ser

185

Arg

Trp

Gln

Gln

Gly 190

Asn

Val

Phe

Ser

Cys

195

Ser

Val

Met

His

Glu

200

Ala

Leu

His

Asn

His

205

Tyr

Thr

Gln

Lys Ser Leu Ser Leu Ser Pro Gly

210 215 <210> 282 <211> 216 <212> PRT <213>

Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 282

Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro ProLys

5 1015

Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr CysVal

2530

- 448 046387

Val Val Asp Val Ser His Glu Asp Pro Glu Val

40

Lys Phe Asn Trp Tyr

Val Asp Gly Val

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 55 60

Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 75 80

Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys 85 90

Lys Val Ser Asn Lys

Ala Leu Pro Ala Pro

100

Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln

105 110

Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 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 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn

145 150 155 160

Tyr Asp Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu

165 170 175

Tyr Ser Asp 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

210 215 <210> 283 <211> 216 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 283

Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys

5 10 15

- 449 046387

Pro

Lys

Asp

Thr 20

Leu

Met

Ile

Ser

Arg 25

Thr

Pro

Glu

Val

Thr

Cys

Val

Val

Val

Asp 35

Val

Ser

His

Glu

Asp 40

Pro

Glu

Val

Lys

Phe 45

Asn

Trp

Tyr

Val

Asp 50

Gly

Val

Glu

Val

His 55

Asn

Ala

Lys

Thr

Lys 60

Pro

Arg

Glu

Glu

Gln 65

Tyr

Asn

Ser

Thr

Tyr 70

Arg

Val

Val

Ser

Val 75

Leu

Thr

Val

Leu

His 80

Gln

Asp

Trp

Leu

Asn 85

Gly

Lys

Glu

Tyr

Lys 90

Cys

Lys

Val

Ser

Asn 95

Lys

Ala

Leu

Pro

Ala

100

Pro

Ile

Glu

Lys

Thr

105

Ile

Ser

Lys

Ala

Lys

110

Gly

Gln

Pro

Arg

Glu

115

Pro

Gln

Val

Tyr

Thr

120

Leu

Pro

Pro

Ser

Arg

125

Lys

Glu

Met

Thr

Lys 130

Asn

Gln

Val

Ser

Leu

135

Thr

Cys

Leu

Val

Lys 140

Gly

Phe

Tyr

Pro

Ser

145

Asp

Ile

Ala

Val

Glu

150

Trp

Glu

Ser

Asn

Gly 155

Gln

Pro

Glu

Asn

Asn

160

Tyr

Lys

Thr

Thr

Pro

165

Pro

Val

Leu

Lys

Ser

170

Asp

Gly

Ser

Phe

Phe

175

Leu

Tyr

Ser

Lys

Leu

180

Thr

Val

Asp

Lys

Ser 185

Arg

Trp

Gln

Gln

Gly 190

Asn

Val

Phe

Ser

Cys 195

Ser

Val

Met

His

Glu

200

Ala

Leu

His

Asn

His

205

Tyr

Thr

Gln

Lys

Ser

210

Leu

Ser

Leu

Ser

Pro

215

Gly <210>

<211>

<212>

<213>

284

216

PRT

Artificial sequence <220>

<221>

<223>

source/note=''description of artificial sequence: synthetic polypeptide <400>

284

- 450 046387

