KR101709495B1 - 인간 신경성장인자에 대한 고친화성 인간 항체 - Google Patents
인간 신경성장인자에 대한 고친화성 인간 항체 Download PDFInfo
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- KR101709495B1 KR101709495B1 KR1020157030908A KR20157030908A KR101709495B1 KR 101709495 B1 KR101709495 B1 KR 101709495B1 KR 1020157030908 A KR1020157030908 A KR 1020157030908A KR 20157030908 A KR20157030908 A KR 20157030908A KR 101709495 B1 KR101709495 B1 KR 101709495B1
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Abstract
5 pM 또는 그 미만의 KD로 인간 신경성장인자 (NGF)에 특이적으로 결합하는 인간 항체 또는 항체의 항원-결합 단편은 뉴로트로핀-3 (NT-3)과 교차-반응하지 않으며, 랫트 및 마우스 NGF에 대한 항체 또는 단편의 결합보다 약 2 내지 약 10배 더 큰 KD로 인간 NGF에 결합한다. 이 항체는 간세포암, 유방암 및 간경화증과 같은 질병뿐만 아니라 염증성 통증, 수술-후 절개 통증, 신경병성 통증, 골절 통증, 골다공성 골절 통증, 포진후 신경통, 골관절염, 류마티스성 관절염, 암 통증, 화상으로 인한 통증, 통풍 관절 통증을 포함하는 통증을 치료하는데 유용하다.
Description
본 발명은 인간 신경성장인자 (NGF)에 특이적으로 결합하는 인간 항체 및 인간 항체의 항원-결합 단편, 및 이들 항체를 사용하는 치료학적 방법에 관한 것이다.
신경성장인자 (NGF)는 확인된 최초의 뉴로트로핀 (neurotrophin)이었으며, 말초 및 중추 뉴런 둘 다의 발생 및 생존에 있어서의 이의 역할은 잘 특정화되어 있다. NGF는 말초 교감신경 및 배아 감각신경 뉴런, 및 기저 전뇌 콜린성 뉴런의 발생에 있어서 중요한 생존 및 유지 인자인 것으로 나타났다 [Smeyne et al. (1994) Nature 368:246-249; Crowley et al. (1994) Cell 76:1001-1011]. NGF는 감각신경 뉴런에서 뉴로펩타이드의 발현을 상향조절하며 [Lindsay et al. (1989) Nature 337:362-364], 이의 활성은 두 개의 상이한 막-결합된 수용체인 TrkA 수용체 및 p75 공통 뉴로트로핀 수용체를 통해서 매개된다.
NGF는 류마티스성 관절염 및 그 밖의 다른 유형의 관절염을 앓고 있는 환자에서 활액에서 증가된다. NGF 길항제는 신경병성 및 만성 염증성 통증의 동물 모델에서 통각과민 및 이질통을 예방하는 것으로 나타났다.
항-NGF 항체는 예를 들어, WO 01/78698, WO 02/096458, WO 2004/032870, 미국 특허공개 제2005/0074821, 2004/0237124, 및 2004/0219144호에 기술되어 있다.
첫 번째 관점에서, 본 발명은 약 5 pM 또는 그 미만의 KD로 인간 신경성장인자 (NGF)에 특이적으로 결합하며, 뉴로트로핀-3 (NT-3)과 교차-반응하지 않는 완전한 인간 항체 및 이의 항원-결합 단편을 제공한다. 바람직한 구체예에서, 항-NGF 항체 또는 이의 단편은 1.0 pM 또는 그 미만의 KD로 인간 NGF에 결합한다. 이들 항체는 고친화성, 고특이성으로 NGF에 대한 결합 및 NGF 활성을 중화시키는 능력을 특징으로 한다. 바람직한 구체예에서, 항체 또는 이의 단편은 랫트 NGF 및/또는 마우스 NGF보다 약 2 내지 10배 더 크게 인간 NGF에 결합한다.
항체는 전체-길이일 수 있거나 (예를 들어, IgG1 또는 IgG4 항체), 단지 항원-결합 부분만을 포함할 수 있거나 (예를 들어, Fab, F(ab')2 또는 scFv 단편), 기능성을 나타내도록, 예를 들어, 잔류 효과기 기능을 제거하도록 변형될 수 있다 (잔류 효과기 기능을 제거하는 Glu) [Reddy et al. (2000) J. Immunol. 164:1925-1933].
한가지 구체예에서, 본 발명은 서열번호 4, 20, 36, 52, 68, 84, 100, 104, 108, 112, 116, 132, 136, 140, 156, 160, 176, 180, 184, 200, 204, 208, 224, 228, 232, 236, 240, 256, 260, 264, 280, 284, 288, 304, 308, 312, 328, 332, 336, 352, 356, 360, 376, 380, 384, 400, 404, 420, 424, 440, 456, 460, 464, 480, 484, 488, 504, 508, 512, 528 및 532의 그룹으로부터 선택된 중쇄 가변 부분 (HCVR) 또는 적어도 90%, 적어도 95%, 적어도 98% 또는 적어도 99% 서열 동일성을 갖는 이의 실질적으로 유사한 서열을 포함하는 항체 또는 항체의 항원-결합 단편을 포함하며; 더욱 바람직하게는, 항체 또는 이의 단편은 서열번호 108, 100 또는 84의 HCVR을 포함하고; 더 더욱 바람직하게는, HCVR은 서열번호 108에 나타낸 아미노산 서열을 포함한다.
한가지 구체예에서, 항체 또는 이의 단편은 또한, 서열번호 12, 28, 44, 60, 76, 92, 102, 106, 110, 114, 124, 134, 138, 148, 158, 168, 178, 182, 192, 202, 206, 216, 226, 230, 234, 238, 248, 258, 262, 272, 282, 286, 296, 306, 310, 320, 330, 334, 344, 354, 358, 368, 378, 382, 392, 402, 412, 422, 432, 448, 458, 462, 472, 482, 486, 496, 506, 510, 520, 530, 및 534의 그룹으로부터 선택된 경쇄 가변 부분 (LCVR), 또는 적어도 90%, 적어도 95%, 적어도 98% 또는 적어도 99% 서열 동일성을 갖는 이의 실질적으로 유사한 서열을 추가로 포함한다. 바람직한 구체예에서, LCVR은 서열번호 110, 102 또는 92이고; 더 더욱 바람직하게는, LCVR은 서열번호 110에 나타낸 아미노산 서열이다.
특정한 구체예에서, 항체 또는 이의 단편은 서열번호 4/12, 20/28, 36/44, 52/60, 68/76, 84/92, 100/102, 104/106, 108/110, 112/114, 116/124, 132/134, 136/138, 140/148, 156/158, 160/168, 176/178, 180/182, 184/192, 200/202, 204/206, 208/216, 224/226, 228/230, 232/234, 236/238, 240/248, 256/258, 260/262, 264/272, 280/282, 284/286, 288/296, 304/306, 308/310, 312/320, 328/330, 332/334, 336/344, 352/354, 356/358, 360/368, 376/378, 380/382, 384/392, 400/402, 404/412, 420/422, 424/432, 440/448, 456/458, 460/462, 464/472, 480/482, 484/486, 488/496, 504/506, 508/510, 512/520, 528/530 및 532/534의 그룹으로부터 선택된 HCVR 및 LCVR (HCVR/LCVR) 서열 쌍을 포함한다. 바람직한 구체예에서, HCVR/LCVR 쌍은 서열번호 108/110, 100/102 또는 84/92 중의 하나이며; 더욱 바람직하게는 서열번호 108/110이다.
두 번째 관점에서, 본 발명은 서열번호 10, 26, 42, 58, 74, 90, 122, 146, 166, 190, 214, 246, 270, 294, 318, 342, 366, 390, 410, 430, 446, 470, 494 및 518로부터 선택된 중쇄 CDR3 (HCDR3) 영역 또는 적어도 90%, 적어도 95%, 적어도 98% 또는 적어도 99% 서열 동일성을 갖는 이의 실질적으로 유사한 서열 ; 및 서열번호 18, 34, 50, 66, 82, 98, 130, 154, 174, 198, 222, 254, 278, 302, 326, 350, 374, 398, 418, 438, 454, 478, 502 및 526으로부터 선택된 경쇄 CDR3 (LCDR3) 영역 또는 적어도 90%, 적어도 95%, 적어도 98% 또는 적어도 99% 서열 동일성을 갖는 이의 실질적으로 유사한 서열을 포함하는 항체 또는 항체의 항원-결합 단편을 특징으로 한다. 바람직한 구체예에서, HCDR3/LCDR3 쌍은 서열번호 90 및 98; 214 및 222; 410 및 418; 430 및 438; 또는 446 및 454 중의 하나이며; 더욱 바람직하게는 서열번호 90 및 98이다.
추가의 구체예에서, 본 발명은 서열번호 6, 22, 38, 54, 70, 86, 118, 142, 162, 186, 210, 242, 266, 290, 314, 338, 362, 386, 406, 426, 442, 466, 490, 및 514로부터 선택된 중쇄 CDR1 (HCDR1) 영역 또는 적어도 90%, 적어도 95%, 적어도 98% 또는 적어도 99% 서열 동일성을 갖는 이의 실질적으로 유사한 서열; 서열번호 8, 24, 40, 56, 72, 88, 120, 144, 164, 188, 212, 244, 268, 292, 316, 340, 364, 388, 408, 428, 444, 468, 492 및 516으로부터 선택된 중쇄 CDR2 (HCDR2) 영역 또는 적어도 90%, 적어도 95%, 적어도 98% 또는 적어도 99% 서열 동일성을 갖는 이의 실질적으로 유사한 서열; 서열번호 14, 30, 46, 62, 78, 94, 126, 150, 170, 194, 218, 250, 274, 298, 322, 346, 370, 394, 414, 434, 450, 474, 498, 및 522로부터 선택된 경쇄 CDR1 (LCDR1) 영역 또는 적어도 90%, 적어도 95%, 적어도 98% 또는 적어도 99% 서열 동일성을 갖는 이의 실질적으로 유사한 서열; 및 서열번호 16, 32, 48, 64, 80, 96, 128, 152, 172, 196, 220, 252, 276, 300, 324, 348, 372, 396, 416, 436, 452, 476, 500 및 524로부터 선택된 경쇄 CDR2 (LCDR2) 영역 또는 적어도 90%, 적어도 95%, 적어도 98% 또는 적어도 99% 서열 동일성을 갖는 이의 실질적으로 유사한 서열을 추가로 포함하는 항체 또는 이의 단편을 포함한다. 바람직한 구체예에서, 중쇄 및 경쇄 CDR 서열은 서열번호 86, 88, 90, 94, 96 및 98; 210, 212, 214, 218, 220 및 222; 406, 408, 410, 414, 416 및 418; 442, 444, 446, 450, 452 및 454; 및 426, 428, 430, 434, 436 및 438이며; 더 더욱 바람직하게는, CDR 서열은 서열번호 86, 88, 90, 94, 96 및 98이다.
세 번째 관점에서, 본 발명은 항-NGF 항체 또는 이의 단편을 암호화하는 핵산 분자를 제공한다. 본 발명의 핵산을 포함하는 재조합 발현 벡터, 및 이러한 벡터를 도입시킨 숙주세포도 또한, 숙주세포를 항체의 생산을 허용하는 조건 하에서 배양하고, 생산된 항체를 회수함으로써 항체를 생산하는 방법과 마찬가지로 본 발명에 포함된다.
한가지 구체예에서, 본 발명은 서열번호 3, 19, 35, 51, 67, 83, 99, 103, 107, 111, 115, 131, 135, 139, 155, 159, 175, 179, 183, 199, 203, 207, 223, 227, 231, 235, 239, 255, 259, 263, 279, 283, 287, 303, 307, 311, 327, 331, 335, 351, 355, 359, 375, 379, 383, 399, 403, 419, 423, 439, 455, 459, 463, 479, 483, 487, 503, 507, 511, 527 및 531로부터 선택된 핵산 서열, 또는 이의 적어도 90%, 적어도 95%, 적어도 98%, 또는 적어도 99% 상동성을 갖는 실질적으로 동일한 서열에 의해서 암호화된 HCVR을 포함하는 항체 또는 이의 단편을 제공하며; 더욱 바람직하게는, HCVR은 서열번호 107 또는 99에 의해서 암호화된다.
한가지 구체예에서, 항체 또는 이의 단편은 추가로, 서열번호 11, 27, 43, 59, 75, 91, 101, 105, 109, 113, 123, 133, 137, 147, 157, 167, 177, 181, 191, 201, 205, 215, 225, 229, 233, 237, 247, 257, 261, 271, 281, 285, 295, 305, 309, 319, 329, 333, 343, 353, 357, 367, 377, 381, 391, 401, 411, 421, 431, 447, 457, 461, 471, 481, 485, 495, 505, 509, 519, 529 및 533으로부터 선택된 핵산 서열, 또는 이의 적어도 90%, 적어도 95%, 적어도 98%, 또는 적어도 99% 상동성을 갖는 실질적으로 동일한 서열에 의해서 암호화된 LCVR을 추가로 포함하며; 바람직하게는, LCVR은 서열번호 109 또는 101에 의해서 암호화된다.
한가지 구체예에서, 본 발명은 서열번호 9, 25, 41, 57, 73, 89, 121, 145, 165, 189, 213, 245, 269, 293, 317, 341, 365, 389, 409, 429, 445, 469, 493 및 517로부터 선택된 뉴클레오타이드 서열, 또는 이의 적어도 90%, 적어도 95%, 적어도 98%, 또는 적어도 99% 상동성을 갖는 실질적으로 동일한 서열에 의해서 암호화된 HCDR3 영역; 및 서열번호 17, 33, 49, 65, 81, 97, 129, 153, 173, 197, 221, 253, 277, 301, 325, 349, 373, 397, 417, 437, 453, 477, 501 및 525로부터 선택된 뉴클레오타이드 서열, 또는 이의 적어도 90%, 적어도 95%, 적어도 98%, 또는 적어도 99% 상동성을 갖는 실질적으로 동일한 서열에 의해서 암호화된 LCDR3 영역을 포함하는 항체 또는 항체의 항원-결합 단편을 특징으로 한다. 바람직한 구체예에서, HCDR3 및 LCDR3 서열은 각각 서열번호 89 및 97에 의해서 암호화된다.
추가의 구체예에서, 항체 또는 이의 단편은 추가로, 서열번호 5, 21, 37, 53, 69, 85, 117, 141, 161, 185, 209, 241, 265, 289, 313, 337, 361, 385, 405, 425, 441, 465, 489 및 513으로부터 선택된 뉴클레오타이드 서열, 또는 이의 적어도 90%, 적어도 95%, 적어도 98%, 또는 적어도 99% 상동성을 갖는 실질적으로 동일한 서열에 의해서 암호화된 HCDR1 영역; 서열번호 7, 23, 39, 55, 71, 87, 119, 143, 163, 187, 211, 243, 267, 291, 315, 339, 363, 387, 407, 427, 443, 467, 491 및 515로부터 선택된 뉴클레오타이드 서열, 또는 이의 적어도 90%, 적어도 95%, 적어도 98%, 또는 적어도 99% 상동성을 갖는 실질적으로 동일한 서열에 의해서 암호화된 HCDR2 영역; 서열번호 13, 29, 45, 61, 77, 93, 125, 149, 169, 193, 217, 249, 273, 297, 321, 345, 369, 393, 413, 433, 449, 473, 497 및 521로부터 선택된 뉴클레오타이드 서열, 또는 이의 적어도 90%, 적어도 95%, 적어도 98%, 또는 적어도 99% 상동성을 갖는 실질적으로 동일한 서열에 의해서 암호화된 LCDR1 영역; 및 서열번호 15, 31, 47, 63, 79, 95, 127, 151, 171, 195, 219, 251, 275, 299, 323, 347, 371, 395, 415, 435, 451, 475, 499 및 523으로부터 선택된 뉴클레오타이드 서열, 또는 이의 적어도 90%, 적어도 95%, 적어도 98%, 또는 적어도 99% 상동성을 갖는 실질적으로 동일한 서열에 의해서 암호화된 LCDR2 영역을 추가로 포함한다. 바람직한 구체예에서, 항체 또는 이의 단편은 서열번호 85, 87, 및 89에 의해서 암호화된 중쇄 CDR 서열; 및 서열번호 93, 95 및 97에 의해서 암호화된 경쇄 CDR 서열을 포함한다.
네 번째 관점에서, 본 발명은 HCDR3 및 LCDR3을 포함하는, 인간 NGF에 특이적으로 결합하는 분리된 항체 또는 항체의 항원-결합 단편을 특징으로 하며, 여기에서 HCDR3은 서열식 X1 - X2 - X3 - X4 - X5 - X6 - X7 - X8 - X9 - X10 - X11 - X12 - X13 - X14 - X15 - X16 - X17 - X18 (서열번호 537)의 아미노산 서열 [여기에서 X1은 Ala 또는 Ser이며, X2는 Thr 또는 Lys이고, X3은 Glu 또는 Ile이며, X4는 Phe 또는 Gly이고, X5는 Val 또는 Gly이며, X6은 Val 또는 Trp이고, X7은 Val 또는 Phe이며, X8은 Thr 또는 Gly이고, X9는 Asn 또는 Lys이며, X10은 Phe 또는 Leu이고, X11은 Asp 또는 Phe이며, X12는 Asn 또는 Ser이고, X13은 Ser이거나 부재하며; X14는 Tyr이거나 부재하며; X15는 Gly이거나 부재하고; X16은 Met이거나 부재하며; X17은 Asp이거나 부재하고; X18은 Val이거나 부재한다]을 포함하고; LCDR3은 서열식 X1 - X2 - X3 - X4 - X5 - X6 - X7 - X8 - X9 (서열번호 540)의 아미노산 서열 [여기에서, X1은 Gln이고, X2는 Gln이며, X3은 Tyr이고, X4는 Asn이며, X5는 Arg 또는 Asn이고, X6은 Tyr 또는 Trp이며, X7은 Pro이고, X8은 Tyr 또는 Trp이며, X9는 Thr이다]을 포함한다.
더욱 특정한 구체예에서, 항체 또는 이의 단편은 추가로, 서열식 X1 - X2 - X3 - X4 - X5 - X6 - X7 - X8 (서열번호 535)의 HCDR1 서열 [여기에서, X1은 Gly이고, X2는 Phe이며, X3은 Thr 또는 Asn이고, X4는 Phe 또는 Leu이며, X5는 Thr 또는 Asp이고, X6은 Asp 또는 Glu이며, X7은 Tyr 또는 Leu이고, X8은 Ser 또는 Ala이다]; 서열식 X1 - X2 - X3 - X4 - X5 - X6 - X7 - X8 (서열번호 536)의 HCDR2 서열 [여기에서, X1은 Ile 또는 Phe이고, X2는 Asp 또는 Ser이며, X3은 Pro 또는 Trp이고, X4는 Glu 또는 Asn이며, X5는 Asp 또는 Ser이고, X6은 Gly이며, X7은 Thr, Glu 또는 Ser이고, X8은 Thr 또는 Ile이다]; 서열식 X1 - X2 - X3 - X4 - X5 - X6 - X7 - X8 - X9 - X10 - X11 - X12 - X13 - X14 - X15 - X16 - X17 - X18 (서열번호 537)의 아미노산 서열을 포함하는 HCDR3 [여기에서, X1은 Ala 또는 Ser이고, X2는 Thr 또는 Lys이며, X3은 Glu 또는 Ile이고, X4는 Phe 또는 Gly이며, X5는 Val 또는 Gly이고, X6은 Val 또는 Trp이며, X7은 Val 또는 Phe이고, X8은 Thr 또는 Gly이며, X9는 Asn 또는 Lys이고, X10은 Phe 또는 Leu이며, X11은 Asp 또는 Phe이고, X12는 Asn 또는 Ser이며, X13은 Ser이거나 부재하고, X14는 Tyr이거나 부재하며, X15는 Gly이거나 부재하고, X16은 Met이거나 부재하며, X17은 Asp이거나 부재하고, X18은 Val이거나 부재한다]; 서열식 X1 - X2 - X3 - X4 - X5 - X6 (서열번호 538)의 LCDR1 서열 [여기에서, X1은 Gln 또는 Arg이고, X2는 Ala, Ser 또는 Thr이며, X3은 Val 또는 Ile이고, X4는 Arg 또는 Thr이며, X5는 Asn, Phe 또는 Tyr이고, X6은 Asp 또는 Asn이다]; 서열식 X1 - X2 - X3 (서열번호 539)의 LCDR2 서열 [여기에서, X1은 Gly 또는 Ala이고, X2는 Ala이며, X3은 Ser 또는 Phe이다]; 및 서열식 X1 - X2 - X3 - X4 - X5 - X6 - X7 - X8 - X9 (서열번호 540)의 아미노산 서열을 포함하는 LCDR3 [여기에서, X1은 Gln이고, X2는 Gln이며, X3은 Tyr이고, X4는 Asn이며, X5는 Arg 또는 Asn이고, X6은 Tyr 또는 Trp이며, X7은 Pro이고, X8은 Tyr 또는 Trp이며, X9는 Thr이다]을 추가로 포함한다.
다섯 번째 관점에서, 본 발명은 시험관내 PC12 세포-기본 시험방법 (이하에 기술됨)에서 측정된 바와 같이, 약 10 nM 미만의 IC50으로 NGF 활성을 차단하는 완전한 인간 항체 또는 항체 단편을 특징으로 한다. 바람직한 구체예에서, 본 발명의 항체는 약 500 pM 또는 그 미만의 IC50; 더 더욱 바람직하게는, 약 100 pM 또는 그 미만; 약 50 pM 또는 그 미만; 또는 약 25 pM 또는 그 미만의 IC50을 나타낸다.
한가지 구체예에서, 본 발명은 표면 플라즈몬 공명 (비아코어 (BIACORE™)에 의해서 측정된 것으로서, 약 500 pM 미만, 바람직하게는 약 300 pM 미만, 더 더욱 바람직하게는 약 100 pM 미만, 약 50 pM 미만, 약 20 pM 미만, 약 10 pM 미만, 약 5 pM 미만, 또는 약 1 pM 미만의 KD로 NGF에 결합하는 분리된 인간 항체, 또는 이의 항원-결합 부분을 제공한다. 바람직한 구체예에서, 본 발명의 항-NGF 인간 항체 또는 항체 단편은 약 0.5 pM 또는 그 미만의 KD로 인간 NGF에 결합한다. 바람직한 구체예에서, 항체 또는 이의 단편은 랫트 NGF보다 약 1.5배, 2배, 3배, 4배, 5배, 6배, 7배, 8배, 9배 또는 10배 더 큰 친화성 및 마우스 NGF보다 약 1.5배, 2배, 2.5배, 3배, 4배, 5배, 6배, 7배, 8배, 9배, 또는 10배 더 큰 친화성으로 인간 NGF에 결합한다.
바람직한 구체예에서, 항체 또는 이의 단편은 인간 NGF에 대해 고친화성을 나타내며, 예를 들어, 밀접하게 관련된 뉴로트로핀-3 (NT-3)과 교차-반응하지 않는다. 따라서, 바람직한 구체예에서, 고친화성 및 고선택성 항체 또는 이의 단편은 표면 플라즈몬 공명에 의해서 측정되는 바와 같이, 인간 NGF에 대해서 1.0 pM 또는 그 미만의 KD를 나타내며, 수용체 TrkA 및 p75에 대한 NGF의 결합을 억제하고, 인간 NT-3과 교차-반응하지 않는다. NT-3은 예를 들어, 근육운동 뉴런 공조와 같은 생리학적 과정에 있어서 결정적인 역할을 하며, 따라서 NT-3과 교차-반응하지 않는 항체 또는 항체 단편은 선행기술의 항체에 비해서 예기치 못한 임상적 및 치료학적 이점을 제공한다. NT-3은 신경병성 통증의 CCI 모델에서 온열 통각과민의 발생을 방지하는 것으로 나타났다 [참조: 예를 들어, Wilson-Gerwing et al. (2005) J Neuroscience 25:758-767]. 더욱 최근에, 외인성 NT-3은 신경병성 통증의 생성에 있어서 역할을 하는 것으로 보이는 2 개의 나트륨 채널의 발현을 상당히 감소시키는 것으로 나타났다 [Wilson-Gerwing & Verge (2006) Neuroscience 141:2075-2085]. 이들 데이터는 신경병성 통증에서의 NT-3의 유익한 역할을 시사한다.
본 발명은 변형된 글리코실화 패턴을 갖는 항-NGF 항체를 포함한다. 일부의 적용 시에는, 바람직하지 않은 글리코실화 부위를 제거하는 변형이 유용할 수 있거나, 예를 들어, 항체 의존적 세포성 세포독성 (ADCC) 기능을 증가시키기 위하여 올리고사카라이드 쇄 상에 존재하는 푸코즈 부위가 결여된 항체가 사용될 수도 있다 [참조: Shield et al. (2002) JBC 277:26733]. 다른 적용 시에는, 보체 의존적 세포독성 (CDC)을 변형시키기 위해서 갈락토실화의 변형이 이루어질 수 있다.
여섯 번째 관점에서, 본 발명은 NGF에 특이적으로 결합하는 재조합 인간 항체 또는 이의 단편, 및 허용되는 담체를 포함하는 조성물을 특징으로 한다. 관련된 관점에서, 본 발명은 NGF 억제제 및 제2 치료학적 약제의 조합인 조성물을 특징으로 한다. 한가지 구체예에서, NGF 억제제는 항체 또는 이의 단편이다. 바람직한 구체예에서, 제2 치료학적 약제는 NGF 억제제와 유리하게 조합되는 어떤 적합한 치료학적 약제라도 된다.
일곱 번째 관점에서, 본 발명은 본 발명의 항-NGF 항체 또는 항체의 항원-결합 부분을 사용하여 인간 NGF 활성을 억제하는 방법을 특징으로 한다. 치료되는 장애는 NGF 활성의 제거, 억제 또는 감소에 의해서 호전, 개선, 억제 또는 예방되는 모든 질병 또는 상태이다. 더욱 구체적으로, 본 발명은 본 발명의 항체 또는 항체 단편과 같은 NGF 억제제를 단일 약제로서, 또는 제2 치료학적 약제와 함께 투여함으로써 간세포암, 유방암 및 간경화증뿐만 아니라 염증성 통증, 수술-후 절개 통증, 복합부위 통증 증후군, 원발성 또는 전이성 골암 통증, 신경병성 통증, 골절 통증, 골다공성 골절 통증, 화상으로 인한 통증, 골다공증, 통풍 관절 통증, 겸상세포 발증과 연관된 통증, 및 그 밖의 다른 침해수용성 통증과 같은 NGF-매개된 상태 또는 질병을 치료하는 방법을 제공한다. 신경병성 통증의 바람직한 구체예에서는, 관련된 삼차 신경통, 포진후 신경통, 환상지통, 섬유근육통, 반사성 교감신경성 이영양증 및 신경원성 통증 상태가 바람직하게 치료된다. 제2 치료학적 약제는 인터류킨-1 (IL-1) 억제제, 예를 들어, U.S. 6,927,044에 기술된 것과 같은 융합 단백질; 또는 가바펜틴, 프레가발린, 토피라메이트와 같은 항간질제; 또는 아미트리프틸린과 같은 트리사이클릭 항우울제; 셀레콕시브; IL-1, IL-6, IL-6R, IL-18 또는 IL-18R에 대한 길항제 단백질 또는 항체와 같은 사이토킨 길항제일 수 있다. 한가지 구체예에서, 제2 치료학적 약제는 또 다른 뉴로트로핀, 예를 들어, NT-3이다.
여덟 번째 관점에서, 본 발명은 인간에서 NGF-매개된 질병 또는 상태를 약화시키거나 억제하는 용도를 위한 상술한 바와 같은 항체 또는 항원-결합 단편을 제공한다. NGF-매개된 상태 또는 질병은 운동 공조의 상당한 손상이 없이 억제되며, 염증성 통증, 수술-후 절개 통증, 신경병성 통증, 골절 통증, 통풍 관절 통증, 포진후 신경통, 화상으로 인한 통증, 암 통증, 골관절염 또는 류마티스성 관절염 통증, 좌골 신경통, 겸상세포 발증과 연관된 통증, 또는 포진후 신경통 중의 하나이다.
관련된 관점에서, 본 발명은 인간에서 NGF-매개된 질병 또는 상태를 약화시키거나 억제하기 위한 용도의 의약의 제조에 있어서의 상술한 바와 같은 항체 또는 항체의 항원-결합 단편의 용도를 제공한다.
그 밖의 다른 목적 및 이점은 이하의 상세한 설명을 검토함으로써 명백하게 될 것이다.
본 발명의 방법을 기술하기에 앞서서, 본 발명은 특정한 방법 및 기술된 실험조건으로 제한되지는 않는 것으로 이해되어야 하는데, 이는 이러한 방법 및 조건은 변화할 수 있기 때문이다. 또한, 본 발명의 범위는 단지 첨부된 특허청구범위에 의해서만 제한되기 때문에, 여기에서 사용된 용어는 단지 특정한 구체예를 기술하기 위한 것이며, 제한하고자 하는 것은 아님을 이해하여야 한다.
다른 식으로 정의되지 않는 한, 본 명세서에서 사용된 모든 기술적 및 과학적 용어들은 본 발명이 속하는 기술분야에서 통상적으로 숙련된 전문가에 의해서 일반적으로 이해되는 것과 같은 의미를 갖는다. 본 명세서에 기술된 것과 유사하거나 동등한 어떤 방법 및 물질이라도 본 발명을 실시하거나 시험하는데 사용될 수 있지만, 이하에서는 바람직한 방법 및 물질이 기술된다.
정의
본 명세서에서 사용된 것으로서, 용어 "인간 신경성장인자" 또는 "NGF"는 서열번호 1에 나타낸 핵산 서열 및 서열번호 2의 아미노산 서열을 갖는 인간 NGF, 또는 이의 생물학적으로 활성인 단편을 의미한다.
본 명세서에서 사용된 것으로서, 용어 "항체"는 디설파이드 결합에 의해서 서로 연결된 두 개의 중쇄 (H) 및 두 개의 경쇄 (L)인 4 개의 폴리펩타이드 쇄를 포함하는 면역글로불린 분자를 나타내고자 하는 것이다. 각각의 중쇄는 중쇄 가변 부분 (여기에서는 HCVR 또는 VH로 약칭함) 및 중쇄 불변 부분을 포함한다. 중쇄 불변 부분은 3 개의 영역 CH1, CH2 및 CH3를 포함한다. 각각의 경쇄는 경쇄 가변 부분 (여기에서는 LCVR 또는 VL로 약칭함) 및 경쇄 불변 부분을 포함한다. 경쇄 불변 부분은 한 개의 영역 CL을 포함한다. VH 및 VL 부분은 골격 부분 (FR)이라 불리는 더 잘 보존된 부분이 산재된, 상보성 결정 부분 (CDR)이라 불리는 고가변성의 부분으로 더 세분될 수 있다. 각각의 VH 및 VL은 다음의 순서로 아미노-말단으로부터 카복시-말단 쪽으로 배열된 3 개의 CDR 및 4 개의 FR로 구성된다: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.
