TW201022442A - Multicomponent immunogenic composition for the prevention of beta-hemolytic streptococcal (BHS) disease - Google Patents
Multicomponent immunogenic composition for the prevention of beta-hemolytic streptococcal (BHS) disease Download PDFInfo
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- Vascular Medicine (AREA)
Description
201022442 六、發明說明: 【發明所屬之技術領域】 本發明概言之係關於β-溶血性鏈球菌(BHS)多肽及多核 普酸,具體而言係關於釀腹鏈球菌 •多肽及多核苷酸,及其在預防BHS疾病之多組份免疫原性 '組合物中之用途。更具體而言,本發明係關於表面定位之 釀膿鏈球菌多肽。本發明另外係關於免疫原性組合物,及 針對β-溶血性鏈球菌感染實施免疫及降低該感染之方法, ® 該等組合物包含兩種或更多種多狀之組合。 【先前技術】 鏈球菌分類之傳統表型標準包括溶也反應及蘭斯菲爾德 (Lancefield)血清學分型二者。然而,隨著分類學的進展, 現已瞭解到,β-溶血性(定義為綿羊紅血球在瓊脂平板中 完全溶解)鏈球菌(BHS)之無關物種可產生相同蘭斯菲爾德 抗原,且在物種級上遺傳相關之菌株可具有異類蘭斯菲爾 德抗原。儘管傳統鏈球菌分類規則存在該等例外,但作為 魯 臨床分離株鑒定之第一步驟,仍可使用溶血反應及蘭斯菲 爾德血清學測試來將鏈球菌分為較寬類別。Ruoff, K.L. ' R.A. Whiley 及 D. Beighton. 1999 5 Streptococcus » P.R. Murray、E.J. Baron、M.A. Pfaller、F.C. Tenover、及 R.H. Yolken(編輯),Manual of Clinical Microbiology,American Society of Microbiology Press, Washington D.C. o 可將具有蘭斯菲爾德A型、C型或G型抗原之β-溶血性分 離株細分為兩種類型:大菌落(直徑>0.5 mm)及小菌落(直 144293.doc 201022442 徑<0.5 mm)形成株。形成大菌落之A型(釀膿鏈球菌)、c型 及G型菌株係「化膿性」鏈球菌,其具有多種有效毒力機 制。無乳鏈球菌(Sirepiococcws aga/aciiae)(B型)仍可藉由 其蘭斯菲爾德B型抗原的產生或其他表型性徵來可靠地繁 定。 各種BHS物種之間之相似性不僅包括毒力因子,且亦包 括疾病表現。疾病表現包括肺炎、關節炎、膿腫、鼻咽 炎、子宮炎、產後膿毒病、新生兒敗血病、傷口感染、腦 膜k、腹膜炎、蜂窩織炎、膿皮病' 壞死性筋膜炎、中毒 性休克症候群、敗血病、感染性心内膜炎、心包炎腎小 球腎炎、及骨髓炎。 釀膿鏈球菌係定殖在人類咽部及皮膚之革蘭氏(Gran^陽 性雙球菌,該等位點隨後可用作此生物體之主要庫。作為 專性寄生菌,此細菌可藉由呼吸道分泌物之直接接觸或藉 由手口方式來傳播。釀膿鏈球菌感染大部分係相對較輕之 疾病,例如咽炎或膿皰病。當前,僅在美國即有兩千萬至 三千五百萬例咽炎,花費約二十億$用於醫生出診及其他 相關費用。此外,釀膿鏈球菌感染可導致非化膿性後遺 症,例如風濕熱、猩紅熱、及腎小球腎炎。在世界上,急 性風濕熱(ARF)係兒童心臟病之最常見病因(1997.以代 definitions for Infectious Conditions Under Public Health Surveillance. CDC.)。 酿膿鏈球g可藉由初始人侵門戶咽及皮膚散佈至通常不 存在細菌之其他身體部分(例如血液 '深部肌肉及脂肪組 144293.doc 201022442 織或肺),且可引發侵入性感染。兩種最嚴重但最不常見 之侵入性釀膿鏈球菌疾病形式係壞死性筋膜炎及鏈球菌中 毒性休克症候群(STSS)。壞死性筋膜炎(媒體稱作「食肉 菌」)係對肌肉及脂肪組織之破壞性感染。STSS係快速進 '.展之感染,其可引發休克及諸如腎、肝及肺等内臟之損 ' 傷。此類損傷大多係因毒血症所致,而非因細菌生長導致 之局部損傷。 在1995年,侵入性釀膿鏈球菌感染及STSS成為強制通 ® 報之疾病。與數百萬患有咽炎及膿皰病之個體相比,美國 疾病控制與預防中心(U.S· Centers for Disease Control and Prevention) (CDC)強制之病例報告顯示,在1997年美國出 現15,000至20,000例侵入性釀膿鏈球菌疾病,導致超過 2,000例死亡(1997. Case definitions for Infectious Conditions
I
Under Public Health Surveillance. CDC.)。其他報導估計侵 入性疾病可高達10_20例/100,000個體/年(Stevens, D. L. • 1995. Streptococcal toxic-shock syndrome: spectrum of disease, pathogenesis, and new concepts in treatment. Emerg Infect Dis. 1:69-78)。更具體而言,在 15,000 至 ^ 20,000例侵入性疾病中,1,1〇〇至1,500例係壞死性筋膜炎 病例及1,000至1,400例係STSS病例,死亡率分別為20%及 * 60%。嚴重侵入性疾病亦包括肌炎病例,其死亡率為80% 至100% »另外10%至15%個體因其他形式之侵入性A型鏈 球菌疾病而死亡。該等數字自1995年開始病例報告後一直 增加,且反映過去十年或二十年出現的一般趨勢。此外, 144293.doc 201022442 一般認為病例定義之嚴格性導致較低數字及誤導數字,許 多病例在符合定義之前因早期診斷及治療而成功痊癒。 儘管釀膿鏈球菌仍對青黴素及其衍生物敏感,但治療不 一定能根除該生物體。儘管實施抗生素治療,有約5%至 20%人群為帶菌者,視季節而定(Stevens, D. L. 1995. Streptococcal toxic-shock syndrome: spectrum of disease, pathogenesis, and new concepts in treatment. Emerg Infect Dis. 1:69-78)。導致此情形之原因尚未完全明瞭且可能涉 及多種機制。在嚴重侵入性感染情形中,治療經常需要侵 入性外科手術介入。對於涉及STSS或相關疾病之病例,克 林黴素(clindamycin)(蛋白質合成抑制劑)係較佳抗生素, 因其可有效滲透組織且防止產生外毒素。有一些抗四環 素、磺胺類藥物(sulfa),及最近抗紅黴素之報導。顯然, 仍需要可預防並治療β-溶血性感染之組合物。 已鑒定出釀膿鏈球菌之多種毒力因子,某些係分泌因 子,某些係表面定位因子。儘管其已經囊封,但莢膜係由 透明質酸組成且不適合作為含於免疫原性組合物中之候選 抗原,此乃因其一般係由哺乳動物細胞來表現且係非免疫 原性(Dale,J. Β.、R. G. Washburn、Μ. B. Marques及 Μ. R. Wessels,1996,Hyaluronate capsule and surface M protein in resistance to opsonization of group A streptococci, Infect Immun. 64:1495-501)。T抗原及碳水化合物型抗原 係其他候選抗原,但亦可引發針對心臟組織之交叉反應性 抗體。脂磷壁酸存於釀膿鏈球菌表面上,但產生與LPS類 144293.doc 201022442 似之安全性問題。 豐度最高之表面蛋白因其結構類似性而歸為稱作Μ或 「Μ樣」蛋白之蛋白質家族。儘管此類別之成員具有抑制 吞噬作用之相似生物學作用,但其各自具有獨特的受質結 ^ 合特性。此家族中表徵最充分之蛋白為螺旋狀Μ蛋白。已
'顯示針對同源Μ菌株之抗體可具有調理性及保護性(Dale, J. Β·、R. W. Baird、H. S. Courtney、D. L. Hasty、及M. S. Bronze. 1994,Passive protection of mice against group A 修 streptococcal pharyngeal infection by lipoteichoic acid,J
Infect Dis. 169:319-23 ; Dale, J. B. ' M. Simmons ' E. C. Chiang、及 E. Y. Chiang. 1996,Recombinant ; Ellen,R. P. 及 R. J. Gibbons. 1972,M protein-associated adherence of Streptococcus pyogenes to epithelial surfaces: prerequisite for virulence,Infect Immun. 5:826-830)。使M蛋白作為候 選抗原之應用變複雜的係以下事實:已鑒定出約100種不 同Μ蛋白血清型,且有更多種尚未分類。通常,I類Μ血清 Φ 型(例示為血清型]^1、厘3、!^6、;\112及1418)與咽炎、猩 紅熱、及風濕熱有關且不表現免疫球蛋白結合蛋白。Π類 Μ血清型(例如M2及Μ49)與更多常見局部皮膚感染及後遺 症腎小球腎炎有關,且不表現免疫球蛋白結合蛋白 % (Podbielski, A.、A. Flosdorff及 J. Weber-Heynemann. 1995,
The group A streptococcal virR49 gene controls expression of four structural vir regulon genes,Infect Immun. 63:9-20)。重要的是應注意,針對M血清型之抗體存在少量(若 144293.doc 201022442 存在)異源交叉反應性。同樣重要的是該等抗體在風濕熱 中所具有之作用。Μ蛋白之特定區域引發可與宿主心臟組 織交叉反應之抗體,從而引發細胞損傷或至少與細胞損傷 相關(Cunningham, Μ. W.及 A. Quinn. 1997,Immunological crossreactivity between the class I epitope of streptococcal M protein and myosin 5 Adv Exp Med Biol. 418:887-921 ; Quinn, A.、K. Ward、V. A. Fischetti、M· Hemric及 M. W· Cunningham. 1998,Immunological relationship between the class I epitope of streptococcal M protein and myosin, Infect Immun. 66:4418-24.) o M及M樣蛋白屬於藉由分選酶靶向LPXTG基序定義之大 型表面定位蛋白家族(Mazmanian,S. K.、G. Liu、Η. Ton-That及 O. Schneewind. 1999,Staphylococcus aureus sortase, an enzyme that anchors surface proteins to the cell wall., Science. 285:760-3 ; Ton-That,H.、G. Liu、S. K. Mazmanian、K. F. Faull 及 O. Schneewind. 1999 >
Purification and characterization of sortase, the transpeptidase that cleaves surface proteins of Staphylococcus aureus at the LPXTG motif,Proc Natl Acad Sci U S A. 96:12424-12429)。此基序位於蛋白質之羧基末端附近,其首先在 LPXTG基序之蘇胺酸與甘胺酸殘基之間經分選酶裂解。一 旦裂解,蛋白質經由蘇胺酸之羧基共價連接至肽聚糖中胺 基酸橫橋之游離醯胺基團上,由此使蛋白質永久性地連接 至細菌細胞表面上。此分選酶靶向蛋白質家族中包括C5 a 144293.doc 201022442
肽酶(Chen, C. C·及 P. P. Cleary. 1989,Cloning and expression of the streptococcal C5a peptidase gene in Escherichia coli: linkage to the type 12 M protein gene, Infect. Immun· 57:1740-1745 ; Chmouryguina, I.、A. Suvorov、P. Ferrieri及 P. P. Cleary. 1996,Conservation of the C5a peptidase genes in group A and B streptococci, Infect. Immun. 64:2387-2390)、纖連蛋白黏附素(Courtney, H. S.、Y. Li、J· B. Dale及 D. L. Hasty. 1994,Cloning, sequencing, and expression of a fibronectin/fibrinogen-binding protein from group A streptococci,Infect Immun. 62:3937-46 ; Fogg,G. C·及M. G. Caparon. 1997,Constitutive expression of fibronectin binding in Streptococcus pyogenes as a result of anaerobic activation of rofA,J Bacteriol. 179:6172-80 ; Hanski, E.及 M. Caparon. 1992, Protein F, a fibronectin-binding protein, is an adhesion of the group A streptococcus Streptococcus pyogenes,Proc Natl Acad Sci·,USA. 89:6172-76 ; Hanski,E.、P. A. Horwitz 及 M. G. Caparon. 1992,Expression of protein F, the fibronectin-binding protein of Streptococcus pyogenes JRS4, in heterologous streptococcal and enterococcal strains promotes their adherence to respiratory epithelial cells,Infect Immun. 60:5119-5125)、玻連蛋白、及 IV 型膠 原、及其他結合纖溶酶原之Μ樣蛋白、IgA、IgG、及白蛋 白(Kihlberg,Β· Μ·、M. Collin、A. Olsen、及 L. Bjorck. 144293.doc 201022442 1999,Protein H, an antiphagocytic surface protein in Streptococcus pyogenes > Infect Immun. 67:1708-14) o 已闡述多種分泌蛋白,其中若干種被視為毒素。大多數 釀膿鏈球菌分離物來自嚴重侵入性疾病及鏈球菌中毒性休 克症候群(STSS)病例之產生鏈球菌化膿性外毒素(SPE) A ' 及C(Cockerill,F· R.三世、R. L. Thompson、J. M. Musser、 · P, M. Schlievert、J. Talbot、Κ· E. Holley、W. S· Harmsen ' D. M. Ilstrup ' P. C. Kohner ' Μ. H. Kim ' B. Frankfort ' J. M. Manahan ' J. M. Steckelberg ' F. ^
Roberson 及 W. R. Wilson. 1998 » Molecular, serological, and clinical features of 16 consecutive cases of invasive streptococcal disease. Southeastern Minnesota Streptococcal Working Group,Clin Infect Dis. 26:1448-58)。亦已在基 因組釀膿鏈球菌序列(在俄克拉荷馬大學(University of Oklahoma)完成,提交至GenBank並分配到登錄號AE004092) 中鑒定出其他化膿性外毒素且已經表徵(Proft,T.、S.