Ala 1

Pro

Glu

Leu

Leu 5

Gly

Gly

Pro

Ser

Val 10

Phe

Leu

Phe

Pro

Pro 15

Lys

Pro

Lys

Asp

Thr

Leu

Met

Ile

Ser

Arg 25

Thr

Pro

Glu

Val

Thr

Cys

Val

Val

Val

Asp 35

Val

Ser

His

Glu

Asp 40

Pro

Glu

Val

Lys

Phe 45

Asn

Trp

Tyr

Val

Asp 50

Gly

Val

Glu

Val

His 55

Asn

Ala

Lys

Thr

Lys 60

Pro

Arg

Glu

Glu

Gln 65

Tyr

Asn

Ser

Thr

Tyr 70

Arg

Val

Val

Ser

Val 75

Leu

Thr

Val

Leu

His 80

Gln

Asp

Trp

Leu

Asn 85

Gly

Lys

Glu

Tyr

Lys 90

Cys

Lys

Val

Ser

Asn 95

Lys

Ala

Leu

Pro

Ala

100

Pro

Ile

Glu

Lys

Thr

105

Ile

Ser

Lys

Ala

Lys

110

Gly

Gln

Pro

Arg

Glu

115

Pro

Gln

Val

Cys

Thr

120

Leu

Pro

Pro

Ser

Arg 125

Glu

Glu

Met

Thr

Lys

130

Asn

Gln

Val

Ser

Leu

135

Thr

Cys

Leu

Val

Lys 140

Gly

Phe

Tyr

Pro

Ser

145

Asp

Ile

Ala

Val

Glu

150

Trp

Glu

Ser

Asn

Gly 155

Gln

Pro

Glu

Asn

Asn

160

Tyr

Asp

Thr

Thr

Pro

165

Pro

Val

Leu

Asp

Ser

170

Asp

Gly

Ser

Phe

Phe

175

Leu

Tyr

Ser

Asp

Leu

180

Thr

Val

Asp

Lys

Ser

185

Arg

Trp

Gln

Gln

Gly 190

Asn

Val

Phe

Ser

Cys 195

Ser

Val

Met

His

Glu

200

Ala

Leu

His

Asn

His

205

Tyr

Thr

Gln

Lys Ser Leu Ser Leu Ser Pro Gly

210 215 <210> 285 <211> 216 <212> PRT <213> Artificial <220>

<221> source sequence

- 451 046387 <223> /note=’’description of the polypeptide of the artificial sequence:

synthetic <400> 285

Ala Pro Glu Leu 1

Leu Gly Gly Pro 5

Ser Val Phe Leu

Phe Pro Pro Lys 15

Pro Lys Asp Thr

Leu Met Ile Ser

Arg Thr Pro Glu 25

Val Thr Cys Val 30

Val Val Asp Val

Ser His Glu Asp 40

Pro Glu Val Lys

Phe Asn Trp Tyr 45

Val Asp Gly Val 50

Glu Val His Asn

Ala Lys Thr Lys 60

Pro Arg Glu Glu

Gln Tyr Asn Ser 65

Thr Tyr Arg Val 70

Val Ser Val Leu

Thr Val Leu His

Gln Asp Trp Leu

Asn Gly Lys Glu 85

Tyr Lys Cys Lys 90

Val Ser Asn Lys

Ala Leu Pro Ala

100

Pro Ile Glu Lys

Thr Ile Ser Lys 105

Ala Lys Gly Gln 110

Pro Arg Glu Pro

115

Gln Val Tyr Thr

120

Leu Pro Pro Cys

Arg Lys Glu Met 125

Thr Lys Asn Gln 130

Val Ser Leu Thr

135

Cys Leu Val Lys

140

Gly Phe Tyr Pro

Ser Asp Ile Ala 145

Val Glu Trp Glu

150

Ser Asn Gly Gln

155

Pro Glu Asn Asn

160

Tyr Lys Thr Thr

Pro Pro Val Leu 165

Lys Ser Asp Gly

170

Ser Phe Phe Leu

175

Tyr Ser Lys Leu

180

Thr Val Asp Lys

Ser Arg Trp Gln 185

Gln Gly Asn Val

190

Phe Ser Cys Ser

195

Val Met His Glu

200

Ala Leu His Asn

His Tyr Thr Gln 205

Lys Ser Leu Ser Leu Ser Pro Gly

210 215 <210> 286 <211> 216 <212> PRT

- 452 046387 <213> Artificial sequence <220>

<221> source <223> /note=description of artificial sequence: synthetic polypeptide” <400> 286