본 명세서에서 사용된 것으로서, 용어 항체의 "항원-결합 부분" (또는 간단하게 "항체 부분" 또는 "항체 단편")은 항원 (예를 들어, NGF)에 특이적으로 결합하는 능력을 보유하는 항체의 하나 또는 그 이상의 단편을 나타낸다. 항체의 항원-결합 기능은 전체-길이 항체의 단편에 의해서 수행될 수 있는 것으로 나타났다. 용어 항체의 "항원-결합 부분"에 포함되는 결합 단편의 예로는 (i) VL, VH, CL 및 CH1 영역으로 구성된 일가 단편인 Fab 단편; (ii) 힌지 (hinge) 부분에서 디설파이드 브릿지에 의해서 연결된 두 개의 Fab 단편을 포함하는 2가 단편인 F(ab')2 단편; (iii) VH 및 CH1 영역으로 구성된 Fd 단편; (iv) 항체의 단일 팔 (arm)의 VL 및 VH 영역으로 구성된 Fv 단편; (v) VH 영역으로 구성된 dAb 단편 [Ward et al. (1989) Nature 241:544-546]; 및 (vi) 분리된 상보성 결정 부분 (CDR)이 포함된다. 또한, Fv 단편의 두 개의 영역인 VL 및 VH는 별도의 유전자에 의해서 암호화되지만, 이들은 재조합방법을 사용하여, 이들을 VL 및 VH 부분이 쌍을 이루어서 일가 분자를 형성한 단일 단백질 쇄로 만들 수 있는 합성 링커에 의해서 결합될 수 있다 [단일쇄 Fv (scFv)로 공지됨; 참조: 예를 들어, Bird et al. (1988) Science 242:423-426; 및 Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883]. 이러한 단일쇄 항체도 또한, 용어 항체의 "항원-결합 부분"에 포함시키고자 한다. 디아바디 (diabody)와 같은 단일쇄 항체의 다른 형태로 또한 포함된다. 디아바디는 VH 및 VL 영역이 단일 폴리펩타이드 쇄 상에서, 그러나 너무 짧아서 동일한 쇄 상의 두 개의 영역 사이에서 쌍을 이루도록 하지 못하는 링커를 사용하여 발현됨으로써 영역들이 강제적으로 또 다른 쇄의 상보적 영역과 쌍을 이루도록 하여 두 개의 항원 결합 부위를 발생시키는 2가의 이중특이성 (bispecific) 항체이다 [참조: 예를 들어, Holliger et al. (1993) Proc. Natl. Acad Sci. USA 90:6444-6448; Poljak et al. (1994) Structure 2:1121-1123].
또한, 추가로 항체 또는 이의 항원-결합 부분은 하나 또는 그 이상의 다른 단백질 또는 펩타이드와 항체 또는 항체 부분과의 공유적 또는 비공유적 회합에 의해서 형성된 더 큰 면역부착 (immunoadhesion) 분자의 일부분일 수도 있다. 이러한 면역부착 분자의 예는 테트라머성 (tetrameric) scFv 분자를 제조하기 위한 스트렙타비딘 코어 부분의 사용 [Kipriyanov et al. (1995) Human Antibodies and Hybridomas 6:93-101], 및 2가의 비오티닐화된 scFv 분자를 제조하기 위한 시스테인 잔기, 마커 (marker) 펩타이드 및 C-말단 폴리히스티딘 태그 (tag)의 사용 [Kipriyanov et al. (1994) Mol. Immunol. 31:1047-1058]을 포함한다. Fab 및 F(ab')2 단편과 같은 항체 부분은 전체 항체로부터, 각각 전체 항체의 파파인 또는 펩신 분해와 같은 통상적인 기술을 사용하여 제조할 수 있다. 또한, 항체, 항체 부분 및 면역부착 분자는 본 명세서에 기술된 바와 같은 표준 재조합 DNA 기술을 사용하여 수득할 수 있다.
본 명세서에서 사용된 것으로서, 용어 "인간 항체"는 인간 배선 (germline) 면역글로불린 서열로부터 유도된 가변 및 불변 부분을 갖는 항체를 포함하고자 하는 것이다. 본 발명의 인간 항체는 예를 들어, CDR, 특히 CDR3에서 인간 배선 면역글로불린 서열에 의해 암호화되지 않은 아미노산 잔기 (예를 들어, 시험관내에서의 랜덤 또는 부위-특이적 돌연변이유발에 의해서, 또는 생체내에서의 체세포 돌연변이에 의해서 도입된 돌연변이)를 포함할 수 있다. 그러나, 본 명세서에서 사용된 것으로서, 용어 "인간 항체"는 마우스와 같은 또 다른 포유동물 종의 배선으로부터 유도된 CDR 서열이 인간 골격구조 서열 상에 그래프트된 항체는 포함하지 않는다.
본 명세서에서 사용된 것으로서, 용어 "재조합 인간 항체"는 숙주세포 내에 형질감염된 재조합 발현 벡터를 사용하여 발현된 항체 (이하에 더 기술됨), 재조합, 조합적 인간 항체 라이브러리로부터 분리된 항체 (이하에 더 기술됨), 인간 면역글로불린 유전자에 대해 유전자 이식된 동물 (예를 들어, 마우스)로부터 분리된 항체 [참조: 예를 들어, Taylor et al. (1992) Nucl. Acids Res. 20:6287-6295], 또는 다른 DNA 서열에 대한 인간 면역글로불린 유전자 서열의 접합 (splicing)을 수반하는 다른 어떤 수단에 의해서 제조, 발현, 발생 또는 분리된 항체와 같이 재조합 수단에 의해서 제조, 발현, 발생 또는 분리된 모든 인간 항체를 포함하고자 하는 것이다. 이러한 재조합 인간 항체는 인간 배선 면역글로불린 서열로부터 유도된 가변 및 불변 부분을 갖는다. 그러나, 특정의 구체예에서 이러한 재조합 인간 항체는 시험관내 돌연변이유발 (또는, 인간 Ig 서열에 대한 유전자 이식 동물이 사용되는 경우에는, 생체내 체세포 돌연변이유발)에 적용되며, 따라서 재조합 항체의 VH 및 VL 부분의 아미노산 서열은 인간 배선 VH 및 VL 서열로부터 유도되고 이에 관련되지만, 생체내의 인간 항체 배선 레퍼토리 내에 자연적으로 존재하지 않을 수 있는 서열이다.
본 명세서에서 사용된 것으로서, "분리된 항체"는 상이한 항원적 특이성을 갖는 다른 항체를 실질적으로 갖지 않는 항체를 나타내는 것이다 (예를 들어, NGF에 특이적으로 결합하는 분리된 항체는 NGF 이외의 다른 항원에 특이적으로 결합하는 항체를 실질적으로 갖지 않는다). 그러나, NGF에 특이적으로 결합하는 분리된 항체는 다른 종으로부터 유래한 NGF 분자와 같은 다른 항원에 대한 교차-반응성을 가질 수 있다. 더구나, 분리된 항체는 다른 세포성 물질 및/또는 화학물질을 실질적으로 갖지 않을 수 있다.
본 명세서에서 사용된 것으로서, "중화 항체" (또는 "NGF 활성을 중화시키는 항체")는 NGF에 대한 이의 결합이 NGF의 생물학적 활성의 억제를 야기하는 항체를 나타내고자 하는 것이다. 이러한 NGF의 생물학적 활성의 억제는 NGF-유도된 세포성 활성화 및 NGF 수용체에 대한 NGF 결합과 같은 NGF 생물학적 활성의 하나 또는 그 이상의 지표를 측정함으로써 평가될 수 있다. 이들 NGF 생물학적 활성의 지표는 본 기술분야에서 공지된 몇 가지 표준 시험관내 또는 생체내 시험방법 중의 하나 또는 그 이상에 의해서 평가될 수 있다 (이하의 실시예 참조).
"CDR" 또는 상보성 결정 부분은 "골격 부분"이라 불리는 더 잘 보존된 부분이 산재된 고가변성의 부분이다. CDR의 그룹은 아미노산 공통서열 (consensus sequence)로 정의될 수 있다.
본 명세서에서 사용된 것으로서, 용어 "표면 플라즈몬 공명"은 예를 들어, 비아코어 (BIACORETM) 시스템 (Pharmacia Biosensor AB, Uppsala, Sweden and Piscataway, N.J.)을 사용하여 바이오센서 매트릭스 내에서 단백질 농도의 변화를 검출함으로써 실시간 생물특이적 (biospecific) 상호작용을 분석할 수 있도록 하는 광학적 현상을 의미한다.
본 명세서에서 사용된 것으로서, 용어 "KD"는 특정의 항체-항원 상호작용의 평형 해리상수를 나타내고자 하는 것이다.
NGF에 결합하는 항체 또는 항체 부분 (예를 들어, VH, VL, CDR3)을 암호화하는 핵산에 관해서 본 명세서에서 사용된 것으로서, 용어 "분리된 핵산 분자"는 항체 또는 항체 부분을 암호화하는 뉴클레오타이드 서열이, 천연적으로 인간 게놈 DNA 내에서 핵산의 측면에 존재할 수 있는 것으로서 NGF 이외의 다른 항원에 결합하는 항체 또는 항체 부분을 암호화하는 다른 뉴클레오타이드 서열을 갖지 않는 핵산 분자를 나타내고자 하는 것이다. 따라서, 예를 들어, 항-NGF 항체의 VH 부분을 암호화하는 본 발명의 분리된 핵산은 인간 NGF 이외의 다른 항원에 결합하는 다른 VH 부분을 암호화하는 다른 서열을 함유하지 않는다.
용어 "에피토프"는 면역글로불린 또는 T-세포 수용체에 대해 특이적으로 결합할 수 있는 모든 결정인자 (determinant), 바람직하게는 폴리펩타이드 결정인자를 포함한다. 특정의 구체예에서, 에피토프 결정인자는 아미노산, 당 측쇄, 포스포릴 그룹, 또는 설포닐 그룹과 같은 분자의 화학적 활성 표면 그룹을 포함하며, 특정의 구체예에서는 특이적인 삼차원 구조적 특징 및/또는 특이적인 전하 특징을 가질 수 있다. 에피토프는 항체에 의해서 결합된 항원의 부분이다. 특정의 구체예에서, 항체는 이것이 단백질 및/또는 거대분자의 복잡한 혼합물 내에서 이의 표적 항원을 선택적으로 인식하는 경우에 항원을 특이적으로 결합시킨다고 말한다. 바람직한 구체예에서, 항체는 평형 해리상수가 10-8 M 또는 그 미만인 경우, 더욱 바람직하게는 평형 해리상수가 10-9 M 또는 그 미만인 경우, 가장 바람직하게는 해리상수가 10-10 M 또는 그 미만인 경우에 항원을 특이적으로 결합시킨다고 말한다.
핵산 또는 이의 단편을 언급하는 경우에, 용어 "실질적인 동일성" 또는 "실질적으로 동일한"은 적절한 뉴클레오타이드 삽입 또는 결실을 가지고 또 다른 핵산 (또는 이의 상보적 스트랜드)과 함께 최적으로 정렬되는 경우에, 상기 거론한 바와 같은 FASTA, BLAST 또는 GAP와 같은 서열 동일성의 잘 알려진 어떤 알고리즘에 의해서나 측정되는 것으로서 뉴클레오타이드 염기의 적어도 약 90%, 더욱 바람직하게는 적어도 약 95%, 96%, 97%, 98% 또는 99%에서 뉴클레오타이드 서열 동일성이 있는 것을 시사한다.
폴리펩타이드에 대해서 적용되는 것으로서, 용어 "실질적인 유사성" 또는 "실질적으로 유사한"은 예를 들어, 디폴트 갭 (default gap) 가중치를 사용하는 프로그램 GAP 또는 BESTFIT에 의해서 최적으로 정렬되는 경우에, 두 개의 펩타이드 서열이 적어도 90% 서열 동일성, 더 더욱 바람직하게는 적어도 95%, 98% 또는 99% 서열 동일성을 공유하는 것을 의미하다. 바람직하게는, 동일하지 않은 잔기 위치는 보존적 아미노산 치환에 의해서 상이하다. "보존적 아미노산 치환"은 아미노산 잔기가 유사한 화학적 특성 (예를 들어, 전하 또는 소수성)을 갖는 측쇄 (R 그룹)를 갖는 또 다른 아미노산 잔기에 의해서 치환된 것이다. 일반적으로, 보존적 아미노산 치환은 단백질의 기능적 특성을 실질적으로 변화시키지 않을 것이다. 두 개 또는 그 이상의 아미노산 서열이 보존적 치환에 의해서 서로 상이한 경우에, 유사성의 퍼센트 또는 정도는 치환의 보존적 성질을 교정하여 상향 조정될 수 있다. 이러한 조정을 이루기 위한 방법은 본 기술분야에서 숙련된 전문가에게 잘 알려져 있다 [참조: 예를 들어, Pearson (1994) Methods Mol. Biol. 24: 307-331]. 유사한 화학적 특성을 갖는 측쇄를 갖는 아미노산의 그룹의 예로는 1) 지방족 측쇄: 글리신, 알라닌, 발린, 류신 및 이소류신; 2) 지방족-하이드록실 측쇄: 세린 및 트레오닌; 3) 아미드-함유 측쇄: 아스파라긴 및 글루타민; 4) 방향족 측쇄: 페닐알라닌, 타이로신 및 트립토판; 5) 염기성 측쇄: 리신, 아르기닌 및 히스티딘; 6) 산성 측쇄: 아스파르테이트 및 글루타메이트; 및 7) 황-함유 측쇄: 시스테인 및 메티오닌이 포함된다. 바람직한 보존적 아미노산 치환 그룹은 발린-류신-이소류신, 페닐알라닌-타이로신, 리신-아르기닌, 알라닌-발린, 글루타메이트-아스파르테이트 및 아스파라긴-글루타민이다. 대신으로, 보존적 치환은 문헌 [Gonnet et al. (1992) Science 256: 1443 45]에 기술된 PAM250 로그-우도 (log-likelihood) 매트릭스에서 양의 값을 갖는 어떤 변화라도 된다. "중등도의 보존적" 치환은 PAM250 로그-우도 매트릭스에서 비음 (nonnegative)의 값을 갖는 어떤 변화라도 된다.
폴리펩타이드에 대한 서열 유사성은 일반적으로, 서열 분석 소프트웨어를 사용하여 측정된다. 단백질 분석 소프트웨어는 보존적 아미노산 치환을 포함한 다양한 치환, 결실 및 그 밖의 다른 변형에 대해서 지정된 유사성의 척도를 사용하여 유사한 서열을 대응시킨다. 예를 들어, GCG는 상이한 종의 유기체로부터의 상동성 폴리펩타이드와 같은 밀접하게 관련된 폴리펩타이드 사이, 또는 야생형 단백질과 이의 뮤테인 사이의 서열 상동성 또는 서열 동일성을 측정하기 위한 디폴트 파라메터와 함께 사용될 수 있는 GAP 및 BESTFIT와 같은 프로그램을 함유한다 (참조: 예를 들어, GCG Version 6.1). 폴리펩타이드 서열은 또한, 디폴트 또는 추천된 파라메터를 이용하는 FASTA; GCG 버전 6.1의 프로그램을 사용하여 비교될 수도 있다. FASTA (예를 들어, FASTA2 및 FASTA3)는 조회 서열과 검색 서열 사이의 최대 중복이 있는 부분의 정렬 및 서열 동일성 퍼센트를 제공한다 [Pearson (2000) supra]. 본 발명의 서열을 다양한 유기체로부터의 다수의 서열을 함유하는 데이터베이스와 비교하는 경우에 바람직한 또 다른 알고리즘은 디폴트 파라메터를 사용하는 컴퓨터 프로그램 BLAST, 특히 BLASTP 또는 TBLASTN이다 [참조: 예를 들어, Altschul et al. (1990) J. Mol. Biol. 215:403-410 및 Altschul et al. (1997) Nucleic Acids Res. 25:3389-402].
인간 항체의 제조
인간 항체를 생성시키는 방법은 예를 들어, 벨록이뮨 (VELOCIMMUNETM), 제노마우스 (XENOMOUSETM) 기술 [Green et al. (1994) Nature Genetics 7:13-21], "미니로커스 (minilocus)" 방법, 및 파지 디스플레이 (phage display)를 포함한다. 벨록이뮨 (VELOCIMMUNETM) 기술 (US 6,596,541, Regeneron Pharmaceuticals)은 선택 항원에 대한 고특이성의 완전 인간 항체를 생성시키는 방법을 포함한다. 이 기술은 마우스가 항원성 자극에 대한 반응으로 인간 가변 부분 및 마우스 불변 부분을 포함하는 항체를 생산하도록 내인성 마우스 불변 부분의 유전자좌에 작동적으로 연결된 인간 중쇄 및 경쇄 가변 부분을 포함하는 게놈을 갖는 유전자 이식 마우스를 생성시키는 것을 수반한다. 항체의 중쇄 및 경쇄의 가변 부분을 암호화하는 DNA를 분리시키고, 인간 중쇄 및 경쇄 불변 부분을 암호화하는 DNA에 작동적으로 연결시킨다. 그 후, DNA를 완전 인간 항체를 발현할 수 있는 세포에서 발현시킨다. 특정한 구체예에서, 세포는 CHO 세포이다.
항체는 보체의 고정화 및 보체-의존적 세포독성 (CDC)에 대한 참여를 통해서 세포를 사멸시키거나 항체-의존적 세포-매개된 세포독성 (ADCC)를 통해서 세포를 사멸시킴에 의해서가 아니라, 리간드-수용체 상호작용을 차단하거나 수용체 성분 상호작용을 억제하는데 치료학적으로 유용할 수 있다. 따라서, 항체의 불변 부분은 보체를 고정하고, 세포-의존적 세포독성을 매개하는 항체의 능력에 있어서 중요하다. 따라서, 항체의 이소타입 (isotype)은 항체가 세포독성을 매개하는데 대해서 바람직한지 여부를 기준으로 하여 선택될 수 있다.
인간 면역글로불린은 힌지 이질성 (hinge heterogeneity)과 연관된 두 가지 형태로 존재할 수 있다. 한 가지 형태에서, 면역글로불린 분자는 약 150 내지 160 kDa의 안정한 4쇄 구조를 포함하는데, 여기에서 다이머는 쇄간 (interchain) 중쇄 디설파이드 결합에 의해서 함께 유지된다. 두 번째 형태에서, 다이머는 쇄간 디설파이드 결합을 통해서 연결되지 않고, 공유적으로 커플링된 경쇄 및 중쇄로 (반-항체 (half-antibody)) 구성된 약 75 내지 80 kDa의 분자가 형성된다. 이들 형태는 친화성 정제한 후에 조차도 분리시키기 매우 어렵다.
다양한, 온전한 IgG 이소타입에서 두 번째 형태의 출현 빈도는 항체의 힌지 부분 이소타입과 연관된 구조적 차이에 기인하지만, 이것으로 제한되지는 않는다. 인간 IgG4 힌지의 힌지 부분에서 단일 아미노산 치환은 두 번째 형태의 출현을 인간 IgG1 힌지를 사용하여 일반적으로 관찰되는 수준까지 현저하게 감소시킬 수 있다 [Angal et al. (1993) Molecular Immunology 30: 105]. 본 발명은 예를 들어, 생산 시에 목적하는 항체 형태의 수율을 개선시키는데 바람직할 수 있는 힌지, CH2 또는 CH3 부분에서의 하나 또는 그 이상의 돌연변이를 갖는 항체를 포함한다.
본 발명의 항체는 바람직하게는, 벨록이뮨 (VELOCIMMUNETM)기술을 사용하여 제조된다. 내인성 면역글로불린 중쇄 및 경쇄 가변 부분이 상응하는 인간 가변 부분으로 치환된 유전자 이식 마우스를 관심이 있는 항원으로 공격하고, 항체를 발현한 마우스로부터 림프세포 (예를 들어, B-세포)를 회수한다. 림프세포를 골수종 세포주와 융합시켜 불멸하는 하이브리도마 세포주를 제조할 수 있으며, 이러한 하이브리도마 세포주를 스크리닝하고, 관심이 있는 항원에 대해 특이적인 항체를 생산하는 하이브리도마 세포주를 확인하여 선택한다. 중쇄 및 경쇄의 가변 부분을 암호화하는 DNA를 분리시키고, 중쇄 및 경쇄의 바람직한 이소타입 불변 부분에 연결시킬 수 있다. 이러한 항체 단백질은 CHO 세포와 같은 세포에서 생산될 수 있다. 대신으로, 항원-특이적 키메릭 항체 또는 경쇄 및 중쇄의 가변 영역을 암호화하는 DNA를 항원-특이적 림프구로부터 직접 분리시킬 수도 있다.
일반적으로, 본 발명의 항체는 고체상 위에 고정화되거나 용액 상태인 항원에 대한 결합에 의해 측정되는 경우에, 일반적으로 약 10-9 내지 약 10-12 M 또는 그 이상, 예를 들어, 적어도 약 10-9 M, 적어도 10-10 M, 적어도 10-11 M 또는 적어도 10-12 M의 KD를 갖는 매우 높은 친화성을 갖는다.
처음에는, 인간 가변 부분 및 마우스 불변 부분을 갖는 고친화성 키메릭 항체가 분리된다. 이하에 기술하는 바와 같이, 항체는 친화성, 선택성, 에피토프 등을 포함한 바람직한 특징에 대해서 특정화되고 선택된다. 마우스 불변 부분을 원하는 인간 불변 부분으로 치환시켜 본 발명의 완전한 인간 항체, 예를 들어, 야생형 또는 변형된 IgG1 또는 IgG4 (예를 들어, 서열번호 541, 542 또는 543)를 생성시킨다. 선택된 불변 부분은 특정한 용도에 따라 달라질 수 있지만, 고친화성 항원-결합 및 표적 특이성 특징은 가변 부분에 존재한다.
에피토프
지도작성 (mapping) 및 관련된 기술
특정한 에피토프에 결합하는 항체 (예를 들어, 이의 고친화성 수용체에 대한 IgE의 결합을 차단하는 것)에 대해서 스크리닝하기 위해서, 문헌 [Harlow and Lane (1990) supra]에 기술된 것과 같은 일상적인 교차-차단 시험방법 (cross-blocking assay)이 수행될 수 있다. 다른 방법으로는 알라닌 스캐닝 (scanning) 돌연변이체, 펩타이드 블럿 (blot) [Reineke (2004) Methods Mol Biol 248:443-63], 또는 펩타이드 절단 분석이 포함된다. 또한, 에피토프 절제, 에피토프 추출 및 항원의 화학적 변형과 같은 방법이 이용될 수 있다 [Tomer (2000) Protein Science 9:487-496].
용어 "에피토프"는 B 및/또는 T 세포가 반응하는 항원 상의 부위를 의미한다. B-세포 에피토프는 접속 (contiguous) 아미노산 또는 단백질의 삼차 접힘 (tertiary folding)에 의해서 병렬된 비접속 아미노산 둘 다로부터 형성될 수 있다. 접속 아미노산으로부터 형성된 에피토프는 일반적으로, 변성 용매에 대한 노출 시에 유지되는 반면에, 삼차 접힘에 의해서 형성된 에피토프는 일반적으로 변성 용매로 처리하면 상실된다. 에피토프는 일반적으로, 독특한 공간적 구조 내에 적어도 3 개, 더욱 통상적으로는 적어도 5 개 또는 8 내지 10 개의 아미노산을 포함한다.
항원 구조-기본 항체 프로파일링 (ASAP)으로 또한 알려져 있는 변형-보조된 프로파일링 (Modification-Assisted Profiling; MAP)은 화학적으로 또는 효소적으로 변형된 항원 표면에 대한 각각의 항체의 결합 프로필의 유사성에 따라 동일한 항원에 대해 유도된 다수의 모노클로날 항체 (mAb)를 분류하는 방법이다 [US 2004/0101920]. 각각의 카테고리는 또 다른 카테고리로 표현되는 에피토프와 명백히 상이하거나, 부분적으로 중복되는 독특한 에피토프를 나타낼 수 있다. 이 기술은, 특정화가 유전적으로 전혀 다른 항체에 집중될 수 있도록 유전적으로 동일한 항체를 빨리 여과할 수 있도록 허용한다. 하이브리도마 스크리닝에 적용되는 경우에, MAP는 원하는 특징을 갖는 mAb를 생산하는 희귀한 하이브리도마 클론의 확인을 용이하게 할 수 있다. MAP를 사용하여 본 발명의 항-NGF 항체를 상이한 에피토프에 결합하는 항체의 그룹으로 구분할 수 있다.
면역접합체
본 발명은 사이토톡신, 화학요법적 약물, 면역억제제 또는 방사성 동위원소와 같은 치료학적 부위에 접합된 인간 항-NGF 모노클로날 항체 ("면역접합체 (immunoconjugate)")를 포함한다. 사이토톡신 약제는 세포에 해로운 어떤 약제라도 포함한다. 면역접합체를 형성시키는데 적합한 사이토톡신 약제 및 화학요법적 약제는 본 기술분야에서 공지되어 있다 [참조: 예를 들어, WO 05/103081].
이중특이성
(
Bispecifics
)
본 발명의 항체는 단일특이성, 이중특이성 또는 다중특이성일 수 있다. 다중특이성 항체는 하나의 표적 폴리펩타이드의 상이한 에피토프에 대해 특이적일 수 있거나, 하나 이상의 표적 폴리펩타이드에 대해 특이적인 항원-결합 영역을 함유할 수 있다 [참조: 예를 들어, Tutt et al. (1991) J. Immunol. 147:60-69]. 인간 항-NGF 항체는 또 다른 기능적 분자, 예를 들어, 또 다른 펩타이드 또는 단백질에 연결되거나, 이와 공동-발현될 수 있다. 예를 들어, 항체 또는 이의 단편은 또 다른 항체 또는 항체 단편과 같은 하나 또는 그 이상의 다른 분자 실체에 기능적으로 연결되어 (예를 들어, 화학적 커플링, 유전적 융합, 비공유적 회합 또는 그 밖의 방법에 의해서) 제2 결합 특이성을 갖는 이중특이성 또는 다중특이성 항체를 생산할 수 있다.
치료학적 투여 및 제제
본 발명은 본 발명의 항-NGF 항체 또는 이의 항원-결합 단편을 포함하는 치료학적 조성물을 제공한다. 본 발명에 따르는 치료학적 조성물의 투여는 개선된 수송, 전달, 내성 등을 제공하기 위해서 제제에 혼입되는 적합한 담체, 부형제 및 그 밖의 다른 성분과 함께 투여될 수 있다. 다수의 적절한 제제는 모든 약화학자에게 공지된 규격서 (formulary) [Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA]에서 볼 수 있다. 이들 제제에는 예를 들어, 분말, 페이스트, 연고, 젤리, 왁스, 오일, 지질, 지질 (양이온성 또는 음이온성) 함유 소포 (vesicle) (예를 들어, 리포펙틴 (LIPOFECTINTM)), DNA 접합체, 무수 흡수 페이스트, 수중유 및 유중수 에멀전, 에멀전 카보왁스 (다양한 분자량의 폴리에틸렌 글리콜), 반고체 겔, 및 카보왁스를 함유하는 반고체 혼합물이 포함된다. 또한, 문헌 [Powell et al. "Compendium of excipients for parenteral formulations" PDA (1998) J Pharm Sci Technol 52:238-311]을 참고로 한다.
용량은 투여될 대상체의 연령 및 체격, 표적 질병, 상태, 투여의 경로 등에 따라 달라질 수 있다. 본 발명의 항체가 성인 환자에서 염증성 통증, 신경병성 및/또는 침해수용성 통증, 간세포암, 유방암, 간경화증 등을 포함한 NGF와 연관된 다양한 상태 및 질병을 치료하기 위해서 사용되는 경우에, 본 발명의 항체는 통상적으로 약 0.01 내지 약 20 mg/kg (체중), 더욱 바람직하게는 약 0.02 내지 약 7, 약 0.03 내지 약 5, 또는 약 0.05 내지 약 3 mg/kg (체중), 바람직하게는 약 0.1 내지 약 10 mg/kg (체중), 더욱 바람직하게는 약 0.1 내지 약 5 mg/kg (체중)의 단일 용량으로 정맥내 투여하는 것이 유리하다. 상태의 중증도에 따라서, 치료의 빈도 및 기간이 조정될 수 있다.
다양한 전달 시스템, 예를 들어, 리포좀 내의 캅셀화, 미립자, 마이크로캅셀, 돌연변이체 바이러스를 발현할 수 있는 재조합 세포, 수용체 매개된 세포내이입 (endocytosis)이 공지되어 있으며, 본 발명의 약제학적 조성물을 투여하기 위해서 사용될 수 있다 [참조: 예를 들어, Wu et al. (1987) J. Biol. Chem. 262:4429-4432]. 도입의 방법에는 피내, 근육내, 복강내, 정맥내, 피하, 비내, 경막외, 및 경구 경로가 포함되나, 이들로 제한되지 않는다. 조성물은 모든 통상적인 경로에 의해서, 예를 들어, 주입 또는 볼루스 (bolus) 주사에 의해서, 상피 또는 점막피부 라이닝 (lining) (예를 들어, 구강 점막, 직장 및 장 점막 등)을 통한 흡수에 의해서 투여될 수 있으며, 다른 생물학적 활성 약제와 함께 투여될 수도 있다. 투여는 전신적이거나 국소적일 수 있다.
약제학적 조성물은 또한, 소포내에서, 특히 리포좀 내에서 전달될 수도 있다 [참조: Langer (1990) Science 249:1527-1533; Treat et al. (1989) in Liposomes in the Therapy of Infectious Disease and Cancer, Lopez Berestein and Fidler (eds.), Liss, New York, pp. 353-365; Lopez-Berestein, ibid., pp. 317-327; 일반적으로 ibid 참조].
특정의 상황에서, 약제학적 조성물은 조절 방출 시스템으로 전달될 수 있다. 한가지 구체예에서는, 펌프가 사용될 수 있다 [참조: Langer, supra; Sefton (1987) CRC Crit. Ref. Biomed. Eng. 14:201]. 또 다른 구체예에서는, 폴리머성 물질이 사용될 수 있다 [참조: Medical Applications of Controlled Release, Langer and Wise (eds.), CRC Pres., Boca Raton, Florida (1974)]. 또 다른 구체예에서, 조절 방출 시스템은 조성물의 표적에 인접하게 배치함으로써 전신적 용량의 단지 일부분만을 필요로 할 수 있다 [참조: 예를 들어, Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138, 1984]. 다른 조절 방출 시스템은 문헌 [Langer (1990) Science 249:1527-1533]의 검토에 의해서 논의된다.