Louise Moffatt、C. J. Berkahn 及 J. D. Fraser. 1999,
Identification and Characterization of Novel Superantigens from Streptococcus pyogenes,J Exp Med. 189:89-102)。諸 如中毒性休克樣症候群毒素、鏈球菌超抗原(Reda,K. B.、 V. Kapur、D. Goela、J. G. Lamphear、J. M. Musser及 R. R. Rich. 1996,Phylogenetic distribution of streptococcal superantigen SSA allelic variants provides evidence for horizontal transfer of ssa within Streptococcus pyogenes > 144293.doc -10- 201022442
Infect Immun. 64:1161-5)、及促有絲分裂因子(Yutsudo, Τ·、K. Okumura、M. Iwasaki、A. Hara、S· Kamitani、W. Minamide、H. Igarashi 及 Y. Hinuma. 1994,The gene encoding a new mitogenic factor in a Streptococcus pyogenes strain is distributed only in group A streptococci. Infection and Immunity. 62:4000-4004)等其他毒素在疾病 中之作用尚不確定。鏈球菌溶血素O亦可視為可能的候選 抗原,此乃因其可引發IL-β之釋放。此外,亦已鑒定出多 種分泌酶,包括半胱胺酸蛋白酶(1^11]<;〇11131<;丨,8.、(3.八· Montgomery、J. Rurangirwa、R. S. Geske、J. P. Barrish、 G. J. Adams及 J. M. Musser. 1999,Extracellular cysteine protease produced by Streptococcus pyogenes participates in the pathogenesis of invasive skin infection and dissemination in mice , Infect Immun. 67:1779-88 ; Matsuka,Y. V.、S. Pillai、S. Gubba、J. M. Musser及 S. B. Olmsted. 1999,Fibrinogen cleavage by the Streptococcus pyogenes extracellular cysteine protease and generation of antibodies that inhibit enzyme proteolytic activity,Infect Immun. 67:4326-33)、鍵激酶(Huang, T. T.、H. Malke 及 J. J. Ferretti. 1989,The streptokinase gene of group A streptococci: cloning, expression in Escherichia coli, and sequence analysis,Mol Microbiol. 3:197-205 ; Nordstrand, A.、W. M. McShan、J. J. Ferretti、S. E. Holm 及 Norgren. 2000,Allele substitution of the streptokinase gene 144293.doc -11 - 201022442 reduces the nephritogenic capacity of group A streptococcal strain NZ131,Infect Immun. 68:1019-25)及透明質酸酶 (Hynes, W. L.、A. R. Dixon、S. L. Walton及L. J. Aridgides· 2000,The extracellular hyaluronidase gene (hylA) of Streptococcus pyogenes > FEMS Microbiol Lett. 184:109-12 ; Hynes, W. L. > L. Hancock及 J. J. Ferretti. 1995, Analysis of a second bacteriophage hyaluronidase gene from Streptococcus pyogenes: evidence for a third hyaluronidase involved in extracellular enzymatic activity,Infect Immun. 63:3015-20) ° 考慮到釀膿鏈球菌所產生已知毒力因子之數量,可瞭解 到成功β-溶血性鏈球菌免疫原性組合物之重要特徵應為其 在感染過程早期刺激可預防或限制定殖之應答之能力。此 保護性應答可阻斷黏附及/或增強細胞經由調理吞噬作用 之清除。已顯示針對Μ蛋白質之抗體具有調理性且可提供 克服蛋白質抗呑噬特性之機制(Jones,K. F.及V. Α· Fischetti. 1988 » The importance of the location of antibody binding on the M6 protein for opsonization and phagocytosis of group A M6 streptococci,J Exp Med. 167:1 114-23),其 方式非常類似於抗血清型B莢膜抗體所顯示抵抗由流感嗜 血菌(i/aewop/n’/MS B所引發疾病之方式(Madore, D. V. 1998,Characterization of immune response as an indicator of Haemophilus influenzae type b vaccine efficacy,Pediatr Infect Dis J. 17:S207-10)。此外,已顯示 144293.doc -12- 201022442 蛋白F特異性抗體可阻斷組織培養細胞之黏附及内化 (Molinari, G. ' S. R. Talay ' P. Valentin-Weigand ' M. Rohde 及 G. S. Chhatwal. 1997,The fibronectin-binding protein of Streptococcus pyogenes, Sfbl, is involved in the internalization of group A streptococci by epithelial cells > Infect Immun. 65:1357-63) ° 業内仍需要研發可預防或改善由β-溶血性鏈球菌(包括A 型、B型、C型及G型)所引發感染之免疫原性組合物及方 法。業内亦需要提供可針對眾多種BHS細菌提供免疫之免 疫原性組合物。 【發明内容】 為滿足該等及其他需要,且鑒於本發明之目的,本發明 提供防止易感哺乳動物發生包括A型、B型、C型及/或D型 鏈球菌(包括彼等來自釀膿鏈球菌者)在内之β-溶血性鏈球 菌定技或感染之免疫原性組合物。該等免疫原性組合物包 含兩種或更多種多肽之混合物,下文更詳細地闡述該等多 肽。本發明亦提供藉由在易感哺乳動物中投與有效量之免 疫原性組合物以產生針對該免疫原性組合物内所含特定多 肽之抗體來預防或改善該定殖之方法。本發明另外提供釀 膿鏈球菌多肽及多核苷酸、重組體材料、及其製造方法。 本發明另一態樣係關於使用該等釀膿鏈球菌多肽及多核苷 酸之方法。亦可使用該等多肽及多核苷酸來製造預防或改 善β-溶血性鏈球菌所引發感染之藥物。 本發明免疫原性組合物中所用多肽包括經分離多肽,其 144293.doc -13· 201022442 包含圖2、4、6、8或1()中任—者之至少—種胺基酸序列。 本發明亦包括與上述胺基酸序列中任一者具有至少9〇%一 致性之胺基酸序列,及該等序狀錢多肽。本發明另外 包括該等多肽之免疫原性片段及生㈣效物。亦提供與本 發明多肽免疫特異性結合之抗體。 本發明多核苷酸包括經分離多核苷酸,其包含編碼本發 明多肽之核苷酸序列。該等多核苷酸包括包含圖i'3、 5、7或9任一者中至少一種核苷酸序列之經分離多核苷 酸,且亦包括因遺傳密碼簡並性亦編碼本發明多肽之其他 核苷酸序列。本發明亦包括包含與編碼本發明多肽之核普 酸序列具有至少90°/。一致性之核苷酸序列的經分離多核普 酸’及包含與任一上述核苷酸序列具有至少9〇%一致性之 核苷酸序列的經分離多核苷酸《此外,本發明經分離多核 苷酸包括在嚴格雜交條件下與編碼本發明多肽之核苷酸序 列雜交之核苷酸序列、在嚴格雜交條件下與具有任一上述 序列之核苷酸序列雜交之核苷酸序列、及與該等多核苷酸 完全互補之核苷酸序列。此外,本發明包括包含該等多核 苷酸之表現載體及宿主細胞。 本發明亦提供免疫原性組合物,其包含免疫原性量之至 少兩種或更多種選自以下之組份:SCP(圖2 (SEQ ID NO:2))及由ORF 554編碼之肽(肽基丙基異構酶(圖4 (SEQ ID NO:4))、ORF 1218(假定蛋白(圖 6 (SEQ ID NO:6))、 ORF 1358(推定黏附蛋白(圖 8 (SEQ ID NO:8))、及 ORF 2459(表面脂蛋白(圖10 (SEQ ID NO: 10)),其各自以可在 144293.doc 14 201022442 易感哺乳動物巾有效肋或改善p_溶血性鏈球^ 染之量包含本發明多肽。各組份可包含多肽 或感 含多肽及任何其他可幫助驗及/或改善β_溶血性^可, 殖或感染之物質(例如一或多種化學試劑、蛋白質等)菌: :免=性組合物可另外包含至少一部分視需要與肽: 肽或蛋白質、或多糖偶合或連接之多肽。
本發明亦包括防止易感哺乳祕發終溶血性鏈球菌定 殖或感染之方法。在-實施例中,該方法包含向哺乳動物 投與有效量之兩種或更多種免疫原性組合物,其包含免疫 原性量之本發明多肽,該量可在易感哺乳動物中有效預防 或改善β-溶血性鏈球菌定殖或感染。人們已發現,各組份 之該等組合可向眾多動物種類有效提供該保護,且其所提 供免疫應答一般大於分開投與單獨組份之情形。可藉由任 何習用途徑來投與本發明免疫原性組合物,例如皮下或肌 内注射、經口攝取、或鼻内。 本發明另外提供免疫原性組合物。在一實施例中,該免 疫原性組合物包含至少一種本發明多肽。在另一實施例 中’免疫原性組合物包含至少一種本發明多核苷酸。 應瞭解’上文一般說明及下文詳細說明二者僅為例示 性,而非限制本發明。 【實施方式】 本發明提供免疫原性組合物來預防或改善由β·溶血性鏈 球菌(包括Α型、Β型、C型及G型)引發之感染。將本文所 列舉之兩種或更多種多肽組合在一起以製備免疫原性組合 144293.doc •15- 201022442 物。 具體而言,在一實施例中,本發明免疫原性組合物包含 兩種或更多種多肽之混合物,編碼各多肽之核酸序列與選 自由以下組成之群之核酸序列具有至少90%之一致性: (a) C5a 肽酶(「SCP」)(圖 1 (SEQ ID ΝΟ:1)); (b) 開放閱讀框(「ORF」)554(圖 3 (SEQ ID NO:3)); (c) ORF 1218(圖 5 (SEQ ID N0:5)); (d) ORF 1358(圖 7 (SEQ ID N0:7));及 (e) ORF 2459(圖 9 (SEQ ID ΝΟ··9))。 在另一實施例中,本發明免疫原性組合物包含兩種或更 多種多肽之混合物,各多肽與選自由以下組成之群之胺基 酸序列具有至少90%之一致性: (a) SCP(圖 2 (SEQ ID NO:2)); (b) 肽基丙基異構酶(圖4(SEQIDNO:4)); (c) 假定蛋白(圖 6(SEQIDNO:6)); (d) 推定黏附蛋白(圖8 (SEQ ID NO:8));及 (e) 表面脂蛋白(圖 10(SEQIDNO:10))。 在又一實施例中,本發明免疫原性組合物包含以下之混 合物: (a) SCP多肽,其係由與圖1核酸序列(SEQ ID ΝΟ:1)具 有至少90%—致性之核酸序列編碼; (b) 肽基丙基異構酶多肽,其係由與圖3核酸序列(SEQ ID NO:3)具有至少90%—致性之核酸序列編碼;及 (c) 至少一種其他多肽,其係由與選自由以下組成之群 144293.doc -16- 201022442 之核酸序列具有至少90% —致性之核酸序列編碼:(i)圖5 (SEQ ID NO:5) ; (ii)圖 7 (SEQ ID NO:7);及(iii)圖 9 (SEQ ID NO:9)。 在另一實施例中,本發明免疫原性組合物包含以下之混 合物: (a) SCP多肽,其與圖2胺基酸序列(SEQ ID NO:2)具有 至少90%—致性; (b) 肽基丙基異構酶多肽,其與圖4胺基酸序列(SEQ ID ΝΟ·_4)具有至少90%—致性;及 (c) 至少一種其他多肽,其與由以下組成之群之胺基酸 序列具有至少90%之一致性:⑴圖6 (SEQ ID NO:6) ; (ii) 圖 8 (SEQ ID NO:8);及(iii)圖 10 (SEQ ID NO:10)。 術語「多核苷酸」、「核酸」及「核酸片段」在本文中 可互換使用。該等術語涵蓋由磷酸二酯鍵連接之核苷酸。 「多核苷酸」可為單鏈或雙鏈核糖核酸(RNA)或脫氧核糖 核酸(DNA)聚合物,其視需要含有合成、非天然或經改變 核苷酸鹼基。呈DNA聚合物形式之多核苷酸可包含一或多 個cDNA、基因組DNA、合成DNA、或其混合物之區段。 在本文中藉由單字母密碼來表示核苷酸鹼基:腺嘌呤 (A)、鳥嘌呤(G)、胸腺嘧啶(T)、胞嘧啶(C)、肌苷(I)及尿 鳴咬(U)。 本文所述鏈球菌多核苷酸可使用標準選殖及篩選技術來 獲得。該等多核苷酸可自(例如)基因組DNA、得自mRNA 之cDNA庫、基因組DNA庫來獲得,或可使用熟知及市售 144293.doc 17 201022442 技術來合成,例如藉由PCR自cDNA庫獲得或經由RT-PCR(反轉錄-聚合酶鏈式反應)來獲得。 有若干種熟習此項技術者可獲得且熟知之方法來獲得全 長cDNA或延伸短cDNA,例如彼等基於快速擴增cDNA末 端(RACE)者。參見 Frohman 等人,Proc. Natl. Acad. Sci. USA 85, 8998-9002,1988。例如,該技術之最新修改形式 例示為 MARATHONTM 技術(Clontech Laboratories 公司), 其顯著簡化了針對較長cDNA之搜索。在 術中’ cDNA可自提取自選定組織之mRNA來獲得且在每一 末端連接有「接頭」序列。然後實施核酸擴增(PCR)以使 用基因特異性及接頭特異性寡核苷酸引物來擴增cDNA之 「缺失」5’末端。然後使用「巢式」引物重複實施Pcr反 應’亦即使用設計為在擴增產物内複性之引物(通常為接 頭特異性引物’其在接頭序列中之遠端3,處複性;及基因 特異性引物’其在已知基因序列中之遠端5,處複性)。然後 藉由DNA測序來分析此反應之產物,且藉由將產物直接連 接至已有cDNA以產生完整序列,或藉由使用設計5,引物之 新序列資訊實施單獨全長PCR來構建全長cDNA。 術語「重組體」意指(例如)藉由人工組合兩種或更多種 原本分離之多核苷酸區段來製備多核苷酸,例如藉由化學 合成或藉由使用遣傳工程技術處理經分離多核苷酸來組 合。「重組體DNA構成物」包含與至少一種調控元件可操 作連接之任一本發明經分離多核苷酸。 鏈球菌多核苷酸之直系同源體及等位變體可使用業内熟 144293.doc -18· 201022442 知之方法容易地鑒定。多核苷酸之等位變體及直系同源體 可包含通常與圖1_9中奇數號圖所示任何一或多種核苷酸 序列(SEQ ID NO./S 1-9中之奇數號序列)或其片段具有至 少約90-95°/。或更高一致性之核苷酸序列。該等多核苷酸之 等位變體及直系同源體可編碼包含與圖2-10中偶數號圖之 任何一或多者所示胺基酸序列(SEQ ID NO:,S 2-10中之偶 數號序列)具有至少90%—致性之胺基酸序列的多肽。該等 多核苷酸因其能在嚴格條件下與任何一或多種具有圖1-9 中所示核苷酸序列(SEQ ID NO:,S 1-9中之奇數號序列)或 其片段之多核苷酸雜交而可容易地鑒定。 熟習此項技術者充分理解,多種程度之序列一致性可用 於鑒定相關多核苷酸及多肽序列。序列比對及一致性百分 比計算可使用LASERGENE™生物信息學計算程式組 (DNASTAR公司,Madison,Wis.)中之 MEGALIGN™程式來 實施。序列之多重比對可使用Clustal比對方法(Higgins and Sharp, Gene,73(1):237-44, 1988)以默認參數(例如 GAP PENALTY=10 且 GAP LENGTH PENALTY=10)來實施。使 用Clustal方法實施成對比對之默認參數可為(例如) KTUPLE 1,GAP PENALTY=3,WINDOW=5且DIAGONALS SAVED=5。 本發明多肽序列可與所述序列一致,亦即100% 一致, 或其可相對於參照序列包括最多某一整數之胺基酸改變, 從而使得一致性%低於1 〇〇%。該等改變包括至少一個胺基 酸缺失、取代(包括保守性及非保守性取代)或插入。改變 144293.doc -19- 201022442 可發生在參照多肽序列之胺基-或羧基末端位置或介於彼 等末端位置之間之任何位置,其單獨散佈於參照胺基酸序 列中各胺基酸之間或以一或多個鄰接組散佈於參照胺基酸 序列内。 因此,本發明亦提供與所述序列中所含胺基酸序列具有 序列一致性之經分離多肽。端視具體序列,序列一致度較 - 佳大於90%(例如90%、95%、97%、99%或更高)。該等同 源蛋白包括突變體及等位變體。 業内所知「一致性」係兩種或更多種多肽序列或兩種或 ® 更多種多核苷酸序列之間之關係,其係藉由比較該等序列 來確定。在業内,「一致性」亦意指多肽或多核苷酸序列 之間之序列相關度,根據具體情況,其可藉由該等序列各 鏈之間之匹配來確定。「一致性」.及「相似性」可藉由已 知方法容易地計算,該等已知方法包括(但不限於)彼等闡 述於以下文獻中者:Computational Molecular Biology,
Lesk,A. Μ.編輯,Oxford University Press,New York, ❹ 1988 ; Biocomputing: Informatics and Genome Projects,