Ala Pro Glu Leu 1

Leu Gly Gly Pro 5

Ser Val Phe Leu

Phe Pro Pro Lys 15

Pro Lys Asp Thr

Leu Met Ile Ser

Arg Thr Pro Glu 25

Val Thr Cys Val 30

Val Val Asp Val

Ser His Glu Asp 40

Pro Glu Val Lys

Phe Asn Trp Tyr 45

Val Asp Gly Val 50

Glu Val His Asn

Ala Lys Thr Lys 60

Pro Arg Glu Glu

Gln Tyr Asn Ser 65

Thr Tyr Arg Val 70

Val Ser Val Leu

Thr Val Leu His

Gln Asp Trp Leu

Asn Gly Lys Glu 85

Tyr Lys Cys Lys 90

Val Ser Asn Lys

Ala Leu Pro Ala

100

Pro Ile Glu Lys

Thr Ile Ser Lys 105

Ala Lys Gly Gln 110

Pro Arg Glu Pro

115

Gln Val Tyr Thr

120

Cys Pro Pro Ser

Arg Lys Glu Met 125

Thr Lys Asn Gln 130

Val Ser Leu Thr

135

Cys Leu Val Lys

140

Gly Phe Tyr Pro

Ser Asp Ile Ala 145

Val Glu Trp Glu

150

Ser Asn Gly Gln

155

Pro Glu Asn Asn

160

Tyr Lys Thr Thr

Pro Pro Val Leu 165

Lys Ser Asp Gly

170

Ser Phe Phe Leu

175

Tyr Ser Lys Leu

180

Thr Val Asp Lys

Ser Arg Trp Gln 185

Gln Gly Asn Val

190

Phe Ser Cys Ser

195

Val Met His Glu

200

Ala Leu His Asn

His Tyr Thr Gln 205

Lys Ser Leu Ser Leu Ser Pro Gly

210 215

- 453 046387 <210> 287 <211> 216 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 287

Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys

5 1015

Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 2530

Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr

4045

Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 5560

Gln Tyr Gly Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 7580

Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 9095

Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln

100 105110

Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Lys Glu Met

115 120125

Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro

130 135140

Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn

145 150 155160

Tyr Lys Thr Thr Pro Pro Val Leu Lys Ser Asp Gly Ser Phe Phe Leu

165 170175

Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val

180 185190

Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln

195 200205

- 454 046387

Lys Ser Leu Ser Leu Ser Pro Gly

210 215 <210> 288 <211> 216 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 288

Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys

5 1015

Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 2530

Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 4045

Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 5560

Gln Tyr Gly Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 7580

Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 9095

Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln

100 105110

Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Lys Glu Met

115 120125

Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro

130 135140

Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn

145 150 155160

Tyr Lys Thr Thr Pro Pro Val Leu Lys Ser Asp Gly Ser Phe Phe Leu

165 170175

Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val

180 185190

- 455 046387

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

210 215 <210> 289 <211> 216 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 289

Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro ProLys

5 1015

Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr CysVal

2530

Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr

4045

Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 5560

Gln Tyr Gly Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 7580

Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 9095

Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln

100 105110

Pro Arg Glu Pro Gln Val Tyr Thr Cys Pro Pro Ser Arg Glu Glu Met

115 120125

Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro

130 135140

Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn

145 150 155160

Tyr Lys Thr Thr Pro Pro Val Leu Lys Ser Asp Gly Ser Phe Phe Leu

165 170175

- 456 046387

Tyr Ser Lys Leu Thr Val Asp Lys

180

Ser Arg Trp Gln Gln Gly Asn Val

185 190

Phe Ser Cys

195

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln

200 205

Lys Ser Leu Ser Leu Ser Pro Gly

210 215 <210> 290 <211> 216 <212> PRT <213>

Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 290

Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys

5 10 15

Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 25 30

Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr

40 45

Val Asp Gly Val Glu Val His Asn Cys Lys Thr Lys Pro Arg Glu Glu 50 55 60

Gln Tyr Gly Ser Thr Tyr Arg Val Val Ser Val Cys Thr Val Leu His 65 70 75 80

Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 90 95

Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln

100 105 110

Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Lys 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 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn

145 150 155 160

- 457 046387

Tyr

Lys

Thr

Thr

Pro

165

Pro

Val

Leu

Lys

Ser

170

Asp

Gly

Ser

Phe

Phe

175

Leu

Tyr

Ser

Lys

Leu

180

Thr

Val

Asp

Lys

Ser

185

Arg

Trp

Gln

Gln

Gly 190

Asn

Val

Phe

Ser

Cys 195

Ser

Val

Met

His

Glu

200

Ala

Leu

His

Asn

His

205

Tyr

Thr

Gln

Lys Ser Leu Ser Leu Ser Pro Gly

210 215 <210> 291 <211> 216 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 291

Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys

5 1015

Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 2530

Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr

4045

Val Asp Gly Val Glu Val His Asn Cys Lys Thr Lys Pro Arg Glu Glu 50 5560

Gln Tyr Gly Ser Thr Tyr Arg Val Val Ser Val Cys Thr Val Leu His 65 70 7580

Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 9095

Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln

100 105110

Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Lys Glu Met

115 120125

Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro

130 135140

- 458 046387

Ser

145

Asp

Ile

Ala

Val

Glu

150

Trp

Glu

Ser

Asn

Gly 155

Gln

Pro

Glu

Asn

Asn

160

Tyr

Lys

Thr

Thr

Pro

165

Pro

Val

Leu

Lys

Ser

170

Asp

Gly

Ser

Phe

Phe

175

Leu

Tyr

Ser

Lys

Leu

180

Thr

Val

Asp

Lys

Ser

185

Arg

Trp

Gln

Gln

Gly 190

Asn

Val

Phe

Ser

Cys 195

Ser

Val

Met

His

Glu

200

Ala

Leu

His

Asn

His

205

Tyr

Thr

Gln

Lys Ser Leu Ser Leu Ser Pro Gly

210 215 <210> 292 <211> 209 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 292

Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile

5 1015

Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 20 2530

Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 35 4045

Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 50 5560

Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 65 70 7580

Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 85 9095

Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr

100 105110

Thr Leu Pro Pro Ser Arg Lys Glu Met Thr Lys Asn Gln Val Ser Leu

115 120125

- 459 046387

Thr

Cys 130

Leu

Val

Lys

Gly

Phe

135

Tyr

Pro

Ser

Asp

Ile

140

Ala

Val

Glu

Trp

Glu

145

Ser

Asn

Gly

Gln

Pro

150

Glu

Asn

Asn

Tyr

Lys

155

Thr

Thr

Pro

Pro

Val

160

Leu

Lys

Ser

Asp

Gly 165

Ser

Phe

Phe

Leu

Tyr

170

Ser

Lys

Leu

Thr

Val

175

Asp

Lys

Ser

Arg

Trp 180

Gln

Gln

Gly

Asn

Val

185

Phe

Ser

Cys

Ser

Val

190

Met

His

Glu

Ala

Leu

195

His

Asn

His

Tyr

Thr

200

Gln

Lys

Ser

Leu

Ser

205

Leu

Ser

Pro

Gly <210> 293 <211> 209 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 293

Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile

5 1015

Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 20 2530

Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 35 4045

Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 50 5560

Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 65 70 7580

Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 85 9095

Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr

100 105110

- 460 046387

Thr

Leu

Pro

115

Pro

Cys

Arg

Lys

Glu

120

Met

Thr

Lys

Asn

Gln

125

Val

Ser

Leu

Thr

Cys 130

Leu

Val

Lys

Gly

Phe

135

Tyr

Pro

Ser

Asp

Ile 140

Ala

Val

Glu

Trp

Glu

145

Ser

Asn

Gly

Gln

Pro

150

Glu

Asn

Asn

Tyr

Lys

155

Thr

Thr

Pro

Pro

Val

160

Leu

Lys

Ser

Asp

Gly 165

Ser

Phe

Phe

Leu

Tyr 170

Ser

Lys

Leu

Thr

Val

175

Asp

Lys

Ser

Arg

Trp

180

Gln

Gln

Gly

Asn

Val

185

Phe

Ser

Cys

Ser

Val

190

Met

His

Glu

Ala

Leu

195

His

Asn

His

Tyr

Thr

200

Gln

Lys

Ser

Leu

Ser

205

Leu

Ser

Pro

Gly <210> 294 <211> 226 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 294

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly

5 1015

Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr LeuMet

2530

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 4045

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 5560

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser ThrTyr

70 7580

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu AsnGly

9095

- 461 046387

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

100105

Leu Pro Ala Pro Ile

110

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

115 120125

Tyr Thr Leu Pro Pro Ser Arg Lys Glu Met Thr Lys Asn Gln Val Ser

130 135140

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

145 150 155160

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

165 170175

Val Leu Lys Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

180 185190

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

195 200205

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

210 215220

Pro Gly 225 <210> 295 <211> 209 <212> PRT <213> Artificial Sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 295

Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu MetIle

5 1015

Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser HisGlu

2530

Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 35 4045

Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr Arg

5560

- 462 046387

Val 65

Val

Ser

Val

Leu

Thr

Val

Leu

His

Gln

Asp 75

Trp

Leu

Asn

Gly

Lys 80

Glu

Tyr

Lys

Cys

Lys 85

Val

Ser

Asn

Lys

Ala 90

Leu

Pro

Ala

Pro

Ile 95

Glu

Lys

Thr

Ile

Ser

100

Lys

Ala

Lys

Gly

Gln

105

Pro

Arg

Glu

Pro

Gln

110

Val

Tyr

Thr

Leu

Pro

115

Pro

Ser

Arg

Lys

Glu

120

Met

Thr

Lys

Asn

Gln

125

Val

Ser

Leu

Thr

Cys 130

Leu

Val

Lys

Gly

Phe

135

Tyr

Pro

Ser

Asp

Ile

140

Ala

Val

Glu

Trp

Glu

145

Ser

Asn

Gly

Gln

Pro

150

Glu

Asn

Asn

Tyr

Lys

155

Thr

Thr

Pro

Pro

Val

160

Leu

Lys

Ser

Asp

Gly 165

Ser

Phe

Phe

Leu

Tyr 170

Ser

Lys

Leu

Thr

Val

175

Asp

Lys

Ser

Arg

Trp 180

Gln

Gln

Gly

Asn

Val

185

Phe

Ser

Cys

Ser

Val

190

Met

His

Glu

Ala

Leu

195

His

Asn

His

Tyr

Thr

200

Gln

Lys

Ser

Leu

Ser

205

Leu

Ser

Pro

Gly <210> 296 <211> 209 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 296

Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu MetIle

5 1015

Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser HisGlu

2530

Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His

4045

- 463 046387

Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr Arg 50 5560

Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 65 70 7580

Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 85 9095

Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr

100 105110

Thr Leu Pro Pro Cys Arg Lys Glu Met Thr Lys Asn Gln Val

115 120125

Ser Leu

Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp

130 135140

Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val

145 150 155160

Leu Lys Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp

165 170175

Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His

180 185190

Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

195 200205

Gly <210> 297 <211> 209 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 297

Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu MetIle

5 1015

Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser HisGlu

2530

- 464 046387

Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 35 4045

Asn Cys Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr Arg 50 5560

Val Val Ser Val Cys Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 65 70 7580

Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 85 9095

Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr

100 105110

Thr Leu Pro Pro Ser Arg Lys Glu Met Thr Lys Asn Gln Val Ser Leu

115 120125

Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp

130 135140

Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val

145 150 155160

Leu Lys Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp

165 170175

Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His

180 185190

Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

195 200205

Gly <210> 298 <211> 209 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 298

Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile

5 10 15

- 465 046387

Ser Arg Thr Pro Glu Val Thr Cys 20

Val Val Val Asp Val Ser His Glu 25 30

Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 35 4045

Asn Cys Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr Arg 50 5560

Val Val Ser Val Cys Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 65 70 7580