주사용 제제는 정맥내, 피하, 피내 및 근육내 주사, 점적 주입 등을 위한 투약형을 포함할 수 있다. 이들 주사용 제제는 공공연하게 알려진 방법에 의해서 제조될 수 있다. 예를 들어, 주사용 제제는 예를 들어, 상술한 항체 또는 이의 염을 주사를 위해서 통상적으로 사용되는 멸균 수성 매질 또는 오일상 매질 내에 용해, 현탁 또는 유화시킴으로써 제조될 수 있다. 주사를 위한 수성 매질로는 예를 들어, 알콜 (예를 들어, 에탄올), 폴리알콜 (예를 들어, 프로필렌 글리콜, 폴리에틸렌 글리콜), 비이온성 계면활성제 [예를 들어, 폴리소르베이트 80, HCO-50 (수소화 피마자유의 폴리옥시에틸렌 (50 mol) 부가물)] 등과 같은 적절한 가용화제와 함께 사용될 수 있는 생리적 식염수, 글루코즈 및 다른 보조제를 함유하는 등장성 용액 등이 있다. 오일상 매질로는 예를 들어, 벤질 벤조에이트, 벤질 알콜 등과 같은 가용화제와 함께 사용될 수 있는 호마유, 대두유 등이 사용된다. 이렇게 제조된 주사제는 바람직하게는 적절한 앰플 내에 충진된다.
유리하게는, 상술한 경구 또는 비경구적 사용을 위한 약제학적 조성물은 활성성분의 용량을 부합하도록 하는데 적합한 단위 용량의 투약형으로 제조된다. 단위 용량의 이러한 투약형은 예를 들어, 정제, 환제, 캅셀제, 주사제 (앰플), 좌제 등을 포함한다. 함유된 항체의 양은 일반적으로, 단위 용량의 투약형당 약 5 내지 500 mg이며; 주사제 형태에서는 항체가 약 5 내지 100 mg으로, 다른 투약형의 경우에는 약 10 내지 250 mg으로 함유되는 것이 바람직하다.
단일 및 병용 요법. 본 발명은 본 발명의 항체 또는 항체 단편이 NGF를 수반하는 다양한 상태와 연관된 통증을 치료하는데 유용한 치료학적 방법을 제공한다. 본 발명의 항-NGF 항체 또는 항체 단편은 신경원성, 신경병성 또는 침해수용성 통증과 연관된 모든 상태로부터 유래하는 통증을 치료하는데 특히 유용하다. 신경병성 통증의 바람직한 구체예에서는, 관련된 삼차 신경통, 포진후 신경통, 환상지통, 섬유근육통, 반사성 교감신경성 이영양증 및 신경원성 통증 상태가 바람직하게 치료된다. 다른 바람직한 구체예에서는, 암 통증, 특히 골암 통증, 골관절염 또는 류마티스성 관절염 통증, 요통 (lower back pain), 수술후 절개 통증, 골절 통증, 골다공성 골절 통증, 골다공증, 통풍 관절 통증, 당뇨병성 신경병증, 좌골 신경통, 겸상세포 발증과 연관된 통증, 편두통, 및 다른 신경병성 및/또는 침해수용성 통증이 바람직하게 치료된다.
다른 적응증에는 예를 들어, 유방암의 치료가 포함된다 [Adriaenssens et al. (2008) Cancer Res 68:346-51]. 본 발명의 치료학적 방법의 특정한 구체예에서는, 통풍과 연관된 관절 통증을 앓고 있는 대상체를 본 발명의 항체 또는 항체 단편 및 임의로, 제2 치료학적 약제의 조합물로 치료한다. 한가지 구체예에서, 제2 치료학적 약제는 바람직하게는, 릴로나셉트 (rilonacept) ("IL-1 트랩 (trap)"; Regeneron)와 같은 인터류킨-1 (IL-1) 길항제이다. 적합한 제2 치료학적 약제는 릴로나셉트, 아나킨라 (anakinra; KINERET®, Amgen), 인간 IL-1 수용체 길항제 (IL1Ra)의 재조합 비글리코실화 형태, IL-18BP 또는 유도체와 같은 항-IL-18 약물, IL-18 트랩 (Trap), 또는 항-IL-18, 항-IL-18R1, 항-IL-18Racp, 항-IL-6 및/또는 항-IL6Ra 항체와 같은 항체로 구성된 그룹으로부터 선택된 하나 또는 그 이상의 약제일 수 있다. 단독으로 또는 IL-1 길항제와 함께 NGF 항체 또는 이의 항원-결합 단편과 조합할 수 있는 다른 공동-치료법에는 저용량 콜킨, 아스피린 또는 다른 NSAID, 프레드니솔론과 같은 스테로이드, 메토트렉세이트, 저용량 사이클로스포린 A, 엔브렐 (ENBREL®) 또는 후미라 (HUMIRA®)와 같은 TNF 억제제, 카스파제-1, p38, IKK1/2, CTLA-4Ig 등의 억제제와 같은 다른 염증성 억제제, 및/또는 체내에서 요산의 축적을 억제하는 요산 합성 억제제, 예를 들어, 알로푸리놀, 체내에 축적된 요산의 빠른 배설을 촉진시키기 위한 요산 배설 촉진제, 예를 들어, 프로베네시드, 설핀피라존 및/또는 벤즈브로마론과 같은 공동-치료법; 코르티코스테로이드; 비-스테로이드성 소염성 약물 (NSAID), 토피라메이트, 가바펜틴, 프레가바블린, 셀레콕시브와 같은 항간질성 약물; 또는 NT-3과 같은 또 다른 뉴로트로핀이 포함된다.
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이하의 실시예는 본 기술분야에서 통상적으로 숙련된 전문가에게 본 발명의 방법 및 조성물을 어떻게 만들고 사용하는지에 대한 완전한 공개 및 설명을 제공하기 위하여 제시된 것이며, 본 발명자들이 그들의 발명으로 간주하는 범위를 제한하고자 하는 것은 아니다. 사용된 수 (예를 들어, 양, 온도 등)에 대한 정확성을 보장하기 위한 노력이 이루어졌지만, 일부의 실험 오차 및 편차도 고려되어야 한다. 다른 식으로 지시되지 않는 한, 부는 중량부이고, 분자량은 평균 분자량이며, 온도는 섭씨 온도이고, 압력은 대기압 또는 거의 대기압이다. 통계학적 분석은 본드페로니 (Bondferroni) 사후 검증 또는 터키 (Turkey) HSD 사후 검증과 혼합 요인 (mixed Factorial) ANOVA에 따라 수행되었다.
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1. 면역화 및 항체 생성
설치류의 면역화는 본 기술분야에서 공지된 어떤 방법에 의해서나 수행될 수 있다 [참조: 예를 들어, Harlow and Lane, Antibodies: A Laboratory Manual: Cold Spring Harbor Press, New York; Malik and Lillehoj, Antibody techniques: Academic Press, San Diego]. 바람직한 구체예에서는, 인간 NGF 단백질을 면역반응을 자극하는 보조제와 함께, 인간 Ig 중쇄 가변 부분 및 카파 경쇄 가변 부분 둘 다를 암호화하는 DNA 유전자좌 (벨록이뮨 (VELOCIMMUNETM), Regeneron; US 6,596,541)를 갖는 마우스에게 직접 투여한다. 이러한 보조제에는 완전 및 불완전 프로인트 보조제, MPL+TDM 보조제 시스템 (Sigma), 또는 RIBI (뮤라밀 디펩타이드)가 포함된다 [참조: O'Hagan, Vaccine Adjuvant, Human Press, 2000, Totawa, NJ]. 이러한 보조제는 항원을 국소 저장소에 격리시킴으로써 폴리펩타이드의 빠른 분산을 방지할 수 있으며, 숙주 면역반응을 자극할 수 있는 인자를 함유할 수 있다. 한가지 구체예에서, NGF는 NGF 유전자를 함유하며, 생체내에서 항원 폴리펩타이드를 생산하기 위한 숙주 세포성 단백질 발현 기전을 사용하여 NGF를 발현하는 DNA 플라스미드로서 간접적으로 투여된다. 두 가지 접근방법 모두에서, 최적 항-항원 반응을 수득하기 위해서 마우스에게는 매 3~4주마다 부스트 (boost) 주사를 하고, 혈청 샘플은 각각의 주사 후 10일에 수집한다. 항체 면역반응은 표준 항원 직접 결합 ELISA 방법을 사용하여 모니터된다. 3배 계열 희석으로 희석된 부스트-후 혈청 샘플을 NGF 코팅된 플레이트에 적용한다. 혈청 역가는 시험에서 배경 시그날에 비해 2배를 수득한 혈청 샘플의 희석도로서 정의된다. 최적 반응을 갖는 동물에게 희생시키기 3~4일 전에 보조제 없이 정맥내 및 복강내 주사로 최종 부스트를 투여하였다. 수확된 비장세포를 항원 특이적 모노클로날 항체를 수득하기 위해서 이하에 기술된 바와 같이 처리한다.
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2.
모노클로날
항체 분리
한가지 구체예에서, 항체-발현성 B 세포를 마우스 골수종 세포와 융합시켜 하이브리도마 세포를 형성시킨다. 하이브리드 세포를 HAT 선택 하에서 96-웰 플레이트 내에 플레이팅하고, 10 내지 20일 동안 성장하도록 둔다. 하이브리도마 세포를 성장시키면서 웰로부터 조건화된 배지 (conditioned media)를 이하에 기술된 바와 같이 항원 결합 및 수용체 차단 활성에 대해서 스크리닝한다. 해당하는 항체를 발현하는 하이브리도마 세포를 유동 세포분석법을 사용하여 단일-세포 서브-클로닝하고, 클로날 하이브리도마 세포로부터 VH 및 VL 유전자를 클로닝하고 서열을 결정한다. 항체 단백질을 또한, IgG 고갈된 배지 (Invitrogen)를 사용하여 항원 특이적 하이브리도마의 배양물로부터 정제하고, 이하에 기술된 바와 같이 특정화한다.
또 다른 구체예에서, 항원 특이적 항체는 특정의 골수종 세포에 의해서 불멸화되지 않고 항원 양성 B 세포로부터 직접 분리되며, USSN 11/809,482 (US 특허공개 제2007/0280945호)에 기술된 바와 같이 안정한 재조합 항체를 생산하는 숙주 CHO 세포가 생성된다.
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3. 일차 항원 결합 및 수용체 차단 스크리닝
하이브리도마를 생산하는 항원 특이적 항체를 확인하기 위해서, 조건화된 배지를 융합 후 10 내지 20일에 96-웰 배양 플레이트로부터 샘플링하였으며, 항원 결합 특이성은 고처리량 직접 결합 ELISA를 사용하여 측정하였다. 간략하면, 1:10 및 1:100배 희석도에서 조건 배지를 100 ng/웰로 재조합 NGF 단백질 코팅된 맥시소르브 (MAXISORBTM) 플레이트에 결합하도록 하였다. 플레이트-결합된 항체를 염소 항-마우스 IgG Fcγ 특이적 HRP 접합된 폴리클로날 항체 (Jackson Immuno Lab)를 사용하여 검출하였다. 플레이트를 TMB 기질 (BD Pharmigen)을 사용하여 현상하고, OD450nm에서 광학밀도를 기록하였다. 병행하여, 동일한 희석도에서 샘플을 스트렙타비딘 제시된 비오틴-표지 NGF 플레이트에 적용하고, 플레이트 결합된 항체를 검출하였다. 어떤 플레이트에 대해 결합 활성을 나타내는 웰을 세포 배양 증식에 대해서 선택하고, 동결-보존하고, 항체를 함유하는 상청액을 특이성, 친화성 및 기능성 프로필을 수득하기 위한 추가의 분석을 위해서 사용하였다.
직접 항원 결합 스크리닝 이외에도, 바람직한 특성을 갖는 항체를 분비하는 클론을 확인하기 위해서 기능적 스크리닝이 또한 이용되었다. 맥시소르브 플레이트를 4℃에서 100 ng/웰의 재조합 인간 TrkA-hFc로 밤새 코팅하였다. 1:2 및 1:10배 희석도에서 조건화된 배지를 1 시간 동안 용액 중의 2 ng/ml 비오틴-NGF에 결합하도록 한 후에, 플레이트-결합된 비오틴-NGF를 측정하기 위해서 TrkA-hFc 코팅된 플레이트에 전이시켰다. 플레이트-결합된 비오틴-NGF를 HRP 접합된 스트렙타비딘 (Pierce)을 사용하여 검출하고, TMB 기질 (BD Pharmingen)을 사용하여 현상하고, 광학밀도를 기록하였다. 배양 배지가 TrkA-hFc에 대한 비오틴-NGF의 결합을 방지하는 하이브리도마를 잠재적 차단제로서 확인하고, 더 특정화하였다.
유사한 시험관내 스크리닝을 항원 양성 B 세포로부터 직접 분리된 완전한 인간 IgG함유 V 유전자로 형질감염된 CHO 세포로부터 96-웰 조건화 배지에 적용하였다. 또한, 샘플을 그에 대해 항원 특이적 결합된 항체를 PE-접합된 염소 항-인간 IgG Fcγ-특이적 폴리클로날 항체를 사용하여 검출하는 항원-코팅된 루미넥스 (LUMINEXTM) 비드를 사용하여 NGF 결합 활성에 대해서 스크리닝하였다. 항원-결합 항체를 비아코어 (BIACORETM)를 사용하여 친화성 측정에 적용하였다. 간략하면, 조배양물 상청액으로부터 항체를 아민 커플링된 hFc 특이적 폴리클로날 항체 표면 상에 포착시켰다. 단일 농도에서의 항원 결합을 모니터하였다. 동일한 조건 하에서 각각의 항체 상호작용에 대한 반응속도론적 속도상수 (kinetic rate constant) ka 및 kd를 사용하여 항원-결합 친화성 (KD)을 측정하기 위한 결합 센소그램 (sensogram)에 적합하도록 1:1 이분자성 (bimolecular) 상호작용 모델이 사용되었다. 구체적으로, 염소 항-인간 IgG Fcγ-특이적 폴리클로날 항체를 CM-5 칩 (chip) 표면 상에 공유적으로 커플링시키고, 항체-함유 CHO 상청액을 5 분 동안 1 ㎕/분으로 주입하고, 이어서 완충 세척액을 주입하였다. 인간 NGF (25 nM)를 3 분 동안 주입하여 NGF가 인간 항체 고정화된 표면에 결합하도록 하였다. NGF 주입 직후에, 표면에 완충액을 100 ㎕/분으로 약 10분 동안 주입하고, RU 시그날의 붕괴를 기록하였다. 표면을 재생시켜 결합된 항체 및 NGF를 분리시키고, 사이클을 다음의 CHO 상청액 샘플을 사용하여 반복하였다.
실시예
4. 항원 결합 친화성 측정
인간 NGF에 대한 항체의 항원 결합 친화성은 실시간 바이오센서 표면 플라즈몬 공명 시험방법 (BIACORETM)을 사용하여 표면 반응속도론에 의해서 측정하였다. 항체를 비아코어 (BIACORETM) 칩에 대한 포착 항체의 직접적인 아민 커플링에 의해서 생성된 염소, 항-인간 또는 항-마우스 IgG 폴리클로날 항체 표면 상에 포착시켰다. 다양한 농도의 인간 NGF를 포착된 항체 표면 상에 주입하면서 항체에 대한 항원의 회합 및 결합된 복합체의 해리를 실시간으로 모니터하였다. 반응속도론적 분석을 수행하여 평형 해리상수 (KD) 및 해리속도상수를 수득하고, 후자를 사용하여 항원/항체 복합체 해리 t1 /2를 계산하였다 (표 1). 인간화된 항-인간 NGF 모노클로날 항체 E3 ("RN624") (탄네주마브 (tanezumab); CAS Registry No. 880266-57-9; US 특허공개 제2004/0237124호)가 대조군으로 사용되었다.
[표 1]
NGF에 대한 선택된, 정제된 항체의 항원 결합 친화성도 또한, 상술한 바와 같이 실시간 바이오센서 표면 플라즈몬 공명 시험방법 (BIACORETM)을 사용한 표면 반응속도론에 의해서 측정하였다. 편의상, 항체 301272-3H10-A10은 "REGN261" (HCVR/LCVR 서열번호 84/92 및 hIgG1 서열번호 541)로 다시 이름을 붙였으며; 301272-6E07-D10은 "REGN263" (HCVR/LCVR 서열번호 208/216 및 hIgG1 서열번호 541)로 다시 이름을 붙였다. 시험한 유도된 항체에는 REGN472 (HCVR/LCVR 서열번호 100/102 및 hIgG1 서열번호 541), REGN474 (HCVR/LCVR 서열번호 100/102 및 돌연변이체 hIgG4 서열번호 543), REGN475 (HCVR/LCVR 서열번호 108/110 및 돌연변이체 hIgG4 서열번호 543), REGN476 (HCVR/LCVR 서열번호 224/226 및 돌연변이체 hIgG4 서열번호 543), 및 REGN477 (HCVR/LCVR 서열번호 232/234 및 돌연변이체 hIgG4 서열번호 543)이 포함되었다.
[표 2]
실시예
5.
뉴로트로핀
-3 (NT-3)에 대한 교차-반응성
NGF 및 NT-3은 신경성장인자 부류에 속하며, 특정의 뉴런성 집단의 생존을 허용하는 작고, 기본적인 분비성 단백질이다. 이들 두 가지 뉴로트로핀이 약간의 아미노산 동일성을 공유하지만, 생물학적 기능은 상이할 수 있다 [Barde et al. 1990 Prog Growth Factor Res 2(4):237-48].
항-NGF 항체는 인간 NT-3과의 결합 교차-반응성에 대해서 검사하였다. 간략하면, 염소 항-인간 IgG 폴리클로날 항체를 CM5 칩에 화학적으로 연결시켰다. 항-NGF 모노클로날 항체를 주입하여 칩 커플링된 폴리클로날 항체와의 상호작용을 통해서 약 50 내지 900 RU의 고정화된 항체의 표면을 형성시켰다. 20 nM의 농도로 NGF 또는 NT-3 단백질을 표면 상에 주입하고, 이어서 완충 세척액을 주입하여 결합된 리간드가 해리하도록 하였다. 회합 및 해리상을 둘 다 모니터하고, 데이터를 분석하였다. 결과는 표 3에 나타내었다 (NB = 관찰된 결합 활성이 없음). 대조 항체 (RN624)와는 대조적으로, 시험한 모든 항체는 NT-3에 대해 측정할 수 있는 결합을 나타내지 않았으며, 이것은 대조 항체에 비해서 더 높은 정도의 항원 특이성을 시사하는 것이다.
[표 3]
OCTETTM-기본 용액 경쟁 시험방법을 또한 사용하여 용액 중에서 NT-3, NGF 또는 인간 뇌 유도된 신경영양성 인자 (hBDNF)에 대해 결합에 대해서 경쟁하는 REGN475 및 RN624의 능력을 측정하였다. 간략하면, 항체-항원 샘플은 대조 항체 RN624 (2.5 ㎍/ml) 또는 REGN475 (2.5 ㎍/ml)를 다양한 농도의 NT-3 (0 내지 4 μM), hBDNF (0 내지 4 μM) 또는 NGF (0 내지 0.2 μM)과 30℃에서 1 시간 동안 예비-항온처리함으로써 제조하였다. 스트렙타비딘 고-결합성 FA 센서 (HBS, ForteBio, Inc., CA)를 2 ㎍/ml로 비오틴-NGF과 함께 30℃에서 10 분 동안 항온처리하였다. 그 후, 비오틴-NGF 결합된 센서를 예비-항온처리된 항원-항체 샘플과 30℃에서 10 분 동안 항온처리하였다. 항온처리 후에 생물학적 층의 두께에 있어서의 변화를 측정하였다. 결합은 경쟁물질의 부재 하에서 항체의 결합에 대한 결합의 백분율로서 표준화되었다. 표 4에 나타낸 바와 같이, NGF와 RN624 사이의 결합은 NT-3에 의해서 용량-의존적 방식으로 차단되었으며, 그 반면에 REGN475와 NGF 사이의 결합은 NT-3에 의해서 차단되지 않았다. hBDNF의 존재는 RN624 또는 REGN475의 NGF에 대한 결합을 차단하지 않았으며, 반면에 가용성 NGF의 존재는 고정화된 NGF에 대한 RN624 및 REGN475 둘 다의 결합을 거의 완전히 차단하였다.
[표 4]
선택된, 정제된 인간 항-NGF 항체 REGN472, REGN474, REGN475, REGN476, REGN477, 또는 대조 항체 RN624와 NT-3 사이의 결합은 또한 1.25 nM 내지 40 nM 범위의 NT-3 농도로 비아코어 (BIACORETM) 시험방법을 사용하여 평가하였다. 대조 항체 (RN624)는 1.1 nM의 KD로 NT-3에 결합한 반면에, 시험한 항체 중의 어떤 것도 NT-3에 대해 측정할 수 있는 친화성을 나타내지 않았다.
실시예
6. 쥐 및
랫트
NGF
에 대한 교차-반응성
인간 NGF (NGF)는 마우스 NGF (mNGF) 및 랫트 NGF (rNGF)에 대해서 약 90% 동일성을 가지고 아미노산 서열에 있어서 매우 상동성이다. mNGF 및 rNGF 둘 다에 대한 항체의 결합 친화성은 상술한 바와 같이 측정되었다. 모든 항체는 mNGF 및 rNGF 둘 다에 대해서 교차-반응성을 나타내었다. 항체의 한 그룹은 모든 종으로부터의 NGF에 10 pM 미만의 KD 값으로 강력하게 결합했으며; 두 번째 그룹은 바람직하게는 NGF에 결합하고, mNGF 및 rNGF에 대해서 KDs > 약 100 pM을 나타내었다 (대조군 = RN624) (표 5).
[표 5]
mNGF 및 rNGF에 대한 선택된, 정제된 항-NGF 항체의 결합 친화성도 또한 측정되었다 (표 6).
[표 6]
실시예
7. 수용체
TrkA
/hFc 및
p75
/hFc에 대한
NGF
결합의 억제
차단 항체를 확인하기 위하여, 수용체 차단 시험방법이 비아코어 (BIACORETM) 3000 기구를 사용하여 디자인되었다. 재조합 인간 TrkA-hFc 및 인간 p75-hFc 단백질을 약 5000 내지 6000 RU의 밀도로 CM5 칩에 아민-커플링시켰다. 인간 NGF (10 nM 내지 25 nM)를 TrkA 및 p75 표면에 결합시켜 NGF 결합에 대한 최대 RU를 측정하였다. 그 후, 표면을 재생시키고, 10 nM 내지 25 nM NGF를 개별적인 항체 또는 가용성 수용체 바디 (receptorbody)의 과잉 몰 농도와 혼합시키고, 용액을 재생된 칩 표면 상에 주입하여 잔류하는 유리 NGF 결합 시그날을 측정하였다. 표 7은 항체 또는 수용체 바디의 존재 하에서 TrkA 및 p75에 결합된 유리 NGF의 백분율을 나타낸다. 항체의 존재 하에서 인간 NGF의 최대 RU 결합은 100%의 상대값으로 제시되었다. 양성 대조군으로는, 용액 중의 RN624, TrkA-hFc 및 p75-hFc가 사용되었으며, 음성 결합 대조군으로는 IgG1 대조군 (아바스틴 (AVASTIN®); Genentech, CA)이 사용되었다.
[표 7]
인간 TrkA 및 p75 수용체에 대한 인간 NGF 결합을 차단하는 선택된 시험 항체 REGN472, REGN474, REGN475, REGN476 및 REGN477, 및 대조 항체 RN624의 능력은 또한, 경쟁적 샌드위치 (competition sandwich) ELISA에 의해서 정량적으로 측정되었으며, 여기에서는 용액 중에서 고정된 농도의 NGF와 함께 항체가 존재하는 것이 NGF가 미량역가 플레이트 상에 코팅된 TrkA-hFc 또는 p75-hFc에 대해 결합하는 것을 방지하였다. 이 시험에 사용된 인간 NGF는 이. 콜라이 (E. coli) 내에서 생산된 재조합 단백질이었으며, 인간 TrkA-hFc 및 p75-hFc 단백질은 인간 IgG1의 Fc 부분과 인-라인 융합된 각각의 수용체의 세포외 영역으로 구성된 다이머성 융합 단백질이었다. 50 pM의 고정 농도에서 비오틴-표지된 NGF 단백질을 용액 중의 1.5 pM 내지 1.5 nM의 항체의 다양한 양으로 실온에서 1 시간 동안 적정하였다. 그 후, 용액 혼합물 내의 비결합된 유리 비오틴-NGF의 양은 비오틴-NGF를 hTrkA-hFc 또는 hp75-hFc 코팅된 미량역가 플레이트 상에 포착시키고, 이어서 플레이트 결합된 비오티닐화-NGF를 스트렙타비딘-HRP로 검출함으로써 정량화하였다. 구체적으로, 미량역가 플레이트는 플레이트를 PBS 완충액 중의 0.5 ㎍/ml hTrkA-hFc 또는 1 ㎍/ml hp75-hFc 용액으로 4℃에서 밤새 코팅하고, 이어서 플레이트를 사용하기 전에 0.5% BSA로 차단시킴으로써 제조되었다. 비결합된 비오틴-NGF를 측정하기 위해서, 예비-항온처리된 항체 및 비오틴-NGF 용액을 수용체-코팅된 플레이트에 전이시키고, 이어서 실온에서 1 시간 동안 항온처리하였다. 플레이트-결합된 비오티닐화-NGF를 스트렙타비딘-HRP로 검출하고, 비색성 (colorimetric) TMB 기질에 의해서 현상시키고, OD450 nm를 기록하였다. 전-결합성 용액 내의 REGN475 농도에 대한 OD450 nm 값의 의존성을 프리즘 (PRISMTM; Graph Pad, CA)에 의해서 제공된 S-자형 용량-반응 모델을 사용하여 분석하였다. 수용체 코팅된 플레이트에 대한 50 pM 비오티닐화-NGF의 결합을 50% 차단하는데 필요한 항체 농도로 정의되는 예견된 IC50 값은 hTrkA-hFc 또는 hp75-hFc에 대한 NGF 결합을 차단하는데 있어서의 항체의 효력의 지표로 사용되었다. 표 8은 hTrkA-hFc 및 hp75-hFc에 대한 각각의 시험된 항체의 IC50 값을 나타낸다. 대조군 mAb = RN624.
[표 8]
실시예 8. 수용체 TrkA -, TrkB -, TrkC - 및 p75 -hFc에 대한 NT-3 결합의 억제
500 nM의 REGN475, RN624 및 아바스틴 (AVASTIN®, IgG1 대조군)의 존재 하에서 인간 TrkA-, TrkB-, TrkC- 및 p75-hFc 표면 각각에 대한 20 nM 인간 NT-3의 결합을 또한 시험하였다. 인간 TrkA-hFc (9300 RU), 인간 TrkB-hFc (6000 RU), 인간 TrkC-hFc (9100 RU) 및 인간 p75-hFc (7500 RU)를 아민-커플링 방법에 의해서 비아코어 (BIACORE® CM5 칩 표면에 공유적으로 커플링시켰다. 20 nM의 인간 NT-3을 용액 중에서 500 nM의 대조군 (IgG1 대조군 아바스틴 (AVASTIN®), REGN475, RN624, hTrkA-hFc, TrkB-hFc, TrkC-hFc 또는 p75-hFc와 혼합시켰다. 결합 혼합물을 우선, 평형에 도달하도록 실온에서 항온처리 (약 1 시간)한 다음에, 상기의 TrkA-hFc, TrkB-hFc, TrkC-hFc 및 p75-hFc 표면 상에 주입하였다. 각각의 샘플 내의 인간 NT-3 결합의 수준을 측정하였다. 각각의 샘플 혼합물로부터의 결합 RU를 음성 대조군 샘플 (즉, 500 nM 아바스틴 (AVASTIN®)과 함께 20 nM 인간 NT-3)로부터의 RU 값에 따라 표준화시키고, Trk 표면에 대한 결합률 %로 제시하였다 (표 9). REGN475는 수용체에 대한 NT-3 결합의 저해를 거의 저해하지 않는 것으로 나타났으며, 반면에 나머지 샘플은 수용체에 대한 NT-3 결합의 상당한 차단을 나타내었다.
[표 9]
실시예
9.
시험관내에서
NGF
생물학적 활성의 중화
NGF-의존적 및 TrkA 수용체-매개된 세포 성장 활성을 차단하는 NGF 항체의 능력은 인간 TrkA 수용체를 암호화하는 플라스미드에 의해서 안정적으로 형질감염된 MG87 세포를 사용하여 수행되었다. 간략하면, 형질감염된 세포를 트립신 처리하고, ml당 대략 2.5 x 105 세포로 재현탁시키고, 96-웰 조직 배양 플레이트 내에 웰당 5,000 세포로 플레이팅하였다. 정제된 항체 단백질을 0.1% BSA를 포함하는 확정 배지 (defined medium) 내에서 계열 희석하고, 0 내지 500 nM 범위의 농도로 플레이팅된 세포에 첨가하였다. 인간 NGF를 373 pM의 최종 농도로 웰에 첨가하였다. 세포를 가습된 5% CO2 배양기 내에서 37℃로 3일 동안 배양한 후에 반응을 측정하였다. 세포 성장 활성을 CCK8 키트 (Dojindo)에 의해서 측정하고, OD450nm를 기록하였다. 항체의 농도에 대한 시그날의 의존성을 분석하고, IC50 값을 보고하였다 (표 10, 칼럼 2).
NGF 시그날링 p75 및 TrkA 수용체-매개된 활성을 차단하는 NGF 항체의 능력은 또한, 내인적으로 두 가지 수용체 모두를 발현하는 랫트 부신 수질 세포주 PC12를 사용하여 시험관내에서 측정하였다 [Urdiales et al. 1998 J. Neuroscience 18(17):6767-6775]. 간략하면, PC12 세포를 루시퍼라제 유전자에 연결된 혈청 반응 요소 (SRE)를 함유하는 리포터 (reporter) 플라스미드에 의해 안정적으로 형질감염시켰다. 형질감염된 세포를 ml당 대략 2.5 x 105 세포로 재현탁시키고, 옵티-MEM (Opti-MEM) 배지 내에서 96-웰 조직 배양 플레이트 내의 웰당 50,000 세포로 밤새 플레이팅하였다. 정제된 항체 단백질을 배지 (DMEM + 0.1% BSA) 내에서 계열 희석하고, 플레이팅된 세포에 0 내지 100 nM 범위의 농도로 첨가하였다. 인간 NGF를 웰에 12.5 pM의 최종 농도로 첨가하였다. 브라이트 글로우 (BRIGHT GLOWTM) 루시퍼라제 시험 시스템 (Promega)을 사용하여, 세포를 가습된 7.5% CO2 배양기 내에서 37℃로 6 시간 동안 배양한 후에 루시퍼라제 활성을 측정하였다. IC50 값을 상술한 바와 같이 결정하고, 표 10, 칼럼 3에 보고하였다. 대조군 mAb = RN624.