Smith, D. W.編輯,Academic Press, New York,1993 ; Computer Analysis of Sequence Data,第 I部分,Griffin, A. M.及 Griffin, H. G.編輯,Humana Press,New Jersey,
1994 ; Sequence Analysis in Molecular Biology, von Heinje,G.,Academic Press,1987 ;及 Sequence Analysis Primer,Gribskov, M.及 Devereux,J.編輯,M Stockton Press, New York, 1991 ;及 Carillo,H.及 Lipman,D., SIAM 144293.doc -20- 201022442 J. Applied Math·,48: 1073 (1988)。確定一致性之較佳方法 設計為可給出所測試序列之間之最大匹配。確定一致性及 相似性之方法編籑於可公開獲得之電腦程式中。確定兩種 序列之間之一致性及相似性之較佳電腦程式方法包括(但 不限於)GCG程式包(Devereux, J.等人,1984)、BLASTP、 BLASTN及 FASTA(Altschul,S. F·,等人,1990)。BLASTX 程式可自NCBI及其他資源公開獲得(BLAST Manual, Altschul,S.等人,NCBI NLM NIH Bethesda,Md· 20894; Altschul,S·等人,1990)。亦可使用熟知 Smith-Waterman演 算法來確定一致性。 舉例而言,可藉由以下確定所示一致性%之胺基酸改變 之數目:將圖2-10中偶數圖(8丑(^1〇>^〇:'8 2、4、6、8及 10)之一的胺基酸總數乘以各別一致性百分比之數字百分 比(除以100),隨後自該圖2-1〇中偶數圖(SEQ.ID NO:'S 2、
4、6、8及10)之一的胺基酸總數減去該乘積’或: na < xfl-(xfl*y) J 其中nfl係胺基酸改變之數目’ χα係圖2_10中偶數圖(SEQ ID NO./S 2、4、6、8及1〇)之一之胺基酸總數’ y係例如0.90 (90%)、0.95 (95%)、〇·97 (97%)等’其中將χα 與 y 之任何非 整數乘積四捨五入為最接近之整數’之後自Xfl減去。 本發明亦涵蓋在各卜溶企性鏈球菌產株中基本上保守之 分離之多狀。此外’本發明亦涵蓋在各β -溶血性鍵球菌菌 株中基本上保守立可有效預防或改善β_溶企性鏈球菌在易 感個體中定殖或感染之分離之多肽。本文所用術語「保 144293.doc -21 - 201022442 守」係指例如未發生插入、取代及/或缺失之胺基酸數, 以蛋白質中胺基酸總數之百分比表示。舉例而言,若蛋白 質為90°/。保守且具有例如263個胺基酸,則在蛋白質中有 237個胺基酸位置之胺基酸未發生取代。同樣,若蛋白質 為95%保守且具有例如約28〇個胺基酸,則有抖個胺基酸 位置之胺基酸可能發生取代且有266(即280減14)個胺基酸 位置之胺基酸未發生取代。根據本發明一個實施例,分離 之多肽在各β-溶血性鏈球菌菌株中較佳為至少約9〇0/〇保 守’在各菌株中更佳為至少約95%保守,在各菌株中甚至 更佳為至少約97%保守,且在各菌株中最佳為至少約99% 保守,並不限於此。 各種修飾及改變可在多肽結構中實施且仍可獲得具有卜 溶血性鏈球菌及/或釀膿鏈球菌活性及/或抗原性之多肽。 舉例而言,可用某些胺基酸取代序列中之其他胺基酸而不 顯著損失活性及/或抗原性。由於多肽之交互作用能力及 性質決定該多肽之生物功能活性,故可在多肽序列(當 然,或其基礎DNA編碼序列)中實施某些胺基酸序列取 代,而仍獲得具有類似特性之多肽。 本發明包括任何經分離多肽,其可提供本文所述期望反 應性之生物等效物。術語「期望反應性」係指可由熟習此 項技術者制為可用於本發明目的之結果的反應性。期望 本文中’包括(但不限於)期望保護程 度、期望抗體效冑、期望調理吞嗟活性及/或期望交叉反 應性,例如可由熟習此項技術者識別為可用於本發明目的 144293.doc -22- 201022442 者。期望調理吞嗟活性表示為細菌之殺滅百分比,其係藉 由OPA中菌洛形成單元(CFU)相對於陰性對照之降低來量 測不又限於此,期望調理吞嗔活性較佳為至少約, 1佳為至少約鳩’甚至更佳為至少物% 為 至少約篇,且最佳為至少約 本發月包括多肽,其係包含圖2_10中偶數號圖(SEQ m s 4 6、8及10)之胺基酸序列之多肽的變體。本文 φ π用術#變體」包括不同於參照多肽但保留基本特性之 夕肽 般而s,差異有限,從而使得參照多肽與變體之 序列總體上非常相似且在多個區域中一致(即生物上等 效)。變體與參照多肽在胺基酸序列上之差異可在於一或 =個呈任一組合之取代、添加、缺失。經取代或插入胺基 酸殘基可為或不為由遺傳密碼編碼多1變體可為天然 存在變體,例如等位基因變體,或其可為已知非天然存在 之變體。非天然存在之多肽變體可藉由直接合成或藉由誘 Φ 變技術來製備。 在實施該等改變時,可考慮胺基酸之親水性指數。親水 性胺基酸指數在賦予多肽以交互作用生物功能中之重要性 • 為業内眾所周知(Kyte & Doolittle, 1982)。已知可用某些 胺基酸取代具有類似親水性指數或分數之其他胺基酸,且 仍然獲得具有相似生物活性之多肽。已根據每一胺基酸之 疏水性及電荷特徵分配給其一親水性指數。彼等指數如下 所述列於每一胺基酸後之括號中:異白胺酸(+4 5);纈氨 酸(+4.2);白胺酸(+38);苯丙胺酸(+28);半胱胺酸/半胱 144293.doc -23- 201022442 胺酸(+2·5) ; f硫胺酸(+1.9);丙胺酸(+1·8);甘胺酸 HM);.蘇胺酸(-〇·7);絲胺酸(_〇.8);色胺酸(_〇.9);酿胺 酸(-1.3);脯氨酸(].6);乡且胺酸(_32);賴酸鹽(_35); 楚胺醯胺(3.5) ’天冬胺酸鹽(_35);天冬酿胺(_35);離胺 酸(-3.9);及精胺酸(_4 5)。 據信胺基酸之相龍水丨轉徵決定了所得多肽之二級及 三級結構’此繼而決定了該多肽與其他分子(例如,酶、 丈質、党體、抗體、抗原及諸如此類)之交互作用。業内 已知可藉由一胺基酸來取代具有類似親水性指數之另一 胺基酸且仍獲得功能上等效之多肽。在該等改變中,親水 性指數在+/-2以内之胺基酸取代較佳’彼等在+/-1以内之 胺基酸取代尤佳’ 彼等在+/_G5以内之胺基酸取代甚至 更佳。 亦可根據親水性來實施相似胺基酸之取代,尤其在意欲 將由此產生之生物功能等效多狀或肽用於免疫學方案中 時。美國專利第4,554,101號(以引用方式併入本文中)闡述 多肽受其相鄰胺基酸親水性控制之最大局部平均親水性與 其免疫原性及抗原性相關’即與多肽之生物學特性相關。 如美國專利第4,554,1 01號(以引用方式併入本文中)中所 詳述’已將以下親水性數值分配給各胺基酸殘基:精胺酸 (+3.0);離胺酸(+3.0);天冬胺酸鹽(+3.0±1);麵胺酸鹽 (+3.0±1);絲胺酸(+0.3);天冬醯胺(+〇·2);麩胺醯胺 (+0.2);甘胺酸(〇);脯胺酸(-0.5土1);蘇胺酸(_0.4);丙胺 酸(-0.5);組胺酸(-0.5);半胱胺酸(-1.0); f硫胺酸 144293.doc •24- 201022442 纈胺酸(-1.5);白胺酸(-1.8);異白胺酸(-1.8);酪胺酸(-2.3) ;苯丙胺酸(-2.5);及色胺酸(-3.4)。應理解,可用一胺基 酸取代具有類似親水性數值之另一胺基酸且仍獲得生物等 效且具體而言免疫等效之多肽。在該等改變中,親水性數 值在土 2以内之胺基酸取代較隹,彼等在±1以内之胺基酸取 代尤佳,且彼等在±0.5以内之胺基酸取代甚至更佳。 如上所述,因此胺基酸取代通常係基於胺基酸側鏈取代 基之相對相似性,例如其疏水性、親水性、電荷、大小及 諸如此類。慮及上述各種特徵之實例性取代為熟習此項技 術者所熟知且包括:精胺酸與離胺酸;麩胺酸鹽與天冬胺 酸鹽;絲胺酸與蘇胺酸;麩胺醯胺與天冬醯胺;及纈胺 酸、白胺酸與異白胺酸。如下表I所示,適宜胺基酸取代 包括以下取代: 表1 :
初始殘基 實例性殘基取代 Ala Gly ; Ser Arg Lys Asn Gin ; His Asp Glu Cys Ser Gin Asn Glu Asp Gly Ala His Asn ; Gin lie Leu ; Val Leu lie ; Val Lys Arg Met Met ; Leu ; Tyr Ser Thr 144293.doc -25- 201022442
Thr Ser Trp Tyr Tyr Trp ; Phe Val lie ; Leu 因此,本發明包括具有圖2-10中偶數號圖(SEQ ID NO:,S 2、4、6、8及10)之序列之多肽之功能或生物等效物,其 含有一或多個胺基酸取代。 多肽之生物或功能等效物亦可使用位點特異性誘變來製 備。位點特異性誘變係可用於經由對基礎DNA之特異性誘 變來製備第二代多肽或衍生自其序列之生物、功能等效多 肽之技術。如上所述,倘若期望胺基酸取代則可期望該等 改變。該技術另外能藉由(例如)將一或多個核苦酸序列改 變引入DNA中容易地製備並測試序列變體,同時慮及一或 多個上述因素。位點特異性誘變使得可經由使用編碼具有 期望突變以及足量相鄰核苷酸之DNA序列之特異性募核苦 酸序列產生突變體,以提供具有足夠大小及序列複雜性之 引物序列’從而在交叉缺失交界兩側皆形成穩定雙鏈。通 常,長度為約17至25個核苷酸之引物較佳,其中在經改變 序列交界處兩側有約5至1 〇個殘基。 一般而言’位點特異性誘變技術為業内所熟知。應瞭 解,該技術通常採用可以單鏈及雙鏈形式存在之噬菌體載 體。通常,藉由以下方式來實施本發明定點誘變:首先獲 付單鏈載體,其在其序列内包括編碼所選釀膿鏈球菌多肽 序列之全部或一部分之DNA序列。具有期望突變序列之寡 核苷酸引物係藉由(例如)熟知技術(例如合成方式)來製 144293.doc 201022442 備。然後使此引物與單鏈載體複性且藉由使用酶(例如大 腸桿菌(五.π/纟)聚合酶I Klen〇w片段)進行延伸以完成具突 變鍵之合成。由此形成異源雙鏈’其中一鏈編碼初始無突 變序列’且第二鍵具有期望突變。然後使用此異源雙鏈載 體來轉化適宜細胞’例如大腸桿菌細胞,且選擇包括具有 突變之重組體載體之純系。市售套組提供所需試劑。 本發明多肽及多肽抗原應理解為包括任何多肽,其與包 含圖2-10中偶數號圖(SEQ ID N0:,S 2、4、6、8及10)之任 一者之胺基酸序列的多肽具有顯著序列相似性、結構相似 性及/或功能相似性。此外,本發明多肽或多肽抗原不受 限於特定來源。因此,本發明提供多種來源之一般性多肽 檢測及分離。 本發明多肽可呈「成熟」蛋白質形式或可為諸如融合蛋 白等較大蛋白之一部分。其經常有利地包括另一胺基酸序 列,其含有(例如)分泌或引導序列、前導序列、辅助純化 之序列(例如多組胺酸殘基)、或用於在重組體產生期間保 持穩定之另一序列。 本文所用術語「免疫原性組合物」係指呈可投與形式之 任一類型的生物試劑,該免疫原性組合物能在經其接種之 個體中刺激免疫應答。免疫應答可包括抗體之誘導及/或τ 細胞應答之誘導。在本文中結合免疫原性組合物使用時, 術扣保護」係指改善(部分或完全)與所述疾病或病況相 關之任症狀。因此,藉由本發明免疫原性組合物保護個 體免受鏈球菌屬物種(例如缺乳鏈球菌(&办(包 144293.doc -27- 201022442 括缺乳鍵球菌及似馬鍵球菌(五分亞 種))感染一般導致細菌生長降低及/或一或多種與鏈球菌感 染相關之臨床症狀減小,包括關節炎、心内膜炎、腦膜 炎、多漿膜炎、支氣管肺炎、腦膜炎、永久性聽力損失及 膿毒性休克。 本文所揭示方法可包括誘導針對一或多種病原體之免疫 應答’該等病原體包括鏈球菌屬物種(例如缺乳鏈球菌、 缺乳鏈球菌似馬鏈球菌亞種、缺乳鏈球菌缺乳鍵球菌亞 種、壞腹鍵球菌、無乳鍵球菌、咽峽炎鍵球菌(j ^ awgkosws)、星座鍵球菌(& 、似馬鏈球菌及 中鏈球菌(& 。舉例而言,該方法可包括誘 導針對一或多種鏈球菌病原體(例如缺乳鏈球菌似馬鏈球 菌亞種)之多株抗體產生。 如上所述免疫原性組合物包含兩種或更多種本發明多 肽。為達成此目的,將一或多種多肽調節至適宜濃度,且 可使用任何適宜佐劑、稀釋劑、醫藥上可接受之載劑、或 其組合加以調配。本文所用詞組「醫藥上可接受之載劑」 ❿ 意欲包括適合醫藥投與之任何及所有溶劑、分散介質、塗 料、抗細菌及抗真菌藥劑、等滲劑及吸收延遲藥劑及類似 物。該等用於醫藥活性物質之介質及藥劑的應用為業内所· 熟知。可使用±理上可接受之媒劑作為載劑及/或稀釋 劑。醫藥上可接受之媒劑應理解為指定引入醫藥組合物或 免疫原性組合物中之化合物或化合物組合,其不引發副作 用且其使得可(例如)促進活性化合物之投與,延長活性化 144293.doc -28- 201022442 合物在體内之壽命及/或其在體内之效能,增強活性化合 在合液中之☆解度或増強其防腐性。該等醫藥上可接受 之媒劑為熟f此項技術者所熟知,且可由熟習此項技術者 根據所選活性化合物之性質及投與模式加以調整。該等媒 劑包括(但不限於)水、林格氏溶液(Ringer,"—)、適 宜等渗介皙、> / 、乙酵及其他習用溶劑、磷酸鹽緩衝鹽 水、及諸如此類。 it於主射I H组合物包括無菌水性溶液或分散液 及用於即時製備無菌注射溶液或分散液之無菌粉劑。對於 靜脈内杈與而s,冑宜載劑包括生理鹽水、抑菌水、 phor ELtm(baSF,Parsippany, NJ)或鱗酸鹽緩衝鹽水 (_ )在所有情況下,該組合物必須為無菌且其流動性 ,該達到容易注射的程度。其在製造及儲存條件下必須穩 ^且必須針對諸如細菌與真菌等微生物之污染作用加以 防腐。。載劑可為含有(例如)水乙醇、多元醇(例如甘油、 2—醇、聚乙二醇及諸如此類)及其適宜混合物之溶劑或 刀散介質。可藉由(例如)使用諸如卵磷脂等塗料、藉由在 分散物情況下維持所需粒徑以及藉由使用表面活性劑來維 ¥々IL動〖生。可藉由各種抗細菌劑及抗真菌劑(例如對 羥基苯甲酸、氣丁醇、苯酚、抗壞血酸、及諸如此類)來 預防微生物之作用。在多種情況下,組合物中包括等滲 劑例如糖類、諸如甘露醇、山梨醇等多元醇及/或氯化 鈉。可藉由在組合物中引入可延遲吸收之試劑(例如單硬 脂酸鋁及明膠)來實現可注射組合物之延長吸收。 144293.doc •29· 201022442 無菌可注射溶液可藉由以下方式來製備:以所需量將多 肽納入含有上文所列舉-種成份或多種成份組合(視需要 而定)之適宜溶劑中,隨後實施過據滅菌。一般而言,可 藉由將活性化合物納人含有基本分散介質及選自上文所列 舉成份之其他所需成份的無菌媒劑中來製備分散物。在使 用無菌粉劑來製備無菌可注射溶液之情況下,較佳製備方 法係真空乾燥及冷;東乾燥,從而自其先前經無菌過滤之溶 液產生具有活性成份及任何其他期望成份之粉劑。 在某些實施例中’本文所述免疫原性組合物亦包含一或 多種佐劑。佐劑係在與免疫原或抗原—起投與時可增強免 疫應答之物質。已顯示多種細胞因子或淋巴因子具有免疫 調節活性,且因此可用作佐劑,包括(但不限於)白細胞介 素1·α、1-β、2、4、5、6、7、8及 1〇、12(例如,參見美國 專利第 5,723,127號)、13、14、15、16、17及 18(及其突變 體形式),干擾素-α、β及γ ;粒細胞_巨嗤細胞集落刺激因 子(GM-CSF)(例如,參見美國專利第5 〇78 996號及ATCC 登錄號39900);巨嗤細胞集落刺激因子(M_CSF);粒細胞 集落刺激因子(G-CSF);及腫瘤壞死因子α及β,可與本文 所述免疫原性組合物一起使用之其他佐劑包括趨化因子, 包括(但不限於)MCP-1、ΜΙΡ-1α、ΜΙΡ-Ιβ、&RANTES ; 黏附分子,例如選擇蛋白(例如L-選擇蛋白、p_選擇蛋白及 E-選擇蛋白);黏蛋白樣分子,例如CD34、GlyCAM-Ι及 MadCAM-Ι,整聯蛋白家族成員,例如LFA-1、VLA-1、 Mac-1及ρ150·95;免疫球蛋白超家族成員,例如pec AM、 144293.doc -30- 201022442 ICAM(例如 ICAM-l、ICAM-2及 ICAM-3)、CD2及 LFA-3 ; 輔刺激分子,例如CD40及CD40L ;生長因子,包括血管生 長因子、神經生長因子、成纖維細胞生長因子、表皮生長 因子、B7.2、PDGF、BL_1、及血管内皮生長因子;受體 分子,包括 Fas、TNF 受體、Fit、Apo-1、p55、WSL-1、 DR3、TRAMP、Apo-3、AIR、LARD、NGRF、DR4、 DR5、KILLER、TRAIL-R2、TRICK2、及 DR6 ;以及半胱 天冬酶(ICE)。 用於增強免疫應答之適宜佐劑另外包括(但不限 於)MPLTM(3-0-脫醯基化單磷醯脂質A ; Corixa, Hamilton,MT),其闡述於美國專利第4,912,094號中。同 樣適合用作佐劑者係合成脂質A類似物或胺基烷基葡糖胺 磷酸酯化合物(AGP)或其衍生物或類似物,其可自Corixa (Hamilton,MT)購得且其闡述於美國專利第6,113,918號 中。一種此類AGP係2-[(R)-3-十四烷醯氧基十四烷醯胺基] 乙基2-去氧-4-0-磷醯基-3-0-[(R)-3-十四烷醯氧基十四烷 醯基]-2-[(R)-3-十四烷醯氧基十四烷醯基-胺基]-b-D-°比喃 葡萄糖苷,其亦稱作529(先前稱作RC529)。將該529佐劑 調配成水性形式(AF)或穩定乳液形式(SE)。 其他佐劑包括胞壁醯基肽,例如N-乙醯基-胞壁醯基-L-蘇胺醯基-D-異麩胺醯胺(thr-MDP)、N-乙醯基-降胞壁醯 基-L-丙胺酸-2-(1'-2'二棕櫊醯基-sn-甘油-3-羥基磷醯氧 基)-乙胺(MTP-PE);水包油乳液’例如MF59(美國專利第 6,299,884號)(含有5%角鯊烯、0.5〇/〇丁\^61180及0.5〇/〇8口311 144293.doc 31 201022442 85(視需要含有各種量之ΜΤΡ-ΡΕ) ’使用諸如110Y型微射 流均質機(Microfluidics, Newton,MA)等微射流均質機將其 調配為亞微米顆粒)、及SAF(含有10%角鯊烯、0.4°/〇 Tween 80、5°/。普流尼克(pluronic)阻斷聚合物 L121、及 thr-MDP,將其微射流均質化為亞微米乳液或對其實施渦旋以 產生粒徑較大之乳液);銘鹽(alum),例如氫氧化銘、墙酸 銘、硫酸銘;Amphigen ; Avridine ; L121/角鯊稀;D-丙 交酯-聚交酯/糖苷;普流尼克多元醇;死博德特氏菌 (Bordetella);皂苷,例如闡述於美國專利第5,057,540號中 之 StimulonTM QS-21 (Antigenics,Framingham, MA.)