TW520289B - Anti-selectin antibodies for prevention of multiple organ failure after polytrauma and for prevention of acute organ damage after extracorporeal blood circulation - Google Patents

Anti-selectin antibodies for prevention of multiple organ failure after polytrauma and for prevention of acute organ damage after extracorporeal blood circulation Download PDF

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TW520289B
TW520289B TW85112858A TW85112858A TW520289B TW 520289 B TW520289 B TW 520289B TW 85112858 A TW85112858 A TW 85112858A TW 85112858 A TW85112858 A TW 85112858A TW 520289 B TW520289 B TW 520289B
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selectin
pharmaceutical composition
ser
selectin antibody
antibody
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TW85112858A
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Man Sung Co
Ulrich Martin
Anton Haselbeck
Gunter Schumacher
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Protein Design Labs Inc
Scil Biomedicals Gmbh
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Abstract

Anti-selectin antibodies are used for reducing probability of incidence of polytraumatic events, such as organ failure. A pharmaceutical composition for treating polytraumatic event, comprising a therapeutically effective amount of an anti-selectin antibody in combination with a pharmaceutically acceptable carrier.

Description

520289 A7 B7 五、發明説明(i ) 本發明是有關使用抗選擇素抗體以預防和多重創傷有 關之多數器官衰竭,及預防和體外血液循環有關之急性器 官衰竭。尤佳者爲E -選擇素,L 一選擇素,及/或P — 選擇素之抗體。 發明背景 多重創傷經了解爲許多組織(骨骼或軟組織)之損傷 。於多重創傷事件中,介體系統(如細胞動素,花生四烯 酸產物,氧自由基,蛋白酶)以及白血球及其他細胞均被 活化。此可造成二次器官傷害(如由釋出之蛋白酶破壞組 織結構)。此種二次器官傷害可於全身發生,而與初以外 傷之位置無關。 多重創傷也可能與出血性休克有關。出血性休克終了 解爲特徵是血液向內或外側快速且相當程度流失之休克。 目前出血性休克可以澈底的醫療成功地處理,尤其是體液 替補及輸血。出血性休克加上創傷稱之爲出血性創傷休克 。和純粹的出血性休克相反的,目前對於創傷或出血性創 傷休克並無特異的療法,且對於多重創傷後之器官衰竭根 本無預防之道。 多數器官衰竭(MOF )爲在多重創傷經常會發生的 一個嚴重問題。受損的器官愈多,死亡率愈高。會衰竭的 器官及系統包括心臟、肺、腎、肝、胃、腸系統及中樞神 經系統。雖然近年來經由援救服務及急診醫療之改善,已 可將創傷患者之極高死亡率減少約2 0 %,然而對於器官 本紙張尺度適用中.國國家標準(CNS ) A4規格(210X297公釐) 一 4 — (請先閲讀背面之注意事項再填寫本頁) 訂 經濟部智慧財產局員工消費合作社印製 520289 A7 ____B7__ 五、發明説明(2 ) 衰竭仍無特異的療法。 M a r z i 等人,J · T r a u m a 35 : 110 - 119 ( 1 9 9 3 )揭示超氧物歧化酶可於創傷後2 4小時給予。 然而結果並不明率,且對部份改善僅有些傾向。然而並未 觀察到死亡率有實質的減少。Mileski, W. J. et al., Surgery 108:206 — 212 (1990)揭示嗜中 性球或其聚集物之結合,可實質地造成器官傷害後出血性 休克之發展。在此例中,實驗動物於9 0分鐘出血性休克 期後立即給予抗-C D 1 8抗體。Mileski並未描述多重 創傷後多數器官衰竭之療法。Vedder N. B. et al., Surgery 106:509-516(1989)也提出使 用抗一 CD 1 8抗體治療出血性休克。 經濟部中央標準局員工消費合作社印製 (請先閱讀背面之注意事項再填寫本頁) 頃發現選擇素,如L,E及P -選擇素與絕血及再灌 注過程中組織之傷害有關。在此關聯上嗜中性球扮演重要 角色。假設選擇素爲嗜中性球補充的必要的。明顯地L 一 選擇素爲骨机肌以及肺中傷害完全發展的必要的。( Seekamp a. et al., Am. J. Pathol. 1 1 : 5 9 2 -598 (1994) 。 Mulligan, M. S. et al·, J. Immunol· 151:832 — 840 (1994)描述一 個相似的現象e 人化抗一L一選擇素抗體之產製述於WO 94/ 1 2 2 1 5,已列爲參考文獻。提議使用此抗體治療發炎 性疾病且特別是心肌梗塞。提建1 - 5毫克劑量可預防急 性肺衰竭。然而,參考劑量並未描述於多重創傷後預防 本紙張尺度適用中國國家標準(CNS ) Α4規格(210X 297公釐) ~ _ -5 - 520289 A7 _B7___ 五、發明説明(3 ) Μ〇F之方法。 (請先閲讀背面之注意事項再填寫本頁) 因此在此有需要有效的療法以可預防及/或治療多重 創傷後之多數器官衰竭。 急性器官傷害也可在心血管手術中造成,如大動脈一 冠狀靜脈迴路手術或心臟瓣膜手術,在此病人的血液經由 心肺機器在體外循環。傷害程度依機器操作期間而定。此 可造成如肺之衰竭,此使病人在手術後之人口呼吸成爲必 要(B i rnbaura, D. e t a 1. , Z. Kardiol. 79,Suppl· 4 :87 — 93 (1990))。其他的器官如心、腎、肝 ,或系統如血液及凝血系統也會受損及衰竭。 由 Mulligan, M. S. e t a 1. , J. Immunol. 1 5 1 : 832 — 840 (1994)已知,可促進粘附作用之分 子,如L,E及P -選擇素係涉及於急性發炎過程。這些 分子可調介白血球與內皮細胞之粘附交互作用。在此相互 關係中,L -選擇素在急性肺內發光反應之最初階段(滾 動期)似乎扮演重要角色。Mulligan進一步陳述道,抗一 L 一選擇素抗體適於縮短由L -選擇素啓動之肺傷害期。 經濟部智慧財產局員工消費合作社印製 再者迄今尙無預防性療法已知,可被用於預防由於血 液體外循環所造成的急性器官傷害。因此,在此需要有效 的療法以預防因血液體外循環所造成的急性器官傷害。 發明目標 本發明目標是提出一種方法及治療組成物,可用於有 效地預防人體多重創傷後之多數器官衰竭,及可相當程度 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) ~ -6 - 520289 A7 B7 五、發明説明(4) 地減低多重創傷患者之死亡率。本發明是有關治療性使用 抗-選擇素抗體,及產製可用於預防多重器官衰竭及多重 創傷後死亡之藥學組成物。 本發明的目標也是提出含有抗-選擇素抗體之方法及 治療性組成物之用法,以預防體外循環後急性器官傷害。 此種器官傷害以本方法及步驟可大部份避免。方法的一個 特殊優點爲體外應用,其可造成器官併發病有效地減少β 附圖說明 圖1示出在觀察時間實驗動物肺之濕重。 圖2示出各種實驗動物關於時間之心血管變數C0( 心輸出量)。 圖3示出實驗動物關於時間之心血管變數MAP (平 均動脈血壓)。 圖4示出實驗動物關於時間之B E值(動脈超出基準 值)。 圖5示出各種實驗動物關於時間之白血球細胞數目。 經濟部中央標準局員工消費合作社印製 (請先閱讀背面之注意事項再填寫本頁) 詳細說明 本發明是有關使用至少一種抗選擇素抗體以產製藥學 組成物,以預防病人血液經由心肺機器體外循環後之急性 器官傷害,其中在體外循環結束前1至3 0分鐘時將抗選 擇素抗體以體外方式加入心肺機器之管路系統中’劑量爲 每公斤病人體重1·0—10毫克,且較好是2—4毫克 本紙張尺度適用中國國家標率(CNS ) A4規格(210X 公釐) 一 Ί 一 520289 A7 B7 五、發明説明(5 ) /公斤。 令人驚訝地,以此預防性體外投藥,可將病人血液體 外循環後之急性器官傷害大程度地預防。於一個較佳具體 實例中,在1 一 3天內將1一 4毫克/公斤抗選擇素抗體 ,如抗一 L 一選擇素抗體共1 一 3進一步劑量投予至患者 。多株或單株,鼠類,人類,嵌合體或人化的抗體/免疫 球蛋白及其結合片段可充作抗-選擇素抗體。在本發明一 方面治療性組成物並非投予至病人體內,而是經體外的, 即直接至心肺機器之管路系統內。 經濟部中央標準局員工消費合作社印製 (請先閱讀背面之注意事項再填寫本頁) 如此中所用的 >抗-選擇素抗體'係指可與選擇素結 合的任何抗體。尤佳者爲可特異結合至L -選擇素,E -選擇素或P -選擇素之一之抗體,以及其組合。而可與一 種以上選擇素反應之抗體也較佳,如可與L -及E -選擇 素二者反應之抗體。L -選擇素爲已知之糖蛋白,其可爲 所有的白血球原構地表現。L -選擇素及其鼠類同質物, GP 9 0及Me 1 1 4,均涉及淋巴細胞之正常再循環’ 其各自調升淋巴樣器官高內皮小靜脈(HEV s )中循環 淋巴細胞及血管配體(也稱之爲請求素〜addressins") 間之交互作用(L. A. Lasky,et al·,Cell 6 9:9 2 7- 9 38 (1992) ; Ε· L. Berg, et al·,J· Cell Biol. 114:343-349(1991))。除了在充作淋巴細胞回歸受體之角色外’ L -選擇素也涉及循環中白血球對非淋巴樣組織之粘附’如 發光中之內皮。L 一選擇素在白血球活化後可自白血球表 面脫落(Τ· K· Kishimoto, et al., Science 245:1238- 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) 一 8 - 520289 A7 _B7_ 五、發明説明(6 ) 124 1 ( 1 98 9 )),且此在發光部位上保留活化之白血球方 面是一個重要過程。L -選擇素具有與C型外源凝集素相 當同質的一個胺基末端碳水化合物確認區域(CRD)( K. Tr i ckhamer, J. Biol. Chem. 2 6 3 9 5 5 7 - 9 5 6 0 ( 1 9 8 8 ) ),繼之爲單一類上皮生長因子區域,補體調控區域,單 一穿膜多肽及羧基末端胞體漿區域。L -選擇素經由胺基 末端CRD,以一種與鈣有關之方式與其關聯配體交互作 用。 依據本發明,抗選擇素抗體較好可調控且更好可抑制 C R D區域及細胞表面相當碳水化合物受體間之交互作用 。此種碳水化合物受體由R. B. Parekh, Tibtech 12: 339-345 (1994)所述,已列爲參考文獻。這些碳水化合物 受體可爲磷醯化或硫酸化之糖類。 經濟部中央標率局員工消費合作社印製 (請先閱讀背面之注意事項再填寫本頁) 於本發明進一步的具體實例中,抗- P —及/或抗一 E —選擇素抗體可用於替代,或加上抗- L -選擇素抗體 。此種抗體可利用P -或E -選擇素產生(述於R. B. Parekh and T. F. Tedder, FASEB Journal 9:866-873( 1995),已列爲此中參考)。在本發明之特佳之具體實例中 ,使用抗一 P -及/或抗一 E -選擇素抗體,其可與L 一 選擇素抗體顯示相當的交叉反應性,尤其是與抗體 HuDreg-55或 HuDreg-200之交叉反 應性。 如此中所用的,a人化的免疫球蛋白#指含有人類架 構之免疫球蛋白,至少一個來自非人類抗體之互補決定區 本紙張尺度適用中國國家標準(CNS )八4規格(210X29?公釐) -9 - 520289 A7 B7 五、發明説明(7 ) (CDR),且其中任何存在的固定區均實質上和人類免 疫球蛋白固定區相同,即至少約8 5 — 9 0%,較好至少 9 5%相同。因此,人化免疫球蛋白的所有部份,可能 CDR s除外,均實質上和一個以上天然人類免疫球蛋白 序列的相當部份相同。