[표 10]
PC12 세포주 내에서 p75 및 TrkA 수용체-매개된 활성을 통한 NGF 시그날링을 차단하는 선택된, 정제된 항-NGF 항체, REGN472, REGN474, 및 REGN475, 및 대조군 mAb RN624의 능력을 또한, 상술한 루시퍼라제 시험방법에 의해서 평가하였다 (표 11).
[표 11]
PC12 세포주 내에서 p75 및 TrkA 수용체-매개된 활성을 통한 NT-3 시그날링을 차단하는 항-NGF 항체, REGN475, 및 대조 항체의 능력을, 12.5 pM NGF를 75 nM NT-3로 대체시킴으로써 변형된 상술한 루시퍼라제 시험방법에 의해서 평가하였다. 결과는, 대조군 mAb RN624가 약 104.8 nM의 IC50으로 NT-3 시그날링을 차단하였으며, 반면에 REGN475는 현재의 실험 조건 하에서 NT-3 시그날링에 영향을 미치지 않았음을 나타내었다.
추가로, 시험관내에서 TrkC를 통한 NT-3 매개된 세포성 기능을 중화시키는 항-NGF 항체, REGN475 및 RN624의 능력을 측정하기 위한 생물학적 시험방법 (bioassay)이 개발되었다. TrkC를 발현하는 조작된 HEK293 세포주를 SRE-루시퍼라제 리포터 플라스미드로 형질감염시켰다. NT-3은 6-시간 시험방법에서 루시퍼라제 발현을 유도한다. 이러한 조작된 세포주에서 TrkC 수용체-매개된 활성을 통한 NT-3 시그날링을 차단하는 REGN475 및 RN624의 능력은 루시퍼라제 시험방법에 의해서 평가되었다. 조작된 HEK293 세포주를 혈청-부재 배지 내에서 1 x104 세포/웰로 96-웰 플레이트 상에 접종하고, 37℃, 5% CO2에서 밤새 배양하였다. 1.6 μM 내지 28 pM 범위의 농도로 REGN475 및 RN624를 15 pM NT-3과 함께 1 시간 동안 예비항온처리하고, 혼합물을 세포에 첨가하였다. 그 후, 세포를 37℃, 5% CO2에서 6 시간 동안 배양하였다. 루시퍼라제 활성은 동등한 웰 용적의 브라이트 글로우 (BRIGHT GLOWTM; Promega)를 첨가함으로써 측정하였다. 결과는, RN624가 일정한 농도의 15 pM NGF의 존재 하에서 약 150 내지 200 nM의 IC50으로 NT-3-매개된 루시퍼라제 활성을 억제하였으며, 반면에 REGN475는 NT-3 매개된 루시퍼라제 활성을 억제하지 않았음을 나타내었다.
실시예
10.
생체내에서
NGF
생물학적 활성의 중화
염증성 통증의 완전 프로인트 보조제 (CFA) 시험. 항-NGF 항체가 만성 말초 염증성 마우스 모델에서 통증을 완화시킬 수 있었는지 여부를 측정하기 위해서, 완전 프로인트 보조제 (CFA)를 C57BL/6 수컷 마우스의 뒷발에 피하 (s.c.)로 주사하여 온열 통각과민을 야기시키고, 이것을 하그리브스 시험 (Hargreaves' test)을 사용하여 측정하였다 [Torres et al. (2007) Pain 130:267-278]. 대조군 마우스에게는 비히클 (즉, PBS)만을 투여하였다. 마우스를 3일 동안 매일 2 내지 3시간 동안 하그리브스 장치 (모델 336, IITC Life Science)에 순응시킨 후에, 이들을 장치 내에서 17%의 활성 강도 셋팅으로 시험하였다. 25초의 컷-오프 (cut-off) 시간을 사용하여 조직 손상을 피하였다. 각각의 마우스에 대해서, 1일에 30 분의 기간에 걸쳐 3 개의 판독치 (reading)를 수득하였으며, 중앙 잠복기 (median latency)가 분석을 위해서 사용되었다. 하그리브스 장치에서 기준선 판독치를 수득한 후에, 시험 항-NGF 항체, 301272-7E05-F6 (REGN268) 및 301272-7G09-E4 (REGN270), 및 양성 대조군으로서 인간화된 항-NGF 항체 (RN624)를 10 mg/kg 또는 25 mg/kg으로 피하 (s.c.) 주사하고, 1 시간 후에 CFA의 50% 용액 (10 mg/20 ㎕)을 뒷발의 족저내로 주사하였다. 하그리브스 시험은 CFA 주사한 후 4일까지 동안 매일 반복하였으며, 발 움츠림 잠복기 (paw withdrawal latency)에 있어서의 기준선으로부터의 감소율 %을 계산하였다 (표 12 및 13, 평균 변화율 % ± SEM). 비히클 만을 투여한 대조군 마우스에 비해서 온열 통각과민에 있어서의 상당한 감소가 시험한 항체 각각에 대해서 검사한 날 중의 적어도 1일에 관찰되었다 (p<0.001-0.05). 여기에서, 시험한 항체와 대조 항체 사이에 통계학적 차이는 없었다. 표 12: 각각의 그룹에 대해서 n=7; 모든 그룹 10 mg/kg. 표 13: 비히클: n=5; 대조군 RN624: n=5, 10 mg/kg; 두 가지의 REGN269: n=9).
[표 12]
[표 13]
수술-후 절개 통증 모델. 뒷발 족저 절개가 증가된 접촉 민감성, 방어적 행동 및 온열 통각과민을 야기한 수술-후 통증의 설치류 모델을 사용하여 항-NGF 항체 요법의 효능을 시험하였다. 족저 절개수술을 위해서는, 이소플루란 마취 하의 C57BL/6 마우스를 피부, 색대를 통해서 절개한 다음에, 기저 굴근을 분리시키고, 수직으로 양분하였다. 봉합 및 회복시킨 후에, 마우스를 5일 동안 하그리브스 시험에서 온열 통각과민에 대해서, 및 체중부하시험 (weight bearing test) (모델 600, IITC Life Science)에서 방어적 행동에 대해서 시험하였다. 10 mg/kg의 비히클 (n=7), mAb REGN268 (n=7), 또는 대조군 mAb RN624 (n=7)를 절개하기 1 시간 전에 단일 피하 (s.c.) 주사로 투여하였다 (표 14, 하그리브스 기준선으로부터의 평균 변화율 % ± SEM). 표 15는 체중부하시험의 결과를 나타낸다 (영향을 받은 사지에 대한 평균 체중 분포율 % ± SEM) (각각의 그룹에 대해서 n=7, 대조군 RN624 및 REGN268 각각 10 mg/kg). 두 가지 시험 모두에서, 시험 항체 또는 대조 항체에 의한 전-처리는 비히클 만을 투여한 대조군 마우스에 비해서 수술-후 통증을 상당히 감소시켰다 (p<0.001-0.05).
[표 14]
[표 15]
항-NGF 항체가 수술-후 절개 통증 모델에서 정착된 통증을 완화시킬 수 있는지 여부를 시험하기 위해서, REGN475 (25 mg/kg, n=7), RN624 (25 mg/kg, n=7), 및 IgG1 대조 항체 (25 mg/kg, n=7)를 행동 작업을 수행한 후, 수술-후 1일에 복강내 (i.p.) 주사하였다. 온열 통각과민은 하그리브스 시험에서 시험하였으며, 기계적 이질통은 폰 프라이 시험 (von Frey test)에서 시험하였다. 이러한 후자의 시험에서, 마우스는 와이어 메쉬 (wire mesh) 바닥을 갖는 장치 내에서 4일 동안에 2 내지 3시간 동안씩 순응시킨 후에 시험하였다. 시험은 일련의 폰 프라이 헤어 (hair)를 와이어 메쉬를 통해서 절개가 있는 뒷발의 족저 표면 상에 오름차순으로 적용함으로써 수행되었다. 발이 필라멘트의 적용에 대한 반응으로 플랫폼으로부터 들어올려졌다면 반응은 양성으로 간주하였다. 가장 얇은 헤어를 시작으로 하여, 각각의 폰 프라이 필라멘트를 반응이 관찰될 때까지 5 회까지 적용하였다. 하그리브스 시험으로부터의 결과 (표 16)는, REGN475 항체 처리가 수술-후 72 시간까지 온열 통각과민의 상당한 반전을 유도하였음을 나타내었다 (p<0.001-0.01). 기준선으로의 이러한 복귀는 IgG 대조군 처리된 그룹과 유사하게 행동하는 마우스의 RN624 치료된 코호트 (cohort)에서 관찰되었다. 폰 프라이 시험 (발 움츠림 역치) (g) (표 17)에서, 두 가지 항-NGF 항체는 모두 기계적 이질통의 유사한 완화를 야기하였다 (p<0.001-0.05) (IgG1 대조군 = 아바스틴 (AVASTIN®), 25 mg/kg, n=7; RN624, 25 mg/kg, n=7; REGN475, 25 mg/kg, n=7).
[표 16]
[표 17]
제4일에, 절개-후 통증 모델로부터의 행동 시험을 완료한 후, 마우스의 혈청을 수집하고, 샌드위치 ELISA를 사용하여 뉴로트로핀-3 (NT-3)의 순환 수준에 대해서 분석하였다. 검출의 한계 (약 40 pg/ml)는 농도에 대한 반응곡선을 정의하기 위한 5 개의 NT-3 표준 중의 최소를 갖는 배경 상의 2 표준 편차 (2σ)로 정의되었다. RN624로 처리된 마우스로부터의 NT-3 수준 (평균 ± 표준 편차 pg/ml, 표 18)은 REGN475 (검출되지 않음 =ND, n=7) 또는 IgG 대조군 (아바스틴 (AVASTIN®); ND, n=7)으로 처리된 마우스로부터 상당한 증가 (172±114 pg/ml, n=7)를 나타내었다.
[표 18]
비교를 위해서, 이소플루란 마취 하의 순수한 C57BL/6 마우스에게 REGN475, RN624 또는 IgG1 대조군 mAb (AVASTIN®)를 한번 피하 (s.c.) 주사하고 (50 mg/kg), 이들의 혈청을 샌드위치 ELISA를 사용하여 NT-3 수준에 대해서 처리 후 1, 7 및 14일에 분석하였다. 검출의 한계 (약 40 pg/ml)는 농도에 대한 반응곡선을 정의하기 위한 5 개의 NT-3 표준 중의 최소를 갖는 배경 상의 2 표준 편차 (2σ)로 정의되었다. RN624 처리된 마우스 (131-199 pg/ml, n=6)에서 NT-3 수준 (표 19)은 상술한 수술-후 절개 통증 모델에 의해서 관찰된 바와 같이, REGN475 (ND, n=6) 또는 IgG 대조군 (ND, n=6)에 비해 상승되었다.
[표 19]
급성 통풍 관절 통증 모델. 발목 내로 모노나트륨 우레이트 (MSU) 결정을 주사함으로써 야기된 관절 통증의 마우스 모델을 사용하여 통풍 관절염성 관절 통증을 치료하는 본 발명의 항체의 효능을 시험하였다. 내독소-부재 MSU 결정 (0.5 mg/20 ㎕)을 C57BL/6 마우스의 발목 내로 관절내 주사한 다음에, 마우스를 MSU 결정 주사-후 3일까지 동안 하그리브스 시험에서 발뒤꿈치 온도 통증에 대해서 시험하였다. 하그리브스 시험을 위한 순응 파라메터 및 장치 셋팅은 상술한 바와 같다. 시험 mAb 7E05-F6 (REGN268; n=7), 6E07-D10 (REGN263; n=7), 또는 대조군 인간화된 mAb (RN624; n=7), 또는 비히클 (n=7)을, MSU 결정을 발목 주사하기 1 시간 전에 10 mg/kg으로 피하 (s.c.) 주사하였다. 표 20 및 21에 나타낸 바와 같이, 시험 항체는 비히클 만을 투여한 대조군 마우스에 비해서 관절 통증을 상당히 감소시켰다 (p<0.001-0.05).
[표 20]
[표 21]
급성 통풍 모델에서 정착된 통증을 완화시키는 항-NGF 항체의 능력은 또한, IL-1 길항제 [IL-1 트랩 (리놀라셉트), Economides et al. (2003) Nature 9:47-52) 또는 콜히친을 주사한 마우스에서 더 시험하였다. MSU 결정을 발목 내로 주사한 후 1일에 마우스에게 mIL-1 트랩 (35 mg/kg; n=7), 콜히친 (1 mg/kg; n=7), 대조군 mAb RN624 (10 mg/kg; n=7), 또는 비히클 (n=7)을 주사하고, 상술한 바와 같이 온열 통각과민에 대해서 시험하였다. 추가로, 마우스의 또 다른 코호트 (n=3)에게 mIL-1 트랩 및 대조군 RN624 둘 다에 의한 공동-치료를 적용하였다. 항-NGF 항체 및 IL-1 길항제의 병용 치료는 치료-후 2일에, 비히클 단독 (p<0.001-0.05) 또는 항-NGF 항체 단독 (p<0.001) 또는 IL-1 길항제 단독 (p<0.001)으로 치료한 경우에 비해서 정착된 온열 통각과민을 상당히 완화시켰다 (표 22).
[표 22]
신경병성 통증. 신경병성 통증의 마우스 셀처 모델 (Seltzer model) [Malmberg et al. (1998) Pain 76:215-222]이 C57BL/6 수컷 마우스에 의해서 사용되었는데, 여기에서는 마우스당 하나의 단일 넓적다리의 좌골신경의 직경의 대략 1/3 내지 1/2 주위를 7-0 실크 봉합사로 단단히 결찰하여 묶어줌으로써 부분적 신경 손상을 발생시켰다. 수술 후에, 마우스는 적어도 2일 동안 회복하도록 한 다음에, 이들을 하그리브스 시험에서 온열 통각과민에 대해서 수술-후 몇 주일 동안 시험하였다. 대조군은 좌골신경은 노출시키고 묶지 않고 평가하는 겉보기-수술한 마우스였다. 수술 후에, 마우스를 수술-후 4일 및 7일에 시험하여 온열 통각과민이 발생하였는지 확인하였다. 수술-후 7일에, 마우스에게 mAb REGN268 (100 mg/kg), IgG1 대조군 (아바스틴 (AVASTIN®) 100 mg/kg), 및 비히클을 피하 (s.c.) 주사하였다. REGN268은 이러한 신경 손상 모델에서 정착된 온열 통각과민을 상당히 완화시켰다 (표 23; p<0.05). 이러한 통증 완화는 겉보기-수술한 마우스에서는 관찰되지 않았다. 결과는 하그리브스 기준선으로부터의 평균 변화율 % ± SEM으로 표현하였다 (겉보기-비히클, n=3; 겉보기-100 mg/kg IgG1 대조군 (AVASTIN®), n=4; 겉보기-100 mg/kg REGN268, n=5; 셀처-비히클, n=5; 셀처-100 mg/kg IgG1 대조군 (AVASTIN®), n=5; 셀처-100 mg/kg REGN268, n=8).
[표 23]
두 번째 실험에서는, 항-NGF 처리가 수술-후 7일이 지나서 온열 통각과민을 완화시킬 수 있었는지 여부를 조사하기 위해서, 항-NGF REGN268 (100 mg/kg)을 수술-후 7, 14 또는 21일에 피하 (s.c.) 주사하였다. 상당한 통증 완화가 IgG1 대조군 (아바스틴 (AVASTIN®) 100 mg/kg; p<0.05)에 비해 3 개의 시점 모두에서 수득되었다 (표 24, 하그리브스 기준선으로부터의 평균 변화율 % ± SEM; 100 mg/kg IgG1 대조군, n=6; 100 mg/kg REGN268, n=7).
[표 24]
세 번째 실험에서는, 또 다른 항-NGF 항체 REGN475의 능력을 셀처 모델에서 시험하였다. 셀처 수술 후에, 마우스는 수술-후 5 및 7일에 온열 통각과민이 발생하였는지를 확인하기 위하여 시험하였다. 그 후, 수술-후 7일에 마우스는 REGN475 (50 mg/kg), 대조군 mAb RN624 (50 mg/kg) 또는 IgG1 대조군 (아바스틴 (AVASTIN®) (50 mg/kg)을 피하 (s.c.) 또는 복강내 (i.p.) 경로로 주사하였다. s.c. (표 25) 또는 i.p. (표 26) 주사한 마우스의 두 가지 코호트 모두에서 항-NGF 항체 모두에 의해 상당한 통증 완화가 관찰되었으며, 그 반면에 대조군 IgG1은 효과를 나타내지 않았다 (p<0.001-0.05) (하그리브스 기준선으로부터의 평균 변화율 % ± SEM; 50 mg/kg IgG1 대조군, n=7; 50 mg/kg RN624, n=7; 50 mg/kg REGN475, n=7).
[표 25]
[표 26]
생체내에서 인간 NGF 활성을 중화시키는 항체의 능력을 측정하기 위해서, 이의 내인성 마우스 NGF 유전자좌를 인간 NGF 유전자로 대체시킨 유전자 이식 마우스를 준비하였다. 이들 마우스를 셀처 신경병성 통증 모델에서 사용하여 REGN268 및 대조군 mAb를 시험하였다. 셀처 수술 후에, 이들 마우스를 수술-후 4일 및 8일에 시험하여 온열 통각과민이 발생하였는지를 확인하였다. 그 후, 수술-후 8일에 마우스에게 50 mg/kg mAb REGN268 (n=7), 50 mg/kg 대조군 RN624 (n=8), 또는 50 mg/kg IgG1 대조군 (아바스틴 (AVASTIN®) (n=6)을 피하 (s.c.) 주사하였다. 결과 (표 27)는, REGN268이 인간화된 NGF 마우스에서 신경병성 통증을 완화시키는데 있어서 인간화된 항-NGF 항체 (RN624)만큼 효과적이었으며, 반면에 IgG1 대조군은 효과를 갖지 않았음을 나타내었다 (p<0.05).
[표 27]
실시예
11. 동물 운동기능에 대한 항-
NGF
의 효과
항-NGF 처리가 운동기능을 변화시킬 수 있었는지 여부를 시험하기 위해서, 순수한 C57BL/6 수컷 마우스에서의 로타로드 시험 (rotarod test)에서 운동 공조를 평가하였다. 동물을 우선, 점진적으로 더 고속 (최대 속도 10 rpm)으로 회전하는 로타로드 (Columbus Instruments, 3.5 cm 직경, 9 cm 폭) 상에 머물도록 훈련시켰다. 마우스는 이들이 60 초 동안 연속적으로 걸을 수 있을 때까지, 또는 이들이 연속 3일 동안 매일 10 rpm의 로타로드 상에서 걷는데 총 2분을 소비할 때까지 10 rpm에서 훈련을 유지하였다. 훈련 후에, 각각의 마우스를 10 rpm의 로타로드 상에 연속해서 3 회 (실험 사이에 짧은 휴지기를 두고) 배치하고, 떨어질 때까지의 잠복기를 기록하였다. 동물을 1 분 후에 치우고, 이들이 떨어지지 않았다면 60 초의 점수를 주었다. 각각의 마우스에 대한 3 번의 실험의 중앙 점수를 분석에 사용하였다. 로타로드에서의 기준선 판독치를 수득한 후에, mAb REGN475, RN624, 또는 IgG 음성 대조군을 50 mg/kg 또는 100 mg/kg으로 피하 (s.c.) 주사하였다. 그 후, 마우스를 항체 주사-후 20일까지 동안 시험하였다. 결과 (표 28, 떨어질 때까지의 잠복기를 초로 표현함) (평균 ± sem)는, REGN475가 아닌 RN624로 처리한 마우스가 상당히 손상된 운동 공조를 가졌음을 나타내었다 (p<0.001-0.05). 흥미롭게도, NT-3 및 TrkC 녹아웃 마우스는 비정상적인 운동 및 자세 및 상실된 고유수용을 나타낸 것으로 보고되었다 [Ernfors et al. (1994) Cell 77:503-512; 및 Klein et al. (1994) Nature 368:249-251]. 로타로드 이외에도, 항-NGF 항체를 주사한 순수한 마우스에 대한 하그리브스 및 폰 프라이 시험을 또한 수행하였다. 항체 투여-후 20일 중에 하그리브스 및 폰 프라이 시험에서 마우스의 어떤 그룹에 대해서도 통계학적으로 유의적인 차이는 관찰되지 않았다 (각각의 그룹에 대해서 n=6).
[표 28]
실시예
12.
포진후
신경통을 앓고 있는 환자의 치료
대상포진 발진의 부위에서 만성 통증을 나타낸 환자를 포진후 신경통으로 진단한다. 환자는 본 발명의 항-NGF mAb를 포함하는 약제학적으로 허용되는 조성물의 치료학적 유효량을 투여함으로써 치료된다. 투여는 바람직하게는 0.1 내지 10 mg/kg (체중)의 항-NGF 항체 농도로 피하 또는 정맥내 주사에 의해서 이루어질 수 있다. 치료의 빈도는 매 1 내지 12주 마다가 될 수 있거나, 또는 필요에 따를 수 있다. 항-NGF 항체 조성물의 투여 후 수일 이내에, 환자의 통증은 실질적으로 경감된다. 항-NGF mAb 조성물의 반복된 투여는 이 통증의 완화를 유지시킨다.
실시예
13. 골관절염 통증을 앓고 있는 환자의 치료
어떤 관절에서든 골관절염에 의해서 야기된 중등도 내지 중증의 통증을 앓고 있는 환자는 본 발명의 항-NGF mAb를 포함하는 약제학적으로 허용되는 조성물의 치료학적 유효량을 투여함으로써 치료된다. 조성물은 10 ㎍/kg (체중) 내지 10 mg/kg (체중)의 항-NGF 항체의 농도로 정맥내 투여될 수 있다. 치료의 빈도는 매 1 내지 12주 마다가 될 수 있거나, 또는 필요에 따를 수 있다. 항-NGF 항체 조성물의 투여 후 수일 이내에, 환자의 통증은 실질적으로 경감되며, 병이 침범한 관절의 이동성을 회복한다. 치료는 필요한 만큼 길게 반복될 수 있다.
<110> Regeneron Pharmaceuticals, Inc.