、闡述 於美國專利第 5,254,339號中之ISCOMATRIX (CSL Limited, Parkville,Australia)、及免疫刺激複合物(ISCOMS);結核 分枝桿菌(Mycobacterium tuberculosis);細菌脂多糖;合 成多核苷酸,例如含有CpG基序之寡核苷酸(例如美國專利 第6,207,646號);闡述於歐洲專利第1,296,713號及第 1,326,634號中之 IC-31 (Intercell AG,Vienna, Austria);百 曰咳毒素(PT)或其突變體、霍亂毒素或其突變體(例如美國 專利第7,285,281號、第7,33 2,174號、第7,361,3 55號及第 7,3 84,640號);或大腸桿菌不耐熱毒素(LT)或其突變體, 具體而言LT-K63、LT-R72(例如美國專利第6,149,919號、 第 7,1 15,730號及第 7,291,588號)。 多肽亦可包括視需要與肽、多肽、或蛋白質、或與多糖 偶合或連接之至少一部分多肽。預期免疫原性組合物亦可 含有其他組份,例如單獨存在或與蛋白質偶合之多糖,其 144293.doc -32- 201022442 可引發免疫應答。 使用各種測試來評價包含本發明免疫原性組合物之多狀 之體外免疫原性。舉例而言,藉由一起培養鏈球菌屬細 ⑯、含有針對所述多肽之特異性抗體之熱滅活血清、及外 源I·生補體來源之混合物來實施體外調理性分析。在新分離 夕φ核細胞(PMN)與抗體/補體/鏈球菌屬細胞混合物之培 養期間進行調理吞嗟作用。在調理吞嗤作用後殺滅塗佈有 &體及補體之細菌細胞。藉由平板接種分析混合物來確定 逃脫調理吞嗟作用之存活細菌之菌落形成單元(cfu)。如藉 由與刀析對照比較來測定,以導致匕5〇%細菌殺滅之最高 稀釋度的倒數來報告效價。將在所測試最低血清稀釋度 (1.8)下顯不小於5〇%殺滅之試樣報告為調理吞噬作用抗體 ()效價為4。上述方法係格雷氏(Gray's)方法之修改形 式(Gray,Conjugate Vaccines Supplement,第 694-697, 1990頁)。 ’ φ 引入含有測試血清以及細菌細胞及熱滅活補體之測試血 清對照用於各個別血清。使用此對照來評價抗生素或其他 血清組份之存在是否能直接(即在不存在補體或PMN時)殺 - 滅細菌菌株。使用具有已知調理效價之人類血清作為陽性 人類血清對照。根據與無血清對照相比導致5 0% cfu降低 之血清的初始稀釋度之倒數來計算各未知血清之調理抗體 效價。 亦可使用全細胞ELISA分析來評價多肽抗原之體外免疫 原性及表面暴露,其中將目標細菌菌株塗佈至諸如%孔板 144293.doc •33- 201022442 等平板上,且使來自經免疫動物之測試血清與細菌細胞反 應。若任何對測試多肽抗原具有特異性之抗體可與多肽抗 原之表面暴露表位發生反應,則可藉由熟習此項技術者已 知之標準方法對其進行檢測。類似方法係使用流式細胞術 及抗原特異性抗體來監測細胞表面上之抗原。 然後可在體内動物攻擊模型中測試任何顯示期望體外活 性之多肽。在某些實施例中,在動物(例如小鼠)免疫中藉 由熟習此項技術者已知之免疫方法及途徑(例如鼻内、非 經腸、肌内、經口、經直腸、經陰道、經皮、腹膜腔内、 靜脈内皮下荨)來使用免疫原性組合物。在用鏈球菌免 疫原組合物對動物實施免疫後,用一或多種鏈球菌物種 攻擊動物且分析其對鏈球菌屬感染之抗性。 藉由引入兩種或更多種本發明多肽、以及藉由將一或多 種本發明多肽與一或多種已知釀膿鏈球菌多肽(包括(但不 限於)Μ蛋白、黏附素 '及諸如此類)組合來提供組合免疫 原性組合物。 在調配後’可將本發明免疫原性組合物直接投與個體, 離體遞送至取自個體之細胞,或在體外用於表現重組體蛋 白。對於直接遞送至個體’可藉由任何習用形式來投與, 例如鼻内、非經腸、經口、腹膜腔内、靜脈内、皮下、或 藉由(例如)氣溶膠喷霧局部施用至任何黏膜表面,例如鼻 内、口腔、眼、肺、陰道、或直腸表面。 有利地’以單位劑型來調配經口或非經腸組合物以便於 投與及使劑量均一。本文所用單位劑型係指適合作為單一 144293.doc -34- 201022442 劑量用於欲治療個體之物理離散單位;每一單位含有預定 量之活性化合物,該預定量經計算可結合所需醫藥載劑產 生期望治療效應。本發明單位劑型之規格取決於且直接依 賴於以下因素:活性化合物之獨特特徵及欲達成之特定療 效,以及配製此—活性化合物用於個體治療之技術中之固 有限制。 根據已知技術使用適宜分散劑或潤濕劑及懸浮劑來調配 ❹
可注射製劑’例如錢可注射水性懸浮液或油性懸浮液。 無菌可注射製劑亦可為存於無毒非經腸可接受稀釋劑或溶 劑中之無菌可注射溶液或懸浮液,例如存於丨,3_丁二醇中 之溶液。 對於非經腸投與,可以存於生理上可接受之稀釋劑以及 醫藥上可接受之載劑中之可注射劑量來投與本發明免疫原 性組合物’ t亥醫藥上可接受之載劑可為無菌液體,例如 X油孤水甘油、或乙醇。此外,辅助物質(例如潤 濕劑或乳化劑、表面活性劑、pH緩衝物質及諸如此類)亦 可存於組合物中。其他組份可包括彼等具有石油、動物、 植物或合成來源者,例如花生油、大豆油及礦物油。一般 而言,諸如丙二酵或聚乙-砖笙-祐衫, G —醇等一醇係較佳液體載劑,尤 其對於可注射溶液而言。 通常,將組合物製備為注射物,例如液體溶液或懸浮 液;亦可製備為適合在注射前溶解或懸浮於液體媒劑中之 固體形式。如上所述,亦可將製劑乳化或囊封於脂質體或 微粒中’例如聚交醋、.聚乙醇酸交酿 '或共聚物,從而增 144293 .doc • 35 · 201022442 強佐劑效應(參見 Langer,Science 249: 1527 (1990)及 Hanes, Advanced Drug Delivery Reviews 28:97 (1997)) ° 可 以積存注射或植入製劑形式投與本發明免疫原性組合物, 其調配方式可使得容許持續或脈衝釋放活性成份。 個體一般為人類。以適宜劑量數將免疫有效量之免疫原 性組合物投與個體以引發免疫應答。本文所用免疫有效量 意指以單一劑量或以一系列劑量之一部分向哺乳動物宿主 (人類較佳)投與該量足以使所治療個體之免疫系統至少產 生可降低細菌感染臨床影響之免疫應答。術語「免疫應 _ 答」或「免疫學應答」包括體液(抗體介導)及/或細胞(由 抗原特異性T細胞或其分泌產物介導)應答。可藉由單一劑 量之免疫原性組合物來賦予保護,或者除加強劑量外可能 需要隨後多次投與若干劑量以維持保護。該保護介於細菌 負荷之最小降低與預防感染之間。理想地,所治療個體不 會顯示更嚴重之β-溶血性鏈球菌感染之臨床表現。劑量量 可端視個體之具體情況而改變,例如年齡及體重。該量可 在常規試驗中藉由熟習此項技術者已知之方式來確定。 ◎ 在預防性施用中’將免疫原性組合物投與對β溶血性鏈 球菌感染易感或具有該風險之個體,其投與量足以消除或 降低疾病風險、降低其嚴重度、或延遲其發作,該疾病包 ‘ 括與感染相關之疾病之生化、組織學及/或行為症狀、其 — 併發症及在疾病發作期間表現之中間病理表型。在治療性 靶用中,將組合物投與懷疑患有或已患有此一疾病之串 者,投與量足以治癒或至少部分阻止疾病症狀(生化、 144293.doc •36· 201022442 織學及/或行為症狀)’包括其併發症及疾病發作中之中間 病理表型。 尚未觀察到有任何單一肽序列可針對所有BHS菌株(包 括A型、B型、C型及G型)提供保護。如下表〗〗中所示(下文 實例1中所述),每一抗原針對該等類型之亞型提供免疫應 答。 一般而言’預期兩種或更多種來自BHS之表面表現抗原 之任一組合可提供上述增強免疫應答。該等抗原可包括上 述抗原:BHS莢膜抗原、Μ蛋白、ABC轉運蛋白、或任何 其他表面暴露抗原。然而’已發現以下抗原表現對免疫原 性組合物之產生尤其有益之特性: SCP(C5a肽酶) 肽基丙基異構酶(由ORF 554編碼) 推定黏附蛋白(由ORF 1358編碼) 表面脂蛋白(由ORF 2459編碼) 假定蛋白(由ORF 1218編碼) 將兩種或更多種該等抗原組合至單一多組份免疫原性組合 物中可提供針對一或多種BHS類型之增強保護且產生針對 其之增強免疫應答。 實例 以下實例為闡述性且不欲使本發明受限於該等實例。 實例1-抗體結合 抗體與細菌之結合係稱為調理素作用之過程,其可導致 吞噬細胞吸收並殺滅細菌。使用對該等抗體之篩選來測定 144293.doc -37- 201022442 針對特定血清型產生之抗體殺滅表面上表現或不表現該血 清型之細菌之效率。 對於所篩選各血清型而言,在小鼠中針對由所述〇rf編 碼之抗體來產生各種抗體。然後針對各種BHS菌株對各抗 體實施篩選。藉由螢光活化細胞分選(FACS)來實施抗體篩 選。簡言之,在冰上將熱殺滅鏈球菌與所述抗體一起培養 45分鐘’隨後洗滌兩次。然後在冰上將鏈球菌與山早抗小 鼠 Alexa-488 抗體(Molecular Probes,Eugene, OR)— 起培養 30分鐘’隨後洗滌兩次。在FACS機器中分析由此處理之 細胞(例如,參見DeMaster等人,Infect. Immun., 70 ⑴: 3 50-3 59, 2002)。結果概述於表2中。 在篩選彼等抗β溶企性鍵球菌抗血清及抵抗各種β溶灰性 鍵球菌(BHS)菌株之單株抗體的過程中,人們注意到某些 抗血清及抗體具有針對多種BHS菌株之交叉反應性,包括 釀膿鏈球菌(Α型鏈球菌)、無乳鏈球菌(Β型鏈球菌)及c型 以及G型鏈球菌(其包括以下鏈球菌物種:咽峽炎鍵球菌、 星座鏈球菌、中鏈球菌、缺乳鏈球菌亞種似馬鏈球菌及缺 乳鏈球菌亞種缺乳鍵球菌)。此交叉反應性亦意指可在免 疫原性組合物中使用所述多肽或由相關ORF編碼之多狀以 誘導可針對以下感染有效保護之免疫應答:Α型或Β型鏈 球菌、以及C型或G型鏈球菌。 在表2中,符號「+」意指與抗原反應之抗體超過背景至 少三倍;符號「+/-」意指與抗原反應之抗體超過背景兩倍 與三倍之間;且符號「-」意指抗體信號檢測等於或低於 背景。 144293.doc 38· 201022442 + + WVSWTSO «Ti^.50 + /+,/+ + + -/+ + -/+ + + -/+ -/+ + δ°·1Ε + < + Τ + ^+ + .+ ·ΗΡ+ + + + + + + +έζέζΖ2ΖΖ2ζέζΖ+ ^r + i+ . + + + + + + + + + + + + + +έζέζζζζζζζέζζ ....................έέέζέέέζέέέζέ ^+ + +^ + + +^ + ^+^+ + + + + + + + + + + +^ + ^ + + +^ + + + + + + + + I + + + V-i α. 〇 + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + (Ο
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201022442 <110>美商惠氏 <120>預防β-溶血性鏈球菌(BHS)疾病之多組份免疫原性組合物 <130> ΑΜ103175 <140> 098137615 <141> 2009-11-05 <150> 61/111,485 <151> 2008-11-05 <160> 10 <170> Patentln version 3.2 <210> 1 <211> 3505 <212> DNA <213>釀膿鏈球菌 <400> 1 ttgcgtaaaa aacaaaaatt accatttgat aaacttgcca ttgcgctcat gtctacgagc atcttgctca atgcacaatc agacattaaa gcaaatactg tgacagaaga cactcctgct accgaacaag ctgtagaaac cccacaacca acagcggttt ctgaggaagc accatcatca aaggaaacca aaaccccaca aactcctgat gacgcagaag aaacaatagc agatgacgct aatgatctag cccctcaagc tcctgctaaa actgctgata caccagcaac ctcaaaagcg actattaggg atttgaacga cccttctcag gtcaaaaccc tgcaggaaaa agcaggcaaa ggagctggga ctgttgttgc agtgattgat gctggttttg ataaaaatca tgaagcgtgg cgcttaacag acaaaaccaa ascacgttac caatcaaaag aagatcttga aaaagctaaa aaagagcacg gtattaccta t£gcgagtgg gtcaatgata aggttgctta ttaccacgac tatagtaaag atggtaaaac cgctgtcgat caagagcacg gcacacacgt gtcagggatc ttgtcaggaa atgctccatc tgaaacgaaa gaaccttacc gcctagaagg tgcgatgcct gaggctcaat tgcttttgat gcgtgtcgaa attgtaaatg gactagcaga ctatgctcgt aactacgctc aagctatcat agatgctgtc aacttgggag ctaaggtgat taatatgagc tttggtaatg ctgcactagc ctatgccaac cttccagacg aaaccaaaaa agcctttgac tatgccaaat caaaaggtgt tagcattgtg acctcagctg gtaatgatag tagctttggs ggcaagaccc gtctacctct agcagatcat cctgattatg gggtggttgg gacacctgca gcggcagact caacattgac agttgcttct tacagcccag ataaacagct cactgaaact gctacggtca aaacagccga tcagcaagat aaagaaatgc ctgttctttc aacaaaccgt tttgagccaa acaaggctta cgactatgct tatgctaatc gtgggatgaa agaggatgat tttaaggatg tcaaaggtaa gattgccctt attgaacgtg gcgatattga tttcaaagat aagattgcaa acgctaaaaa agctggtgct gtaggagtct tgatctatga caatcaggac aagggcttcc cgattgaatt gccaaatgtt gatcagatgc ctgcggcctt tatcagtcga aaagatggtc tcttattaaa agagaatccc caaaaaacca tcaccttcaa tgcgacacct aaggtattgc caacagcaag tggcaccaaa ctaagccgct tctcaagctg gggtctgaca gctgacggca atattaagcc agatattgca gcacccggcc aagatatttt gtcatcagtg gctaacaaca agtatgccaa actttctgga actagtatgt ctgcgccatt agtagcgggt 144293·序列表.doc 60 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 201022442 atcatgggac tgttgcaaaa gcaatatgag acacagtatc ctgatatgac accatcagag 1620 cgtcttgatt tagctaaaaa agtattgatg agctcagcaa ctgccttata tgatgaagat 1680 gaaaaagctt atttttctcc tcgccaacaa ggagcaggag cagtcgatgc taaaaaagct 1740 tcagcagcaa cgatgtatgt gacagataag gataatacct caagcaasgt tcacctgaac 1800 aatgtttctg ataaatttga agtaacagta acagttcaca acaaatctga taaacctcaa 1860 gagttgtatt accaagcaac tgttcaaaca gataaagtag atggaaaact ctttgccttg 1920 gctcctaaag cattgtatga £acatcatg£ caaaaaatca caattccagc caatagcagc 1980 aaacaagtca ccattccaat cgatgttagt caatttagca aggacttgct tsccccaatg 2040 aaaaatggct atttcttaga aggttttgtt cgtttcaaac aagatcctac aaaagaagag 2100 cttatgagta ttccctatat tggtttccga ggtgattttg gcaatctstc agccttagaa 2160 aaaccaatct atgatagcaa agacggtagc agctactatc atgaagcaaa tagtgatgcc 2220 aaagaccaat tagatggtga tggattacag ttttacgctc tgaaaaataa ctttacagca 2280 cttactacag agtctaatcc atggacgatt attaaagctg tcaaa^aagg ggttgaaaac 2340 atagaggata tcgaatcttc agagatcaca gaaaccattt ttgcaggtac ttttgcaaaa 2400 caagacgats atagccacta ctatatccac cgtcacecta atggcaagcc atatgctgcg 2460 atctctccaa atggggacgg taacagagat tatgtccaat tccaaggtac tttcttgcgt 2520 aat£Ctaaaa accttgtggc tgaagtcttg gacaaagaag gaaatgttgt ttggacaagt 2580 gaggtaaccg ascaagttgt taaaaactac aacaatgact tggcaagcac acttggttca 2640 acccgttttg aaaaaacgcg ttgggacggt aaagataaag acggcaaagt tgttgctaac 2700 ggaacataca cctatcgtgt tcgctacact ccgattagct caggtgcaaa agaacaacac 2760 actgattttg atgtgattgt agacaatacg acacctgaag tcgcaacatc gscaacattc 2820 tcaacagaag atcgtcgttt gacacttgca tctaaaccaa aaaccagcca accggtttac 2880 cgtgagcgta ttgcttacac ttatatggat eass^tctgc caacaacaga gtatatttct 2940 ccaaatgaag atggtacctt tactcttcct gaagagsctg aaacaatsea aggcgctact 3000 gttccattga aaatgtcaga ctttacttat gttgttgaag atatssctgg taacatcact 3060 tatacaccag tgactaagct attggaaggc cactctaata aaccagaaca agacggttca 3120 gatcaagcac cagacaaaaa accagaaact aaaccagaac aagacggttc aggtcaagca 3180 ccagataaaa aaccagaaac taaaccagaa caagacggtt caggtcaaac accagacaaa 3240 aaaccagaaa ctaaaccaga acaagacggt tcaggtcaaa caccagataa aaaaccagaa 3300 actaaaccag aaaaagatag ttcaggtcaa acaccag£ta aaactcctca aaaaggtcaa 3360 ccttctcgta ctctagagaa acgatcttct aagcgtgctt tagctacaaa agcatcaaca 3420 aaagatcagt taccaacgac taatgacaag gatacaaatc gtttacatct ccttaagtta 3480 gttatgacca ctttcttctt gggat 3505 菌 球 鏈 81T 膿 11PR釀 <210> <211> <212> <213> <400> 2- 144293-序列表.doc 201022442