如,人化的免疫球蛋白將不包括嵌 合的老鼠可變區域/人類固定區域抗體。如見歐洲專利案 EP A 451216,已列爲本案參考。 本發明也是有關此種抗一選擇素抗體之用法,以減少 多重創傷後之MO F及死亡率。令人驚訝地判知,在多重 創傷後十分快速地投予抗選擇素抗體’尤其是抗- L -選 擇素抗體時,將有可能避免多數器官衰竭。也十分驚訝之 處在於於此早期階段並無確實的症狀生成,且因此並無理 由投予此一劑量作爲預防措施。 經濟部中央標準局員工消費合作社印製 (請先閲讀背面之注意事項再填寫本頁) 也十分驚訝地判知,抗選擇素抗體劑量爲1·Ο-ΐ 0 毫克 / 公斤 ,較好 2 - 4毫克 / 公斤, 於多重 創傷後 投予1至5次,較好1或2次是有益的,在此第一次施用 儘可能的早,較好是多重創傷事件後〇 . 5 - 8小時,尤 佳爲0 · 5 — 4小時。個別施用之間隔爲約6及約7 2小 時之間,較好是6及3 6小時之間。 於一個較佳的具體實施例中,二次及接續之劑量及時 間可依血中抗-選擇素抗體之濃度而定,較好是血漿或血 清中之濃度,此爲早期可決定之變數。在此關聯下,較好 抗選擇素抗體之血漿濃度維持在1 0 - 1 0 0微克/毫升 ,在多重創傷事件後歷7 - 1 0天。此濃度相當於血漿中 本紙張尺度適用中國國家標準(CNS ) Λ4規格(210Χ 297公釐) 一 10 - 520289 A7 __^_B7 五、發明説明(8 ) 可溶性選擇素濃度之1 0 - 1 0 0倍過量。二次及接續施 用之劑量及時間可在6 - 2 4間隔下決定出血液,血清或 血漿中抗-選擇素抗體濃度而決定,且當血漿濃度下降至 10微克/毫升抗體下時立即投予基本上相當於第一次施 用劑量之劑。當抗體濃度介於1 0及5 0微克/毫升之間 時,投予第一次施用濃度約一半之抗體,且在5 0及 1 0 0微克/毫升之抗體濃度下則不進一步投予抗體。在 此例中僅有抗體濃度被進一步追踪。 血液,血清或血漿中之抗-選擇素抗體濃度以一般方 法決定,較好是免疫學決定法。此種方法爲精藝者已知的 。利用可利用E L I S A試驗決定,其中經標記之選擇素 特異抗體,較好是也治療性使用之抗體,共同競爭特異的 選擇素。於接下來的步驟中,再決定已結合至抗原之經標 記抗體含量,並由此決定出樣品中抗選擇素抗體之濃度。 本發明之治療用組成物通常採腸外方式投藥,如靜脈 內,動脈內,腹膜內,皮下或肌內。以靜脈內(i . ν . 經濟部中央標準局員工消費合作社印製 (請先閱讀背面之注意事項再填寫本頁) )爲較佳β組成物中之活性組份可呈液體或固體型式使用 ,較好呈經冷凍乾燥型式,且加上適合的稀釋劑或載劑一 起使用,如水或氯化鈉,右旋糖,緩衝物質之水溶液等。 也可加入其他適合的藥用輔佐物質。 選擇素之抗體可由技藝陳述中得知,且述於如:Ε Ρ —Α 0 3 8 6 9 0 6 * W 0 93/00111 及 W 0 94/12215,及 Kishimoto, Τ· K. et ai. ,Blood 78:8 0 5- 8 1 1 ( 1 9 9 1 )及 Proc· Natl· Acad· Sci. 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) " 一 一 11 一 520289 A7 B7 五、發明説明(9 ) USA 87:2241-2248(1990),以上均列爲參考用。文獻中L 一選擇素也稱爲LECAM-1 ,Me1 14或Lam (請先閱讀背面之注意事項再填寫本頁) 一 1。Lam - 1之選殖及序列已述於WO 9 3/ 0 2 6 9 8中。以可與選擇素特異結合的抗體爲適合的。 以人化的抗體爲適合的,尤其是HuDreg 200, 其述於WO 94/12215且列爲本案參考之用。可 與選擇素結合的其他抗體,如HuDr eg 55 (序列 :SEQ ID NO: 1 - 4)也特別佳。 經濟部中央標準局員工消費合作社印製 如此中所用的a抗體'經了解爲一種蛋白質,其由一 個以上的多肽鏈所組成,基本上由抗體基因所編碼。抗體 基因指導合成抗原特異的可變區,且也可指導合成基因之 固定區。抗體在本發明之意義中經了解可以是抗體的各種 衍生物及片段,如FV,Fab及F (ab)2,及個別 的抗體鏈(Houston et al·, PNAS USA 85 5 8 79-5883 ( 1988),Bird et al·, Science 242:423-426(1988), Hood et a 1. , Immunology, Benjamin N. Y. , 2nd edition ( 1984), Hunkapiller and Hood, Nature 323 15-16 ( 1986))。較好使用單株抗體及其片段,且特別是I g G 1 或I gG4亞型之嵌合體或人化抗體。 抗體較好含有至少二個輕的多肽鏈及二個重的多肽鏈 。這些鏈各自含有可變區(通常爲多肽鏈之N -末端部份 ),其依序含有可與抗原結合之區域。重及輕鏈可額外地 含有多肽之固定區(通常是C -末端部份),其調介抗體 與白血球(嗜中性球,淋巴球等)之結合。通常輕及重鏈 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐) - 12 - 520289 A7 B7 五、發明説明(ίο) 爲完全的抗體鏈,其由可變區及完全的固定區所組成。在 此關聯上,可變區及固定區可衍生自不同的抗體,如不同 的同型。如,含有抗-選擇素抗體r - 1同型重鏈可變區 之多肽,可與來自另一類(或亞類)抗體重鏈之固定區鏈 結。 其中一個以上的胺基酸被替換的抗-選擇素抗體也是 適合的。在此例中,胺基酸較好以具有相似特色之其他胺 基酸所置換(如酸性胺基酸A s p爲酸性胺基酸G 1 u置 換)。以此置換並不改變原先序列之結構特性。此種多肽 結構之實例述於 Proteins, Structures and Molecular Principles, Creighton (editor ), W. H. Freeman and Company, New York ( 1 9 84 ) ; Introduction to Protein Structure, C. Brandon and J. Tooze, Garland Pub 1 i-s shing , New York (1981); Thornton et al., Nature 354 105 (1991)。一般而言,適合充作抗一選擇素抗體之 抗體爲可結合L 一選擇素,E -選擇素,及P -選擇素一 種以上者及/或可抑制白血球之波動(如嗜中性球)。 經濟部中央標準局員工消費合作社印製 (請先閱讀背面之注意事項再填寫本頁) 除了此處特述之人化免疫球蛋白之外’利用精藝者熟 知的各種重組體D N A技術可容易地設計及製造其他~實 質上均質的"經修飾之免疫球蛋白。人類抗體’包括如 E u或GAL抗體,以及技藝中已知的其他人類抗體均可 充作架構序列來源。這些架構序列應可與C D R s衍生出 處之老鼠Dr eg 55或老鼠Dr eg 200可變區 域呈現高度的序列同質性。重及輕鏈可變架構區可衍生自 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) 一 13 - 520289 A7 ____B7 五、發明説明(11) 相同或不同的人類抗體序列。確實,重及輕鏈架構區域各 自可衍生自一種以上的人類抗體。人類抗體序列可爲自然 生成的人類抗體序列,或可爲許多人類抗體之一致序列。 見 Carteretal·, w〇 92/22653(1992) ,已列爲本案參考之用。 經濟部中央標準局員工消費合作社印製 (請先閱讀背面之注意事項再填寫本頁) A可以相當方式結合之抗體'經了解是可與選擇素相 同的或重疊的表位結合之抗體。表位重疊可以技藝中已知 之方法決定,如藉競爭性測試系統之助。可針對此進行競 爭性結合分析法,並決定出抗體與如HuDr eg 55 共同競爭與經固化之L -選擇素抗原結合之程度。針對此 ’以適合的方式固化之L -選擇素(較好是在白血球上之 L 一選擇素)與經標記型之HuDr eg 55培育,再 測試過量之抗體。決定出欲測試抗體與L -選擇素結合之 程度並與HuDr eg 55比較,此中係決定抗一白血 球-結合之標幟中已結合之標幟。若經標記之 H u D r e g 5 5爲欲測試之抗體置換至少5 0 %則表 示存在有重疊表位。和HuD r e g 5 5以相當方式結 合之抗體爲本發明中較佳者。 >可以相當方式結合之抗體〃也可由阻斷嗜中性球-內皮細胞交互作用能力之篩選中予以鑑和。偵測此種交互 作用的單純的目視分析法由Kishimoto et al. (Blood, 78:805(1991))所述。簡言之,將人類臍帶靜脈細胞單層 以間白素一 1刺激之。嗜中性球在有或無抗體於試驗中預 處理之下,加入在明確條件下之單片中,再以顯微鏡檢決 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) -14 - 520289 A7 B7_ 五、發明説明(l2) 定所粘附之嗜中性球之數目。於一個方法中,嗜中性球可 得自缺乏人類白血球粘附作用之患者。見Anderson et al ·, Ann. Rev. Med· 38:1 7 5 ( 1 9 8 7 )。得自此病患之嗜中性 球缺少整合素受體,其與嗜中性球之結合可能會遮蔽阻斷 L 一選擇素結合之作用。 抗體可使用者有完全的單株抗體,其片段(Fv,( Fv)2,Fab/,F(ab>)2),嵌合體,人化或 人類抗體。也可使用僅含有C D R區域其部份,但可與L 一選擇素特異地結合之短的抗體片段。 抗體且特別是單株抗體及其片段,其產製爲精藝者所 熟知的,且述於如 E.Harlow and D. Lane, Antibodies:A Laboratory Manual, Cold Spring Harbor Press (1988) ,Bessler et al., Immunobiol. 170:239-244(1985), Jung et al·, ,Angewandte Chemie’ 97:883(1985), Cianfiglia et al., Hybridoma Vol. 2: 451-457(1993) o 經濟部中央標準局員工消費合作社印製 (請先閲讀背面之注意事項再填寫本頁) 依據本發明可使用之抗-選擇素抗體也可以重組體方 法產生。此種過程述於Sambrook et al·, Molecular Cloning: A Laboratory Manual, 2nd edition (1989), Cold Spring Harbor, New York, Berger and Kimmel, M ethods in Enzymo 1 ogy, Vol. 152, Guide to Molecu-lar Cloning Techn i ques( 1 9 8 7 ), Academic Press Inc., San Diego CA,其已列入本案參考。此種重組體抗體可技 藝中已知之方法在真核或原核細胞中產生。哺乳動物,尤 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) 經濟部中央標準局員工消費合作社印製 520289 A7 B7 五、發明説明(I3) 其是淋巴細胞株,爲較佳之宿主細胞。嵌合體,人化或人 類抗體較好以重組方法產生。可被選出用於抗體非抗原結 合區域之區域,如 E· A· Kabat et al·, Sequences of Proteins of Immunological Interest (1987), Nation-al Institute of Health, , Bethesda MD中所述。重組 抗體一L一選擇素人化及人類抗體之產製述於WO 94 /1 2 2 1 5中,也列爲本案參考。特佳的人化抗一 L 一 選擇素抗體是HuDreg 55,其和此中所述之 HuDr eg 200以相同方式構築,且含有二個具 SEQ IN NO: 2序列之輕鏈,及二個其SEQ IN NO: 4序列之重鏈。 較佳之人化免疫球蛋白爲在標準結合條件下以至少1 X 1 0 7 M-1結合親和力與選擇素結合者(標準條件如 加有2%胚牛血清之2 5 °C下磷酸鹽緩衝之食鹽水)。此 人化免疫球蛋白之實例爲HuDr eg 55及 HuDreg 200。較佳的人化抗體爲在標準結合條 件下以至少1 X 1 0 8 Μ -1親和力,且更好是至少1 X 1 0 9 Μ-1之親和力,且更有益的是至少lxlO1。 Μ-1以上之親和力與人類選擇素結合者。通常人化免疫球 蛋白之結合親和力爲其衍生出處之老鼠免疫球蛋白3 -1 0因數之內。如,老鼠Dr eg 200抗體之親和力 爲約108 M-1,且老鼠Dr eg 55爲約109 Μ - 1 〇 以下的實例,序列策略,刊物及圖片進一步闡明本發 I紙張尺度適用中國國家標準(CNS ) Α4規格(210Χ 297公釐) " ' ~ 一 16 - (請先閲讀背面之注意事項再填寫本頁) 訂 520289 A7 ___B7_ 五、發明説明(Η) 明。應了解所述之過程僅爲說明用之實例,非予以限制, 其他在修飾之後描述本發明主題。 實例1 使用杭- L -選擇素抗體以減低創傷後之器官衰媪 證明人化抗體拮抗L -選擇素(抗一 L 一選.擇素)在 減少創傷後器官衰竭上之保護作用,如常見於嚴重多重創 傷患者損傷後發生的。