<120> High affinity human antibodies to human nerve growth factor
<130> 6060A-WO
<150> US 60/964,224
<151> 2007-08-10
<150> US 60/994,526
<151> 2007-09-20
<150> US 61/062,860
<151> 2008-01-28
<150> US 61/079,259
<151> 2008-07-09
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gaggtgcagc tggtggagtc tgggggaggc ttggtacagc cgggggggtc cctgagactc 60
tcctgtgcag cctctggatt caccttcagt agctacgaca tacactgggt ccgccaagct 120
acaggaaaag gtctggagtg ggtctcagct atcggtgctg ctggtgacac atactattca 180
ggctccgtga agggccgatt caccatctcc agagaaaatg ccaagaactc cttgtatctt 240
gaaatgaata aattgagagc cggggacacg gctgtgtatt actgtgcaag agagggaacc 300
ggaactacga actactatta tggtatggac gtctggggcc aagggaccac ggtcaccgtc 360
tcctcag 367
<210> 20
<211> 122
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 20
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Asp Ile His Trp Val Arg Gln Ala Thr Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Gly Ala Ala Gly Asp Thr Tyr Tyr Ser Gly Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Glu Asn Ala Lys Asn Ser Leu Tyr Leu
65 70 75 80
Glu Met Asn Lys Leu Arg Ala Gly Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Glu Gly Thr Gly Thr Thr Asn Tyr Tyr Tyr Gly Met Asp Val Trp
100 105 110
Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 21
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 21
ggattcacct tcagtagcta cgac 24
<210> 22
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 22
Gly Phe Thr Phe Ser Ser Tyr Asp
1 5
<210> 23
<211> 21
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 23
atcggtgctg ctggtgacac a 21
<210> 24
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 24
Ile Gly Ala Ala Gly Asp Thr
1 5
<210> 25
<211> 48
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 25
gcaagagagg gaaccggaac tacgaactac tattatggta tggacgtc 48
<210> 26
<211> 16
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 26
Ala Arg Glu Gly Thr Gly Thr Thr Asn Tyr Tyr Tyr Gly Met Asp Val
1 5 10 15
<210> 27
<211> 322
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 27
gaaattgtat tgacgcagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 60
ctctcctgca gggccagtca gagtgttagc aggcacttag cctggtacca gcagaactct 120
ggccaggctc ccaggctcct catctatagt gcatccagca gggccactgg catcccagac 180
aggttcagtg gcagggggtc tgggacagac ttcactctca ccatcagcag actggagcct 240
gaggaatttg cagtgtatta ctgtcagcag tatagtagct caccgatcac cttcggccaa 300
gggacacgac tggagattaa tc 322
<210> 28
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 28
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Arg His
20 25 30
Leu Ala Trp Tyr Gln Gln Asn Ser Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly
50 55 60
Arg Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro
65 70 75 80
Glu Glu Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Ser Ser Ser Pro Ile
85 90 95
Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Asn
100 105
<210> 29
<211> 18
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 29
cagagtgtta gcaggcac 18
<210> 30
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 30
Gln Ser Val Ser Arg His
1 5
<210> 31
<211> 9
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 31
agtgcatcc 9
<210> 32
<211> 3
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 32
Ser Ala Ser
1
<210> 33
<211> 27
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 33
cagcagtata gtagctcacc gatcacc 27
<210> 34
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 34
Gln Gln Tyr Ser Ser Ser Pro Ile Thr
1 5
<210> 35
<211> 367
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 35
gaggtgcagc tggtggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60
tcctgtgcag cctcgggatt caccttcaga gcctacgaca tgcactgggt ccgccaaaca 120
gcaggaaaag gtctggagtg ggtctcagct attggttctg ctggtgacac atactattca 180
ggctccgtga agggccgatt caccatctcc agagaaaatg ccaagaagtc cttgtatctt 240
caaatgaata gcctgagagc cggggacacg gctgtgtatt tttgtgcaag agaggcaact 300
ggaactacga actactacta cggtatggac gtctggggcc aagggaccac ggtcaccgtc 360
tcctccg 367
<210> 36
<211> 122
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 36
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ala Tyr
20 25 30
Asp Met His Trp Val Arg Gln Thr Ala Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Gly Ser Ala Gly Asp Thr Tyr Tyr Ser Gly Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Glu Asn Ala Lys Lys Ser Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Gly Asp Thr Ala Val Tyr Phe Cys Ala
85 90 95
Arg Glu Ala Thr Gly Thr Thr Asn Tyr Tyr Tyr Gly Met Asp Val Trp
100 105 110
Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 37
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 37
ggattcacct tcagagccta cgac 24
<210> 38
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 38
Gly Phe Thr Phe Arg Ala Tyr Asp
1 5
<210> 39
<211> 21
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 39
attggttctg ctggtgacac a 21
<210> 40
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 40
Ile Gly Ser Ala Gly Asp Thr
1 5
<210> 41
<211> 48
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 41
gcaagagagg caactggaac tacgaactac tactacggta tggacgtc 48
<210> 42
<211> 16
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 42
Ala Arg Glu Ala Thr Gly Thr Thr Asn Tyr Tyr Tyr Gly Met Asp Val
1 5 10 15
<210> 43
<211> 325
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 43
gaaaatgtgt tgacgcagtc tccaggcacc ctgtctttgt ctccagggga aagaggcacc 60
ctctcctgca gggccagtca gaatattagc ggcaggtcct tagcctggta ccaccagaaa 120
cctggccaga ctcccaaact cctcatcttt ggtgcgtcca ggagggccac tggcatccca 180
gacaggttca gtggcagcgg gtctggaaca gacttcactc tcaccatcag cagactggag 240
cctgaagatt ttgcagtgta ttactgtcag caatatggta gctcaccgat caccttcggc 300
caagggacac gactggagat taaac 325
<210> 44
<211> 108
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 44
Glu Asn Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Gly Thr Leu Ser Cys Arg Ala Ser Gln Asn Ile Ser Gly Arg
20 25 30
Ser Leu Ala Trp Tyr His Gln Lys Pro Gly Gln Thr Pro Lys Leu Leu
35 40 45
Ile Phe Gly Ala Ser Arg Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro
85 90 95
Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys
100 105
<210> 45
<211> 21
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 45
cagaatatta gcggcaggtc c 21
<210> 46
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 46
Gln Asn Ile Ser Gly Arg Ser
1 5
<210> 47
<211> 9
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 47
ggtgcgtcc 9
<210> 48
<211> 3
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 48
Gly Ala Ser
1
<210> 49
<211> 27
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 49
cagcaatatg gtagctcacc gatcacc 27
<210> 50
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 50
Gln Gln Tyr Gly Ser Ser Pro Ile Thr
1 5
<210> 51
<211> 367
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 51
gaggtgcagc tggtggagtc tgggggaggc ttgatacagc ctggggggtc cctgagactc 60
tcctgtgcag cctctggatt caccttcagt aacttcgaca tgcactgggt ccgccaagct 120
acaggaaaag gtctggagtg ggtcgcagct attggttctg ctggtgacac atactatccg 180
gactccgtga ggggccgatt caccatctcc agagaaaatg ccaagaactc cttgtttctt 240
caaatgaaca gcctacgaga cggggacacg gctgtgtatt attgtgcaag agagggaact 300
ggaactacga actattacta cggtatggac gtctggggcc aagggaccac ggtcaccgtc 360
tcgtcag 367
<210> 52
<211> 122
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 52
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Phe
20 25 30
Asp Met His Trp Val Arg Gln Ala Thr Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ala Ile Gly Ser Ala Gly Asp Thr Tyr Tyr Pro Asp Ser Val Arg
50 55 60
Gly Arg Phe Thr Ile Ser Arg Glu Asn Ala Lys Asn Ser Leu Phe Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Asp Gly Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Glu Gly Thr Gly Thr Thr Asn Tyr Tyr Tyr Gly Met Asp Val Trp
100 105 110
Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 53
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 53
ggattcacct tcagtaactt cgac 24
<210> 54
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 54
Gly Phe Thr Phe Ser Asn Phe Asp
1 5
<210> 55
<211> 21
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 55
attggttctg ctggtgacac a 21
<210> 56
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 56
Ile Gly Ser Ala Gly Asp Thr
1 5
<210> 57
<211> 48
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 57
gcaagagagg gaactggaac tacgaactat tactacggta tggacgtc 48
<210> 58
<211> 16
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 58
Ala Arg Glu Gly Thr Gly Thr Thr Asn Tyr Tyr Tyr Gly Met Asp Val
1 5 10 15
<210> 59
<211> 322
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 59
gaaattatgt tgacgcagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 60
ctctcctgca gggccagtca gagtgttagc agtcacttag cctggtacca gcagacctct 120
ggccaggctc ccaggctcct catctatggt gcttccagca ggaccactgg catcccagac 180
aggttcagtg gcagtgggtc tgggacagac ttcactctca ccatcagtag actggagcct 240
gaagattttg cagtgtatta ctgtcaacat tatagtaagt caccgatcac cttcggccaa 300
gggacacgac tggagattaa tc 322
<210> 60
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 60
Glu Ile Met Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser His
20 25 30
Leu Ala Trp Tyr Gln Gln Thr Ser Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Ser Arg Thr Thr Gly Ile Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Tyr Ser Lys Ser Pro Ile
85 90 95
Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Asn
100 105
<210> 61
<211> 18
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 61
cagagtgtta gcagtcac 18
<210> 62
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 62
Gln Ser Val Ser Ser His
1 5
<210> 63
<211> 9
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 63
ggtgcttcc 9
<210> 64
<211> 3
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 64
Gly Ala Ser
1
<210> 65
<211> 27
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 65
caacattata gtaagtcacc gatcacc 27
<210> 66
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 66
Gln His Tyr Ser Lys Ser Pro Ile Thr
1 5
<210> 67
<211> 367
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 67
gaggtgcagc tggtggagtc tgggggaggc ttggaacagc ctggggggtc cctgagactc 60
tcctgtgtag cctctggatt caccttcagt aactacgaca tgcactgggt ccgccaagcc 120
acaggaaaag gtctggagtg ggtctcagct attggtgctg ctggtgacac atactattca 180
ggctccgtga agggccgatt caccatcgcc agagaaaatg gcaagaactc cctgtatctt 240
caaatgaatg gcctgagagc cggggacacg gctgtgtatt actgtgcaag agagggaact 300
ggaactacga actactacta cggtatggac gtctggggcc aagggaccac ggtcaccgtc 360
tcctctg 367
<210> 68
<211> 122
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 68
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Glu Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Asp Met His Trp Val Arg Gln Ala Thr Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Gly Ala Ala Gly Asp Thr Tyr Tyr Ser Gly Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ala Arg Glu Asn Gly Lys Asn Ser Leu Tyr Leu
65 70 75 80
Gln Met Asn Gly Leu Arg Ala Gly Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Glu Gly Thr Gly Thr Thr Asn Tyr Tyr Tyr Gly Met Asp Val Trp
100 105 110
Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 69
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 69
ggattcacct tcagtaacta cgac 24
<210> 70
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 70
Gly Phe Thr Phe Ser Asn Tyr Asp
1 5
<210> 71
<211> 21
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 71
attggtgctg ctggtgacac a 21
<210> 72
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 72
Ile Gly Ala Ala Gly Asp Thr
1 5
<210> 73
<211> 48
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 73
gcaagagagg gaactggaac tacgaactac tactacggta tggacgtc 48
<210> 74
<211> 16
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 74
Ala Arg Glu Gly Thr Gly Thr Thr Asn Tyr Tyr Tyr Gly Met Asp Val
1 5 10 15
<210> 75
<211> 322
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 75
gaaattgtgt tgacgcagtc tccagacacc ctgtcgttgt ctctagggga gagagccatc 60
ctctcctgca gggccagtca gagtgttagc agctacttag cctggtacca gcagacctct 120
ggccaggctc ccaggctcct catctttggt gcgtccagca gggccactgg catcccagac 180
aggttcagtg gcagtgggtc tgggacagac ttcactctca ccatcaacag actggaacct 240
ggagattttg cagtgtatta ctgtcagcag tatgctagtt caccgatcac cttcggccaa 300
gggacacgac tggatattaa tc 322
<210> 76
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 76
Glu Ile Val Leu Thr Gln Ser Pro Asp Thr Leu Ser Leu Ser Leu Gly
1 5 10 15
Glu Arg Ala Ile Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Thr Ser Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Phe Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn Arg Leu Glu Pro
65 70 75 80
Gly Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Ala Ser Ser Pro Ile
85 90 95
Thr Phe Gly Gln Gly Thr Arg Leu Asp Ile Asn
100 105
<210> 77
<211> 18
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 77
cagagtgtta gcagctac 18
<210> 78
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 78
Gln Ser Val Ser Ser Tyr
1 5
<210> 79
<211> 9
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 79
ggtgcgtcc 9
<210> 80
<211> 3
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 80
Gly Ala Ser
1
<210> 81
<211> 27
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 81
cagcagtatg ctagttcacc gatcacc 27
<210> 82
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 82
Gln Gln Tyr Ala Ser Ser Pro Ile Thr
1 5
<210> 83
<211> 357
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 83
caggtgcagc tggtacagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtc 60
tcctgcaagg tttccggatt caccctcact gaattatcca ttcactgggt gcgacaggct 120
cctggaaaag ggcttgagtg gatgggaggt tttgatcctg aagatggtga aacaatctac 180
gcacagaagt tccagggcag agtcaccatg accgaggaca catctacaga cacagcctac 240
atggagctga ccagcctgag atcggaagac acggccgtgt attactgttc aacgattttt 300
ggagtggtta ccaactttga caactggggc cagggaaccc tggtcaccgt ctcctca 357
<210> 84
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 84
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Val Ser Gly Phe Thr Leu Thr Glu Leu
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Gly Phe Asp Pro Glu Asp Gly Glu Thr Ile Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Glu Asp Thr Ser Thr Asp Thr Ala Tyr
65 70 75 80
Met Glu Leu Thr Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ser Thr Ile Phe Gly Val Val Thr Asn Phe Asp Asn Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 85
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 85
ggattcaccc tcactgaatt atcc 24
<210> 86
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 86
Gly Phe Thr Leu Thr Glu Leu Ser
1 5
<210> 87
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 87
tttgatcctg aagatggtga aaca 24
<210> 88
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 88
Phe Asp Pro Glu Asp Gly Glu Thr
1 5
<210> 89
<211> 36
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 89
tcaacgattt ttggagtggt taccaacttt gacaac 36
<210> 90
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 90
Ser Thr Ile Phe Gly Val Val Thr Asn Phe Asp Asn
1 5 10
<210> 91
<211> 324
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 91
gacatccgga tgacccagtc tccatcctcc ctgtctgcat ctgcaggaga cagagtcacc 60
atcacttgcc gggcaagtca ggccattaga aatgatttag gctggtatca gcagaaacca 120
gggaaagccc ctaagcgcct gatctatgct gcattcaatt tgcaaagtgg ggtcccatca 180
agattcagcg gcagtggatc tgggacagaa ttcactctca caatcagtag cctgcagcct 240
gaagatcttg caagttatta ctgtcaacag tataatagat acccgtggac gttcggccaa 300
gggaccaagc tggagatcaa acga 324
<210> 92
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 92
Asp Ile Arg Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Ala Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ala Ile Arg Asn Asp
20 25 30
Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile
35 40 45
Tyr Ala Ala Phe Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Leu Ala Ser Tyr Tyr Cys Gln Gln Tyr Asn Arg Tyr Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 93
<211> 18
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 93
caggccatta gaaatgat 18
<210> 94
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 94
Gln Ala Ile Arg Asn Asp
1 5
<210> 95
<211> 9
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 95
gctgcattc 9
<210> 96
<211> 3
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 96
Ala Ala Phe
1
<210> 97
<211> 27
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 97
caacagtata atagataccc gtggacg 27
<210> 98
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 98
Gln Gln Tyr Asn Arg Tyr Pro Trp Thr
1 5
<210> 99
<211> 357
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 99
caggtgcagc tggtgcagtc cggcgccgag gtgaagaagc ccggcgcctc cgtgaaggtg 60
tcctgcaagg tgtccggctt caccctgacc gagctgtcca tgcactgggt gcggcaggcc 120
cccggcaagg gcctggagtg gatgggcggc ttcgaccccg aggacggcga gaccatctac 180
gcccagaagt tccagggccg ggtgaccatg accgaggaca cctccaccga caccgcctac 240
atggagctgt cctccctgcg gtccgaggac accgccgtgt actactgctc caccatcttc 300
ggcgtggtga ccaacttcga caactggggc cagggcaccc tggtgaccgt gtcctcc 357
<210> 100
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 100
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Val Ser Gly Phe Thr Leu Thr Glu Leu
20 25 30
Ser Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Gly Phe Asp Pro Glu Asp Gly Glu Thr Ile Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Glu Asp Thr Ser Thr Asp Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ser Thr Ile Phe Gly Val Val Thr Asn Phe Asp Asn Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 101
<211> 324
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 101
gacatccaga tgacccagtc cccctcctcc ctgtccgcct ccgtgggcga ccgggtgacc 60
atcacctgcc gggcctccca ggccatccgg aacgacctgg gctggtacca gcagaagccc 120
ggcaaggccc ccaagcggct gatctacgcc gccttcaacc tgcagtccgg cgtgccctcc 180
cggttctccg gctccggctc cggcaccgag ttcaccctga ccatctcctc cctgcagccc 240
gaggacttcg ccacctacta ctgccagcag tacaaccggt acccctggac cttcggccag 300
ggcaccaagg tggagatcaa gcgg 324
<210> 102
<211> 108
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 102
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ala Ile Arg Asn Asp
20 25 30
Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile
35 40 45
Tyr Ala Ala Phe Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Arg Tyr Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105
<210> 103
<211> 357
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 103
caggtgcagc tggtgcagtc cggcgccgag gtgaagaagc ccggcgcctc cgtgaaggtg 60
tcctgcaagg tgtccggctt caccctgacc gagctgtcca tgcactgggt gcggcaggcc 120
cccggcaagg gcctggagtg gatgggcggc ttcgaccccg aggacggcga gaccatctac 180
gcccagaagt tccagggccg ggtgaccatg accgaggaca cctccaccga caccgcctac 240
atggagctgt cctccctgcg gtccgaggac accgccgtgt actactgctc caccatcttc 300
ggcgtggtga ccaacttcga caactggggc cagggcaccc tggtgaccgt gtcctcc 357
<210> 104
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 104
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Val Ser Gly Phe Thr Leu Thr Glu Leu
20 25 30
Ser Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Gly Phe Asp Pro Glu Asp Gly Glu Thr Ile Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Glu Asp Thr Ser Thr Asp Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ser Thr Ile Phe Gly Val Val Thr Asn Phe Asp Asn Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 105
<211> 324
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 105
gacatccaga tgacccagtc cccctcctcc ctgtccgcct ccgtgggcga ccgggtgacc 60
atcacctgcc gggcctccca ggccatccgg aacgacctgg gctggtacca gcagaagccc 120
ggcaaggccc ccaagcggct gatctacgcc gccttctccc tgcagtccgg cgtgccctcc 180
cggttctccg gctccggctc cggcaccgag ttcaccctga ccatctcctc cctgcagccc 240
gaggacttcg ccacctacta ctgccagcag tacaaccggt acccctggac cttcggccag 300
ggcaccaagg tggagatcaa gcgg 324
<210> 106
<211> 108
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 106
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ala Ile Arg Asn Asp
20 25 30
Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile
35 40 45
Tyr Ala Ala Phe Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Arg Tyr Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105
<210> 107
<211> 357
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 107
caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtc 60
tcctgcaagg tttccggatt caccctcact gaattatcca ttcactgggt gcgacaggct 120
cctggaaaag ggcttgagtg gatgggaggt tttgatcctg aagatggtga aacaatctac 180
gcacagaagt tccagggcag agtcaccatg accgaggaca catctacaga cacagcctac 240
atggagctga ccagcctgag atcggaagac acggccgtgt attactgttc aacgattttt 300
ggagtggtta ccaactttga caactggggc cagggaaccc tggtcaccgt ctcctca 357
<210> 108
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 108
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Val Ser Gly Phe Thr Leu Thr Glu Leu
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Gly Phe Asp Pro Glu Asp Gly Glu Thr Ile Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Glu Asp Thr Ser Thr Asp Thr Ala Tyr
65 70 75 80
Met Glu Leu Thr Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ser Thr Ile Phe Gly Val Val Thr Asn Phe Asp Asn Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 109
<211> 324
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 109
gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgcaggaga cagagtcacc 60
atcacttgcc gggcaagtca ggccattaga aatgatttag gctggtatca gcagaaacca 120
gggaaagccc ctaagcgcct gatctatgct gcattcaatt tgcaaagtgg ggtcccatca 180
agattcagcg gcagtggatc tgggacagaa ttcactctca caatcagtag cctgcagcct 240
gaagatcttg caagttatta ctgtcaacag tataatagat acccgtggac gttcggccaa 300
gggaccaagg tggaaatcaa acga 324
<210> 110
<211> 108
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 110
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Ala Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ala Ile Arg Asn Asp
20 25 30
Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile
35 40 45
Tyr Ala Ala Phe Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Leu Ala Ser Tyr Tyr Cys Gln Gln Tyr Asn Arg Tyr Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105
<210> 111
<211> 357
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 111
caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtc 60
tcctgcaagg tttccggatt caccctcact gaattatcca ttcactgggt gcgacaggct 120
cctggaaaag ggcttgagtg gatgggaggt tttgatcctg aagatggtga aacaatctac 180
gcacagaagt tccagggcag agtcaccatg accgaggaca catctacaga cacagcctac 240
atggagctga ccagcctgag atcggaagac acggccgtgt attactgttc aacgattttt 300
ggagtggtta ccaactttga caactggggc cagggaaccc tggtcaccgt ctcctca 357
<210> 112
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 112
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Val Ser Gly Phe Thr Leu Thr Glu Leu
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Gly Phe Asp Pro Glu Asp Gly Glu Thr Ile Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Glu Asp Thr Ser Thr Asp Thr Ala Tyr
65 70 75 80
Met Glu Leu Thr Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ser Thr Ile Phe Gly Val Val Thr Asn Phe Asp Asn Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 113
<211> 324
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 113
gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgcaggaga cagagtcacc 60
atcacttgcc gggcaagtca ggccattaga aatgatttag gctggtatca gcagaaacca 120
gggaaagccc ctaagcgcct gatctatgct gcattctcct tgcaaagtgg ggtcccatca 180
agattcagcg gcagtggatc tgggacagaa ttcactctca caatcagtag cctgcagcct 240
gaagatcttg caagttatta ctgtcaacag tataatagat acccgtggac gttcggccaa 300
gggaccaagg tggaaatcaa acga 324
<210> 114
<211> 108
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 114
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Ala Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ala Ile Arg Asn Asp
20 25 30
Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile
35 40 45
Tyr Ala Ala Phe Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Leu Ala Ser Tyr Tyr Cys Gln Gln Tyr Asn Arg Tyr Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105
<210> 115
<211> 357
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 115
gaagtgcagc tggtgcagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtc 60
tcctgcaagg tttccggata caccctcact gaattatcca tacactgggt gcgacaggct 120
cctggaaaag ggcttgaatg gatgggaggt tttgatcctg aacatggtac aacaatctac 180
gcacagaagt tccagggcag agtcaccatg accgaggaca catctacaga cacagcctac 240
atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgt aatgattttt 300
ggcgtggtta ccaattttga caactggggc cagggaacca cggtcaccgt ctcctca 357
<210> 116
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 116
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Val Ser Gly Tyr Thr Leu Thr Glu Leu
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Gly Phe Asp Pro Glu His Gly Thr Thr Ile Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Glu Asp Thr Ser Thr Asp Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Val Met Ile Phe Gly Val Val Thr Asn Phe Asp Asn Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser
115
<210> 117
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 117
ggatacaccc tcactgaatt atcc 24
<210> 118
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 118
Gly Tyr Thr Leu Thr Glu Leu Ser
1 5
<210> 119
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 119
tttgatcctg aacatggtac aaca 24
<210> 120
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 120
Phe Asp Pro Glu His Gly Thr Thr
1 5
<210> 121
<211> 36
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 121
gtaatgattt ttggcgtggt taccaatttt gacaac 36
<210> 122
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 122
Val Met Ile Phe Gly Val Val Thr Asn Phe Asp Asn
1 5 10
<210> 123
<211> 321
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 123
gacatcgtga tgacccagtc tccatcctcc ctgtctgcat ccgtgagaga cagagtcacc 60
atcacttgcc gggcaagtca gggcattaga aatgatttag gctggtatca gcagaaacca 120
gggaaagccc ctaagcgcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180
aggttcagcg gcagtggatc tgggacagaa ttcactctca cactcagcag cctgcagcct 240
gaagattttg caacttatta ttgttcacag tataataatt acccgtggac gttcggccaa 300
gggaccaagg tggagatcaa a 321
<210> 124
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 124
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Arg
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp
20 25 30
Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Leu Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Ser Gln Tyr Asn Asn Tyr Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 125
<211> 18
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 125
cagggcatta gaaatgat 18
<210> 126
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 126
Gln Gly Ile Arg Asn Asp
1 5
<210> 127
<211> 9
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 127
gctgcatcc 9
<210> 128
<211> 3
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 128
Ala Ala Ser
1
<210> 129
<211> 27
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 129
tcacagtata ataattaccc gtggacg 27
<210> 130
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 130
Ser Gln Tyr Asn Asn Tyr Pro Trp Thr
1 5
<210> 131
<211> 357
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 131
caggtgcagc tggtgcagtc cggcgccgag gtgaagaagc ccggcgcctc cgtgaaggtg 60
tcctgcaagg tgtccggcta caccctgacc gagctgtcca tgcactgggt gcggcaggcc 120
cccggcaagg gcctggagtg gatgggcggc ttcgaccccg agcacggcac caccatctac 180
gcccagaagt tccagggccg ggtgaccatg accgaggaca cctccaccga caccgcctac 240
atggagctgt cctccctgcg gtccgaggac accgccgtgt actactgcgt gatgatcttc 300
ggcgtggtga ccaacttcga caactggggc cagggcaccc tggtgaccgt gtcctcc 357
<210> 132
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 132
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Val Ser Gly Tyr Thr Leu Thr Glu Leu
20 25 30
Ser Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Gly Phe Asp Pro Glu His Gly Thr Thr Ile Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Glu Asp Thr Ser Thr Asp Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Val Met Ile Phe Gly Val Val Thr Asn Phe Asp Asn Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 133
<211> 321
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 133
gacatccaga tgacccagtc cccctcctcc ctgtccgcct ccgtgggcga ccgggtgacc 60
atcacctgcc gggcctccca gggcatccgg aacgacctgg gctggtacca gcagaagccc 120
ggcaaggccc ccaagcggct gatctacgcc gcctcctccc tgcagtccgg cgtgccctcc 180
cggttctccg gctccggctc cggcaccgag ttcaccctga ccatctcctc cctgcagccc 240
gaggacttcg ccacctacta ctgctcccag tacaacaact acccctggac cttcggccag 300
ggcaccaagg tggagatcaa g 321
<210> 134
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 134
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp
20 25 30
Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Ser Gln Tyr Asn Asn Tyr Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 135
<211> 357
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 135
caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtc 60
tcctgcaagg tttccggata caccctcact gaattatcca tacactgggt gcgacaggct 120
cctggaaaag ggcttgaatg gatgggaggt tttgatcctg aacatggtac aacaatctac 180
gcacagaagt tccagggcag agtcaccatg accgaggaca catctacaga cacagcctac 240
atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgt aatgattttt 300
ggcgtggtta ccaattttga caactggggc cagggtaccc tggtcaccgt ctcctca 357
<210> 136
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 136
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Val Ser Gly Tyr Thr Leu Thr Glu Leu
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Gly Phe Asp Pro Glu His Gly Thr Thr Ile Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Glu Asp Thr Ser Thr Asp Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Val Met Ile Phe Gly Val Val Thr Asn Phe Asp Asn Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 137
<211> 321
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 137
gacatccaga tgacccagtc tccatcctcc ctgtctgcat ccgtgagaga cagagtcacc 60
atcacttgcc gggcaagtca gggcattaga aatgatttag gctggtatca gcagaaacca 120
gggaaagccc ctaagcgcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180
aggttcagcg gcagtggatc tgggacagaa ttcactctca cactcagcag cctgcagcct 240
gaagattttg caacttatta ttgttcacag tataataatt acccgtggac gttcggccaa 300
gggaccaagg tggagatcaa a 321
<210> 138
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 138
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Arg
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp
20 25 30
Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Leu Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Ser Gln Tyr Asn Asn Tyr Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 139
<211> 357
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 139
gaggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtc 60
tcctgcaagg tttccggatt caccctcact gaattatcca ttcactgggt gcgacaggct 120
cctggaaaag ggcttgagtg gatgggaggt tttgatcctg aagatggtga aacaatctac 180
gcacagaagt tccagggcag agtcaccatg accgaggaca catctacaga cacagcctgc 240
atggaactga gcagtctgag atctgaagac acggccgtgt attactgttc aacgattttt 300
ggagtggtta ccaactttga caactggggc cagggaaccc tggtcaccgt ctcctca 357
<210> 140
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 140
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Val Ser Gly Phe Thr Leu Thr Glu Leu
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Gly Phe Asp Pro Glu Asp Gly Glu Thr Ile Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Glu Asp Thr Ser Thr Asp Thr Ala Cys
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ser Thr Ile Phe Gly Val Val Thr Asn Phe Asp Asn Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 141
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 141
ggattcaccc tcactgaatt atcc 24
<210> 142
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 142
Gly Phe Thr Leu Thr Glu Leu Ser
1 5
<210> 143
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 143
tttgatcctg aagatggtga aaca 24
<210> 144
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 144
Phe Asp Pro Glu Asp Gly Glu Thr
1 5
<210> 145
<211> 36
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 145
tcaacgattt ttggagtggt taccaacttt gacaac 36
<210> 146
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 146
Ser Thr Ile Phe Gly Val Val Thr Asn Phe Asp Asn
1 5 10
<210> 147
<211> 321
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 147
gatgttgtga tgactcagtc tccatcctcc ctgtctgcat ctgcaggaga cagagtcacc 60
atcacttgcc gggcaagtca ggccattaga aatgatttag gctggtatca gcagaaacca 120
gggaaagccc ctaaacgcct gatctatgct gcattcaatt tgcaaagtgg ggtcccatca 180
agattcagcg gcagtggatc tgggacagaa ttcactctca caatcagtag cctgcagcct 240
gaagatcttg caagttatta ctgtcaacag tataatagat acccgtggac gttcggccaa 300
gggaccaagc tggagatcaa a 321
<210> 148
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 148
Asp Val Val Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Ala Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ala Ile Arg Asn Asp
20 25 30
Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile
35 40 45
Tyr Ala Ala Phe Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Leu Ala Ser Tyr Tyr Cys Gln Gln Tyr Asn Arg Tyr Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 149
<211> 18
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 149
caggccatta gaaatgat 18
<210> 150
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 150
Gln Ala Ile Arg Asn Asp
1 5
<210> 151
<211> 9
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 151
gctgcattc 9
<210> 152
<211> 3
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 152
Ala Ala Phe
1
<210> 153
<211> 27
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 153
caacagtata atagataccc gtggacg 27
<210> 154
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 154
Gln Gln Tyr Asn Arg Tyr Pro Trp Thr
1 5
<210> 155
<211> 357
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 155
caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtc 60
tcctgcaagg tttccggatt caccctcact gaattatcca ttcactgggt gcgacaggct 120
cctggaaaag ggcttgagtg gatgggaggt tttgatcctg aagatggtga aacaatctac 180
gcacagaagt tccagggcag agtcaccatg accgaggaca catctacaga cacagcctgc 240
atggaactga gcagtctgag atctgaagac acggccgtgt attactgttc aacgattttt 300
ggagtggtta ccaactttga caactggggc cagggaaccc tggtcaccgt ctcctca 357
<210> 156
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 156
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Val Ser Gly Phe Thr Leu Thr Glu Leu
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Gly Phe Asp Pro Glu Asp Gly Glu Thr Ile Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Glu Asp Thr Ser Thr Asp Thr Ala Cys
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ser Thr Ile Phe Gly Val Val Thr Asn Phe Asp Asn Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 157
<211> 321
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 157
gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgcaggaga cagagtcacc 60
atcacttgcc gggcaagtca ggccattaga aatgatttag gctggtatca gcagaaacca 120
gggaaagccc ctaaacgcct gatctatgct gcattcaatt tgcaaagtgg ggtcccatca 180
agattcagcg gcagtggatc tgggacagaa ttcactctca caatcagtag cctgcagcct 240
gaagatcttg caagttatta ctgtcaacag tataatagat acccgtggac gttcggccaa 300
gggaccaagg tggagatcaa a 321
<210> 158
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 158
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Ala Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ala Ile Arg Asn Asp
20 25 30
Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile
35 40 45