Leu Arg Lys Lys Gin Lys Leu Pro Phe Asp Lys Leu Ala lie Ala Leu 15 10 15
Met Ser Thr Ser lie Leu Leu Asn Ala Gin Ser Asp lie Lys Ala Asn 20 25 30
Thr Val Thr Glu Asp Thr Pro Ala Thr Glu Gin Ala Val Glu Thr Pro 35 40 45
Gin Pro Thr Ala Val Ser Glu Glu Ala Pro Ser Ser Lys Glu Thr Lys 50 55 60
Thr Pro Gin Thr Pro Asp Asp Ala Glu Glu Thr lie Ala Asp Asp Ala 65 70 75 80
Asn Asp Leu Ala Pro Gin Ala Pro Ala Lys Thr Ala Asp Thr Pro Ala 85 90 95
Thr Ser Lys Ala Thr lie Arg Asp Leu Asn Asp Pro Ser Gin Val Lys 100 105 110
Thr Leu Gin Glu Lys Ala Gly Lys Gly Ala Gly Thr Val Val Ala Val 115 120 125 lie Asp Ala Gly Phe Asp Lys Asn His Glu Ala Trp Arg Leu Thr Asp 130 135 140
Lys Thr Lys Ala Arg Tyr Gin Ser Lys Glu Asp Leu Glu Lys Ala Lys 145 150 155 160
Lys Glu His Gly lie Thr Tyr Gly Glu Trp Val Asn Asp Lys Val Ala 165 170 175
Tyr Tyr His Asp Tyr Ser Lys Asp Gly Lys Thr Ala Val Asp Gin Glu 180 185 190
His Gly Thr His Val Ser Gly lie Leu Scr Gly Asn Ala Pro Ser Glu 195 200 205
Thr Lys Glu Pro Tyr Arg Leu Glu Gly Ala Met Pro Glu Ala Gin Leu 210 215 220
Leu Leu Met Arg Val Glu lie Val Asn Gly Leu Ala Asp Tyr Ala Arg 225 230 235 240
Asn Tyr Ala Gin Ala lie lie Asp Ala Val Asn Leu Gly Ala Lys Val 245 250 255 lie Asn Met Ser Phe Gly Asn Ala Ala Leu Ala Tyr Ala Asn Leu Pro 260 265 270
Asp Glu Thr Lys Lys Ala Phe Asp Tyr Ala Lys Ser Lys Gly Val Ser 275 280 285 lie Val Thr Ser Ala Gly Asn Asp Ser Ser Phe Gly Gly Lys Thr Arg 290 295 300 144293-序列表.doc 201022442
Leu Pro Leu Ala Asp His Pro Asp Tyr Gly Val Val Gly Thr Pro Ala 305 310 315 320
Ala Ala Asp Ser Thr Leu Thr Val Ala Ser Tyr Ser Pro Asp Lys Gin 325 330 335
Leu Thr Glu Thr Ala Thr Val Lys Thr Ala Asp Gin Gin Asp Lys Glu 340 345 350
Met Pro Val Leu Ser Thr Asn Arg Phe Glu Pro Asn Lys Ala Tyr Asp 355 360 365
Tyr Ala Tyr Ala Asn Arg Gly Met Lys Glu Asp Asp Phe Lys Asp Val 370 375 380
Lys Gly Lys He Ala Leu lie Glu Arg Gly Asp lie Asp Phe Lys Asp 385 390 395 400
Lys lie Ala Asn Ala Lys Lys Ala Gly Ala Val Gly Val Leu lie Tyr 405 410 415
Asp Asn Gin Asp Lys Gly Phe Pro lie Glu Leu Pro Asn Val Asp Gin 420 425 430
Met Pro Ala Ala Phe lie Ser Arg Lys Asp Gly Leu Leu Leu Lys Glu 435 440 445
Asn Pro Gin Lys Thr lie Thr Phe Asn Ala Thr Pro Lys Val Leu Pro 450 455 460
Thr Ala Ser Gly Thr Lys Leu Ser Arg Phe Ser Ser Trp Gly Leu Thr 465 470 475 480
Ala Asp Gly Asn lie Lys Pro Asp lie Ala Ala Pro Gly Gin Asp lie 485 490 495
Leu Ser Ser Val Ala Asn Asn Lys Tyr Ala Lys Leu Ser Gly Thr Ser 500 505 510
Met Ser Ala Pro Leu Val Ala Gly lie Met Gly Leu Leu Gin Lys Gin 515 520 525
Tyr Glu Thr Gin Tyr Pro Asp Met Thr Pro Ser Glu Arg Leu Asp Leu 530 535 540
Ala Lys Lys Val Leu Met Ser Ser Ala Thr Ala Leu Tyr Asp Glu Asp 545 550 555 560
Glu Lys Ala Tyr Phe Ser Pro Arg Gin Gin Gly Ala Gly Ala Val Asp 565 570 575
Ala Lys Lys Ala Ser Ala Ala Thr Met Tyr Val Thr Asp Lys Asp Asn 580 585 590
Thr Ser Ser Lys Val His Leu Asn Asn Val Ser Asp Lys Phe Glu Val 595 600 605 -4· 144293·序列表.doc 201022442
Thr Val Thr Val His Asn Lys Ser Asp Lys Pro Gin Glu Leu Tyr Tyr 610 615 620
Gin Ala Thr Val Gin Thr Asp Lys Val Asp Gly Lys Leu Phe Ala Leu 625 630 635 640
Ala Pro Lys Ala Leu Tyr Glu Thr Ser Trp Gin Lys lie Thr lie Pro 645 650 655
Ala Asn Ser Ser Lys Gin Val Thr lie Pro lie Asp Val Ser Gin Phe 660 665 670
Ser Lys Asp Leu Leu Ala Pro Met Lys Asn Gly Tyr Phe Leu Glu Gly 675 680 685
Phe Val Arg Phe Lys Gin Asp Pro Thr Lys Glu Glu Leu Met Ser lie 690 695 700
Pro Tyr He Gly Phe Arg Gly Asp Phe Gly Asn Leu Ser Ala Leu Glu
705 710 715 720
Lys Pro He Tyr Asp Ser Lys Asp Gly Ser Ser Tyr Tyr His Glu Ala 725 730 735
Asn Ser Asp Ala Lys Asp Gin Leu Asp Gly Asp Gly Leu Gin Phe Tyr 740 745 750
Ala Leu Lys Asn Asn Phe Thr Ala Leu Thr Thr Glu Ser Asn Pro Trp 755 760 765
Thr lie lie Lys Ala Val Lys Glu Gly Val Glu Asn lie Glu Asp lie 770 775 780
Glu Ser Ser Glu lie Thr Glu Thr lie Phe Ala Gly Thr Phe Ala Lys 785 790 795 800
Gin Asp Asp Asp Ser His Tyr Tyr lie His Arg His Ala Asn Gly Lys 805 810 815
Pro Tyr Ala Ala lie Ser Pro Asn Gly Asp Gly Asn Arg Asp Tyr Val 820 825 830
Gin Phe Gin Gly Thr Phe Leu Arg Asn Ala Lys Asn Leu Val Ala Glu 835 840 845
Val Leu Asp Lys Glu Gly Asn Val Val Trp Thr Ser Glu Val Thr Glu 850 855 860
Gin Val Val Lys Asn Tyr Asn Asn Asp Leu Ala Ser Thr Leu Gly Ser 865 870 875 880
Thr Arg Phe Glu Lys Thr Arg Trp Asp Gly Lys Asp Lys Asp Gly Lys 885 890 895
Val Val Ala Asn Gly Thr Tyr Thr Tyr Arg Val Arg Tyr Thr Pro lie 144293·序列表.doc 201022442 900 905 910
Ser Ser Gly Ala Lys Glu Gin His Thr Asp Phe Asp Val lie Val Asp 915 920 925
Asn Thr Thr Pro Glu Val Ala Thr Ser Ala Thr Phe Ser Thr Glu Asp 930 935 940
Arg Arg Leu Thr Leu Ala Ser Lys Pro Lys Thr Ser Gin Pro Val Tyr 945 950 955 960
Arg Glu Arg lie Ala Tyr Thr Tyr Met Asp Glu Asp Leu Pro Thr Thr 965 970 975
Glu Tyr lie Ser Pro Asn Glu Asp Gly Thr Phe Thr Leu Pro Glu Glu 980 985 990
Ala Glu Thr Met Glu Gly Ala Thr Val Pro Leu Lys Met Ser Asp Phe 995 1000 1005
Thr Tyr Val Val Glu Asp Met Ala Gly Asn lie Thr Tyr Thr Pro 1010 1015 1020
Val Thr Lys Leu Leu Glu Gly His Ser Asn Lys Pro Glu Gin Asp 1025 1030 1035
Gly Ser Asp Gin Ala Pro Asp Lys Lys Pro Glu Thr Lys Pro Glu 1040 1045 1050
Gin Asp Gly Ser Gly Gin Ala Pro Asp Lys Lys Pro Glu Thr Lys 1055 1060 1065
Pro Glu Gin Asp Gly Ser Gly Gin Thr Pro Asp Lys Lys Pro Glu 1070 1075 1080
Thr Lys Pro Glu Gin Asp Gly Ser Gly Gin Thr Pro Asp Lys Lys 1085 1090 1095
Pro Glu Thr Lys Pro Glu Lys Asp Ser Ser Gly Gin Thr Pro Gly 1100 1105 1110
Lys Thr Pro Gin Lys Gly Gin Pro Ser Arg Thr Leu Glu Lys Arg 1115 1120 1125
Ser Ser Lys Arg Ala Leu Ala Thr Lys Ala Ser Thr Lys Asp Gin 1130 1135 1140
Leu Pro Thr Thr Asn Asp Lys Asp Thr Asn Arg Leu His Leu Leu 1145 1150 1155
Lys Leu Val Met Thr Thr Phe Phe Leu Gly Leu Val Ala His lie 1160 1165 1170
Phe Lys Thr Lys Arg Thr Glu Asp 1175 1180 -6- 144293-序列表.doc
<210> 3 <211> 1056 <212> DNA
201022442 <213>釀膿鏈球菌 <400> 3 atgaaaaact caaataaact cattgctagt gttgtgacat tggcctcagt gatggcttta gcagcttgtc aatcaactaa tgacaatact aaggttattt cgatgaaagg tgatacaatt agcgttagtg atttttacaa tgaaacaaaa aacacagaag tatcgcaaaa agcgatgcta aatctggtaa ttagtcgtgt ttttgaagct caatatggtg ataaggtttc aaaaaaagaa gttgaaaagg cgtatcataa aacagctgaa cagtatggcg cttcattctc tgctgctttg gcacaatcaa gcttgacacc tgagactttt aagcgtcaga tccgctcttc aaaattagta gaatatgcgg ttaaagaagc agctaaaaaa gaattgacaa cacaagaata taasaaagca tatgaatctt atactccaac aatggcagtc gaaatgatta ctttagataa tgaagagaca gctaaatcag tcttagagga actaaaagcc gaaggcgcag actttaca^c tattgctaaa gaaaaaacaa caacacctga gaaaaaagtg acctataaat ttgattcagg tgcgacaaat gtaccgactg atgtcgtaaa agcggcttca agtttgaatg agggtggcat atcagacgtt atctcggttt tagatccaac ttcttatcaa aagaagtttt acattgttaa ggtgactaaa aaagcagaaa aaaaatcaga ttggcaagaa tataagaaac gtttgaaagc tatcattata gctgaaaaat caaaagatat gaatttccaa aacaaggtta ttgcaaatgc attggataaa gctaatgtaa aaattaaaga caaagctttt gctaatattt tggcgcaata tgcaaatctt ggtcaaaaaa ctaaagctgc aagtgaaagt tcaacaacca gcgaatcatc aaaagctgca gaagagaacc catcagaatc agagcaaaca cagacatcat cagctgaaga accaactgag actgaggctc agacgcaaga gccagctgca caataa <210> 4 <211> 351 <212> PRT <213>釀膿鍵球菌 <400> 4