以人化之抗一 L -選擇素抗體(520289 A7 B7 5. Description of the invention (i) The present invention relates to the use of anti-selectin antibodies to prevent most organ failures related to multiple trauma, and to prevent acute organ failure related to extracorporeal blood circulation. Particularly preferred are antibodies to E-selectin, L-selectin, and / or P-selectin. BACKGROUND OF THE INVENTION Multiple trauma is known as damage to many tissues (bone or soft tissue). During multiple trauma events, mediator systems (such as cytokines, arachidonic acid products, oxygen free radicals, proteases), as well as white blood cells and other cells are activated. This can cause secondary organ damage (such as tissue damage caused by released proteases). This secondary organ injury can occur throughout the body, regardless of the location of the primary injury. Multiple trauma may also be associated with hemorrhagic shock. Hemorrhagic shock is finally understood as a shock characterized by rapid and considerable loss of blood inward or outward. Currently, hemorrhagic shock can be successfully treated with medical treatment, especially fluid replacement and blood transfusion. Hemorrhagic shock plus trauma is called hemorrhagic traumatic shock. In contrast to pure hemorrhagic shock, there is currently no specific treatment for traumatic or hemorrhagic traumatic shock, and there is no way to prevent organ failure after multiple traumas. Most organ failure (MOF) is a serious problem that often occurs in multiple trauma. The more organs damaged, the higher the mortality rate. Organs and systems that fail include the heart, lungs, kidneys, liver, stomach, intestine, and central nervous system. Although in recent years through the improvement of rescue services and emergency medical care, the extremely high mortality rate of trauma patients has been reduced by about 20%, but the paper size of the organ is applicable. National Standard (CNS) A4 specification (210X297 mm) 4 — (Please read the notes on the back before filling this page) Order printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 520289 A7 ____B7__ 5. Description of the invention (2) There is no specific treatment for exhaustion. Ma r z i et al., J. T r a u m a 35: 110-119 (193 9) revealed that superoxide dismutase can be administered 24 hours after trauma. However, the results are not clear, and there is only a slight tendency for partial improvement. However, no substantial reduction in mortality has been observed. Mileski, W. J. et al., Surgery 108: 206 — 212 (1990) revealed that the combination of neutrophils or their aggregates can substantially cause the development of hemorrhagic shock following organ damage. In this example, the experimental animals were given anti-CD18 antibody immediately after the 90-minute hemorrhagic shock period. Mileski does not describe treatments for most organ failures after multiple trauma. Vedder N.B. et al., Surgery 106: 509-516 (1989) also proposed the use of anti-CD 18 antibody for the treatment of hemorrhagic shock. Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the notes on the back before filling this page). It was found that selectins, such as L, E, and P-selectin, are related to tissue damage during hemostasis and reperfusion. The neutrophil plays an important role in this connection. It is assumed that selectin is necessary for neutrophil supplementation. Obviously L-selectin is necessary for the complete development of osteoclastic muscle and lung injury. (Seekamp a. Et al., Am. J. Pathol. 1 1: 5 9 2 -598 (1994). Mulligan, MS et al., J. Immunol. 151: 832 — 840 (1994) describe a similar phenomenon e The production of humanized anti-L-selectin antibody is described in WO 94/1 2 2 1 5 and has been listed as a reference. It is proposed to use this antibody to treat inflammatory diseases, especially myocardial infarction. Build 1-5 mg The dose can prevent acute lung failure. However, the reference dose is not described in the prevention of multiple trauma. The paper size applies the Chinese National Standard (CNS) A4 specification (210X 297 mm) ~ _ -5-520289 A7 _B7___ 5. Description of the invention ( 3) The method of MOF. (Please read the precautions on the back before filling out this page) Therefore there is a need for effective therapies to prevent and / or treat most organ failures after multiple trauma. Acute organ injury can also be taken into consideration Caused by vascular surgery, such as aorta-coronary venous circuit surgery or heart valve surgery, where the patient's blood is circulated extracorporeally through a cardiopulmonary machine. The degree of injury depends on the operation of the machine. This can cause lung failure, which can cause after surgery Respiration is necessary (B i rnbaura, D. eta 1., Z. Kardiol. 79, Suppl. 4: 87-93 (1990)). Other organs such as the heart, kidney, liver, or systems such as blood and blood coagulation The system can also be damaged and fail. Known by Mulligan, MS eta 1., J. Immunol. 1 5 1: 832 — 840 (1994), molecules that promote adhesion, such as L, E, and P-selectin It is involved in the process of acute inflammation. These molecules can mediate the adhesion interaction between leukocytes and endothelial cells. In this relationship, L-selectin appears to play an important role in the initial phase (rolling phase) of the acute lung luminescence response. Mulligan further stated that anti-L-selectin antibodies are suitable for shortening the period of lung injury initiated by L-selectin. Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economics, and so far, no preventive therapies are known and can be used In order to prevent acute organ injury caused by extracorporeal blood circulation, effective therapy is needed to prevent acute organ injury caused by extracorporeal blood circulation. OBJECT OF THE INVENTION The object of the present invention is to propose a method and a treatment group. It can be used to effectively prevent most organ failure after multiple trauma in the human body, and it can be used to a considerable extent. This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) ~ -6-520289 A7 B7 V. Description of the invention (4 ) To reduce mortality in patients with multiple trauma. The present invention relates to the therapeutic use of anti-selectin antibodies and the production of pharmaceutical compositions that can be used to prevent multiple organ failure and multiple trauma deaths. The object of the present invention is also to propose a method containing an anti-selectin antibody and the use of a therapeutic composition to prevent acute organ injury after extracorporeal circulation. Such organ damage can be largely avoided by this method and procedure. A special advantage of the method is the in vitro application, which can cause organs and disease to effectively reduce β. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows the wet weight of the lungs of experimental animals at the observation time. Figure 2 shows the cardiovascular variables C0 (cardiac output) of various experimental animals over time. Figure 3 shows the cardiovascular variable MAP (mean arterial blood pressure) of experimental animals over time. Figure 4 shows the B E value of the experimental animals over time (the arteries exceed the baseline value). Figure 5 shows the number of white blood cell cells in various experimental animals over time. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the notes on the back before filling out this page) Detailed description The present invention is related to the use of at least one anti-selectin antibody to produce pharmaceutical compositions to prevent patient blood from passing through the heart and lung machines Acute organ injury after extracorporeal circulation, in which anti-selectin antibodies are added to the heart and lung machine's pipeline system in vitro from 1 to 30 minutes before the end of extracorporeal circulation. The dosage is 1.0-10 mg per kilogram of patient's body weight, And preferably 2-4 milligrams. This paper scale is applicable to China National Standards (CNS) A4 specifications (210X mm). Ί 520289 A7 B7 5. Invention description (5) / kg. Surprisingly, with this preventive in vitro administration, acute organ injury after extracorporeal circulation of the patient's blood can be largely prevented. In a preferred embodiment, a total of 1-4 mg / kg anti-selectin antibody, such as anti-L-selectin antibody, is administered to the patient in a further dose within 1 to 3 days. Multiple or single strains, murine, human, chimeric or humanized antibodies / immunoglobulins and their binding fragments can be used as anti-selectin antibodies. In one aspect of the invention, the therapeutic composition is not administered to a patient, but is administered externally, that is, directly into the piping system of a cardiopulmonary machine. Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling this page). ≫ Anti-selectin antibody 'used in this context means any antibody that can bind to selectin. Particularly preferred are antibodies that specifically bind to one of L-selectin, E-selectin or P-selectin, and combinations thereof. Antibodies that can react with more than one selectin, such as antibodies that can react with both L- and E-selectin, are also preferred. L-selectin is a known glycoprotein that can be constitutively expressed for all white blood cells. L-selectin and its murine homologues, GP 90 and Me 1 1 4, are involved in the normal recirculation of lymphocytes' and they each raise circulating lymphocytes and blood vessels in high endothelial veins (HEVs) of lymphoid organs Interactions between ligands (also called requestors ~ addressins ") (LA Lasky, et al ·, Cell 6 9: 9 2 7- 9 38 (1992); Ε · L. Berg, et al ·, J Cell Biol. 114: 343-349 (1991)). In addition to its role as a lymphocyte regression receptor, L-selectin is also involved in the adhesion of white blood cells to non-lymphoid tissues in circulation, such as the endothelium in luminescence. L-selectin can be detached from the surface of white blood cells after activation of white blood cells (T · K · Kishimoto, et al., Science 245: 1238- This paper size applies Chinese National Standard (CNS) A4 specification (210X 297 mm)-8- 520289 A7 _B7_ 5. Description of the invention (6) 124 1 (1 98 9)), and this is an important process in retaining activated white blood cells on the light-emitting site. L-selectin has an amine-terminated carbohydrate confirmation region (CRD) that is quite homogeneous to C-type exogenous lectin (K. Trickhamer, J. Biol. Chem. 2 6 3 9 5 5 7-9 5 6 0 (198 8)), followed by a single epithelial growth factor region, a complement regulatory region, a single transmembrane polypeptide and a carboxy-terminal cytosolic region. L-selectin interacts with its cognate ligand via an amino-terminal CRD in a calcium-related manner. According to the present invention, the anti-selectin antibody is better controllable and can better inhibit the interaction between the CRD region and the equivalent carbohydrate receptor on the cell surface. Such a carbohydrate receptor is described by R. B. Parekh, Tibtech 12: 339-345 (1994) and is listed as a reference. These carbohydrate receptors can be phosphorylated or sulfated sugars. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the notes on the back before filling this page) In a further specific example of the present invention, anti-P — and / or anti-E —selectin antibodies can be used instead , Or add anti-L-selectin antibodies. Such antibodies can be produced using P- or E-selectin (described in R. B. Parekh and T. F. Tedder, FASEB Journal 9: 866-873 (1995), which is incorporated herein by reference). In a particularly preferred embodiment of the present invention, anti-P- and / or anti-E-selectin antibodies are used, which can show comparable cross-reactivity with L-selectin antibodies, especially with antibodies HuDreg-55 or HuDreg Cross-reactivity of -200. As used herein, a humanized immunoglobulin # refers to an immunoglobulin containing a human structure, at least one from the complementarity determining region of a non-human antibody. The paper size is applicable to the Chinese National Standard (CNS) 8-4 (210X29? Mm). ) -9-520289 A7 B7 V. Description of the invention (7) (CDR), and any existing fixed region is substantially the same as the human immunoglobulin fixed region, that is, at least about 8 5-9 0%, preferably at least 9 5% are the same. Therefore, all parts of the humanized immunoglobulin, except for possible CDRs, are substantially identical to a considerable portion of more than one natural human immunoglobulin sequence. For example, humanized immunoglobulins will not include embedded mouse variable region / human fixed region antibodies. See, for example, European Patent EP A 451216, which has been incorporated by reference in this case. The invention also relates to the use of such anti-selectin antibodies to reduce MOF and mortality after multiple trauma. Surprisingly, it is possible to avoid most organ failures when anti-selectin antibody ', especially anti-L-selectin antibody, is administered very quickly after multiple trauma. It is also very surprising that no actual symptoms develop at this early stage, and therefore there is no reason to administer this dose as a precautionary measure. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page). It is also very surprising to know that the dose of anti-selectin antibody is 1.0--0 0 mg / kg, preferably 2- 4 mg / kg, it is beneficial to administer 1 to 5 times, preferably 1 or 2 times after multiple trauma. The first application is as early as possible, preferably 0.5 to 8 hours after the multiple trauma event. , Particularly preferably 0 · 5-4 hours. Individual application intervals are between about 6 and about 72 hours, preferably between 6 and 36 hours. In a preferred embodiment, the secondary and subsequent doses and time may depend on the concentration of anti-selectin antibody in the blood, preferably the concentration in plasma or serum, which is a variable that can be determined at an early stage. In this connection, the plasma concentration of the better anti-selectin antibody is maintained at 10-100 micrograms / ml, which lasts 7-10 days after the multiple trauma event. This concentration is equivalent to the Chinese paper standard (CNS) Λ4 specification (210 × 297 mm) in blood plasma. 10-520289 A7 __ ^ _ B7 V. Description of the invention (8) Soluble selectin concentration 1 0-1 0 0 Times excess. The dose and time of secondary and subsequent administration can be determined at 6-24 intervals by determining the concentration of anti-selectin antibodies in blood, serum or plasma, and administered immediately when the plasma concentration drops to 10 μg / ml antibody Substantially equivalent to the first dose. When the antibody concentration is between 10 and 50 μg / ml, about half of the antibody at the first administration is administered, and no further antibody is administered at the antibody concentration of 50 and 100 μg / ml . In this case only the antibody concentration was tracked further. The concentration of anti-selectin antibodies in blood, serum, or plasma is determined by a general method, preferably an immunological determination method. This method is known to the artisan. The determination can be made using the ELISA test, in which the labeled selectin-specific antibody, preferably the antibody that is also used therapeutically, competes for the specific selectin. In the next step, the labeled antibody content bound to the antigen is determined, and the concentration of anti-selectin antibody in the sample is determined from this. The therapeutic composition of the present invention is usually administered parenterally, such as intravenously, intra-arterially, intraperitoneally, subcutaneously or intramuscularly. Intravenous (i.v. printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page)) as the active component in the preferred β composition can be used in liquid or solid form , Preferably in a freeze-dried form, and used with a suitable diluent or carrier, such as water or sodium chloride, dextrose, an aqueous solution of a buffer substance, and the like. Other suitable medicinal auxiliary substances can also be added. Antibodies to selectins can be known from technical statements and described, for example: ΕΡ—Α 0 3 8 6 9 0 6 * W 0 93/00111 and W 0 94/12215, and Kishimoto, T.K. et ai. , Blood 78: 8 0 5- 8 1 1 (1 9 9 1) and Proc · Natl · Acad · Sci. This paper size is applicable to China National Standard (CNS) A4 specification (210X 297 mm) " 1-11 1 1 520289 A7 B7 V. Description of the Invention (9) USA 87: 2241-2248 (1990), all of which are listed for reference. In the literature, L-selectin is also called LECAM-1, Me1 14 or Lam (please read the notes on the back before filling this page). The selection and sequence of Lam-1 has been described in WO 9 3/0 2 6 9 8. An antibody capable of specifically binding to a selectin is suitable. Humanized antibodies are suitable, especially HuDreg 200, which is described in WO 94/12215 and listed for reference herein. Other antibodies that can bind to selectin, such as HuDr eg 55 (sequences: SEQ ID NOs: 1 to 4) are also particularly preferred. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. The a-antibody used in this is known as a protein, which is composed of more than one polypeptide chain, which is basically encoded by the antibody gene. Antibody genes direct the synthesis of antigen-specific variable regions, and may also direct the synthesis of fixed regions of genes. It is understood in the sense of the present invention that antibodies can be various derivatives and fragments of antibodies, such as FV, Fab and F (ab) 2, and individual antibody chains (Houston et al., PNAS USA 85 5 8 79-5883 ( 1988), Bird et al., Science 242: 423-426 (1988), Hood et a 1., Immunology, Benjamin NY, 2nd edition (1984), Hunkapiller and Hood, Nature 323 15-16 (1986)). Monoclonal antibodies and fragments thereof, and particularly chimeric or humanized antibodies of the IgG1 or IgG4 subtype are preferred. The antibody preferably contains at least two light polypeptide chains and two heavy polypeptide chains. Each of these chains contains a variable region (usually the N-terminal portion of a polypeptide chain), which in turn contains regions that can bind to an antigen. The heavy and light chains may additionally contain a fixed region of the polypeptide (usually the C-terminal portion) that mediates the binding of antibodies to white blood cells (neutrophils, lymphocytes, etc.). Generally, the paper size of the light and heavy chains is in accordance with the Chinese National Standard (CNS) A4 (210X 297 mm)-12-520289 A7 B7 V. The description of the invention (ίο) is a complete antibody chain, which consists of a variable region and a complete Composed of fixed areas. In this connection, the variable and fixed regions can be derived from different antibodies, such as different isotypes. For example, a polypeptide containing the variable region of an anti-selectin antibody r-1 isotype heavy chain may be linked to a fixed region from the heavy chain of another type (or subtype) of antibody. Anti-selectin antibodies in which more than one amino acid is replaced are also suitable. In this example, the amino acid is preferably replaced with another amino acid having similar characteristics (for example, the acid amino acid Asp is replaced by the acid amino acid G 1 u). This substitution does not change the structural characteristics of the original sequence. Examples of such polypeptide structures are described in Proteins, Structures and Molecular Principles, Creighton (editor), WH Freeman and Company, New York (1894); Introduction to Protein Structure, C. Brandon and J. Tooze, Garland Pub 1 is shing, New York (1981); Thornton et al., Nature 354 105 (1991). In general, antibodies suitable as anti-selectin antibodies are those that can bind more than one of L-selectin, E-selectin, and P-selectin and / or can suppress fluctuations in white blood cells (such as neutrophils) . Printed by the Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the notes on the back before filling out this page) In addition to the humanized immunoglobulins described here, it is easy to use various recombinant DNA technologies well known to the artisan To design and manufacture other ~ substantially homogeneous " modified immunoglobulins. Human antibodies ' including, for example, Eu or GAL antibodies, as well as other human antibodies known in the art, can be used as sources of architectural sequences. These structural sequences should be highly sequence homogeneous with the mouse Dr eg 55 or mouse Dr eg 200 variable regions from which CDRs are derived. The heavy and light chain variable architecture regions can be derived from the paper size applicable to China National Standard (CNS) A4 specifications (210X 297 mm)-13-520289 A7 ____B7 V. Description of the invention (11) The same or different human antibody sequences. Indeed, each of the heavy and light chain framework regions can be derived from more than one human antibody. The human antibody sequence may be a naturally occurring human antibody sequence, or it may be the consensus sequence of many human antibodies. See Carteretal, WO 92/22653 (1992), which has been listed for reference in this case. Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the notes on the back before filling out this page) A. Antibodies that can be bound in a considerable way are known to be antibodies that can bind to the same or overlapping epitopes. Epitope overlap can be determined by methods known in the art, such as with the help of competitive testing systems. A competitive binding assay can be performed to determine this, and determine the extent to which the antibody will compete with HuDr eg 55 for binding to the solidified L-selectin antigen. For this, L-selectin (preferably L-selectin on white blood cells) solidified in a suitable manner was incubated with labeled HuDr eg 55, and then tested for excess antibody. Determine the degree of binding of the antibody to L-selectin to be tested and compare it with HuDr eg 55. This is to determine the combined flag in the anti-leukocyte-binding flag. If the labeled Hu D r e g 5 5 is at least 50% replaced by the antibody to be tested, this indicates the presence of overlapping epitopes. Antibodies that bind to HuD r g 5 5 in a comparable manner are preferred in the present invention. > Antibodies that can be combined in a comparable manner can also be identified by screening for the ability to block neutrophil-endothelial cell interaction. A simple visual analysis to detect such interactions is described by Kishimoto et al. (Blood, 78: 805 (1991)). In brief, a single layer of human umbilical vein cells was stimulated with melatonin-1. The neutrophil was pretreated in the test with or without antibodies, added to a single piece under clear conditions, and then examined with a microscope to determine the paper size. Applicable to China National Standard (CNS) A4 (210X 297 mm). -14-520289 A7 B7_ 5. Description of the Invention (l2) Determine the number of neutrophils to be attached. In one approach, neutrophils can be obtained from patients lacking human leukocyte adhesion. See Anderson et al., Ann. Rev. Med. 38: 1 7 5 (19 8 7). The neutrophil from this patient lacks the integrin receptor, and its binding to the neutrophil may obscure the effect of blocking L-selectin binding. The antibody may be a user having a complete monoclonal antibody, a fragment thereof (Fv, (Fv) 2, Fab /, F (ab >) 2), a chimera, a humanized or a human antibody. Short antibody fragments containing only a portion of the CDR region, but specifically binding to L-selectin can also be used. Antibodies, especially monoclonal antibodies and fragments thereof, are well-known by the artisan and are described in, for example, E. Harlow and D. Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Press (1988), Bessler et al. al., Immunobiol. 170: 239-244 (1985), Jung et al.,, Angewandte Chemie '97: 883 (1985), Cianfiglia et al., Hybridoma Vol. 2: 451-457 (1993) Printed by the Consumer Bureau of Standards Bureau (please read the notes on the back before filling out this page) The anti-selectin antibodies that can be used according to the present invention can also be produced by recombinant methods. This process is described in Sambrook et al., Molecular Cloning: A Laboratory Manual, 2nd edition (1989), Cold Spring Harbor, New York, Berger and Kimmel, M ethods in Enzymo 1 ogy, Vol. 152, Guide to Molecu-lar Cloning Techn ques (189 7), Academic Press Inc., San Diego CA, which has been included in this case for reference. Such recombinant antibodies can be produced in eukaryotic or prokaryotic cells by methods known in the art. Mammals, the paper size of the paper applies the Chinese National Standard (CNS) A4 specification (210X 297 mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 520289 A7 B7 V. Description of the invention (I3) It is a lymphocyte strain. Best host cell. Chimeric, humanized or human antibodies are preferably produced recombinantly. Regions that can be selected for non-antigen-binding regions of antibodies are described in E.A. Kabat et al., Sequences of Proteins of Immunological Interest (1987), Nation-al Institute of Health, Bethesda MD. Recombinant antibody-L-selectin humanization and production of human antibodies are described in WO 94/1/2 2 15 and are also incorporated herein by reference. A particularly good humanized anti-L-selectin antibody is HuDreg 55, which is constructed in the same manner as the HuDr eg 200 described herein, and contains two light chains with the sequence of SEQ IN NO: 2 and two of them. SEQ IN NO: 4 The heavy chain of the sequence. Preferred humanized immunoglobulins are those that bind to the selectin with a binding affinity of at least 1 X 1 0 7 M-1 under standard binding conditions (standard conditions such as phosphate buffer at 25 ° C with 2% embryonic bovine serum added) Of salt water). Examples of such humanized immunoglobulins are HuDr eg 55 and HuDreg 200. A preferred humanized antibody is an affinity of at least 1 X 108 M-1 under standard binding conditions, and more preferably an affinity of at least 1 X 109 M-1, and even more beneficial is at least lxlO1. Binding agent with affinity above M-1 and human selectin. Usually the binding affinity of humanized immunoglobulins is within the 3-10 factor of the mouse immunoglobulins from which it is derived. For example, the affinity of the mouse Dr eg 200 antibody is about 108 M-1, and the mouse Dr eg 55 is about 109 M-10. The following examples, sequence strategies, publications, and pictures further clarify that the paper standard of this publication is applicable to Chinese national standards ( CNS) Α4 specification (210 × 297 mm) " ~ ~ 16-(Please read the precautions on the back before filling this page) Order 520289 A7 ___B7_ 5. Description of the invention (Η). It should be understood that the processes described are merely examples for illustration and are not limiting, others describe the subject matter of the present invention after modification. Example 1 Use of Hang-L-selectin antibody to reduce post-traumatic organ failure proves that humanized antibodies antagonize the protective effect of L-selectin (anti-L-selection.selectin) on reducing post-traumatic organ failure, as is common Occurs after injury in patients with severe multiple trauma. Humanized anti-L-selectin antibody (

H u D r e g 55)充作抗體。其也可與狒狒的L 一選 擇素反應。此抗體之老鼠型式由Kishimoto述於PNAS , USA 87 (1990) 2244-2248。人化序列示於 S E Q ID N 〇:1 一 4 0 經濟部中央標準局員工消費合作社印製 (請先閲讀背面之注意事項再填寫本頁)Hu Dre e 55) acts as an antibody. It can also react with L-selectin of baboons. The mouse version of this antibody is described by Kishimoto in PNAS, USA 87 (1990) 2244-2248. The humanization sequence is shown in S E Q ID N 〇: 1 to 4 0 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page)

HuDreg 55及HuDreg 200抗體可 與人類白血球上之L -選擇素反應,然而僅有 HuDreg 5 5可與狒狒白血球之L 一選擇素反應。 因此使用HuDreg 55。由於HuDreg 55 及HuDr eg 200在相同的濃度範圍下與人類白血 球結合(如於FACS分析中),狒狒上HuDr eg 5 5之作用大部份和HuDr eg 200的作用相當。 至於模式,可在狒狒中誘生體有血容積減少之嚴重的 組織傷害(二向內及/或向外喪失液體及血液)。單純的 血液流失加上接續的休克(出血性休克)和肺部傷害較無 關(Pretorius et al·,J. Trauma 1987; 27:1344-1353 ;Schlag et al·, page 384-402,於 Schlag, Redl: 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) -17 - 520289 A7 __B7 _ 五、發明説明(l5)HuDreg 55 and HuDreg 200 antibodies can react with L-selectin on human white blood cells, but only HuDreg 5 5 can react with L-selectin on baboon white blood cells. Therefore HuDreg 55 was used. Because HuDreg 55 and HuDr eg 200 bind to human leukocytes at the same concentration range (as in the FACS analysis), most of the effects of HuDr eg 5 5 on baboons are comparable to those of HuDr eg 200. As for the pattern, inducers in baboons can have severe tissue damage (two inward and / or outward fluid and blood loss) with reduced blood volume. Pure blood loss plus subsequent shock (hemorrhagic shock) is less relevant to lung injury (Pretorius et al., J. Trauma 1987; 27: 1344-1353; Schlag et al., Page 384-402, in Schlag, Redl: This paper size applies to Chinese National Standard (CNS) A4 (210X 297 mm) -17-520289 A7 __B7 _ V. Description of the invention (l5)