Tyr Ala Ala Phe Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Leu Ala Ser Tyr Tyr Cys Gln Gln Tyr Asn Arg Tyr Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 159
<211> 357
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 159
gaggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtc 60
tcctgcaagg tttccggatt caccctcaat gaattatcca ttcactgggt gcgacaggct 120
cctggaaaag ggcttgagtg gatgggaggt tttgatcctg aagatggtga agtaatttat 180
gcacagaagt tccagggcag agtcaccatg accgaggaca catctacaga cacagcctac 240
atggaactga ggagcctgag atctgaggac acggccgtgt tttattgtgt aatgattttt 300
ggagtggtta ccaactttga caattggggc cagggaacca cggtcaccgt ctcctca 357
<210> 160
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 160
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Val Ser Gly Phe Thr Leu Asn Glu Leu
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Gly Phe Asp Pro Glu Asp Gly Glu Val Ile Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Glu Asp Thr Ser Thr Asp Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Glu Asp Thr Ala Val Phe Tyr Cys
85 90 95
Val Met Ile Phe Gly Val Val Thr Asn Phe Asp Asn Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser
115
<210> 161
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 161
ggattcaccc tcaatgaatt atcc 24
<210> 162
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 162
Gly Phe Thr Leu Asn Glu Leu Ser
1 5
<210> 163
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 163
tttgatcctg aagatggtga agta 24
<210> 164
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 164
Gly Phe Asp Pro Glu Asp Gly Glu Val
1 5
<210> 165
<211> 36
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 165
gtaatgattt ttggagtggt taccaacttt gacaat 36
<210> 166
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 166
Val Met Ile Phe Gly Val Val Thr Asn Phe Asp Asn
1 5 10
<210> 167
<211> 321
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 167
gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtgagaga cagagtcacc 60
atcacttgcc gggcaagtca gggcattaga aatgatttag gctggtatca gcagaaacca 120
gggaaagccc ctaagcgcct gatctatggt gcattcagtt tgcaaagtgg ggtcccatca 180
aggttcagcg gcagtggatc tgggacagaa ttcactctca caatcagcag cctgcagcct 240
gaagattttg caacttatta ctgtctacag tataatactt atccgtggac gttcggccaa 300
gggaccaagg tggagatcaa a 321
<210> 168
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 168
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Arg
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp
20 25 30
Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile
35 40 45
Tyr Gly Ala Phe Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Asn Thr Tyr Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 169
<211> 18
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 169
cagggcatta gaaatgat 18
<210> 170
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 170
Gln Gly Ile Arg Asn Asp
1 5
<210> 171
<211> 9
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 171
ggtgcattc 9
<210> 172
<211> 3
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 172
Gly Ala Phe
1
<210> 173
<211> 27
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 173
ctacagtata atacttatcc gtggacg 27
<210> 174
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 174
Leu Gln Tyr Asn Thr Tyr Pro Trp Thr
1 5
<210> 175
<211> 357
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 175
caggtgcagc tggtgcagtc cggcgccgag gtgaagaagc ccggcgcctc cgtgaaggtg 60
tcctgcaagg tgtccggctt caccctgaac gagctgtcca tgcactgggt gcggcaggcc 120
cccggcaagg gcctggagtg gatgggcggc ttcgaccccg aggacggcga ggtgatctac 180
gcccagaagt tccagggccg ggtgaccatg accgaggaca cctccaccga caccgcctac 240
atggagctgt cctccctgcg gtccgaggac accgccgtgt actactgcgt gatgatcttc 300
ggcgtggtga ccaacttcga caactggggc cagggcaccc tggtgaccgt gtcctcc 357
<210> 176
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 176
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Val Ser Gly Phe Thr Leu Asn Glu Leu
20 25 30
Ser Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Gly Phe Asp Pro Glu Asp Gly Glu Val Ile Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Glu Asp Thr Ser Thr Asp Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Val Met Ile Phe Gly Val Val Thr Asn Phe Asp Asn Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 177
<211> 321
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 177
gacatccaga tgacccagtc cccctcctcc ctgtccgcct ccgtgggcga ccgggtgacc 60
atcacctgcc gggcctccca gggcatccgg aacgacctgg gctggtacca gcagaagccc 120
ggcaaggccc ccaagcggct gatctacggc gccttctccc tgcagtccgg cgtgccctcc 180
cggttctccg gctccggctc cggcaccgag ttcaccctga ccatctcctc cctgcagccc 240
gaggacttcg ccacctacta ctgcctgcag tacaacacct acccctggac cttcggccag 300
ggcaccaagg tggagatcaa g 321
<210> 178
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 178
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp
20 25 30
Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile
35 40 45
Tyr Gly Ala Phe Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Asn Thr Tyr Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 179
<211> 357
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 179
caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtc 60
tcctgcaagg tttccggatt caccctcaat gaattatcca ttcactgggt gcgacaggct 120
cctggaaaag ggcttgagtg gatgggaggt tttgatcctg aagatggtga agtaatttat 180
gcacagaagt tccagggcag agtcaccatg accgaggaca catctacaga cacagcctac 240
atggaactga ggagcctgag atctgaggac acggccgtgt tttattgtgt aatgattttt 300
ggagtggtta ccaactttga caattggggc cagggaaccc tggtcaccgt ctcctca 357
<210> 180
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 180
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Val Ser Gly Phe Thr Leu Asn Glu Leu
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Gly Phe Asp Pro Glu Asp Gly Glu Val Ile Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Glu Asp Thr Ser Thr Asp Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Glu Asp Thr Ala Val Phe Tyr Cys
85 90 95
Val Met Ile Phe Gly Val Val Thr Asn Phe Asp Asn Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 181
<211> 321
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 181
gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtgagaga cagagtcacc 60
atcacttgcc gggcaagtca gggcattaga aatgatttag gctggtatca gcagaaacca 120
gggaaagccc ctaagcgcct gatctatggt gcattcagtt tgcaaagtgg ggtcccatca 180
aggttcagcg gcagtggatc tgggacagaa ttcactctca caatcagcag cctgcagcct 240
gaagattttg caacttatta ctgtctacag tataatactt atccgtggac gttcggccaa 300
gggaccaagg tggagatcaa a 321
<210> 182
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 182
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Arg
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp
20 25 30
Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile
35 40 45
Tyr Gly Ala Phe Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Asn Thr Tyr Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 183
<211> 357
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 183
gaggtgcagc tggtgcagtc tgggactgag gtgaagaagc ctggggcctc agtgaaggtc 60
tcctgcaagg tttccggata caccctcact gaattatcca tgtactgggt gcgacaggct 120
cctggaaaag ggcttgagtg gatgggaggt tttgatcctg aacatggtga aacaatctac 180
gcacagaagt tccagggcag agtcaccatg accgaggact catctacaga cacagcctac 240
atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc aatgattttt 300
ggagtggtta ccaactttga ctcctggggc ctgggaaccc tggtcactgt ctcctca 357
<210> 184
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 184
Glu Val Gln Leu Val Gln Ser Gly Thr Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Val Ser Gly Tyr Thr Leu Thr Glu Leu
20 25 30
Ser Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Gly Phe Asp Pro Glu His Gly Glu Thr Ile Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Glu Asp Ser Ser Thr Asp Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Met Ile Phe Gly Val Val Thr Asn Phe Asp Ser Trp Gly Leu Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 185
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 185
ggatacaccc tcactgaatt atcc 24
<210> 186
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 186
Gly Tyr Thr Leu Thr Glu Leu Ser
1 5
<210> 187
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 187
tttgatcctg aacatggtga aaca 24
<210> 188
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 188
Phe Asp Pro Glu His Gly Glu Thr
1 5
<210> 189
<211> 36
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 189
gcaatgattt ttggagtggt taccaacttt gactcc 36
<210> 190
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 190
Ala Met Ile Phe Gly Val Val Thr Asn Phe Asp Ser
1 5 10
<210> 191
<211> 321
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 191
gaaattgtgt tgacacagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgcc gggcaagtca gggcattaga aatgatttag gctggtatca gcagaaacca 120
gggaaagccc ctaagcgcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180
aggttcagcg gcagtggatc tgggacagaa ttcactctca caatcagcag cctgcagcct 240
gaagattttg caacttatta ctgtctacag tataatagtt acccgtggac gttcggccaa 300
gggaccaagc tggagatcaa a 321
<210> 192
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 192
Glu Ile Val Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp
20 25 30
Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Asn Ser Tyr Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 193
<211> 18
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 193
cagggcatta gaaatgat 18
<210> 194
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 194
Gln Gly Ile Arg Asn Asp
1 5
<210> 195
<211> 9
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 195
gctgcatcc 9
<210> 196
<211> 3
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 196
Ala Ala Ser
1
<210> 197
<211> 27
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 197
ctacagtata atagttaccc gtggacg 27
<210> 198
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 198
Leu Gln Tyr Asn Ser Tyr Pro Trp Thr
1 5
<210> 199
<211> 357
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 199
caggtgcagc tggtgcagtc cggcgccgag gtgaagaagc ccggcgcctc cgtgaaggtg 60
tcctgcaagg tgtccggcta caccctgacc gagctgtcca tgcactgggt gcggcaggcc 120
cccggcaagg gcctggagtg gatgggcggc ttcgaccccg agcacggcga gaccatctac 180
gcccagaagt tccagggccg ggtgaccatg accgaggaca cctccaccga caccgcctac 240
atggagctgt cctccctgcg gtccgaggac accgccgtgt actactgcgc catgatcttc 300
ggcgtggtga ccaacttcga ctcctggggc cagggcaccc tggtgaccgt gtcctcc 357
<210> 200
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 200
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Val Ser Gly Tyr Thr Leu Thr Glu Leu
20 25 30
Ser Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Gly Phe Asp Pro Glu His Gly Glu Thr Ile Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Glu Asp Thr Ser Thr Asp Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Met Ile Phe Gly Val Val Thr Asn Phe Asp Ser Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 201
<211> 321
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 201
gacatccaga tgacccagtc cccctcctcc ctgtccgcct ccgtgggcga ccgggtgacc 60
atcacctgcc gggcctccca gggcatccgg aacgacctgg gctggtacca gcagaagccc 120
ggcaaggccc ccaagcggct gatctacgcc gcctcctccc tgcagtccgg cgtgccctcc 180
cggttctccg gctccggctc cggcaccgag ttcaccctga ccatctcctc cctgcagccc 240
gaggacttcg ccacctacta ctgcctgcag tacaactcct acccctggac cttcggccag 300
ggcaccaagg tggagatcaa g 321
<210> 202
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 202
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp
20 25 30
Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Asn Ser Tyr Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 203
<211> 357
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 203
caggtgcagc tggtgcagtc tgggactgag gtgaagaagc ctggggcctc agtgaaggtc 60
tcctgcaagg tttccggata caccctcact gaattatcca tgtactgggt gcgacaggct 120
cctggaaaag ggcttgagtg gatgggaggt tttgatcctg aacatggtga aacaatctac 180
gcacagaagt tccagggcag agtcaccatg accgaggact catctacaga cacagcctac 240
atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc aatgattttt 300
ggagtggtta ccaactttga ctcctggggc ctgggaaccc tggtcactgt ctcctca 357
<210> 204
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 204
Gln Val Gln Leu Val Gln Ser Gly Thr Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Val Ser Gly Tyr Thr Leu Thr Glu Leu
20 25 30
Ser Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Gly Phe Asp Pro Glu His Gly Glu Thr Ile Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Glu Asp Ser Ser Thr Asp Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Met Ile Phe Gly Val Val Thr Asn Phe Asp Ser Trp Gly Leu Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 205
<211> 321
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 205
gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgcc gggcaagtca gggcattaga aatgatttag gctggtatca gcagaaacca 120
gggaaagccc ctaagcgcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180
aggttcagcg gcagtggatc tgggacagaa ttcactctca caatcagcag cctgcagcct 240
gaagattttg caacttatta ctgtctacag tataatagtt acccgtggac gttcggccaa 300
gggaccaagg tggagatcaa a 321
<210> 206
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 206
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp
20 25 30
Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Asn Ser Tyr Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 207
<211> 375
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 207
gaagtgcagc tggtgcagtc tgggggcggc ttggtacagc ctggcaggtc cctgagactc 60
tcctgtgcag cccctggatt caactttgat gattatgcca tgcactgggt ccggcaaact 120
ccagggaagg gcctggagtg ggtctcaggt attagttgga atagtggtac tataggctat 180
gcggactctg tgaagggccg atttaccatc tccagagaca acgccaagaa ctccctgtat 240
cttcaaatga acagtctgag acctgaggac acggccttgt attactgtgc aaaagaaggg 300
gtatggttcg gaaaattgtt ctcatcctac ggtatggacg tctggggcca agggaccacg 360
gtcaccgtct cctca 375
<210> 208
<211> 125
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 208
Glu Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Pro Gly Phe Asn Phe Asp Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Thr Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Trp Asn Ser Gly Thr Ile Gly Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Lys Glu Gly Val Trp Phe Gly Lys Leu Phe Ser Ser Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 209
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 209
ggattcaact ttgatgatta tgcc 24
<210> 210
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 210
Gly Phe Asn Phe Asp Asp Tyr Ala
1 5
<210> 211
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 211
attagttgga atagtggtac tata 24
<210> 212
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 212
Ile Ser Trp Asn Ser Gly Thr Ile
1 5
<210> 213
<211> 54
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 213
gcaaaagaag gggtatggtt cggaaaattg ttctcatcct acggtatgga cgtc 54
<210> 214
<211> 18
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 214
Ala Lys Glu Gly Val Trp Phe Gly Lys Leu Phe Ser Ser Tyr Gly Met
1 5 10 15
Asp Val
<210> 215
<211> 321
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 215
gacatccgga tgacccagtc tccagccacc ctgtctgtgt ctccagggga aagagccacc 60
ctctcctgca gggccagtca gagtgttact tacaacttag actggtacca gcagaaacct 120
ggccaggctc ccaggctcct catctttggt gcatccacca gggccactgg tatcccagcc 180
aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcaccag cctgcagtct 240
gaagattttg cagtttatta ctgtcagcag tataataact ggccgtacac ttttggccag 300
gggaccaagg tggaaatcaa a 321
<210> 216
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 216
Asp Ile Arg Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Thr Tyr Asn
20 25 30
Leu Asp Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Phe Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Thr Ser Leu Gln Ser
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asn Asn Trp Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 217
<211> 18
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 217
cagagtgtta cttacaac 18
<210> 218
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 218
Gln Ser Val Thr Tyr Asn
1 5
<210> 219
<211> 9
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 219
ggtgcatcc 9
<210> 220
<211> 3
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 220
Gly Ala Ser
1
<210> 221
<211> 27
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 221
cagcagtata ataactggcc gtacact 27
<210> 222
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 222
Gln Gln Tyr Asn Asn Trp Pro Tyr Thr
1 5
<210> 223
<211> 375
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 223
gaggtgcagc tggtggagtc cggcggcggc ctggtgcagc ccggccggtc cctgcggctg 60
tcctgcgccg cccccggctt caacttcgac gactacgcca tgcactgggt gcggcaggcc 120
cccggcaagg gcctggagtg ggtgtccggc atctcctgga actccggcac catcggctac 180
gccgactccg tgaagggccg gttcaccatc tcccgggaca acgccaagaa ctccctgtac 240
ctgcagatga actccctgcg ggccgaggac accgccctgt actactgcgc caaggagggc 300
gtgtggttcg gcaagctgtt ctcctcctac ggcatggacg tgtggggcca gggcaccacc 360
gtgaccgtgt cctcc 375
<210> 224
<211> 125
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 224
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Pro Gly Phe Asn Phe Asp Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Trp Asn Ser Gly Thr Ile Gly Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Lys Glu Gly Val Trp Phe Gly Lys Leu Phe Ser Ser Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 225
<211> 324
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 225
gagatcgtga tgacccagtc ccccgccacc ctgtccgtgt cccccggcga gcgggccacc 60
ctgtcctgcc gggcctccca gtccgtgacc tacaacctgg actggtacca gcagaagccc 120
ggccaggccc cccggctgct gatctacggc gcctccaccc gggccaccgg catccccgcc 180
cggttctccg gctccggctc cggcaccgag ttcaccctga ccatctcctc cctgcagtcc 240
gaggacttcg ccgtgtacta ctgccagcag tacaacaact ggccctacac cttcggccag 300
ggcaccaagc tggagatcaa gcgg 324
<210> 226
<211> 108
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 226
Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Thr Tyr Asn
20 25 30
Leu Asp Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asn Asn Trp Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg
100 105
<210> 227
<211> 375
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 227
gaggtgcagc tggtggagtc cggcggcggc ctggtgcagc ccggccggtc cctgcggctg 60
tcctgcgccg cctccggctt caacttcgac gactacgcca tgcactgggt gcggcaggcc 120
cccggcaagg gcctggagtg ggtgtccggc atctcctgga actccggcac catcggctac 180
gccgactccg tgaagggccg gttcaccatc tcccgggaca acgccaagaa ctccctgtac 240
ctgcagatga actccctgcg ggccgaggac accgccctgt actactgcgc caaggagggc 300
gtgtggttcg gcaagctgtt ctcctcctac ggcatggacg tgtggggcca gggcaccacc 360
gtgaccgtgt cctcc 375
<210> 228
<211> 125
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 228
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Phe Asp Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Trp Asn Ser Gly Thr Ile Gly Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Lys Glu Gly Val Trp Phe Gly Lys Leu Phe Ser Ser Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 229
<211> 324
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 229
gagatcgtga tgacccagtc ccccgccacc ctgtccgtgt cccccggcga gcgggccacc 60
ctgtcctgcc gggcctccca gtccgtgacc tacaacctgg cctggtacca gcagaagccc 120
ggccaggccc cccggctgct gatctacggc gcctccaccc gggccaccgg catccccgcc 180
cggttctccg gctccggctc cggcaccgag ttcaccctga ccatctcctc cctgcagtcc 240
gaggacttcg ccgtgtacta ctgccagcag tacaacaact ggccctacac cttcggccag 300
ggcaccaagc tggagatcaa gcgg 324
<210> 230
<211> 108
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 230
Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Thr Tyr Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asn Asn Trp Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg
100 105
<210> 231
<211> 375
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 231
gaagtgcagc tggtggagtc tgggggcggc ttggtacagc ctggcaggtc cctgagactc 60
tcctgtgcag cccctggatt caactttgat gattatgcca tgcactgggt ccggcaaact 120
ccagggaagg gcctggagtg ggtctcaggt attagttgga atagtggtac tataggctat 180
gcggactctg tgaagggccg atttaccatc tccagagaca acgccaagaa ctccctgtat 240
cttcaaatga acagtctgag acctgaggac acggccttgt attactgtgc aaaagaaggg 300
gtatggttcg gaaaattgtt ctcatcctac ggtatggacg tctggggcca agggaccacg 360
gtcaccgtct cctca 375
<210> 232
<211> 125
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 232
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Pro Gly Phe Asn Phe Asp Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Thr Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Trp Asn Ser Gly Thr Ile Gly Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Lys Glu Gly Val Trp Phe Gly Lys Leu Phe Ser Ser Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 233
<211> 324
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 233
gaaatagtga tgacgcagtc tccagccacc ctgtctgtgt ctccagggga aagagccacc 60
ctctcctgca gggccagtca gagtgttact tacaacttag actggtacca gcagaaacct 120
ggccaggctc ccaggctcct catctttggt gcatccacca gggccactgg tatcccagcc 180
aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcaccag cctgcagtct 240
gaagattttg cagtttatta ctgtcagcag tataataact ggccgtacac ttttggccag 300
gggaccaagc tggagatcaa acga 324
<210> 234
<211> 108
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 234
Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Thr Tyr Asn
20 25 30
Leu Asp Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Phe Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Thr Ser Leu Gln Ser
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asn Asn Trp Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg
100 105
<210> 235
<211> 375
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 235
gaagtgcagc tggtggagtc tgggggcggc ttggtacagc ctggcaggtc cctgagactc 60
tcctgtgcag cctctggatt caactttgat gattatgcca tgcactgggt ccggcaaact 120
ccagggaagg gcctggagtg ggtctcaggt attagttgga atagtggtac tataggctat 180
gcggactctg tgaagggccg atttaccatc tccagagaca acgccaagaa ctccctgtat 240
cttcaaatga acagtctgag acctgaggac acggccttgt attactgtgc aaaagaaggg 300
gtatggttcg gaaaattgtt ctcatcctac ggtatggacg tctggggcca agggaccacg 360
gtcaccgtct cctca 375
<210> 236
<211> 125
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 236
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Phe Asp Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Thr Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Trp Asn Ser Gly Thr Ile Gly Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Lys Glu Gly Val Trp Phe Gly Lys Leu Phe Ser Ser Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 237
<211> 324
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 237
gaaatagtga tgacgcagtc tccagccacc ctgtctgtgt ctccagggga aagagccacc 60
ctctcctgca gggccagtca gagtgttact tacaacttag cctggtacca gcagaaacct 120
ggccaggctc ccaggctcct catctttggt gcatccacca gggccactgg tatcccagcc 180
aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcaccag cctgcagtct 240
gaagattttg cagtttatta ctgtcagcag tataataact ggccgtacac ttttggccag 300
gggaccaagc tggagatcaa acga 324
<210> 238
<211> 108
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 238
Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Thr Tyr Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Phe Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Thr Ser Leu Gln Ser
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asn Asn Trp Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg
100 105
<210> 239
<211> 357
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 239
gaggtgcagc tggtgcagtc tggggctgag gtgaggaagc ctggggcctc agtgaaggtc 60
tcctgcaagg tttccggata caccctcact gaattatcca tacactgggt gcgacaggct 120
cctggaaaag ggcttgagtg gatgggaggt tttgatcctg aagatggtga aacaatctac 180
gcacagaagt tccagggcag agtcatcatg accgaggaca catctacaga cacagcctat 240
atggagctga gcagcctgag atctgaggac acggccgtgt attattgtgt aatgattttt 300
ggcgtggtta ccaactttga caactggggc cagggaaccc tggtcaccgt ctcctca 357
<210> 240
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 240
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Arg Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Val Ser Gly Tyr Thr Leu Thr Glu Leu
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Gly Phe Asp Pro Glu Asp Gly Glu Thr Ile Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Ile Met Thr Glu Asp Thr Ser Thr Asp Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Val Met Ile Phe Gly Val Val Thr Asn Phe Asp Asn Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 241
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 241
ggatacaccc tcactgaatt atcc 24
<210> 242
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 242
Gly Tyr Thr Leu Thr Glu Leu Ser
1 5
<210> 243
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 243
tttgatcctg aagatggtga aaca 24
<210> 244
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 244
Phe Asp Pro Glu Asp Gly Glu Thr
1 5
<210> 245
<211> 36
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 245
gtaatgattt ttggcgtggt taccaacttt gacaac 36
<210> 246
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 246
Val Met Ile Phe Gly Val Val Thr Asn Phe Asp Asn
1 5 10
<210> 247
<211> 321
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 247
gaaattgtgc tgactcagtc tccatcctcc ctgtctgcat ccgtgagaga cagagtcacc 60
atcacttgcc gggcaagtca gggcattaga aatgatttag gctggtatca gcagaaacca 120
gggaaagccc ctaagcgcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180
aggttcagcg gcagtggatc tgggacagaa tccactctca caatcagcag cctgcagcct 240
gaagattttg caacttatta ttgttcacag tataatagtt acccgtggac gttcggccaa 300
gggaccaagg tggagatcaa a 321
<210> 248
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 248
Glu Ile Val Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Arg
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp
20 25 30
Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Ser Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Ser Gln Tyr Asn Ser Tyr Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 249
<211> 18
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 249
cagggcatta gaaatgat 18
<210> 250
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 250
Gln Gly Ile Arg Asn Asp
1 5
<210> 251
<211> 9
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 251
gctgcatcc 9
<210> 252
<211> 3
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 252
Ala Ala Ser
1
<210> 253
<211> 27
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 253
tcacagtata atagttaccc gtggacg 27
<210> 254
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 254
Ser Gln Tyr Asn Ser Tyr Pro Trp Thr
1 5
<210> 255
<211> 357
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 255
caggtgcagc tggtgcagtc cggcgccgag gtgaagaagc ccggcgcctc cgtgaaggtg 60
tcctgcaagg tgtccggcta caccctgacc gagctgtcca tgcactgggt gcggcaggcc 120
cccggcaagg gcctggagtg gatgggcggc ttcgaccccg aggacggcga gaccatctac 180
gcccagaagt tccagggccg ggtgaccatg accgaggaca cctccaccga caccgcctac 240
atggagctgt cctccctgcg gtccgaggac accgccgtgt actactgcgt gatgatcttc 300
ggcgtggtga ccaacttcga caactggggc cagggcaccc tggtgaccgt gtcctcc 357
<210> 256
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 256
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Val Ser Gly Tyr Thr Leu Thr Glu Leu
20 25 30
Ser Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Gly Phe Asp Pro Glu Asp Gly Glu Thr Ile Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Glu Asp Thr Ser Thr Asp Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Val Met Ile Phe Gly Val Val Thr Asn Phe Asp Asn Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 257
<211> 321
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 257
gacatccaga tgacccagtc cccctcctcc ctgtccgcct ccgtgggcga ccgggtgacc 60
atcacctgcc gggcctccca gggcatccgg aacgacctgg gctggtacca gcagaagccc 120
ggcaaggccc ccaagcggct gatctacgcc gcctcctccc tgcagtccgg cgtgccctcc 180
cggttctccg gctccggctc cggcaccgag ttcaccctga ccatctcctc cctgcagccc 240
gaggacttcg ccacctacta ctgctcccag tacaactcct acccctggac cttcggccag 300
ggcaccaagg tggagatcaa g 321
<210> 258
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 258
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp
20 25 30
Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Ser Gln Tyr Asn Ser Tyr Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 259
<211> 357
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 259
caggtgcagc tggtgcagtc tggggctgag gtgaggaagc ctggggcctc agtgaaggtc 60
tcctgcaagg tttccggata caccctcact gaattatcca tacactgggt gcgacaggct 120
cctggaaaag ggcttgagtg gatgggaggt tttgatcctg aagatggtga aacaatctac 180
gcacagaagt tccagggcag agtcatcatg accgaggaca catctacaga cacagcctat 240
atggagctga gcagcctgag atctgaggac acggccgtgt attattgtgt aatgattttt 300
ggcgtggtta ccaactttga caactggggc cagggaaccc tggtcaccgt ctcctca 357
<210> 260
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 260
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Arg Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Val Ser Gly Tyr Thr Leu Thr Glu Leu
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Gly Phe Asp Pro Glu Asp Gly Glu Thr Ile Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Ile Met Thr Glu Asp Thr Ser Thr Asp Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Val Met Ile Phe Gly Val Val Thr Asn Phe Asp Asn Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 261
<211> 321
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 261
gacatccaga tgacccagtc tccatcctcc ctgtctgcat ccgtgagaga cagagtcacc 60
atcacttgcc gggcaagtca gggcattaga aatgatttag gctggtatca gcagaaacca 120
gggaaagccc ctaagcgcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180
aggttcagcg gcagtggatc tgggacagaa tccactctca caatcagcag cctgcagcct 240
gaagattttg caacttatta ttgttcacag tataatagtt acccgtggac gttcggccaa 300
gggaccaagg tggaaatcaa a 321
<210> 262
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 262
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Arg
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp
20 25 30
Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Ser Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Ser Gln Tyr Asn Ser Tyr Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 263
<211> 357
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 263
gaagtgcagc tggtgcagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtc 60
tcctgcaagg tttccggatt caccctcact gaattatcca ttcactgggt gcgacaggct 120
cctggaaaag ggcttgagtg gatgggaggt tttgatcctg aagatggtga aacaatctac 180
gcacagaagt tccagggcag agtcaccatg accgaggaca catctacaga cacagcctac 240
atggagctga gcagcctgag atctgaagac acggccgtgt attactgttc aacgattttt 300
ggagtggtta ccaactttga caactggggc cagggaaccc tggtcaccgt ctcctca 357
<210> 264
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 264
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Val Ser Gly Phe Thr Leu Thr Glu Leu
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Gly Phe Asp Pro Glu Asp Gly Glu Thr Ile Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Glu Asp Thr Ser Thr Asp Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ser Thr Ile Phe Gly Val Val Thr Asn Phe Asp Asn Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 265
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 265
ggattcaccc tcactgaatt atcc 24
<210> 266
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 266
Gly Phe Thr Leu Thr Glu Leu Ser
1 5
<210> 267
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 267
tttgatcctg aagatggtga aaca 24
<210> 268
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 268
Phe Asp Pro Glu Asp Gly Glu Thr
1 5
<210> 269
<211> 36
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 269
tcaacgattt ttggagtggt taccaacttt gacaac 36
<210> 270
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 270
Ser Thr Ile Phe Gly Val Val Thr Asn Phe Asp Asn
1 5 10
<210> 271
<211> 321
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 271
gccatccagt tgacccagtc tccatcctcc ctgtctgcat ctgcaggaga cagagtcacc 60
atcacttgcc gggcaagtca ggccattaga aatgatttag gctggtatca gcagaaacca 120
gggaaagccc ctaagcgcct ggtctatgct gcattcaatt tgcaaagtgg ggtcccatca 180
agattcagcg gcagtggatc tgggacagaa ttcactctca caatcagtag cctgcagcct 240
gaagatcttg caacttatta ctgtctacag tataatagtt acccgtggac gttcggccaa 300
gggaccaaag tggatatcaa a 321
<210> 272
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 272
Ala Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Ala Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ala Ile Arg Asn Asp
20 25 30
Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Val
35 40 45
Tyr Ala Ala Phe Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Leu Ala Thr Tyr Tyr Cys Leu Gln Tyr Asn Ser Tyr Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Asp Ile Lys
100 105
<210> 273
<211> 18
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 273
caggccatta gaaatgat 18
<210> 274
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 274
Gln Ala Ile Arg Asn Asp
1 5
<210> 275
<211> 9
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 275
gctgcattc 9
<210> 276
<211> 3
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 276
Ala Ala Phe
1
<210> 277
<211> 27
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 277
ctacagtata atagttaccc gtggacg 27
<210> 278
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 278
Leu Gln Tyr Asn Ser Tyr Pro Trp Thr
1 5
<210> 279
<211> 357
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 279
caggtgcagc tggtgcagtc cggcgccgag gtgaagaagc ccggcgcctc cgtgaaggtg 60
tcctgcaagg tgtccggctt caccctgacc gagctgtcca tgcactgggt gcggcaggcc 120
cccggcaagg gcctggagtg gatgggcggc ttcgaccccg aggacggcga gaccatctac 180
gcccagaagt tccagggccg ggtgaccatg accgaggaca cctccaccga caccgcctac 240
atggagctgt cctccctgcg gtccgaggac accgccgtgt actactgctc caccatcttc 300
ggcgtggtga ccaacttcga caactggggc cagggcaccc tggtgaccgt gtcctcc 357
<210> 280
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 280
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Val Ser Gly Phe Thr Leu Thr Glu Leu
20 25 30
Ser Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Gly Phe Asp Pro Glu Asp Gly Glu Thr Ile Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Glu Asp Thr Ser Thr Asp Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ser Thr Ile Phe Gly Val Val Thr Asn Phe Asp Asn Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 281
<211> 321
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 281
gacatccaga tgacccagtc cccctcctcc ctgtccgcct ccgtgggcga ccgggtgacc 60
atcacctgcc gggcctccca ggccatccgg aacgacctgg gctggtacca gcagaagccc 120
ggcaaggccc ccaagcggct gatctacgcc gccttctccc tgcagtccgg cgtgccctcc 180
cggttctccg gctccggctc cggcaccgag ttcaccctga ccatctcctc cctgcagccc 240
gaggacttcg ccacctacta ctgcctgcag tacaactcct acccctggac cttcggccag 300
ggcaccaagg tggagatcaa g 321
<210> 282
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 282
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ala Ile Arg Asn Asp
20 25 30
Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile
35 40 45
Tyr Ala Ala Phe Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Asn Ser Tyr Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 283
<211> 357
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 283
caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtc 60
tcctgcaagg tttccggatt caccctcact gaattatcca ttcactgggt gcgacaggct 120
cctggaaaag ggcttgagtg gatgggaggt tttgatcctg aagatggtga aacaatctac 180
gcacagaagt tccagggcag agtcaccatg accgaggaca catctacaga cacagcctac 240