Met Lys Asn Ser Asn Lys Leu lie Ala Ser Vai Val Thr Leu Ala Ser 15 10 15
Val Met Ala Leu Ala Ala Cys Gin Scr Thr Asn Asp Asn Thr Lys Val 20 25 30 lie Ser Met Lys Gly Asp Thr lie Scr Val Ser Asp Phc Tyr Asn Glu 35 40 45
Thr Lys Asn Thr Glu Val Ser Gin Lys Ala Met Leu Asn Leu Val lie 50 55 60
Ser Arg Val Phe Glu Ala Gin Tyr Gly Asp Lys Val Scr Lys Lys Glu 65 70 75 80
Val Glu Lys Ala Tyr His Lys Thr Ala Glu Gin Tyr Gly Ala Ser Phe 85 90 95
Ser Ala Ala Leu Ala Gin Ser Ser Leu Thr Pro Glu Thr Phe Lys Arg 144293-序列表.doc 60 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1056 201022442 100 105 110
Gin lie Arg Ser Ser Lys Leu Val Glu Tyr Ala Val Lys Glu Ala Ala 115 120 125
Lys Lys Glu Leu Thr Thr Gin Glu Tyr Lys Lys Ala Tyr Glu Ser Tyr 130 135 140
Thr Pro Thr Met Ala Val Glu Met lie Thr Leu Asp Asn Glu Glu Thr 145 150 155 160
Ala Lys Ser Val Leu Glu Glu Leu Lys Ala Glu Gly Ala Asp Phe Thr 165 170 175
Ala lie Ala Lys Glu Lys Thr Thr Thr Pro Glu Lys Lys Val Thr Tyr 180 185 190
Lys Phe Asp Ser Gly Ala Thr Asn Val Pro Thr Asp Val Val Lys Ala 195 200 205
Ala Ser Ser Leu Asn Glu Gly Gly lie Ser Asp Val lie Ser Val Leu 210 215 220
Asp Pro Thr Ser Tyr Gin Lys Lys Phe Tyr lie Val Lys Val Thr Lys 225 230 235 240
Lys Ala Glu Lys Lys Ser Asp Trp Gin Glu Tyr Lys Lys Arg Leu Lys 245 250 255
Ala lie lie lie Ala Glu Lys Ser Lys Asp Met Asn Phe Gin Asn Lys 260 265 270
Val lie Ala Asn Ala Leu Asp Lys Ala Asn Val Lys lie Lys Asp Lys 275 280 285
Ala Phe Ala Asn lie Leu Ala Gin Tyr Ala Asn Leu Gly Gin Lys Thr 290 295 300
Lys Ala Ala Ser Glu Ser Ser Thr Thr Ser Glu Ser Ser Lys Ala Ala 305 310 315 320
Glu Glu Asn Pro Ser Glu Ser Glu Gin Thr Gin Thr Ser Ser Ala Glu 325 330 335
Glu Pro Thr Glu Thr Glu Ala Gin Thr Gin Glu Pro Ala Ala Gin 340 345 350 <210〉 5 <211> 3027 <212> DNA <213>釀膿鏈球菌 <400> 5 60 120 180 atgaagaaac atcttaaaac agttgccttg accctcacta cagtatcggt agtcacccac aatcaggaag tttttagttt agtcaaagag ccaattctta aacaaactca agcttcttca tcgatttctg gcgctgacta cgcagaaagt agcggtaaaa gcaagttaaa gattaatgaa 144293-序列表.doc
201022442 acttctggcc ctgttgatga tacagtcact gacttatttt cggataaacg tactactcct gaaaaaataa aagataatct tgctaaaggt ccgagagaac aagagttaaa ggcagtaaca gagaatacag aatcagaaaa gcagatcact tctggatctc aactagaaca atcaaaagag tctctttctt taaataaaac agtgccatca acgtctaatt gggagatttg tgattttatt actaagggga atacccttgt tggtctttca aaatcaggtg ttgaaaagtt atctcaaact gatcatctcg tattgcctag tcaagcagca gatggaactc aattgataca agtagctagt tttgctttta ctccagataa aaagacggca attgcagaat ataccagtag ggctggagaa aatggggaaa taagccaact agatgtggat ggaaaagaaa ttattaac^a ag£tga£gtt tttaattctt atctactaaa gaaggtaaca atcccaactg gttataaaca tattggtcaa gatgcttttg tggacaataa gaatattgct gaggttaatc ttcctgaaag cctcgagact atttctgact atgcttttgc tcacctagct ttgaaacaga tcgatttgcc agataattta aaagcgattg gagaattagc tttttttgat aatcaaatta caggtaaact ttctttgcca cgtcagttaa tgcgattagc agaacgt^ct tttaaatcaa accatatcaa aacaattgag tttagaggaa atagtctaaa agtgataggg gaagctagtt ttcaagataa tgatctgagt caactaatgc tacctgacgg tcttgaaaaa atagaatcag aagcttttac aggaaatcca ggagatgatc actacaataa ccgtgttgtt ttgtggacaa aatctggaaa aaatccttct ggtcttgcta ctgaaaatac ctatgttaat cctgataagt cactatggca ggaaagtcct gagattgatt atactaaatg gttagaggaa gattttacct atcaaaaaaa tagtgttaca ggtttttcaa ataaaggctt acaaaaagta aaacgtaata aaaacttaga aattccaaaa cagcacaatg gtgttactat tactgaaatt ggtgataatg cttttcgcaa tgttgatttt caaaataaaa ctttacgtaa atatgatttg saagaagtaa agcttccctc aactattcgg aaaataggtg cttttgcttt tcaatctaat aacttgaaat cttttgaagc aagtgacgat ttagaagaga ttaaagaggg agcctttatg aataatcgta ttgaaacctt ggaattaaaa gataaattag ttactattgg tgatgcggct ttccatatta atcatattta tgccattgtt cttccagaat ctgtacaaga aatagggcgt tcagcatttc ggcaaaatgg tgcaaataat cttattttta tgggaagtaa sgttaagacc ttaggtgaga tggcatutt atcaaataga cttgaacatc tggatctttc tgiagcaaaaa cagttaacag agattcctgt tcaagccttt tcagacaatg ccttgaaaga agtattatta ccagcatcac tgaaaacgat tcgagaagaa gccttcaaaa agaatcattt aaaacaactg gaagtggcat ctgccttgtc ccatattgct tttaatgctt tagatgataa tgatggtgat gaacaatttg ataataaagt ggttgttaaa acgcatcata attcctacgc actagcagat ggtgagcatt ttatcgttga tccagataag ttatcttcta caatagtaga ccttgaaaag attttaaaac taatcgaagg tttagattat tctacattac gtcagactac tcaaactcag tttagagaca tgactactgc aggtaaagcg ttgttgtcaa aatctaacct ccgacaagga gaaaaacaaa aattccttca agaagcacaa tttttccttg gccgcgttga tttggataaa gccatagcta aagctgagaa ggctttagtg accaagaagg caacaaagaa tggtcagttg cttgaaagaa gtattaacaa agcggtatta gcttataata atagcgctat taaaaaagct aatgttaagc gcttggaaaa agagttagac ttgctaacag gattagttga gggaaaagga ccattagcgc aagctacaat fgtacaagga 144293·序列表.doc -9- 240 300 360 420 480 540 600 66Q 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1680 1740 1800 1860 1920 1980 2040 2100 2160 2220 2280 2340 2400 2460 201022442 gtttatttat taaagacgcc tttgccattg ccagaatatt atatcggatt gaacgtttat tttgacaagt ctggaaaatt gatttatgca cttgatatga gtgatactat caaaaagacg cttatggtaa tcctatatta aatgttgacg aggataatga agsttatcat gccttggcag ttgccacttt agctgattat gaggggctcg acatcaaaac aattttaaat agtaagctta gtcaattaac atctattcgt caggtaccga ctgcagccta tcataga^cc ggtattttcc aagctatcca aaatgcagcg gcagaagcag agcagttatt gcctaaacca ggtacgcact ctgagaagtc aagctcaagt gaatctgcta actctaaaga tagaggattg caatcaaacc caaaaacgaa tagaggacga cactctgcaa tattgcctag gacagggtca aaaggcagct ttgtctatgg aatcttaggt tacactagcg ttgctttact gtcactaata actgctataa aaaagaaaaa atattaa <2I0> 6 <211> 1008 <212> PRT <213>釀膿鏈球菌 <400> 6
Met Lys Lys His Leu Lys Thr Val Ala Leu Thr Leu Thr Thr Val Ser 15 10 15
Val Val Ήιγ His Asn Gin Glu Val Phe Ser Leu Vai Lys Glu Pro lie 20 25 30
Leu Lys Gin Thr Gin Ala Ser Ser Ser lie Ser Gly Ala Asp Tyr Ala 35 40 45
Glu Ser Ser Gly Lys Ser Lys Leu Lys lie Asn Glu Thr Ser Gly Pro 50 55 60
Val.Asp Asp Thr Val Thr Asp Leu Phe Ser Asp Lys Arg Thr Thr Pro 65 70 75 80
Glu Lys lie Lys Asp Asn Leu Ala Lys Gly Pro Arg Glu Gin Glu Leu 85 90 95
Lys Ala Val Thr Glu Asn Thr Glu Scr Glu Lys Gin lie Thr Ser Gly 100 105 110
Ser Gin Leu Glu Gin Ser Lys Glu Ser Leu Ser Leu Asn Lys Thr Val 115 120 125
Pro Ser Thr Ser Asn Trp Glu lie Cys Asp Phe lie Thr Lys Gly Asn 130 135 140
Thr Leu Val Gly Leu Ser Lys Ser Gly Val Glu Lys Leu Ser Gin TTir 145 150 155 160
Asp His Leu Val Leu Pro Ser Gin Ala Ala Asp Gly Thr Gin Leu lie 165 170 175
Gin Val Ala Ser Phe Ala Phe Thr Pro Asp Lys Lys Thr Ala lie Ala 180 185 190 •10- 2520 2580 2640 2700 2760 2820 2880 2940 3000 3027 144293-序列表.d〇c 201022442
Glu Tyr Thr Ser Arg Ala Gly Glu Asn Gly Glu lie Ser Gin Leu Asp 195 200 205
Val Asp Gly Lys Glu lie lie Asn Glu Gly Glu Val Phc Asn Ser Tyr 210 215 220
Leu Leu Lys Lys Val Thr lie Pro Thr Gly Tyr Lys His lie Gly Gin 225 230 235 240
Asp Ala Phe Val Asp Asn Lys Asn lie Ala Glu Val Asn Leu Pro Glu 245 250 255
Ser Leu Glu Thr lie Ser Asp Tyr Ala Phe Ala His Leu Ala Leu Lys 260 265 270
Gin lie Asp Leu Pro Asp Asn Leu Lys Ala lie Gly Glu Leu Ala Phe 275 280 285
Phe Asp Asn Gin lie Thr Gly Lys Leu Ser Leu Pro Arg Gin Leu Met 290 295 300
Arg Leu Ala Glu Arg Ala Phe Lys Ser Asn His lie Lys Thr lie Glu 305 310 315 320
Phe Arg Gly Asn Ser Leu Lys Val lie Gly Glu Ala Ser Phe Gin Asp 325 330 335
Asn Asp Leu Ser Gin Leu Met Leu Pro Asp Gly Leu Glu Lys lie Glu 340 345 350
Ser Glu Ala Phc Thr Gly Asn Pro Gly Asp Asp His Tyr Asn Asn Arg 355 360 365
Val Val Leu Trp Thr Lys Ser Gly Lys Asn Pro Scr Gly Leu Ala Thr 370 375 380
Glu Asn Thr Tyr Val Asn Pro Asp Lys Ser Leu Trp Gin Glu Ser Pro 385 390 395 400
Glu lie Asp Tyr Thr Lys Trp Leu Glu Glu Asp Phc Thr Tyr Gin Lys 405 410 415
Asn Ser Val Thr Gly Phe Scr Asn Lys Gly Leu Gin Lys Val Lys Arg 420 425 430
Asn Lys Asn Leu Glu lie Pro Lys Gin His Asn Gly Val Thr lie Thr 435 440 445
Glu He Gly Asp Asn Ala Phe Arg Asn Val Asp Phe Gin Asn Lys Thr 450 455 460
Leu Arg Lys Tyr Asp Leu Glu Glu Val Lys Leu Pro Ser Thr lie Arg 465 470 475 480
Lys lie Gly Ala Phe Ala Phe Gin Ser Asn Asn Leu Lys Ser Phe Glu -11 - 144293·序列表.doc 201022442 485 490 495
Ala Ser Asp Asp Leu Glu Glu lie Lys Glu Gly Ala Phe Met Asn Asn 500 505 510
Arg lie Glu Thr Leu Glu Leu Lys Asp Lys Leu Val Thr lie Gly Asp 515 520 525