Glu Tyr Lys Cys

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 85 9095

Lys

Thr

Ile

Ser

100

Lys

Ala

Lys

Gly

Gln

105

Pro

Arg

Glu

Pro

Gln

110

Val

Tyr

Thr Leu Pro Pro Cys Arg Lys Glu Met Thr Lys Asn Gln Val Ser Leu

115 120125

Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp

130 135140

Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val

145 150 155160

Leu Lys Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp

165 170175

Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His

180 185190

Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

195 200205

Gly <210> 299 <211> 211 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide

- 466 046387 <400> 299

Gly 1

Gly

Pro

Ser

Val 5

Phe

Leu

Phe

Pro

Pro 10

Lys

Pro

Lys

Asp

Thr 15

Leu

Met

Ile

Ser

Arg 20

Thr

Pro

Glu

Val

Thr

Cys

Val

Val

Val

Asp 30

Val

Ser

His

Glu

Asp 35

Pro

Glu

Val

Lys

Phe 40

Asn

Trp

Tyr

Val

Asp 45

Gly

Val

Glu

Val

His 50

Asn

Ala

Lys

Thr

Lys 55

Pro

Arg

Glu

Glu

Gln 60

Tyr

Asn

Ser

Thr

Tyr 65

Arg

Val

Val

Ser

Val 70

Leu

Thr

Val

Leu

His 75

Gln

Asp

Trp

Leu

Asn 80

Gly

Lys

Glu

Tyr

Lys 85

Cys

Lys

Val

Ser

Asn 90

Lys

Ala

Leu

Pro

Ala 95

Pro

Ile

Glu

Lys

Thr

100

Ile

Ser

Lys

Ala

Lys 105

Gly

Gln

Pro

Arg

Glu

110

Pro

Gln

Val

Tyr

Thr

115

Leu

Pro

Pro

Ser

Arg

120

Lys

Glu

Met

Thr

Lys 125

Asn

Gln

Val

Ser

Leu

130

Thr

Cys

Leu

Val

Lys 135

Gly

Phe

Tyr

Pro

Ser

140

Asp

Ile

Ala

Val

Glu

145

Trp

Glu

Ser

Asn

Gly 150

Gln

Pro

Glu

Asn

Asn

155

Tyr

Lys

Thr

Thr

Pro

160

Pro

Val

Leu

Lys

Ser

165

Asp

Gly

Ser

Phe

Phe

170

Leu

Tyr

Ser

Lys

Leu

175

Thr

Val

Asp

Lys

Ser

180

Arg

Trp

Gln

Gln

Gly 185

Asn

Val

Phe

Ser

Cys 190

Ser

Val

Met

His

Glu

195

Ala

Leu

His

Asn

His

200

Tyr

Thr

Gln

Lys

Ser

205

Leu

Ser

Leu

Ser Pro Gly

210 <210> 300 <211> 211 <212> PRT <213> Artificial sequence <220>

- 467 046387 <221> source <223> /note=’’description of the artificial sequence: synthetic polypeptide <400> 300

Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu

5 1015

Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp ValSer

2530

His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 35 4045

Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 50 5560

Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp LeuAsn

70 7580

Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro AlaPro

9095

Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 100 105110

Val Tyr Thr Leu Pro Pro Cys Arg Lys Glu Met Thr Lys Asn Gln Val

115 120125

Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val

130 135140

Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr ThrPro

145 150 155160

Pro Val Leu Lys Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys LeuThr

165 170175

Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 180 185190

Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 195 200205

Ser Pro Gly

210 <210> 301 <211> 210

- 468 046387 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 301

Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

5 1015

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 20 2530

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 35 4045

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 50 5560

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 65 70 7580

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 85 9095

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

100 105110

Tyr Thr Leu Pro Pro Ser Arg Lys Glu Met Thr Lys Asn Gln Val Ser

115 120125

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

130 135140

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

145 150 155160

Val Leu Lys Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

165 170175

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

180 185190

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

195 200205

Pro Gly

210

- 469 046387 <210> 302 <211> 210 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 302

Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

5 1015

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 20 2530

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 35 4045

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 50 5560

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 65 70 7580

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 85 9095

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

100 105110

Tyr Thr Leu Pro Pro Cys Arg Lys Glu Met Thr Lys Asn Gln Val Ser

115 120125

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

130 135140

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

145 150 155160

Val Leu Lys Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

165 170175

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

180 185190

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

195 200205

- 470 046387

Pro Gly

210 <210> 303 <211> 212 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 303

Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu

5 1015

Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 20 2530

His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 35 4045

Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 50 5560

Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 65 70 7580

Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro 85 9095

Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln

100 105110

Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val

115 120125

Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val

130 135140

Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro

145 150 155160

Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr

165 170175

Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val

180 185190

- 471 046387

Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu

195 200 205

Ser Pro Gly Lys

210 <210> 304 <211> 211 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 304

Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

5 1015

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 20 2530

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 35 4045

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 50 5560

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 65 70 7580

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 85 9095

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

100 105110

Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser

115 120125

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

130 135140

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

145 150 155160

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

165 170175

- 472 046387

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

180 185

Ser Cys Ser Val Met

190

His Glu Ala Leu His Asn His Tyr Thr Gln Lys

195 200

Ser Leu Ser Leu Ser

205

Pro Gly Lys

210 <210> 305 <211> 210 <212> PRT <213> Artificial sequence <220>

<221> source <223> /note=''description of artificial sequence: synthetic polypeptide <400> 305

Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile

5 10 15

Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 20 25 30

Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 35 40 45

Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 50 55 60

Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 65 70 75 80

Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 85 90 95

Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr

100 105 110

Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu

115 120 125

Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp

130 135 140

Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val

145 150 155 160

- 473 046387

Leu Asp

Ser Asp

Lys Ser

Arg Trp

180

Glu Ala

Leu His 195

Gly Ser 165

Gln Gln

Asn His

Phe Phe

Gly Asn

Tyr Thr

200

Leu Tyr

170

Val Phe 185

Gln Lys

Ser Lys

Ser Cys

Ser Leu

Leu Thr

Ser Val

190

Ser Leu 205

Val Asp 175

Met His

Ser Pro

Gly Lys

210

Claims (20)