atggagctga gcagcctgag atctgaagac acggccgtgt attactgttc aacgattttt 300
ggagtggtta ccaactttga caactggggc cagggaaccc tggtcaccgt ctcctca 357
<210> 284
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 284
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Val Ser Gly Phe Thr Leu Thr Glu Leu
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Gly Phe Asp Pro Glu Asp Gly Glu Thr Ile Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Glu Asp Thr Ser Thr Asp Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ser Thr Ile Phe Gly Val Val Thr Asn Phe Asp Asn Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 285
<211> 321
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 285
gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgcaggaga cagagtcacc 60
atcacttgcc gggcaagtca ggccattaga aatgatttag gctggtatca gcagaaacca 120
gggaaagccc ctaagcgcct ggtctatgct gcattcaatt tgcaaagtgg ggtcccatca 180
agattcagcg gcagtggatc tgggacagaa ttcactctca caatcagtag cctgcagcct 240
gaagatcttg caacttatta ctgtctacag tataatagtt acccgtggac gttcggccaa 300
gggaccaagg tggaaatcaa a 321
<210> 286
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 286
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Ala Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ala Ile Arg Asn Asp
20 25 30
Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Val
35 40 45
Tyr Ala Ala Phe Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Leu Ala Thr Tyr Tyr Cys Leu Gln Tyr Asn Ser Tyr Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 287
<211> 375
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 287
gaggtgcagc tggtgcagtc tgggggaggc tcggtacagc ctggcaggtc cctgagactc 60
tcctgtgcag cctctggatt cacttttgat gattattcca tgcactgggt ccggcaaggt 120
ccagggaagg gcctggaatg ggtctcaggt attagttgga atagtggaac tatagtctat 180
gcggactctg tgaagggccg attcaccatc tccagagaca acgtcaagaa caccctgtat 240
ctgcaaatga aaagtctgag agatgaggac acggccgtat attactgtgc aaaagaaggg 300
gtatggttcg ggagattatt ttcatcctac ggtatggacg tctggggcca agggaccctg 360
gtcaccgtct cctca 375
<210> 288
<211> 125
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 288
Glu Val Gln Leu Val Gln Ser Gly Gly Gly Ser Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
Ser Met His Trp Val Arg Gln Gly Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Trp Asn Ser Gly Thr Ile Val Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Val Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Lys Ser Leu Arg Asp Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Glu Gly Val Trp Phe Gly Arg Leu Phe Ser Ser Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 289
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 289
ggattcactt ttgatgatta ttcc 24
<210> 290
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 290
Gly Phe Thr Phe Asp Asp Tyr Ser
1 5
<210> 291
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 291
attagttgga atagtggaac tata 24
<210> 292
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 292
Ile Ser Trp Asn Ser Gly Thr Ile
1 5
<210> 293
<211> 54
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 293
gcaaaagaag gggtatggtt cgggagatta ttttcatcct acggtatgga cgtc 54
<210> 294
<211> 16
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 294
Ala Lys Glu Gly Val Trp Phe Gly Arg Leu Phe Ser Ser Tyr Gly Met
1 5 10 15
<210> 295
<211> 321
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 295
gacatccgga tgacccagtc tccagccacc ctgtctgtgt ctccagggga aagagccacc 60
ctctcctgca gggccagtcc gagtgttagc agcaacttag cctggtacca gcagagacct 120
ggccagcctc ccaggctcct catctatggt gcatccacca gggccactgg tatcccagcc 180
aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagcag cctgcagtct 240
gaagattttg cagtttatta ctgtcaacag tatagtaact ggccgtacac ttttggccag 300
gggaccaagg tggagatcaa a 321
<210> 296
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 296
Asp Ile Arg Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Pro Ser Val Ser Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Arg Pro Gly Gln Pro Pro Arg Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Ser Asn Trp Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 297
<211> 18
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 297
ccgagtgtta gcagcaac 18
<210> 298
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 298
Pro Ser Val Ser Ser Asn
1 5
<210> 299
<211> 9
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 299
ggtgcatcc 9
<210> 300
<211> 3
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 300
Gly Ala Ser
1
<210> 301
<211> 27
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 301
caacagtata gtaactggcc gtacact 27
<210> 302
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 302
Gln Gln Tyr Ser Asn Trp Pro Tyr Thr
1 5
<210> 303
<211> 375
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 303
gaggtgcagc tggtggagtc cggcggcggc ctggtgcagc ccggccggtc cctgcggctg 60
tcctgcgccg cctccggctt caccttcgac gactactcca tgcactgggt gcggcaggcc 120
cccggcaagg gcctggagtg ggtgtccggc atctcctgga actccggcac catcggctac 180
gccgactccg tgaagggccg gttcaccatc tcccgggaca acgccaagaa ctccctgtac 240
ctgcagatga actccctgcg ggccgaggac accgccctgt actactgcgc caaggagggc 300
gtgtggttcg gccggctgtt ctcctcctac ggcatggacg tgtggggcca gggcaccacc 360
gtgaccgtgt cctcc 375
<210> 304
<211> 125
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 304
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
Ser Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Trp Asn Ser Gly Thr Ile Gly Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Lys Glu Gly Val Trp Phe Gly Arg Leu Phe Ser Ser Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 305
<211> 321
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 305
gagatcgtga tgacccagtc ccccgccacc ctgtccgtgt cccccggcga gcgggccacc 60
ctgtcctgcc gggcctcccc ctccgtgtcc tccaacctgg cctggtacca gcagaagccc 120
ggccaggccc cccggctgct gatctacggc gcctccaccc gggccaccgg catccccgcc 180
cggttctccg gctccggctc cggcaccgag ttcaccctga ccatctcctc cctgcagtcc 240
gaggacttcg ccgtgtacta ctgccagcag tactccaact ggccctacac cttcggccag 300
ggcaccaagc tggagatcaa g 321
<210> 306
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 306
Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Pro Ser Val Ser Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Ser Asn Trp Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 307
<211> 375
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 307
gaggtgcagc tggtggagtc tgggggaggc tcggtacagc ctggcaggtc cctgagactc 60
tcctgtgcag cctctggatt cacttttgat gattattcca tgcactgggt ccggcaaggt 120
ccagggaagg gcctggaatg ggtctcaggt attagttgga atagtggaac tatagtctat 180
gcggactctg tgaagggccg attcaccatc tccagagaca acgtcaagaa caccctgtat 240
ctgcaaatga aaagtctgag agatgaggac acggccgtat attactgtgc aaaagaaggg 300
gtatggttcg ggagattatt ttcatcctac ggtatggacg tctggggcca agggaccacg 360
gtcaccgtct cctca 375
<210> 308
<211> 125
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 308
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Ser Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
Ser Met His Trp Val Arg Gln Gly Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Trp Asn Ser Gly Thr Ile Val Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Val Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Lys Ser Leu Arg Asp Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Glu Gly Val Trp Phe Gly Arg Leu Phe Ser Ser Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 309
<211> 321
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 309
gaaatagtga tgacgcagtc tccagccacc ctgtctgtgt ctccagggga aagagccacc 60
ctctcctgca gggccagtcc gagtgttagc agcaacttag cctggtacca gcagagacct 120
ggccagcctc ccaggctcct catctatggt gcatccacca gggccactgg tatcccagcc 180
aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagcag cctgcagtct 240
gaagattttg cagtttatta ctgtcaacag tatagtaact ggccgtacac ttttggccag 300
gggaccaagc tggagatcaa a 321
<210> 310
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 310
Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Pro Ser Val Ser Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Arg Pro Gly Gln Pro Pro Arg Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Ser Asn Trp Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 311
<211> 375
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 311
caggtccagc tggtacagtc tgggggaggc ttggtacagc ctggcaggtc cctgaaactc 60
tcctgtgcag cctctagatt cacctttgaa gattatgcca tgcactgggt ccggcaagct 120
ccagggaagg gcctggaatg ggtctcaggg attagttgga atagtggtag tataggttat 180
gcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctccctgtat 240
ctgcgaatga acagtctgag agctgatgac acggccttgt attattgtgt aaaagaaggg 300
gtatggttcg ggaagttatt ctcatcctac ggtctggacg tctggggcca agggaccacg 360
gtcaccgtct cctca 375
<210> 312
<211> 125
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 312
Gln Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Arg Phe Thr Phe Glu Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Arg Met Asn Ser Leu Arg Ala Asp Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Val Lys Glu Gly Val Trp Phe Gly Lys Leu Phe Ser Ser Tyr Gly Leu
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 313
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 313
agattcacct ttgaagatta tgcc 24
<210> 314
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 314
Arg Phe Thr Phe Glu Asp Tyr Ala
1 5
<210> 315
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 315
attagttgga atagtggtag tata 24
<210> 316
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 316
Ile Ser Trp Asn Ser Gly Ser Ile
1 5
<210> 317
<211> 54
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 317
gtaaaagaag gggtatggtt cgggaagtta ttctcatcct acggtctgga cgtc 54
<210> 318
<211> 16
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 318
Glu Gly Val Trp Phe Gly Lys Leu Phe Ser Ser Tyr Gly Leu Asp Val
1 5 10 15
<210> 319
<211> 321
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 319
gccatccagt tgacccagtc tccagccacc ctgtctgtgt ctccagggga aagagccacc 60
ctctcttgca gggccagtca gagtgttagc agcaacttag cctggtacca gcagaaacct 120
gaccaggctc ccaggctcct catctatggt tcatccacca gggccactgg tatcccagcc 180
aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagcag cctgcagtct 240
gaagattttg cagtttatta ctgtcagcag tataataact ggccgtacac ttttggccag 300
gggaccaagg tggagatcaa a 321
<210> 320
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 320
Ala Ile Gln Leu Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Asp Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Gly Ser Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asn Asn Trp Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 321
<211> 18
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 321
cagagtgtta gcagcaac 18
<210> 322
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 322
Gln Ser Val Ser Ser Asn
1 5
<210> 323
<211> 9
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 323
ggttcatcc 9
<210> 324
<211> 3
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 324
Gly Ser Ser
1
<210> 325
<211> 27
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 325
cagcagtata ataactggcc gtacact 27
<210> 326
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 326
Gln Gln Tyr Asn Asn Trp Pro Tyr Thr
1 5
<210> 327
<211> 375
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 327
gaggtgcagc tggtggagtc cggcggcggc ctggtgcagc ccggccggtc cctgcggctg 60
tcctgcgccg cctcccggtt caccttcgag gactacgcca tgcactgggt gcggcaggcc 120
cccggcaagg gcctggagtg ggtgtccggc atctcctgga actccggctc catcggctac 180
gccgactccg tgaagggccg gttcaccatc tcccgggaca acgccaagaa ctccctgtac 240
ctgcagatga actccctgcg ggccgaggac accgccctgt actactgcgt gaaggagggc 300
gtgtggttcg gcaagctgtt ctcctcctac ggcctggacg tgtggggcca gggcaccacc 360
gtgaccgtgt cctcc 375
<210> 328
<211> 125
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 328
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Phe Thr Phe Glu Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Val Lys Glu Gly Val Trp Phe Gly Lys Leu Phe Ser Ser Tyr Gly Leu
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 329
<211> 321
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 329
gagatcgtga tgacccagtc ccccgccacc ctgtccgtgt cccccggcga gcgggccacc 60
ctgtcctgcc gggcctccca gtccgtgtcc tccaacctgg cctggtacca gcagaagccc 120
ggccaggccc cccggctgct gatctacggc tcctccaccc gggccaccgg catccccgcc 180
cggttctccg gctccggctc cggcaccgag ttcaccctga ccatctcctc cctgcagtcc 240
gaggacttcg ccgtgtacta ctgccagcag tacaacaact ggccctacac cttcggccag 300
ggcaccaagc tggagatcaa g 321
<210> 330
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 330
Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Gly Ser Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asn Asn Trp Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 331
<211> 375
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 331
gaggtgcagc tggtggagtc tgggggaggc ttggtacagc ctggcaggtc cctgaaactc 60
tcctgtgcag cctctagatt cacctttgaa gattatgcca tgcactgggt ccggcaagct 120
ccagggaagg gcctggaatg ggtctcaggg attagttgga atagtggtag tataggttat 180
gcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctccctgtat 240
ctgcgaatga acagtctgag agctgatgac acggccttgt attattgtgt aaaagaaggg 300
gtatggttcg ggaagttatt ctcatcctac ggtctggacg tctggggcca agggaccacg 360
gtcaccgtct cctca 375
<210> 332
<211> 125
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 332
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Arg Phe Thr Phe Glu Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Arg Met Asn Ser Leu Arg Ala Asp Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Val Lys Glu Gly Val Trp Phe Gly Lys Leu Phe Ser Ser Tyr Gly Leu
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 333
<211> 321
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 333
gaaatagtga tgacgcagtc tccagccacc ctgtctgtgt ctccagggga aagagccacc 60
ctctcttgca gggccagtca gagtgttagc agcaacttag cctggtacca gcagaaacct 120
gaccaggctc ccaggctcct catctatggt tcatccacca gggccactgg tatcccagcc 180
aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagcag cctgcagtct 240
gaagattttg cagtttatta ctgtcagcag tataataact ggccgtacac ttttggccag 300
gggaccaagc tggagatcaa a 321
<210> 334
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 334
Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Asp Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Gly Ser Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asn Asn Trp Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 335
<211> 375
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 335
gaagtgcagc tggtgcagtc tgggggcggc ttggtacagc ctggcaggtc cctgagactc 60
tcctgtgcag cccctggatt caactttgat gattatgcca tgcactgggt ccggcaagct 120
ccagggaagg gcctggagtg ggtctcaggt attagttgga atagtggtag tataggctat 180
gcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctccctgtat 240
ctgcaaatga acagtctgag agctgaggac acggccttgt attactgtgc aaaagaaggg 300
gtatggttcg gaaaattatt ctcatcctac ggtatggacg tctggggcca agggaccacg 360
gtcaccgtct cctca 375
<210> 336
<211> 125
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 336
Glu Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Pro Gly Phe Asn Phe Asp Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Lys Glu Gly Val Trp Phe Gly Lys Leu Phe Ser Ser Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 337
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 337
ggattcaact ttgatgatta tgcc 24
<210> 338
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 338
Gly Phe Asn Phe Asp Asp Tyr Ala
1 5
<210> 339
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 339
attagttgga atagtggtag tata 24
<210> 340
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 340
Ile Ser Trp Asn Ser Gly Ser Ile
1 5
<210> 341
<211> 54
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 341
gcaaaagaag gggtatggtt cggaaaatta ttctcatcct acggtatgga cgtc 54
<210> 342
<211> 18
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 342
Ala Lys Glu Gly Val Trp Phe Gly Lys Leu Phe Ser Ser Tyr Gly Met
1 5 10 15
Asp Val
<210> 343
<211> 321
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 343
gatgttgtga tgacccagtc tccagccacc ctgtctgtgt ctccagggga aagagccacc 60
ctctcctgca gggccagtca gagtgttagc agcaacttag actggtacca gcagaaacct 120
ggccaggctc ccaggctcct catctatggt gcatccacca gggccactgg tatcccagcc 180
aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagcag cctgcagtct 240
gaagattttg cagtttatta ctgtcagcag tataataact ggccgtacac ttttggccag 300
gggaccaagc tggagatcaa a 321
<210> 344
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 344
Asp Val Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn
20 25 30
Leu Asp Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asn Asn Trp Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 345
<211> 18
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 345
cagagtgtta gcagcaac 18
<210> 346
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 346
Ser Gln Ser Val Ser Ser Asn
1 5
<210> 347
<211> 9
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 347
ggtgcatcc 9
<210> 348
<211> 3
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 348
Gly Ala Ser
1
<210> 349
<211> 27
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 349
cagcagtata ataactggcc gtacact 27
<210> 350
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 350
Gln Gln Tyr Asn Asn Trp Pro Tyr Thr
1 5
<210> 351
<211> 375
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 351
gaggtgcagc tggtggagtc cggcggcggc ctggtgcagc ccggccggtc cctgcggctg 60
tcctgcgccg cctccggctt caacttcgac gactacgcca tgcactgggt gcggcaggcc 120
cccggcaagg gcctggagtg ggtgtccggc atctcctgga actccggctc catcggctac 180
gccgactccg tgaagggccg gttcaccatc tcccgggaca acgccaagaa ctccctgtac 240
ctgcagatga actccctgcg ggccgaggac accgccctgt actactgcgc caaggagggc 300
gtgtggttcg gcaagctgtt ctcctcctac ggcatggacg tgtggggcca gggcaccacc 360
gtgaccgtgt cctcc 375
<210> 352
<211> 125
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 352
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Phe Asp Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Lys Glu Gly Val Trp Phe Gly Lys Leu Phe Ser Ser Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 353
<211> 321
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 353
gagatcgtga tgacccagtc ccccgccacc ctgtccgtgt cccccggcga gcgggccacc 60
ctgtcctgcc gggcctccca gtccgtgtcc tccaacctgg cctggtacca gcagaagccc 120
ggccaggccc cccggctgct gatctacggc gcctccaccc gggccaccgg catccccgcc 180
cggttctccg gctccggctc cggcaccgag ttcaccctga ccatctcctc cctgcagtcc 240
gaggacttcg ccgtgtacta ctgccagcag tacaacaact ggccctacac cttcggccag 300
ggcaccaagc tggagatcaa g 321
<210> 354
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 354
Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asn Asn Trp Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 355
<211> 375
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 355
gaggtgcagc tggtggagtc tgggggcggc ttggtacagc ctggcaggtc cctgagactc 60
tcctgtgcag cccctggatt caactttgat gattatgcca tgcactgggt ccggcaagct 120
ccagggaagg gcctggagtg ggtctcaggt attagttgga atagtggtag tataggctat 180
gcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctccctgtat 240
ctgcaaatga acagtctgag agctgaggac acggccttgt attactgtgc aaaagaaggg 300
gtatggttcg gaaaattatt ctcatcctac ggtatggacg tctggggcca agggaccacg 360
gtcaccgtct cctca 375
<210> 356
<211> 125
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 356
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Pro Gly Phe Asn Phe Asp Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Lys Glu Gly Val Trp Phe Gly Lys Leu Phe Ser Ser Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 357
<211> 320
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 357
gaaatagtga tgacgcagtc tccagccacc ctgtctgtgt ctccagggga aagagccacc 60
ctctcctgca gggccagtca gagtgttagc agcaacttag actggtacca gcagaaacct 120
ggccaggctc ccaggctcct catctatggt gcatccacca gggccactgg tatcccagcc 180
aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagcag cctgcagtct 240
gaagattttg cagtttatta ctgtcagcag tataataact ggccgtacac ttttggccag 300
ggaccaagct ggagatcaaa 320
<210> 358
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 358
Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn
20 25 30
Leu Asp Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asn Asn Trp Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 359
<211> 375
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 359
gaggtgcagc tggtgcagtc tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60
tcctgtgcag cctctggatt cacctttgat gattatgcca tgcactgggt ccggcaaggt 120
ccagggaagg gcctggagtg ggtctcaggt attagttgga atagtggtag tataggctat 180
gcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctccctgtat 240
ctgcaaatga acagtctgag agctgaggac acggccttgt attactgtgc aaaagaaggg 300
gtatggttcg gggagttatt ttcatcctac ggtatggacg tctggggcca agggaccctg 360
gtcaccgtct cctca 375
<210> 360
<211> 125
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 360
Glu Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Gly Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Lys Glu Gly Val Trp Phe Gly Glu Leu Phe Ser Ser Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 361
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 361
ggattcacct ttgatgatta tgcc 24
<210> 362
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 362
Gly Phe Thr Phe Asp Asp Tyr Ala
1 5
<210> 363
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 363
attagttgga atagtggtag tata 24
<210> 364
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 364
Ile Ser Trp Asn Ser Gly Ser Ile
1 5
<210> 365
<211> 54
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 365
gcaaaagaag gggtatggtt cggggagtta ttttcatcct acggtatgga cgtc 54
<210> 366
<211> 18
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 366
Ala Lys Glu Gly Val Trp Phe Gly Glu Leu Phe Ser Ser Tyr Gly Met
1 5 10 15
Asp Val
<210> 367
<211> 321
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 367
gaaattgtgc tgactcagtc tccagccacc ctgtctgtgt ctccagggga aagagccacc 60
ctctcctgca gggccagtcc gagtgttagc agcaacttag cctggtacca gcagaaacct 120
ggccagcctc ccaggctcct catctatggt gcatccacca gggccactgg tatcccagcc 180
aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagcag cctgcagtct 240
gaagattttg cagtttatta ctgtcagcag tatagtaact ggccgtacac ttttggccag 300
gggaccaagc tggagatcaa a 321
<210> 368
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 368
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Pro Ser Val Ser Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Arg Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Ser Asn Trp Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 369
<211> 18
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 369
ccgagtgtta gcagcaac 18
<210> 370
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 370
Pro Ser Val Ser Ser Asn
1 5
<210> 371
<211> 9
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 371
ggtgcatcc 9
<210> 372
<211> 3
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 372
Gly Ala Ser
1
<210> 373
<211> 27
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 373
cagcagtata gtaactggcc gtacact 27
<210> 374
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 374
Gln Gln Tyr Ser Asn Trp Pro Tyr Thr
1 5
<210> 375
<211> 375
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 375
gaggtgcagc tggtggagtc cggcggcggc ctggtgcagc ccggccggtc cctgcggctg 60
tcctgcgccg cctccggctt caccttcgac gactacgcca tgcactgggt gcggcaggcc 120
cccggcaagg gcctggagtg ggtgtccggc atctcctgga actccggctc catcggctac 180
gccgactccg tgaagggccg gttcaccatc tcccgggaca acgccaagaa ctccctgtac 240
ctgcagatga actccctgcg ggccgaggac accgccctgt actactgcgc caaggagggc 300
gtgtggttcg gcgagctgtt ctcctcctac ggcatggacg tgtggggcca gggcaccacc 360
gtgaccgtgt cctcc 375
<210> 376
<211> 125
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 376
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Lys Glu Gly Val Trp Phe Gly Glu Leu Phe Ser Ser Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 377
<211> 321
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 377
gagatcgtga tgacccagtc ccccgccacc ctgtccgtgt cccccggcga gcgggccacc 60
ctgtcctgcc gggcctcccc ctccgtgtcc tccaacctgg cctggtacca gcagaagccc 120
ggccaggccc cccggctgct gatctacggc gcctccaccc gggccaccgg catccccgcc 180
cggttctccg gctccggctc cggcaccgag ttcaccctga ccatctcctc cctgcagtcc 240
gaggacttcg ccgtgtacta ctgccagcag tactccaact ggccctacac cttcggccag 300
ggcaccaagc tggagatcaa g 321
<210> 378
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 378
Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Pro Ser Val Ser Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Ser Asn Trp Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 379
<211> 375
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 379
gaggtgcagc tggtggagtc tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60
tcctgtgcag cctctggatt cacctttgat gattatgcca tgcactgggt ccggcaaggt 120
ccagggaagg gcctggagtg ggtctcaggt attagttgga atagtggtag tataggctat 180
gcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctccctgtat 240
ctgcaaatga acagtctgag agctgaggac acggccttgt attactgtgc aaaagaaggg 300
gtatggttcg gggagttatt ttcatcctac ggtatggacg tctggggcca agggaccacg 360
gtcaccgtct cctca 375
<210> 380
<211> 125
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 380
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Gly Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Lys Glu Gly Val Trp Phe Gly Glu Leu Phe Ser Ser Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 381
<211> 321
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 381
gaaatagtga tgacgcagtc tccagccacc ctgtctgtgt ctccagggga aagagccacc 60
ctctcctgca gggccagtcc gagtgttagc agcaacttag cctggtacca gcagaaacct 120
ggccagcctc ccaggctcct catctatggt gcatccacca gggccactgg tatcccagcc 180
aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagcag cctgcagtct 240
gaagattttg cagtttatta ctgtcagcag tatagtaact ggccgtacac ttttggccag 300
gggaccaagc tggagatcaa a 321
<210> 382
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 382
Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Pro Ser Val Ser Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Arg Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Ser Asn Trp Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 383
<211> 375
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 383
caggtccagc tggtacagtc tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60
tcctgtgcag cctctggatt cacctttgat gattatgcca tgcactgggt ccggcaaggt 120
ccagggaagg gcctggagtg ggtctcaggt attagttgga atagtggtag tataggctat 180
gcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctccctgtat 240
ctgcaaatga acagtctgag agctgaggac acggccttgt attactgtgc aaaagaaggg 300
gtatggttcg gggagttatt ttcatcctac ggtatggacg tctggggcca agggaccacg 360
gtcaccgtct cctca 375
<210> 384
<211> 125
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 384
Gln Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Gly Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Lys Glu Gly Val Trp Phe Gly Glu Leu Phe Ser Ser Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 385
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 385
ggattcacct ttgatgatta tgcc 24
<210> 386
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 386
Gly Phe Thr Phe Asp Asp Tyr Ala
1 5
<210> 387
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 387
attagttgga atagtggtag tata 24
<210> 388
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 388
Ile Ser Trp Asn Ser Gly Ser Ile
1 5
<210> 389
<211> 54
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 389
gcaaaagaag gggtatggtt cggggagtta ttttcatcct acggtatgga cgtc 54
<210> 390
<211> 18
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 390
Ala Lys Glu Gly Val Trp Phe Gly Glu Leu Phe Ser Ser Tyr Gly Met
1 5 10 15
Asp Val
<210> 391
<211> 321
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 391
gaaatagtga tgacgcagtc tccagccacc ctgtctgtgt ctccagggga aagagccacc 60
ctctcctgca gggccagtcc gagtgttagc agcaacttag cctggtacca gcagaaacct 120
ggccagcctc ccaggctcct catctatggt gcatccacca gggccactgg tatcccagcc 180
aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagcag cctgcagtct 240
gaagattttg cagtttatta ctgtcagcag tatagtaact ggccgtacac ttttggccag 300
gggaccaagg tggagatcaa a 321
<210> 392
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 392
Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Pro Ser Val Ser Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Arg Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Ser Asn Trp Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 393
<211> 18
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 393
ccgagtgtta gcagcaac 18
<210> 394
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 394
Pro Ser Val Ser Ser Asn
1 5
<210> 395
<211> 9
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 395
ggtgcatcc 9
<210> 396
<211> 3
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 396
Gly Ala Ser
1
<210> 397
<211> 27
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 397
cagcagtata gtaactggcc gtacact 27
<210> 398
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 398
Gln Gln Tyr Ser Asn Trp Pro Tyr Thr
1 5
<210> 399
<211> 375
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 399
gaggtgcagc tggtggagtc tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60
tcctgtgcag cctctggatt cacctttgat gattatgcca tgcactgggt ccggcaaggt 120
ccagggaagg gcctggagtg ggtctcaggt attagttgga atagtggtag tataggctat 180
gcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctccctgtat 240
ctgcaaatga acagtctgag agctgaggac acggccttgt attactgtgc aaaagaaggg 300
gtatggttcg gggagttatt ttcatcctac ggtatggacg tctggggcca agggaccacg 360
gtcaccgtct cctca 375
<210> 400
<211> 125
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 400
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Gly Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Lys Glu Gly Val Trp Phe Gly Glu Leu Phe Ser Ser Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 401
<211> 321
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 401
gaaatagtga tgacgcagtc tccagccacc ctgtctgtgt ctccagggga aagagccacc 60
ctctcctgca gggccagtcc gagtgttagc agcaacttag cctggtacca gcagaaacct 120
ggccagcctc ccaggctcct catctatggt gcatccacca gggccactgg tatcccagcc 180
aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagcag cctgcagtct 240
gaagattttg cagtttatta ctgtcagcag tatagtaact ggccgtacac ttttggccag 300
gggaccaagc tggagatcaa a 321
<210> 402
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 402
Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Pro Ser Val Ser Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Arg Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Ser Asn Trp Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 403
<211> 357
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 403
gaggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtc 60
tcctgcaagg tttccggatt cactctcact gaattatcca ttcactgggt gcgacaggct 120
cctggaaaag ggcttgagtg gatgggaggt tttgatcctg aagatggtga aacaatctcc 180
gcacagaagt tccagggcag agtcaccatg accgaggaca catctacaga cacagcctac 240
atggaactga gcagcctgag atctgaagac acggccatat attactgttc aacgattttt 300
ggagtggtta ccaactttga caactggggc cagggaacca cggtcaccgt ctcctca 357
<210> 404
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 404
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Val Ser Gly Phe Thr Leu Thr Glu Leu
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Gly Phe Asp Pro Glu Asp Gly Glu Thr Ile Ser Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Glu Asp Thr Ser Thr Asp Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Ile Tyr Tyr Cys
85 90 95
Ser Thr Ile Phe Gly Val Val Thr Asn Phe Asp Asn Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser
115
<210> 405
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 405
ggattcactc tcactgaatt atcc 24
<210> 406
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 406
Gly Phe Thr Leu Thr Glu Leu Ser
1 5
<210> 407
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 407
tttgatcctg aagatggtga aaca 24
<210> 408
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 408
Phe Asp Pro Glu Asp Gly Glu Thr
1 5
<210> 409
<211> 36
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 409
tcaacgattt ttggagtggt taccaacttt gacaac 36
<210> 410
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 410
Ser Thr Ile Phe Gly Val Val Thr Asn Phe Asp Asn
1 5 10
<210> 411
<211> 321
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 411
gatattgtga tgacccagtc tccatcctcc ctgtctgcat ctgcaggaga cagagtcacc 60
atcacttgcc gggcaagtca ggccattaga aatgatttag gctggtatca gcagaaacca 120
gggaaagccc ctaagcgcct gatctatgct gcattcaatt tgcaaagtgg ggtcccatca 180
agattcagcg gcagtggatc tgggacagaa ttcactctca caatcagtag cctgcagcct 240
gaagatcttg caagttatta ctgtcaacag tataatagat acccgtggac gttcggccaa 300
gggaccaagc tggagatcaa a 321
<210> 412
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 412
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Ala Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ala Ile Arg Asn Asp
20 25 30
Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile
35 40 45
Tyr Ala Ala Phe Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Leu Ala Ser Tyr Tyr Cys Gln Gln Tyr Asn Arg Tyr Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 413
<211> 18
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 413
caggccatta gaaatgat 18
<210> 414
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 414
Gln Ala Ile Arg Asn Asp
1 5
<210> 415
<211> 9
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 415
gctgcattc 9
<210> 416
<211> 3
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 416
Ala Ala Phe
1
<210> 417
<211> 27
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 417
caacagtata atagataccc gtggacg 27
<210> 418
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 418
Gln Gln Tyr Asn Arg Tyr Pro Trp Thr
1 5
<210> 419
<211> 357
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 419
caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtc 60
tcctgcaagg tttccggatt cactctcact gaattatcca ttcactgggt gcgacaggct 120
cctggaaaag ggcttgagtg gatgggaggt tttgatcctg aagatggtga aacaatctcc 180
gcacagaagt tccagggcag agtcaccatg accgaggaca catctacaga cacagcctac 240
atggaactga gcagcctgag atctgaagac acggccatat attactgttc aacgattttt 300
ggagtggtta ccaactttga caactggggc cagggaaccc tggtcaccgt ctcctca 357
<210> 420
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 420
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Val Ser Gly Phe Thr Leu Thr Glu Leu
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Gly Phe Asp Pro Glu Asp Gly Glu Thr Ile Ser Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Glu Asp Thr Ser Thr Asp Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Ile Tyr Tyr Cys
85 90 95
Ser Thr Ile Phe Gly Val Val Thr Asn Phe Asp Asn Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 421
<211> 321
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 421
gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgcaggaga cagagtcacc 60
atcacttgcc gggcaagtca ggccattaga aatgatttag gctggtatca gcagaaacca 120
gggaaagccc ctaagcgcct gatctatgct gcattcaatt tgcaaagtgg ggtcccatca 180
agattcagcg gcagtggatc tgggacagaa ttcactctca caatcagtag cctgcagcct 240
gaagatcttg caagttatta ctgtcaacag tataatagat acccgtggac gttcggccaa 300
gggaccaagg tggaaatcaa a 321
<210> 422
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 422
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Ala Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ala Ile Arg Asn Asp