Ala Ala Phe His lie Asn His lie Tyr Ala lie Val Leu Pro Glu Ser 530 535 540
Val Gin Glu lie Gly Arg Ser Ala Phe Arg Gin Asn Gly Ala Asn Asn 545 550 555 560
Leu lie Phe Met Gly Ser Lys Val Lys Thr Leu Gly Glu Met Ala Phe 565 570 575
Leu Ser Asn Arg Leu Glu His Leu Asp Leu Ser Glu Gin Lys Gin Leu 580 585 590
Thr Glu lie Pro Val Gin Ala Phe Ser Asp Asn Ala Leu Lys Glu Val 595 600 605
Leu Leu Pro Ala Ser Leu Lys Thr lie Arg Glu Glu Ala Phe Lys Lys 610 615 620
Asn His Leu Lys Gin Leu Glu Val Ala Ser Ala Leu Ser His lie Ala 625 630 635 640
Phe Asn Ala Leu Asp Asp Asn Asp Gly Asp Glu Gin Phe Asp Asn Lys 645 650 655
Val Val Val Lys Thr His His Asn Ser Tyr Ala Leu Ala Asp Gly Glu 660 665 670
His Phe lie Val Asp Pro Asp Lys Leu Ser Ser Thr lie Val Asp Leu 675 680 685
Glu Lys lie Leu Lys Leu lie Glu Gly Leu Asp Tyr Ser Thr Leu Arg 690 695 700
Gin Thr Thr Gin Thr Gin Phe Arg Asp Met Thr Thr Ala Gly Lys Ala 705 710 715 720
Leu Leu Ser Lys Ser Asn Leu Arg Gin Gly Glu Lys Gin Lys Phe Leu 725 730 735
Gin Glu Ala Gin Phe Phe Leu Gly Arg Val Asp Leu Asp Lys Ala lie 740 745 750
Ala Lys Ala Glu Lys Ala Leu Val Thr Lys Lys Ala Thr Lys Asn Gly 755 760 765
Gin Leu Leu Glu Arg Ser lie Asn Lys Ala Val Leu Ala Tyr Asn Asn 770 775 780 •12· U4293-序列表.doc 201022442
Ser Ala lie Lys Lys Ala Asn Val Lys Arg Leu Glu Lys Glu Leu Asp 785 790 795 800
Leu Leu Thr Gly Leu Val Glu Gly Lys Gly Pro Leu Ala Gin Ala Thr 805 810 815
Met Val Gin Gly Val Tyr Leu Leu Lys Thr Pro Leu Pro Leu Pro Glu 820 825 830
Tyr Tyr lie Gly Leu Asn Val Tyr Phe Asp Lys Ser Gly Lys Leu lie 835 840 845
Tyr Ala Leu Asp Met Ser Asp Thr lie Gly Glu Gly Gin Lys Asp Ala 850 855 860
Tyr Gly Asn Pro lie Leu Asn Val Asp Glu Asp Asn Glu Gly Tyr His 865 870 875 880
Ala Leu Ala Val Ala Thr Leu Ala Asp Tyr Glu Gly Leu Asp lie Lys 885 890 895
Thr lie Leu Asn Ser Lys Leu Ser Gin Leu Thr Ser lie Arg Gin Val 900 905 910
Pro Thr Ala Ala Tyr His Arg Ala Gly lie Phe Gin Ala lie Gin Asn 915 920 925
Ala Ala Ala Glu Ala Glu Gin Leu Leu Pro Lys Pro Gly Thr His Ser 930 935 940
Glu Lys Ser Ser Ser Ser Glu Ser Ala Asn Ser Lys Asp Arg Gly Leu 945 950 955 960
Gin Ser Asn Pro Lys Thr Asn Arg Gly Arg His Ser Ala lie Leu Pro 965 970 975
Arg Thr Gly Ser Lys Gly Ser Phe Val Tyr Gly lie Leu Gly Tyr Thr 980 985 990
Ser Val Ala Leu Leu Ser Leu lie Thr Ala lie Lys Lys Lys Lys Tyr 995 1000 1005 <210> 7 <211> 1505 <212> DNA <213>釀朦鍵球菌 <400> 7 60 120 180 240 300 360 420 atgaaaaaga aaattctttt aatgatgagt ttaatcagtg tcttttttgc ttggcaactt actcaggcaa aacaagtctt agcagagggt aaagtgaagg tggtgacaac tttctatcct gtttatgaat ttacaaaagg ggttattggt aatgatggcg atgttttcat gettatgaaa gcaggaacgg aacctcatga ttttgagcct tctacaaaag acattaaaaa aatccaagat gcagatgcat ttgtttatat ggatgacaat atggaaactt gggtttctga tgtgaaaaaa tcattgacat ctaaaaaagt gaccatcgtc aagggaactg gtaacatgct cttggtagca ggagctggac atgaccatcc ccatgaggat gctgacaaaa ageatgagea taataaacat •13- 144293·序列表.doc 201022442 agcgaa^aag gacacaacca tgcttttgac ccacac£t£t ggttgtcacc ataccgtagc attacagtcg ttgaaaatat tcscgacagt ctttcaaaag cttacccaga aaaagcagag aacttcaaag ccaatgccgc tacttatatt gaaaaattaa aagagcttga caaagactat acggcagcac tttcagatgc taagcaaaag a^ctttgtga cacaacacgc agcttttggt tatatggcac ttgactatgs cttgaaccaa atttctatta atggtgtcac accagatgca gaaccatcag caaaacgtat tgctactttg tcaaaatacg ttaaaaaata tggcatcaaa tacatttatt ttgaggaaaa tgcgtcaagt aaagtcgcaa aaaccctagc taaagaagca ggagttaaag cggctstgct tagtccgctt gaaggtttga ctgaaaaaga gatgaaagct ggccaagatt actttacggt catgcgtaaa aaccttgaaa ccttacgctt aaccactgat gtggctggta aagaaattct tccagaaaaa gacacgacta agacagttta caatggttat ttcaaagaca aagaagtcaa. agatcgtcaa ttatctgact ggtcaggtag ctggcaatct gtttacccct atctacaaga tggtacttta gaccaagttt gggactacaa ggctaaaaaa tctaaaggta aaatgacagc agccgagtac aaagattact acactactgg ttataaaact gacgtggaac aaatcaaaat caatggtaag aaaaagacca tgacctttgt tcgtaatggt gaaaagaaaa ccttcactta cacatacgcc ggcaaagaaa tcttgaccta tccaaaagga aatcgcgggg ttcgtttcat gtttgaagct aaagaagcag atgctggcga attcaaatac gttcaattca gtgaccatgc cattgctcct gaaaaagcaa agcatttcca cctgtactgg ggtggtgaca gccaagaaaa attacataaa gagttasaac attggccaac ttactacggt tcaga 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1505 <210> 8 <211> 515 <212> PRT <213>醸膿鏈球菌 <400> 8
Met Lys Lys Lys lie Leu Leu Met Met
Ser Leu lie Ser Val Phe Phe 10 15
Ala Trp Gin Leu Thr Gin Ala Lys Gin Val Leu Ala Glu Gly Lys Val 20 25 30
Lys Val Val Thr Thr Phe Tyr Pro Val Tyr Glu Phe Thr Lys Gly Val 35 40 45 lie Gly Asn Asp Gly Asp Val Phe Met Leu Met Lys Ala Gly Thr Glu 50 55 60
Pro His Asp Phe Glu Pro Ser Thr Lys Asp lie Lys Lys lie Gin Asp 65 70 75 80
Ala Asp Ala Phe Val Tyr Met Asp Asp Asn Met Glu Thr Trp Val Ser 85 90 95
Asp Val Lys Lys Ser Leu Thr Ser Lys Lys Val Thr lie Val Lys Gly 100 105 110 144293·序列表.doc -14- 201022442
Thr Gly Asn Met Leu Leu Val Ala Gly Ala Gly His Asp His Pro His 115 120 125
Glu Asp Ala Asp Lys Lys His Glu His Asn Lys His Ser Glu Glu Gly 130 135 140
His Asn His Ala Phe Asp Pro His Val Trp Leu Ser Pro Tyr Arg Ser 145 150 155 160 lie Thr Val Val Glu Asn lie Arg Asp Ser Leu Ser Lys Ala Tyr Pro 165 170 175
Glu Lys Ala Glu Asn Phe Lys Ala Asn Ala Ala Thr Tyr lie Glu Lys 180 185 190
Leu Lys Glu Leu Asp Lys Asp Tyr Thr Ala Ala Leu Ser Asp Ala Lys 195 200 205
Gin Lys Ser Phe Val Thr Gin His Ala Ala Phe Gly Tyr Met Ala Leu 210 215 220
Asp Tyr Gly Leu Asn Gin He Ser lie Asn Gly Val Thr Pro Asp Ala 225 230 235 240
Glu Pro Ser Ala Lys Arg lie Ala Thr Leu Ser Lys Tyr Val Lys Lys 245 250 255
Tyr Gly lie Lys Tyr lie Tyr Phe Glu Glu Asn Ala Ser Ser Lys Val 260 265 270
Ala Lys Thr Leu Ala Lys Glu Ala Gly Val Lys Ala Ala Val Leu Ser 275 280 285
Pro Leu Glu Gly Leu Thr Glu Lys Glu Met Lys Ala Gly Gin Asp Tyr 290 295 300
Phe Thr Val Met Arg Lys Asn Leu Glu Thr Leu Arg Leu Thr Thr Asp 305 310 315 320
Val Ala Gly Lys Glu lie Leu Pro Glu Lys Asp Thr Thr Lys Thr Val 325 330 335
Tyr Asn Gly Tyr Phe Lys Asp Lys Glu Val Lys Asp Arg Gin Leu Ser 340 345 350
Asp Trp Ser Gly Ser Trp Gin Ser Val Tyr Pro Tyr Leu Gin Asp Gly
Thr Leu Asp Gin Val Trp Asp Tyr Lys Ala Lys Lys Ser Lys Gly Lys 370 375 380
Met Thr Ala Ala Glu Tyr Lys Asp Tyr Tyr Thr Thr Gly Tyr Lys Thr 385 390 395 400
Asp Val Glu Gin lie Lys lie Asn Gly Lys Lys Lys Thr Met Thr Phe 405 410 415 -15- 144293·序列表.doc 201022442
Val Arg Asn Gly Glu Lys Lys Thr Phc Thr Tyr Thr Tyr Ala Gly Lys 420 425 430
Glu lie Leu Thr Tyr Pro Lys Gly Asn Arg Gly Val Arg Phe Met Phe 435 440 445
Glu Ala Lys Glu Ala Asp Ala Gly Glu Phc Lys Tyr Val Gin Phe Ser 450 455 460
Asp His Ala lie Ala Pro Glu Lys Ala Lys His Phe His Leu Tyr Trp 465 470 475 480
Gly Gly Asp Ser Gin Glu Lys Leu His Lys Glu Leu Glu His Trp Pro 485 490 495
Thr Tyr Tyr Gly Ser Asp Leu Ser Gly Arg Glu lie Ala Gin Glu lie 500 505 510
Asn Ala His 515 <210> 9 <211> 1629 含忠鍵球菌 <400> 9 gtgtcaaaat acctaaaata cttctctatt atcacgttat ttttgactgg gcttatttta 60 gttgcatgtc aacaacaaaa gcctcaaaca aaagaacgtc agcgcaaaca acgtccaaaa 120 gacgaacttg tcgtttctat gggggcaaag ctccctcatg aattcgatcc aaaggaccgt 180 tatggagtcc acaatgaagg gaatatcact catagcactc tattgaaacg ttctcctgaa 240 ctagatataa aaggagagct tgctaaaaca taccatctct ctgaagatgg gctgacttgg 300 tcgtttgact tgcatgatga ttttaaattc tcaaatggtg agcctgttac tgctgatgat 360 gttaagttta cttatgatat gttgaaagca gatggaaa£g cttgggatct aaccttcatt 420 aagaacgttg aagtagttgg gaaaaatcag gtcaatatcc atttgactga gscgcattcg 480 acatttacag cacagttgac tgaaatccca atcgtcccta aaaaacatta caatgataag 540 tataagagca atcctatcgg ttcaggacct tacatggtaa aagaatataa ggctggagaa 600 caagctattt ttgttcgtaa cccttattgg catgggaaaa aaccatactt taaaaaatgg 660 acttgggtct tacttgatga aaacacagca ctagcagctt tagaatctgg tgatgttgat 720 atgatctacs caacgccaga acttgctgat aaaaaagtca aaggcacccg cctccttgat 780 attccatcaa atgatgtgcg cggcttatca ttaccttatg tgaaaaassg cgtcatcact 840 gattctcctg atggttatcc tgtaggaaat gatgtcacta gtgatccagc aatccgaaaa 900 gccttgacta ttggtttaaa taggcaaaaa gttctcgata cggttttaaa tggttatggt 960 aaaccagctt attcaattat tgataaaaca ccattttgga atccaaaaac agccattaaa 1020 gataataaag tagctaaagc taagcaatta ttgacaaaag cgggatggaa agaacaagca 1080 gacggtagcc gtaaaaaagg tgaccttgat gcagcgtttg atctgtacta ccctactaat 1140 gatcaattgc gagcgaactt agccgttgaa gtagcagagc aagccaaggc cctagggatt 1200 •16· 144293·序列表.doc 201022442 actattaaac tcaaagctag taactgggat gaaatggcaa cgaagtcaca tgactcagcc ttactttatg ccggaggacg tcatcacgcg cagcaatttt atgaatcgca tcatccaagc ctagcaggga aaggttggac caatattacg ttttataaca atcctaccgt gactaagtac cttgacaaag caatgacatc ttctgacctt gataaagcta acgaatattg gaagttagcg cagtgggatg gcaaaacagg tgcttctact cttggagatt tgccaaatgt atggttggtg agccttaacc atacttatat tggtgataaa cgtatcaatg taggtaaaca aggcgtccac agtcatggtc atgattggtc attattgact aacattgccg agtggacttg ggatgaatca actaagtaa <210> 10 <211> 542 <212> PRT <213>釀腺鏈球菌 <400> 10