1. A fusion protein comprising a growth differentiation and factor 15 (GDF15) region fused to a human albumin (HSA) polypeptide, wherein the GDF15 region contains an amino acid sequence that has at least 85% sequence identity to SEQ ID NO: 4, 8 or 12 ; HSA polypeptide contains the amino acid sequence SEQ ID NO: 110; and the GDF15 region is connected to the HSA polypeptide by a polypeptide linker containing the amino acid sequence of SEQ ID NO: 113, 116, 119, 122 or 125. 2. The fusion protein according to claim 1, wherein the GDF15 region contains the amino acid sequence of SEQ ID NO: 4, 8, 12, 25, 52 or 55. 3. The fusion protein according to claim 1, wherein the GDF15 region contains an amino acid sequence that has at least 90% identity to SEQ ID NO: 12, and contains an aspartate or glutamine mutation at position 3. 4. The fusion protein according to claim 3, wherein the mutation at position 3 is an N3Q mutation. 5. The fusion protein according to claim 1, wherein the fusion protein contains the amino acid sequence of SEQ ID NO: 115, 118, 121, 124 or 127. 6. The fusion protein according to any one of claims 1 to 5, further comprising a second HSA polypeptide, wherein the second HSA polypeptide contains the amino acid sequence of SEQ ID NO: 110. 7. A construct comprising (i) a first protein comprising a fusion protein comprising a growth differentiation and factor 15 (GDF15) region fused to a human albumin (HSA) polypeptide, wherein the GDF15 region contains an amino acid sequence that has at least 85% identity sequences SEQ ID NO: 4, 8 or 12; HSA polypeptide contains the amino acid sequence SEQ ID NO: 110; and the GDF15 region is linked to the HSA polypeptide through a polypeptide linker comprising the amino acid sequence of SEQ ID NO: 113, 116, 119, 122 or 125, and (ii) a second protein comprising the GDF15 region, wherein the GDF15 region contains an amino acid sequence that has at least at least 85% sequence identity to SEQ ID NO: 4, 8 or 12. 8. The construct of claim 7, wherein the GDF15 region of the second protein contains the amino acid sequence of SEQ ID NO: 4, 8, 12, 25, 52 or 55. 9. The construct of claim 8, wherein the GDF15 region of the second protein contains an amino acid sequence that has at least 90% sequence identity to SEQ ID NO: 12, and contains an aspartate or glutamine mutation at position 3. 10. The construct of claim 9, wherein the mutation of the GDF15 region of the second protein at position 3 is an N3Q mutation. 11. The construct according to any one of claims 7 to 10, wherein the second protein further comprises a human albumin (HSA) polypeptide, wherein the HSA polypeptide of the second protein contains the amino acid sequence of SEQ ID NO: 110. - 474 046387 12. The construct according to claim 11, wherein the GDF15 region of the second protein is connected to the HSA polypeptide via a polypeptide linker. 13. The construction according to claim 12, where the polypeptide linker of the second protein contains the amino acid sequence SEQ ID NO: 18, 30, 34, 40, 58, 61, 64, 69, 72, 75, 78, 113, 116, 119, 122, 125 or 128. 14. The construct of claim 12 or 13, wherein the polypeptide linker of the second protein contains the amino acid sequence of SEQ ID NO: 18, 113, 116, 119, 122, 125 or 128. 15. The construct of claim 14, wherein the second protein contains the amino acid sequence of SEQ ID NO: 112, 115, 118, 121, 124, 127 or 130. 16. The construct according to any one of claims 11 to 15, wherein the second protein further comprises a second HSA polypeptide, wherein the second HSA polypeptide contains the amino acid sequence of SEQ ID NO: 110. 17. The structure according to any one of claims 7 to 16, wherein the first protein and the second protein are linked via a disulfide bond. 18. A pharmaceutical composition containing a fusion protein according to any one of claims 1 to 6 or a construct according to any of claims 7 to 17, for the treatment of a metabolic disorder. 19. The pharmaceutical composition according to claim 18, wherein the metabolic disorder is diabetes, obesity, dyslipidemia or diabetic nephropathy. 20. A pharmaceutical composition comprising a fusion protein according to any one of claims 1 to 6 or a construct according to any one of claims 7 to 17, for reducing food intake, body weight, insulin levels, triglyceride levels, cholesterol levels or glucose levels in a subject.