20 25 30
Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile
35 40 45
Tyr Ala Ala Phe Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Leu Ala Ser Tyr Tyr Cys Gln Gln Tyr Asn Arg Tyr Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 423
<211> 375
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 423
caggtgcagc tggtacagtc ggggggcggc ttggtacagc ctggcaggtc cctgagactc 60
tcctgtgcag cccctggatt caactttgat gattatgcca tgcactgggt ccggcaaact 120
ccagggaagg gcctggagtg ggtctcaggt attagttgga atagtggtac tataggctat 180
gcggactctg tgaagggccg atttaccatc tccagagaca acgccaagaa ctccctgtat 240
cttcaaatga acagtctgag agctgaggac acggccttgt attactgtgc aaaagaaggg 300
gtatggttcg gaaaattgtt ctcatcctac ggtatggacg tctggggcca agggaccacg 360
gtcaccgtct cctca 375
<210> 424
<211> 125
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 424
Gln Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Pro Gly Phe Asn Phe Asp Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Thr Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Trp Asn Ser Gly Thr Ile Gly Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Lys Glu Gly Val Trp Phe Gly Lys Leu Phe Ser Ser Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 425
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 425
ggattcaact ttgatgatta tgcc 24
<210> 426
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 426
Gly Phe Asn Phe Asp Asp Tyr Ala
1 5
<210> 427
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 427
attagttgga atagtggtac tata 24
<210> 428
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 428
Ile Ser Trp Asn Ser Gly Thr Ile
1 5
<210> 429
<211> 54
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 429
gcaaaagaag gggtatggtt cggaaaattg ttctcatcct acggtatgga cgtc 54
<210> 430
<211> 18
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 430
Ala Lys Glu Gly Val Trp Phe Gly Lys Leu Phe Ser Ser Tyr Gly Met
1 5 10 15
Asp Val
<210> 431
<211> 321
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 431
gaaatagtga tgacgcagtc tccagccacc ctgtctgtgt ctccagggga aagagccacc 60
ctctcctgca gggccagtcg gactgttact tacaacttag actggtacca gcagaagcct 120
ggccaggctc ccaggctcct catctttggt gcatccacca gggccactgg tatcccagcc 180
aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcaccag cctgcagtct 240
gaagattttg cagtttatta ctgtcaacag tataataact ggccgtacac ttttggccag 300
gggaccaagc tggagatcaa a 321
<210> 432
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 432
Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Arg Thr Val Thr Tyr Asn
20 25 30
Leu Asp Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Phe Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Thr Ser Leu Gln Ser
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asn Asn Trp Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 433
<211> 18
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 433
cggactgtta cttacaac 18
<210> 434
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 434
Arg Thr Val Thr Tyr Asn
1 5
<210> 435
<211> 9
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 435
ggtgcatcc 9
<210> 436
<211> 3
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 436
Gly Ala Ser
1
<210> 437
<211> 27
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 437
caacagtata ataactggcc gtacact 27
<210> 438
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 438
Gln Gln Tyr Asn Asn Trp Pro Tyr Thr
1 5
<210> 439
<211> 375
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 439
gaagtgcagc tggtgcagtc tgggggcggc ttggttcagc ctggcgggtc cctgagactc 60
tcctgtgcag cccctggatt caactttgat gattatgcca tgcactgggt ccggcaagct 120
ccagggaagg gcctggagtg ggtctcaggt attagttgga atagtggtag tattggctat 180
gcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctccctgtat 240
ctgcaaatga acagtctgag agctgaggac tcggccttgt atttctgtgc aaaagaaggg 300
gtatggttcg gaaaattatt ttcatcctac ggtatggacg tctggggcca agggaccacg 360
gtcaccgtct cctca 375
<210> 440
<211> 125
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 440
Glu Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Pro Gly Phe Asn Phe Asp Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Ser Ala Leu Tyr Phe Cys
85 90 95
Ala Lys Glu Gly Val Trp Phe Gly Lys Leu Phe Ser Ser Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 441
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 441
ggattcaact ttgatgatta tgcc 24
<210> 442
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 442
Gly Phe Asn Phe Asp Asp Tyr Ala
1 5
<210> 443
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 443
attagttgga atagtggtag tatt 24
<210> 444
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 444
Ile Ser Trp Asn Ser Gly Ser Ile
1 5
<210> 445
<211> 54
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 445
gcaaaagaag gggtatggtt cggaaaatta ttttcatcct acggtatgga cgtc 54
<210> 446
<211> 18
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 446
Ala Lys Glu Gly Val Trp Phe Gly Lys Leu Phe Ser Ser Tyr Gly Met
1 5 10 15
Asp Val
<210> 447
<211> 321
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 447
gaaatagtgt tgacgcagtc tccagccacc ctgtctgcgt ctccagggga cagagcctcc 60
ctctcctgca gggccagtca gagtgttacc ttcaacttag actggtacca gcagaaacct 120
ggccagcctc ccaggctcct catctatggt gcatccacca gggcctctgg tatcccagcc 180
aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagcgg cctgcagtct 240
gaagattttg cagtttatta ctgtcagcag tataataact ggccgtacac ttttggccag 300
gggaccaaag tggatatcaa a 321
<210> 448
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 448
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Ala Ser Pro Gly
1 5 10 15
Asp Arg Ala Ser Leu Ser Cys Arg Ala Ser Gln Ser Val Thr Phe Asn
20 25 30
Leu Asp Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Arg Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Thr Arg Ala Ser Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Gly Leu Gln Ser
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asn Asn Trp Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Asp Ile Lys
100 105
<210> 449
<211> 18
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 449
cagagtgtta ccttcaac 18
<210> 450
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 450
Gln Ser Val Thr Phe Asn
1 5
<210> 451
<211> 9
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 451
ggtgcatcc 9
<210> 452
<211> 3
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 452
Gly Ala Ser
1
<210> 453
<211> 27
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 453
cagcagtata ataactggcc gtacact 27
<210> 454
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 454
Gln Gln Tyr Asn Asn Trp Pro Tyr Thr
1 5
<210> 455
<211> 375
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 455
gaggtgcagc tggtggagtc cggcggcggc ctggtgcagc ccggccggtc cctgcggctg 60
tcctgcgccg cctccggctt caacttcgac gactacgcca tgcactgggt gcggcaggcc 120
cccggcaagg gcctggagtg ggtgtccggc atctcctgga actccggctc catcggctac 180
gccgactccg tgaagggccg gttcaccatc tcccgggaca acgccaagaa ctccctgtac 240
ctgcagatga actccctgcg ggccgaggac accgccctgt actactgcgc caaggagggc 300
gtgtggttcg gcaagctgtt ctcctcctac ggcatggacg tgtggggcca gggcaccacc 360
gtgaccgtgt cctcc 375
<210> 456
<211> 125
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 456
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Phe Asp Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Lys Glu Gly Val Trp Phe Gly Lys Leu Phe Ser Ser Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 457
<211> 321
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 457
gagatcgtga tgacccagtc ccccgccacc ctgtccgtgt cccccggcga gcgggccacc 60
ctgtcctgcc gggcctccca gtccgtgacc ttcaacctgg cctggtacca gcagaagccc 120
ggccagcccg cccggctgct gatctacggc gcctccaccc gggccaccgg catccccgcc 180
cggttctccg gctccggctc cggcaccgag ttcaccctga ccatctcctc cctgcagtcc 240
gaggacttcg ccgtgtacta ctgccagcag tacaacaact ggccctacac cttcggccag 300
ggcaccaagc tggagatcaa g 321
<210> 458
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 458
Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Thr Phe Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Ala Arg Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asn Asn Trp Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 459
<211> 375
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 459
gaggtgcagc tggtggagtc tgggggcggc ttggttcagc ctggcgggtc cctgagactc 60
tcctgtgcag cccctggatt caactttgat gattatgcca tgcactgggt ccggcaagct 120
ccagggaagg gcctggagtg ggtctcaggt attagttgga atagtggtag tattggctat 180
gcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctccctgtat 240
ctgcaaatga acagtctgag agctgaggac tcggccttgt atttctgtgc aaaagaaggg 300
gtatggttcg gaaaattatt ttcatcctac ggtatggacg tctggggcca agggaccacg 360
gtcaccgtct cctca 375
<210> 460
<211> 125
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 460
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Pro Gly Phe Asn Phe Asp Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Ser Ala Leu Tyr Phe Cys
85 90 95
Ala Lys Glu Gly Val Trp Phe Gly Lys Leu Phe Ser Ser Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 461
<211> 321
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 461
gaaatagtga tgacgcagtc tccagccacc ctgtctgcgt ctccagggga cagagcctcc 60
ctctcctgca gggccagtca gagtgttacc ttcaacttag actggtacca gcagaaacct 120
ggccagcctc ccaggctcct catctatggt gcatccacca gggcctctgg tatcccagcc 180
aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagcgg cctgcagtct 240
gaagattttg cagtttatta ctgtcagcag tataataact ggccgtacac ttttggccag 300
gggaccaagc tggagatcaa a 321
<210> 462
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 462
Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Ala Ser Pro Gly
1 5 10 15
Asp Arg Ala Ser Leu Ser Cys Arg Ala Ser Gln Ser Val Thr Phe Asn
20 25 30
Leu Asp Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Arg Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Thr Arg Ala Ser Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Gly Leu Gln Ser
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asn Asn Trp Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 463
<211> 375
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 463
caggtgcagc tggtacagtc ggggggaggc ttggtacagc ctggcaggtc cctgagactc 60
tcctgtgcag cctctggatt cacctttgat gattatgcca tgcactgggt ccggcaaggt 120
ccagggaagg gcctagagtg ggtctcaggt attagttgga atagtggtta taaagactat 180
gcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa gtccctgtat 240
ctgcaaatga acagtctgag acctgaggac acggccttgt attactgtgc aaaagaaggg 300
gtatggttcg gagaattatt ttcatcctac ggtatggacg tctggggcca agggaccacg 360
gtcaccgtct cctca 375
<210> 464
<211> 125
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 464
Gln Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Gly Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Trp Asn Ser Gly Tyr Lys Asp Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Lys Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Lys Glu Gly Val Trp Phe Gly Glu Leu Phe Ser Ser Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 465
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 465
ggattcacct ttgatgatta tgcc 24
<210> 466
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 466
Gly Phe Thr Phe Asp Asp Tyr Ala
1 5
<210> 467
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 467
attagttgga atagtggtta taaa 24
<210> 468
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 468
Ile Ser Trp Asn Ser Gly Tyr Lys
1 5
<210> 469
<211> 54
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 469
gcaaaagaag gggtatggtt cggagaatta ttttcatcct acggtatgga cgtc 54
<210> 470
<211> 18
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 470
Ala Lys Glu Gly Val Trp Phe Gly Glu Leu Phe Ser Ser Tyr Gly Met
1 5 10 15
Asp Val
<210> 471
<211> 321
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 471
gaaattgtga tgacgcagtc tccagccacc ctgtctgtgt ctccagggga aagagccacc 60
ctctcctgca gggccagtcc gagtgttagc agcaacttag cctggtacca gcagaaacct 120
ggccagcctc ccaggctcct catctatggt acatccacca gggccactgg tatcccagcc 180
aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagaag cctgcagtct 240
gaagattttg cagtttatta ctgtcagcag tatagtaact ggccatacac ttttggccag 300
gggaccaaag tggatatcaa a 321
<210> 472
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 472
Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Pro Ser Val Ser Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Arg Leu Leu Ile
35 40 45
Tyr Gly Thr Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Arg Ser Leu Gln Ser
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Ser Asn Trp Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Asp Ile Lys
100 105
<210> 473
<211> 18
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 473
ccgagtgtta gcagcaac 18
<210> 474
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 474
Pro Ser Val Ser Ser Asn
1 5
<210> 475
<211> 9
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 475
ggtacatcc 9
<210> 476
<211> 3
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 476
Gly Thr Ser
1
<210> 477
<211> 27
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 477
cagcagtata gtaactggcc atacact 27
<210> 478
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 478
Gln Gln Tyr Ser Asn Trp Pro Tyr Thr
1 5
<210> 479
<211> 375
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 479
gaggtgcagc tggtggagtc cggcggcggc ctggtgcagc ccggccggtc cctgcggctg 60
tcctgcgccg cctccggctt caccttcgac gactacgcca tgcactgggt gcggcaggcc 120
cccggcaagg gcctggagtg ggtgtccggc atctcctgga actccggcta caagggctac 180
gccgactccg tgaagggccg gttcaccatc tcccgggaca acgccaagaa ctccctgtac 240
ctgcagatga actccctgcg ggccgaggac accgccctgt actactgcgc caaggagggc 300
gtgtggttcg gcgagctgtt ctcctcctac ggcatggacg tgtggggcca gggcaccacc 360
gtgaccgtgt cctcc 375
<210> 480
<211> 125
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 480
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Trp Asn Ser Gly Tyr Lys Gly Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Lys Glu Gly Val Trp Phe Gly Glu Leu Phe Ser Ser Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 481
<211> 321
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 481
gagatcgtga tgacccagtc ccccgccacc ctgtccgtgt cccccggcga gcgggccacc 60
ctgtcctgcc gggcctcccc ctccgtgtcc tccaacctgg cctggtacca gcagaagccc 120
ggccaggccc cccggctgct gatctacggc acctccaccc gggccaccgg catccccgcc 180
cggttctccg gctccggctc cggcaccgag ttcaccctga ccatctcctc cctgcagtcc 240
gaggacttcg ccgtgtacta ctgccagcag tactccaact ggccctacac cttcggccag 300
ggcaccaagc tggagatcaa g 321
<210> 482
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 482
Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Pro Ser Val Ser Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Gly Thr Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Ser Asn Trp Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 483
<211> 375
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 483
gaggtgcagc tggtggagtc tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60
tcctgtgcag cctctggatt cacctttgat gattatgcca tgcactgggt ccggcaaggt 120
ccagggaagg gcctagagtg ggtctcaggt attagttgga atagtggtta taaagactat 180
gcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa gtccctgtat 240
ctgcaaatga acagtctgag acctgaggac acggccttgt attactgtgc aaaagaaggg 300
gtatggttcg gagaattatt ttcatcctac ggtatggacg tctggggcca agggaccacg 360
gtcaccgtct cctca 375
<210> 484
<211> 125
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 484
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Gly Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Trp Asn Ser Gly Tyr Lys Asp Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Lys Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Lys Glu Gly Val Trp Phe Gly Glu Leu Phe Ser Ser Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 485
<211> 321
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 485
gaaatagtga tgacgcagtc tccagccacc ctgtctgtgt ctccagggga aagagccacc 60
ctctcctgca gggccagtcc gagtgttagc agcaacttag cctggtacca gcagaaacct 120
ggccagcctc ccaggctcct catctatggt acatccacca gggccactgg tatcccagcc 180
aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagaag cctgcagtct 240
gaagattttg cagtttatta ctgtcagcag tatagtaact ggccatacac ttttggccag 300
gggaccaagc tggagatcaa a 321
<210> 486
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 486
Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Pro Ser Val Ser Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Arg Leu Leu Ile
35 40 45
Tyr Gly Thr Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Arg Ser Leu Gln Ser
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Ser Asn Trp Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 487
<211> 375
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 487
gaggtgcagc tggtgcagtc tgggggaggc ttggtacagc ccggtaggtc cctgagactc 60
tcctgtacag cctctaaatt cacctttgaa gattatgcca tgcactgggt ccggcaagtt 120
ccagggaagg gcctggaatg ggtctcaggg attagttgga atagtggtaa cataggctat 180
gcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctccctgtat 240
ctgcgaatga atagtctgag agctgatgac acggccttgt attactgtgt gaaggaaggg 300
gtatggttcg ggaagtcatt ttcatcctac ggtttggacg tctggggcca agggaccacg 360
gtcaccgtct cctca 375
<210> 488
<211> 125
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 488
Glu Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Ala Ser Lys Phe Thr Phe Glu Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Val Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Trp Asn Ser Gly Asn Ile Gly Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Arg Met Asn Ser Leu Arg Ala Asp Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Val Lys Glu Gly Val Trp Phe Gly Lys Ser Phe Ser Ser Tyr Gly Leu
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 489
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 489
aaattcacct ttgaagatta tgcc 24
<210> 490
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 490
Lys Phe Thr Phe Glu Asp Tyr Ala
1 5
<210> 491
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 491
attagttgga atagtggtaa cata 24
<210> 492
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 492
Ile Ser Trp Asn Ser Gly Asn Ile
1 5
<210> 493
<211> 54
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 493
gtgaaggaag gggtatggtt cgggaagtca ttttcatcct acggtttgga cgtc 54
<210> 494
<211> 18
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 494
Val Lys Glu Gly Val Trp Phe Gly Lys Ser Phe Ser Ser Tyr Gly Leu
1 5 10 15
Asp Val
<210> 495
<211> 321
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 495
gaaatagtga tgacacagtc tccagccacc ctgtctgtgt ctccggggga aagagccacc 60
ctctcttgca gggccagtca gagtgttagc agcaacttag cctggtatca gcagaaacct 120
ggccaggctc ccaggctcct catctatggt gcatccacca gggccactgg tgtcccagcc 180
aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagcag cctgcagtct 240
gaagattttg cagtttatta ctgtcaacat tataattact ggccgtacac ttttggccag 300
gggaccaaag tggatatcaa a 321
<210> 496
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 496
Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Thr Arg Ala Thr Gly Val Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Tyr Asn Tyr Trp Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Asp Ile Lys
100 105
<210> 497
<211> 18
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 497
cagagtgtta gcagcaac 18
<210> 498
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 498
Gln Ser Val Ser Ser Asn
1 5
<210> 499
<211> 9
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 499
ggtgcatcc 9
<210> 500
<211> 3
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 500
Gly Ala Ser
1
<210> 501
<211> 27
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 501
caacattata attactggcc gtacact 27
<210> 502
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 502
Gln His Tyr Asn Tyr Trp Pro Tyr Thr
1 5
<210> 503
<211> 375
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 503
gaggtgcagc tggtggagtc cggcggcggc ctggtgcagc ccggccggtc cctgcggctg 60
tcctgcgccg cctccaagtt caccttcgag gactacgcca tgcactgggt gcggcaggcc 120
cccggcaagg gcctggagtg ggtgtccggc atctcctgga actccggcaa catcggctac 180
gccgactccg tgaagggccg gttcaccatc tcccgggaca acgccaagaa ctccctgtac 240
ctgcagatga actccctgcg ggccgaggac accgccctgt actactgcgt gaaggagggc 300
gtgtggttcg gcaagtcctt ctcctcctac ggcctggacg tgtggggcca gggcaccacc 360
gtgaccgtgt cctcc 375
<210> 504
<211> 125
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 504
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Lys Phe Thr Phe Glu Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Trp Asn Ser Gly Asn Ile Gly Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Val Lys Glu Gly Val Trp Phe Gly Lys Ser Phe Ser Ser Tyr Gly Leu
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 505
<211> 321
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 505
gagatcgtga tgacccagtc ccccgccacc ctgtccgtgt cccccggcga gcgggccacc 60
ctgtcctgcc gggcctccca gtccgtgtcc tccaacctgg cctggtacca gcagaagccc 120
ggccaggccc cccggctgct gatctacggc gcctccaccc gggccaccgg catccccgcc 180
cggttctccg gctccggctc cggcaccgag ttcaccctga ccatctcctc cctgcagtcc 240
gaggacttcg ccgtgtacta ctgccagcac tacaactact ggccctacac cttcggccag 300
ggcaccaagc tggagatcaa g 321
<210> 506
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 506
Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Tyr Asn Tyr Trp Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 507
<211> 375
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 507
gaggtgcagc tggtggagtc tgggggaggc ttggtacagc ccggtaggtc cctgagactc 60
tcctgtacag cctctaaatt cacctttgaa gattatgcca tgcactgggt ccggcaagtt 120
ccagggaagg gcctggaatg ggtctcaggg attagttgga atagtggtaa cataggctat 180
gcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctccctgtat 240
ctgcgaatga atagtctgag agctgatgac acggccttgt attactgtgt gaaggaaggg 300
gtatggttcg ggaagtcatt ttcatcctac ggtttggacg tctggggcca agggaccacg 360
gtcaccgtct cctca 375
<210> 508
<211> 125
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 508
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Ala Ser Lys Phe Thr Phe Glu Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Val Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Trp Asn Ser Gly Asn Ile Gly Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Arg Met Asn Ser Leu Arg Ala Asp Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Val Lys Glu Gly Val Trp Phe Gly Lys Ser Phe Ser Ser Tyr Gly Leu
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 509
<211> 321
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 509
gaaatagtga tgacgcagtc tccagccacc ctgtctgtgt ctccggggga aagagccacc 60
ctctcttgca gggccagtca gagtgttagc agcaacttag cctggtatca gcagaaacct 120
ggccaggctc ccaggctcct catctatggt gcatccacca gggccactgg tgtcccagcc 180
aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagcag cctgcagtct 240
gaagattttg cagtttatta ctgtcaacat tataattact ggccgtacac ttttggccag 300
gggaccaagc tggagatcaa a 321
<210> 510
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 510
Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Thr Arg Ala Thr Gly Val Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Tyr Asn Tyr Trp Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 511
<211> 357
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 511
gaagtgcagc tggtgcagtc tggggctgat gtgaagaagc ctggggcctc agtgaaggtc 60
tcctgcaagg tttccggata caccctcact gaattatcca tacactgggt gcgacaggct 120
cctggaaaag ggcttgaatg gatgggaggt tttgatcctg aacatggtac aacaatctac 180
gcacagaagt tccagggcag agtcaccatg accgaggaca catctacaga cacagcctac 240
atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgt aatgattttt 300
ggcgtggtta ccaattttga caactggggc cagggaacca cggtcaccgt ctcctca 357
<210> 512
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 512
Glu Val Gln Leu Val Gln Ser Gly Ala Asp Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Val Ser Gly Tyr Thr Leu Thr Glu Leu
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Gly Phe Asp Pro Glu His Gly Thr Thr Ile Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Glu Asp Thr Ser Thr Asp Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Val Met Ile Phe Gly Val Val Thr Asn Phe Asp Asn Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser
115
<210> 513
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 513
ggatacaccc tcactgaatt atcc 24
<210> 514
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 514
Gly Tyr Thr Leu Thr Glu Leu Ser
1 5
<210> 515
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 515
tttgatcctg aacatggtac aaca 24
<210> 516
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 516
Phe Asp Pro Glu His Gly Thr Thr
1 5
<210> 517
<211> 36
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 517
gtaatgattt ttggcgtggt taccaatttt gacaac 36
<210> 518
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 518
Val Met Ile Phe Gly Val Val Thr Asn Phe Asp Asn
1 5 10
<210> 519
<211> 321
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 519
gacattgtga tgacccagtc tccatcctcc ctgtctgcat ccgtgagaga cagagtcacc 60
atcacttgcc gggcaagtca gggcattaga aatgagttag gctggtatca gcagaaacca 120
gggaaagccc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180
aggttcagcg gcagtggatc tgggacagat ttcactctca cattcagcag cctgcagcct 240
gaagattttg caacttacta ttgttcacag gataacaatt tcccgtggac gtttggccaa 300
gggaccaagg tggaaatcaa a 321
<210> 520
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 520
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Arg
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Glu
20 25 30
Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Phe Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Ser Gln Asp Asn Asn Phe Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 521
<211> 18
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 521
cagggcatta gaaatgag 18
<210> 522
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 522
Gln Gly Ile Arg Asn Glu
1 5
<210> 523
<211> 9
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 523
gctgcatcc 9
<210> 524
<211> 3
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 524
Ala Ala Ser
1
<210> 525
<211> 27
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 525
tcacaggata acaatttccc gtggacg 27
<210> 526
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 526
Ser Gln Asp Asn Asn Phe Pro Trp Thr
1 5
<210> 527
<211> 357
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 527
caggtgcagc tggtgcagtc cggcgccgag gtgaagaagc ccggcgcctc cgtgaaggtg 60
tcctgcaagg tgtccggcta caccctgacc gagctgtcca tgcactgggt gcggcaggcc 120
cccggcaagg gcctggagtg gatgggcggc ttcgaccccg agcacggcac caccatctac 180
gcccagaagt tccagggccg ggtgaccatg accgaggaca cctccaccga caccgcctac 240
atggagctgt cctccctgcg gtccgaggac accgccgtgt actactgcgt gatgatcttc 300
ggcgtggtga ccaacttcga caactggggc cagggcaccc tggtgaccgt gtcctcc 357
<210> 528
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 528
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Val Ser Gly Tyr Thr Leu Thr Glu Leu
20 25 30
Ser Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Gly Phe Asp Pro Glu His Gly Thr Thr Ile Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Glu Asp Thr Ser Thr Asp Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Val Met Ile Phe Gly Val Val Thr Asn Phe Asp Asn Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 529
<211> 321
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 529
gacatccaga tgacccagtc cccctcctcc ctgtccgcct ccgtgggcga ccgggtgacc 60
atcacctgcc gggcctccca gggcatccgg aacgagctgg gctggtacca gcagaagccc 120
ggcaaggccc ccaagcggct gatctacgcc gcctcctccc tgcagtccgg cgtgccctcc 180
cggttctccg gctccggctc cggcaccgag ttcaccctga ccatctcctc cctgcagccc 240
gaggacttcg ccacctacta ctgctcccag gacaacaact tcccctggac cttcggccag 300
ggcaccaagg tggagatcaa g 321
<210> 530
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 530
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Glu
20 25 30
Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Ser Gln Asp Asn Asn Phe Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 531
<211> 357
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 531
caggtgcagc tggtgcagtc tggggctgat gtgaagaagc ctggggcctc agtgaaggtc 60
tcctgcaagg tttccggata caccctcact gaattatcca tacactgggt gcgacaggct 120
cctggaaaag ggcttgaatg gatgggaggt tttgatcctg aacatggtac aacaatctac 180
gcacagaagt tccagggcag agtcaccatg accgaggaca catctacaga cacagcctac 240
atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgt aatgattttt 300
ggcgtggtta ccaattttga caactggggc cagggaaccc tggtcaccgt ctcctca 357
<210> 532
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 532
Gln Val Gln Leu Val Gln Ser Gly Ala Asp Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Val Ser Gly Tyr Thr Leu Thr Glu Leu
20 25 30
Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Gly Phe Asp Pro Glu His Gly Thr Thr Ile Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Glu Asp Thr Ser Thr Asp Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Val Met Ile Phe Gly Val Val Thr Asn Phe Asp Asn Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 533
<211> 321
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 533
gacatccaga tgacccagtc tccatcctcc ctgtctgcat ccgtgagaga cagagtcacc 60
atcacttgcc gggcaagtca gggcattaga aatgagttag gctggtatca gcagaaacca 120
gggaaagccc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180
aggttcagcg gcagtggatc tgggacagat ttcactctca cattcagcag cctgcagcct 240
gaagattttg caacttacta ttgttcacag gataacaatt tcccgtggac gtttggccaa 300
gggaccaagg tggaaatcaa a 321
<210> 534
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 534
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Arg
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Glu
20 25 30
Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Phe Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Ser Gln Asp Asn Asn Phe Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 535
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<220>
<221> VARIANT
<222> (1)...(8)
<223> Xaa = Any Amino Acid
<400> 535
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
1 5
<210> 536
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<220>
<221> VARIANT
<222> (1)...(8)
<223> Xaa = Any Amino Acid
<400> 536
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
1 5
<210> 537
<211> 18
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<220>
<221> VARIANT
<222> (1)...(18)
<223> Xaa = Any AMino Acid
<400> 537
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
1 5 10 15
Xaa Xaa
<210> 538
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<220>
<221> VARIANT
<222> (1)...(6)
<223> Xaa = Any Amino Acid
<400> 538
Xaa Xaa Xaa Xaa Xaa Xaa
1 5
<210> 539
<211> 3
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<220>
<221> VARIANT
<222> (1)...(3)
<223> Xaa = Any Amino Acid
<400> 539
Xaa Xaa Xaa
1
<210> 540
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<220>
<221> VARIANT
<222> (1)...(9)
<223> Xaa = Any Amino Acid
<400> 540
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
1 5
<210> 541
<211> 330
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 541
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 542
<211> 327
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 542
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro
100 105 110
Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 543
<211> 327
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 543
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
Claims (25)
- 약제학적으로 허용되는 담체 및 항체 또는 이의 항원-결합 단편을 포함하는 골관절염의 징후를 억제하기 위한 약제학적 조성물로서,
상기 항체 또는 이의 항원-결합 단편이 인간 신경성장인자 (NGF)에 특이적으로 결합하고,
(a) 서열번호 86의 HCDR1, 서열번호 88의 HCDR2 및 서열번호 90의 HCDR3의 세 개의 상보성 결정 영역 (CDR)을 포함하는 중쇄; 및
(b) 서열번호 94의 LCDR1, 서열번호 96의 LCDR2 및 서열번호 98의 LCDR3의 세 개의 상보성 결정 영역 (CDR)을 포함하는 경쇄를 포함하고,
랫트 및 마우스 NGF에 결합하는 것보다 2 내지 10배 더 높은 친화도의 KD로 인간 NGF에 결합하는, 약제학적 조성물. - 제1항에 있어서, 상기 항체 또는 이의 항원-결합 단편이 0.5 pM 이하의 KD로 인간 NGF에 특이적으로 결합하는, 약제학적 조성물.
- 제1항에 있어서, 상기 항체 또는 이의 항원-결합 단편이 중쇄 가변 영역 (HCVR) 및 경쇄 가변 영역 (LCVR)을 포함하고, 상기 HCVR 및 LCVR이 서열번호 108 및 110에 제시된 아미노산 서열을 포함하는, 약제학적 조성물.
- 삭제
- 약제학적으로 허용되는 담체 및 항체 또는 이의 항원-결합 단편을 포함하는 골관절염의 징후를 억제하기 위한 약제학적 조성물로서,
상기 항체 또는 이의 항원-결합 단편이 인간 신경성장인자 (NGF)에 특이적으로 결합하고,
서열번호 84에 나타낸 중쇄 가변 영역 (HCVR) 및 서열번호 92에 나타낸 경쇄 가변 영역 (LCVR); 또는 서열번호 100에 나타낸 중쇄 가변 영역 (HCVR) 및 서열번호 102에 나타낸 경쇄 가변 영역 (LCVR)을 포함하고,
랫트 및 마우스 NGF에 결합하는 것보다 2 내지 10배 더 높은 친화도의 KD로 인간 NGF에 결합하는, 약제학적 조성물. - 제5항에 있어서, 인터류킨-1 (IL-1) 억제제, 항간질성 약물, 사이토킨 길항제 및 또 다른 뉴로트로핀으로부터 선택되는 치료제를 추가로 포함하는, 약제학적 조성물.
- 삭제
- 삭제
- 삭제
- 삭제
- 삭제
- 삭제
- 삭제
- 삭제
- 삭제
- 삭제
- 삭제
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Applications Claiming Priority (9)
| Application Number | Priority Date | Filing Date | Title |
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| US96422407P | 2007-08-10 | 2007-08-10 | |
| US60/964,224 | 2007-08-10 | ||
| US99452607P | 2007-09-20 | 2007-09-20 | |
| US60/994,526 | 2007-09-20 | ||
| US6286008P | 2008-01-28 | 2008-01-28 | |
| US61/062,860 | 2008-01-28 | ||
| US7925908P | 2008-07-09 | 2008-07-09 | |
| US61/079,259 | 2008-07-09 | ||
| PCT/US2008/072561 WO2009023540A1 (en) | 2007-08-10 | 2008-08-08 | High affinity human antibodies to human nerve growth factor |
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| KR1020107005181A Division KR101709488B1 (ko) | 2007-08-10 | 2008-08-08 | 인간 신경성장인자에 대한 고친화성 인간 항체 |
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| KR101709495B1 true KR101709495B1 (ko) | 2017-02-23 |
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| KR1020107005181A Active KR101709488B1 (ko) | 2007-08-10 | 2008-08-08 | 인간 신경성장인자에 대한 고친화성 인간 항체 |
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| KR1020107005181A Active KR101709488B1 (ko) | 2007-08-10 | 2008-08-08 | 인간 신경성장인자에 대한 고친화성 인간 항체 |
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| KR (2) | KR101709495B1 (ko) |
| CN (1) | CN101827609B (ko) |
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| BR (1) | BRPI0815370B8 (ko) |
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| US9498530B2 (en) | 2002-12-24 | 2016-11-22 | Rinat Neuroscience Corp. | Methods for treating osteoarthritis pain by administering a nerve growth factor antagonist and compositions containing the same |
| BRPI0317738B8 (pt) * | 2002-12-24 | 2021-05-25 | Rinat Neuroscience Corp | anticorpos anti-ngf ou fragmentos dos mesmos, seu método de fabricação, uso, polinucleotídeo, vetor e micro-organismo transgênico, bem como composição farmacêutica e kit compreendendo os referidos anticorpos ou fragmentos |
| US20100069614A1 (en) | 2008-06-27 | 2010-03-18 | Merus B.V. | Antibody producing non-human mammals |
| ITRM20030601A1 (it) | 2003-12-24 | 2005-06-25 | Lay Line Genomics Spa | Metodo per l'umanizzazione di anticorpi e anticorpi umanizzati con esso ottenuti. |
| ITRM20050290A1 (it) * | 2005-06-07 | 2006-12-08 | Lay Line Genomics Spa | Uso di molecole in grado di inibire il legame tra ngf e il suo recettore trka come analgesici ad effetto prolungato. |
| US8309088B2 (en) | 2007-08-10 | 2012-11-13 | Regeneron Pharmaceuticals, Inc. | Method of treating osteoarthritis with an antibody to NGF |
| PT2187964E (pt) | 2007-08-10 | 2015-01-14 | Regeneron Pharma | Anticorpos humanos de elevada afinidade para o factor de crescimento neural humano |
| WO2009150623A1 (en) | 2008-06-13 | 2009-12-17 | Pfizer Inc | Treatment of chronic prostatitis |
| TR201802935T4 (tr) | 2008-09-19 | 2018-03-21 | Pfizer | Stabil sıvı antikor formülasyonu. |
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