Val Ser Lys Tyr Leu Lys Tyr Phe Ser lie lie Thr Leu Phc Leu Thr 15 10 15
Gly Leu lie Leu Val Ala Cys Gin Gin Gin Lys Pro Gin Thr Lys Glu 20 25 30
Arg Gin Arg Lys Gin Arg Pro Lys Asp Glu Leu Val Val Ser Met Gly 35 40 45
Ala Lys Leu Pro His Glu Phe Asp Pro Lys Asp Arg Tyr Gly Val His 50 55 60
Asn Glu Gly Asn He Thr His Ser TT^r Leu Uu Lys Arg Ser Pro Glu
Leu Asp lie Lys Gly Glu Leu Ala Lys Thr Tyr His Leu Ser Glu Asp 85 90 95
Gly Leu Π,γ Trp Ser Phe Asp Leu His Asp Asp Phe Lys Phe Ser Asn
Gly Glu Pro Val Thr Ala Asp Asp Val Lys Phc Thr Tyr Asp Met Leu Π5 120 125
LvsAUAspGlvLys AUTrpAspLeuT.^e lie Lys Asn Va, Giu
Val Val Gly Lys Asn Gin Val Asn lie His Leu Thr Glu Ala His Ser 145 150 155 160
Thr Phe Thr Ala Gin Leu Thr Glu lie Pro He Val Pro Lys Lys His 165 170 175
Tyr As, Asp Lys Tyr Lys Ser Asn Pro He Gly Ser Gly Pro Tyr Met
Val LvsGluT.Lys Ala Gly Glu Gin A,a lie Phe Val Ar8 Asn Pro •17- 1260 1320 1380 1440 1500 1560 1620 1629 144293·序列表.doc 201022442
Tyr Trp His Gly Lys Lys Pro Tyr Phe Lys Lys Trp Thr Trp Val Leu 210 215 220
Leu Asp Glu Asn Thr Ala Leu Ala Ala Leu Glu Ser Gly Asp Val Asp 225 230 235 240
Met lie Tyr Ala Thr Pro Glu Leu Ala Asp Lys Lys Val Lys Gly Thr 245 250 255
Arg Leu Leu Asp lie Pro Ser Asn Asp Val Arg Gly Leu Ser Leu Pro 260 265 270
Tyr Val Lys Lys Gly Val lie Thr Asp Ser Pro Asp Gly Tyr Pro Val 275 280 285
Gly Asn Asp Val Thr Ser Asp Pro Ala He Arg Lys Ala Leu Thr lie 290 295 300
Gly Leu Asn Arg Gin Lys Val Leu Asp Thr Val Leu Asn Gly Tyr Gly 305 310 315 320
Lys Pro Ala Tyr Ser lie lie Asp Lys Thr Pro Phe Trp Asn Pro Lys 325 330 335
Thr Ala lie Lys Asp Asn Lys Val Ala Lys Ala Lys Gin Leu Leu Thr 340 345 350
Lys Ala Gly Trp Lys Glu Gin Ala Asp Gly Ser Arg Lys Lys Gly Asp 355 360 365
Leu Asp Ala Ala Phe Asp Leu Tyr Tyr Pro Thr Asn Asp Gin Leu Arg 370 375 380
Ala Asn Leu Ala Val Glu Val Ala Glu Gin Ala Lys Ala Leu Gly He 385 390 395 400
Thr lie Lys Leu Lys Ala Ser Asn Trp Asp Glu Met Ala Thr Lys Ser 405 410 415
His Asp Ser Ala Leu Leu Tyr Ala Gly Gly Arg His His Ala Gin Gin 420 425 430
Phe Tyr Glu Ser His His Pro Ser Leu Ala Gly Lys Gly Trp Thr Asn 435 440 445 lie Thr Phe Tyr Asn Asn Pro Thr Val Thr Lys Tyr Leu Asp Lys Ala 450 455 460
Met Thr Ser Ser Asp Leu Asp Lys Ala Asn Glu Tyr Trp Lys Leu Ala 465 470 475 480
Gin Trp Asp Gly Lys Thr Gly Ala Ser Thr Leu Gly Asp Leu Pro Asn 485 490 495
Val Trp Leu Val Ser Leu Asn His Thr Tyr lie Gly Asp Lys Arg lie 500 505 510 • 18· 144293-序列表.doc 201022442
Asn Val Gly Lys Gin Gly Val His Ser His Gly His Asp Trp Ser Leu 515 520 525
Leu Thr Asn lie Ala Glu Trp Thr Trp Asp Glu Ser Thr Lys 530 535 540
-19- 144293·序列表.doc
Claims (1)
- 201022442 七、申請專利範圍: 1· 一種免疫原性組合物,其包含兩種或更多種多肽之混合 物,各多肽由一種與選自由以下組成之群之核酸序列具 有至少90°/。一致性的核酸序列編碼: (a) C5a肽酶(「SCP」)(圖 1 (seq id ΝΟ:1)); (b) 開放閱讀框(「ORF」)554(圖 3 (SEQ ID NO:3)); (c) ORF 1218(圖 5 (SEQ ID N0:5)); (d) 〇RF 1358(圖 7(SEQIDN0:7));及 ⑷ ORF 2459(圖 9 (SEQ ID n〇:9))。 2. 如請求項1之免疫原性組合物,其另外包含生理上可接 受之媒劑。 3. 如請求項1之免疫原性組合物,其另外包含有效量之佐 劑。 4. 如請求項丨之免疫原性組合物,其中各多肽能產生特異 性識別該多肽之抗體,且其中該免疫原性組合物之量能 有效預防或改善β-溶金性鏈球菌在易感哺乳動物中定殖 或感染。 5. 如請求項丨之免疫原性組合物,其另外包含生理上可接 受之媒劑。 6. 如請求項丨之免疫原性組合物,其另外包含有效量之佐 劑。 7·如請求項4之免疫原性組合物,其中該ρ·溶血性鍵球菌係 Α型(Group)鏈球菌、Β型鏈球菌、c型鏈球菌或g型 菌。 144293.doc 201022442 8. 如請求項4之免疫原性組合物,其中該β_溶血性鏈球菌係 釀膿鏈球菌(Sirepiococcws pyogewej) 〇 9. 一種免疫原性組合物,其包含兩種或更多種多肽之混合 物’各多肽與一種選自由以下組成之群之胺基酸序列具 有至少90%之一致性: ⑷ SCP(圖 2 (SEQ ID NO:2)); (b) 肽基丙基異構酶(圖4(SEQIDNO:4)); (c) 假定蛋白(圖 6 (SEQ ID NO:6)); (d) 推定黏附蛋白(圖8 (SEQ ID NO:8));及 Ο)表面脂蛋白(圖 i〇(seqidno:io))。 10. 如請求項9之免疫原性組合物,其另外包含生理上可接 受之媒劑。 11. 如請求項9之免疫原性組合物,其另外包含有效量之佐 劑。 12. 如請求項9之免疫原性組合物,其中各多肽能產生特異 性識別該多肽之抗體,且其中該免疫原性組合物之量能 有效預防或改善β-溶血性鏈球菌在易感哺乳動物中定殖 或感染。 13. 如請求項12之免疫原性組合物,其另外包含生理上可接 受之媒劑。 14. 如請求項12之免疫原性組合物,其另外包含有效量之佐 劑。 15·如請求項12之免疫原性組合物,其中該卜溶血性鏈球菌 係Α型鏈球菌、β型鏈球菌、c型鏈球菌或G型鏈球菌。 144293.doc 201022442 16. 如請求項15之免疫原性組合物,其中性鍵球菌 係釀膿鏈球菌。 17. -種料易感哺乳動物免於β•溶血性鏈球菌定殖或感染 - m其包含向該哺乳動物投與有效量之如請求項1 之免疫原性組合物’其中各多肽能產生該多肽之特異性 抗體’且其中該免疫原性組合物之量能有效預防或改善 β-溶血性鏈球菌在該易感哺乳動物中定殖或感染。 籲18.如請求項17之方法’其中該免疫原性組合物係藉由皮下 注射、肌内注射、經口攝取、經鼻内、或其組合投與。 19·如請求項17之方法’其中該卜溶血性鏈球菌似型鍵球 菌、Β型鏈球菌、c型鏈球菌或G型鏈球菌。 20.如請求項19之方法,其中該^溶血性鏈球菌係釀膿 菌。 21·如請求項17之方法,其中該哺乳動物係人類。 22· -種保護易感哺乳動物免於β_溶血性鏈球菌定殖或感染 • 之方法,其包含向該哺乳動物投與有效量之如請求項9 之免疫原性組合物,其中各多肽能產生該多肽之特異性 抗體,且其中該免疫原性組合物之量能有效預防或改善 . β-溶也性鏈球菌在該易感哺乳動物中定殖或 23.如請求項22之方法,其中該免疫原性組合物係藉由皮下 注射、肌内注射、經口攝取、經鼻内、或其組合投與。 如π求項22之方法,其中該β_溶血性鏈球菌係a型鍵球 菌、B型鏈球菌、C型鏈球菌或〇型鏈球菌。 25.如明求項24之方法,.其中該卜溶血性鏈球菌係釀膿鏈球 144293.doc 201022442 菌。 26.如請求項22之方法,其中該哺乳動物係人類。 2 7. —種免疫原性組合物,其包含以下之混合物: (a) SCP多肽,其係由一種與圖1核酸序列(SEQ ID NO: 1)具有至少90%—致性之核酸序列編碼; (b) 肽基丙基異構酶多肽,其係由一種與圖3核酸序 列(SEQIDNO:3)具有至少90%—致性之核酸序列編碼;及 (c) 至少一種其他多肽,其係由一種與選自由以下組 成之群之核酸序列具有至少90% —致性之核酸序列編 碼:⑴圖 5 (SEQ ID N0:5) ; (ii)圖 7 (SEQ ID NO: 7);及 (iii)圖 9 (SEQ ID N0:9)。 28. 如請求項27之免疫原性組合物,其另外包含生理上可接 受之媒劑。 29. 如請求項27之免疫原性組合物,其另外包含有效量之佐 劑。 30. 如請求項27之免疫原性組合物,其中各多肽能產生特異 性識別該多肽之抗體,且其中該免疫原性組合物之量能 有效預防或改善β -溶血性鍵球菌在易感哺乳動物中定殖 或感染。 3 1 _如請求項30之免疫原性組合物,其另外包含生理上可接 受之媒劑。 32. 如請求項30之免疫原性組合物,其另外包含有效量之佐 劑。 33. 如請求項30之免疫原性組合物,其中該卜溶血性鏈球菌 144293.doc 201022442 係A型鏈球菌、B型鏈球菌、C型鏈球菌或G型鏈球菌。 34.如請求項33之免疫原性組合物,其中該β-溶血性鏈球菌 係釀膿鍵球菌。 3 5 · —種免疫原性組合物,其包含以下之混合物: (a) SCP多肽,其與圖2胺基酸序列(SEQ ID NO:2)具 有至少90%—致性; (b) 肽基丙基異構酶多肽,其與圖4胺基酸序列(seq ID NO:4)具有至少90%—致性;及 (c) 至少一種其他多肽’其與一種選自由以下組成之 群之胺基酸序列具有至少90%—致性:⑴圖6 (SEQ ID NO:6) ; (ii)圖 8 (SEQ ID NO:8);及(iii)圖 1〇 (SEQ Π) NO:10)。 36·如請求項35之免疫原性組合物,其另外包含生理上可接 受之媒劑。 37. 如請求項36之免疫原性組合物,其另外包含有效量之佐 劑。 38. 如請求項35之免疫原性組合物,其中各多肽能產生特異 性識別該多肽之抗體,且其中該免疫原性組合物之量能 有效預防或改善β-溶血性鏈球菌在易感哺乳動物中定殖 或感染。 39. 如請求項38之免疫原性組合物,其另外包含生理上可接 受之媒劑。 40. 如請求項38之免疫原性組合物,其另外包含有效量之佐 劑0 144293.doc 201022442 41.如請求項38之免疫原性組合物,其中該卜溶血性鏈球菌 係A型鏈球菌、b型鏈球菌、c型鏈球菌或G型鏈球菌。 42·如請求項41之免疫原性組合物’其中該卜溶血性鏈球菌 係釀膿鏈球菌。 43. —種保護易感哺乳動物免於卜溶血性鏈球菌定殖或感染 之方法,其包含向該哺乳動物投與有效量之如請求項π 之免疫原性組合物,其中各多肽能產生該多肽之特異性 抗體’且其中該免疫原性組合物之量能有效預防或改善 β-溶企性鏈球菌在易感哺乳動物中 从如請求項批方法,其中該免疫録組合^藉由皮下 注射、肌内注射、經σ攝取、經鼻内、或其組合投與。 45·如請求項43之方法,丨•溶域鏈球菌似型鍵球 菌、B型鏈球菌、C型鏈球菌或G型鏈球菌。 其中該β-溶血性鏈球菌係釀膿鏈球 46.如請求項45之方法 菌。 47.如請求項43之方法 其中該哺乳動物係人類。 从一種保護易感哺乳動物免於β_溶血性鏈球菌定殖或感染 之方法,其包含向該哺乳動物投與有效量之如請求項Μ ,免疫原性組合物’其中各多肽能產生該多肽之特異性 抗體’且其中該免疫原性組合物之量能有效預防或改善 β-洛血性鏈球菌在易感哺乳動物中定殖或感染。 49. 如請求項48之方法,其中該免疫原性組合物係藉由皮下 注射肌内注射、經口攝取、經鼻内、或其組合投與。 50. 如請求項48之方法’纟中師_溶血性鏈球㈣a型鍵球 144293.doc 201022442 菌、B型鏈球菌、C型鏈球菌或G型鏈球菌。 5 1 ·如請求項50之方法,其中該β-溶血性鏈球菌係釀膿鏈球 菌。 52.如請求項48之方法,其中該哺乳動物係人類。144293.doc
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WO2010053986A1 (en) | 2010-05-14 |
EP2356135A1 (en) | 2011-08-17 |
BRPI0921286B1 (pt) | 2021-11-23 |
DK2356135T3 (en) | 2017-12-04 |
NZ592368A (en) | 2013-11-29 |
ES2648231T3 (es) | 2017-12-29 |
CN107050442B (zh) | 2022-09-13 |
CN102203122A (zh) | 2011-09-28 |
EP2356135B1 (en) | 2017-10-25 |
CA2741691C (en) | 2019-11-26 |
RU2011116286A (ru) | 2012-12-20 |
JP2012508174A (ja) | 2012-04-05 |
US9127050B2 (en) | 2015-09-08 |
IL212491A0 (en) | 2011-06-30 |
US8563001B2 (en) | 2013-10-22 |
AU2009313615B2 (en) | 2012-11-29 |
MX2011004755A (es) | 2011-10-10 |
RU2478396C2 (ru) | 2013-04-10 |
AR074273A1 (es) | 2011-01-05 |
AU2009313615A1 (en) | 2010-05-14 |
BRPI0921286A8 (pt) | 2018-01-02 |
CA2741691A1 (en) | 2010-05-14 |
ZA201102894B (en) | 2012-06-27 |
KR20110081282A (ko) | 2011-07-13 |
US20100119534A1 (en) | 2010-05-13 |
PE20120116A1 (es) | 2012-02-18 |
US20140037669A1 (en) | 2014-02-06 |
CO6382162A2 (es) | 2012-02-15 |
BRPI0921286A2 (pt) | 2015-03-24 |
CN107050442A (zh) | 2017-08-18 |
NO2356135T3 (zh) | 2018-03-24 |
BRPI0921286B8 (pt) | 2022-10-25 |
NZ614064A (en) | 2015-04-24 |
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