Pathophysiology of Shock, Sepsis, and Organ Failu-re, Springer Verlag, Berlin, 1 9 9 3 )。此符合臨床的經 驗,即肺併發症罕見於單純的出血性休克(Sch lag et a 1 •,1 9 9 3見上)。 爲了決定創傷後肺衰竭之頻率及嚴重度,必須觀察動 物數天(即:SELEC 971 ,SELEC 9 7 9 (處理組);及(:〇 968,Co 969,Co 9 7 0 (對照組));然後基於道德理由無法在意識清楚 之動物中誘生骨折並且使之未處理達數天之久,如此在此 亞慢性模式中組織創傷係模擬的。補體系統之活化似乎是 細胞系統活化中最早開始的,且在身體的非細菌發炎反應 之快速發生中扮演關鑑角色(Schlag et al., 1 9 9 3,上 示)。因此,在模式中補體由眼鏡蛇毒液因子所活化。在 嚴重多重創傷後多數器官衰竭之死亡率在相關文獻中爲 1 5 — 3 0%。於本動物模式中,多重創傷之嚴重生增加 至死亡率至少高於先前在人類中之2倍以上之程度。因此 觀察期限於3天。 經濟部中央標準局員工消費合作社印製 (請先閱讀背面之注意事項再填寫本頁) 體重(BW)在1 8及2 2公斤之成年狒狒在3個月 的檢疫後許可進行研究。經禁食的動物以氯胺酮(6 - 8 毫克/公斤)鎮靜,再插管並接上CPAP呼吸器(連續 的正氣管壓力)(25±2%的吸氣〇2濃度)。以1 一 3毫克/公斤/小時戊巴比妥維持麻醉。動物可自主地呼 吸。將Swan Ganz導管推入肺動脈內,利用右頸靜脈。抽 血及測血壓之導管綁在右臂動脈。大的管腔導管引入頸動 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) 520289 A7 _B7_ 五、發明説明(I6) 經濟部中央標準局員工消費合作社印製 (請先閲讀背面之注意事項再填寫本頁) 脈以暫時收集血液。再將輸血,醫療及採血用之導管引入 左臂靜脈。膀胱插管以偵測尿產量。Swan Ganz導管及動 脈導管留置3天。爲使流體平衡,動物在麻醉期間接受5 毫升/公斤/小時林格氏液(供腸外液體替補用之電解質 溶液)。藉紅外燈之助將動物之血液溫度保持在237 °C 。進行血液氣體分析(P〇2,pC02,pH,BE, HC03-)並決定血液動力學變數(MAP,RAP, PAP ,CO,HR)。利用呼吸速率(RR)及最末呼 出之C 0 2決定肺功能。重覆採血以偵測白血球細胞數目 (WBCs)。眼鏡蛇毒液因子以每i ·ν.10單位/ 公斤之劑量於再輸血之初投予,並於再輸血後1小時再給 予5單位/公斤劑量。調節啓動血容積減少之抽血’如此 MAP (平均動脈壓力)可在4 0及5 0毫米汞柱之間, 且C〇(心輸出量)減少5 0 - 7 0 %。針對此通常抽取 約5 0毫升/公斤,且貯存直到再輸血爲止。有缺陷的縮 環維持2 - 3小時,並以此方式控制使其線超出不多於一 5至一 7mE Q。於此休克期末了,開始先前所收集血液 之再輸血。此時期持續4小時。 額外地投予林格氏液以補充再輸血。人化抗體 H u D r e g 5 5或相當體積之食鹽水充作空白組’於 再輸血開始後1 5分鐘於靜脈內投藥。抗- L -選擇素抗 體以2毫克/公斤劑雩投予。於再輸血末了,動物自麻醉 中醒來、並回檻內再觀察。於2 4小時,4 8小時及7 2 小時,再以誘導低水平之麻醉,並登記偵測變數且抽血。 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) ^ 19 - 520289 經濟部中央標準局員工消費合作社印製 A7 B7 五、發明説明(Π) 若動物在三天觀察期末了前未死亡,再予以犧牲及驗屍。 研究的主要終點爲死亡,存活期及對肺之器官傷害。 於第一次實驗中,三隻對照組動物以空白溶液處理, 且二隻給予HuD I· e g 5 5人化抗體。於三隻對照組 動物中,二隻在三天觀察期末了前之第3 8及4 1小時時 死亡,而二隻以抗-L-選擇素處理的動物則存活。在以 抗體處理之動物中,以肺濕重表示器官傷害程度η乎是正 常的(正常值7 — 8克/公斤BW),而其在所有三隻以 空白組處理之對照動物中則相當的增加(圖1 )。此係由 於滲透性失調症後流體之浸潤所致。在存活動物中,其心 血管變數C02&MAP (圖2及3 )於2 4小時時更佳 於對照動物。瀕死的對照組動物也有負面的動脈基線過量 (BE),顯示混亂的酸一鹼平衡(圖4)。於對照組動 物中所觀察到的白血球增多(白血球增加)並不見於抗體 動物中(圖5 )。 賨例2 使用抗- L -選擇素抗體以減低創傷後之死亡率 繼續實例1所報告之實驗,並擴大以包括2 8隻狒狒 ,其任意指定至如實例1所述進行的二個實驗組之一。狒 狒接受2毫升/公斤,i · v ·的抗—L —選擇素抗體, 或充作對照組之適合的空白體積-劑量,此係在絕血期後 開始再灌注後1 5分鐘時注射。研究統計分析的主要終點 是3天觀察期末了時之死亡率及存活時間。以Fisher’s確 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) (請先閱讀背面之注意事項再填寫本頁) 訂 - 20 - 520289 A7 B7 五、發明説明(18) 實試驗進行死亡率分析,而對數-排列-試驗前行存活時 間分析。報告單方的P值(經由活性處理減少死亡率或延 長存活時間)。只有當所估計統計可能性(P ) < 0.05時,才排斥無益的假說。 抗- L -選擇素抗體在對照組中可減低死亡率,由 14隻狒狒中之10隻( = 70%) (ρ<0·05)至 活性處理組中之3隻(=2 1 % ),具統計意義。此外, 抗一L一選擇素組中之存活時間延長至64.4小時,而 對照組動物較早死亡(Ρ<0·05),平均爲42小時 。此差異具統計意義。 下表縮合結果ζ (請先閱讀背面之注意事項再填寫本頁)Pathophysiology of Shock, Sepsis, and Organ Failu-re, Springer Verlag, Berlin, 1 9 9 3). This is consistent with clinical experience that pulmonary complications are rarer than purely hemorrhagic shock (Sch lag et a 1 •, 193 supra). In order to determine the frequency and severity of post-traumatic lung failure, animals must be observed for several days (ie: SELIC 971, SELIC 9 7 9 (treatment group); and (: 0968, Co 969, Co 9 7 0 (control group)) ; Then, for moral reasons, fractures cannot be induced in unconscious animals and left untreated for several days, so that tissue trauma is simulated in this subchronic model. The activation of the complement system seems to be the earliest of the cellular system It starts and plays a key role in the rapid occurrence of non-bacterial inflammatory reactions in the body (Schlag et al., 193, shown above). Therefore, complement is activated by cobra venom factor in the model. In severe multiple The mortality rate for most post-traumatic organ failures is 15-30% in the relevant literature. In this animal model, the severity of multiple trauma increases to at least twice as high as the previous rate in humans. Therefore, The observation period is 3 days. Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling out this page). Adult baboons with weights (BW) of 18 and 22 kg are in 3 Research is permitted after quarantine. Fasted animals are sedated with ketamine (6-8 mg / kg), then intubated and connected to a CPAP respirator (continuous positive tracheal pressure) (25 ± 2% inspiratory 〇2 Concentration). Maintain anesthesia with pentobarbital at 1.3 mg / kg / h. Animals can breathe spontaneously. Push the Swan Ganz catheter into the pulmonary artery and use the right jugular vein. The catheter for drawing blood and measuring blood pressure is tied to the right arm Arteries. Large lumen catheters are introduced into the neck. The paper size is applicable to Chinese National Standard (CNS) A4 (210X 297 mm) 520289 A7 _B7_ V. Description of Invention (I6) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please first Read the instructions on the back and fill in this page) to temporarily collect blood. Then introduce the blood transfusion, medical and blood collection catheter into the left arm vein. Bladder cannula to detect urine production. Swan Ganz catheter and arterial catheter are left for 3 days. For fluid balance, animals receive 5 ml / kg / hr Ringer's solution (an electrolyte solution for parenteral fluid replacement) during anesthesia. The temperature of the animal's blood is maintained at 237 ° C with the help of infrared lamps Perform blood gas analysis (P02, pC02, pH, BE, HC03-) and determine hemodynamic variables (MAP, RAP, PAP, CO, HR). Use respiratory rate (RR) and the last exhaled C 0 2 Determine lung function. Repeat blood collection to detect the number of white blood cells (WBCs). Cobra venom factor is administered at the beginning of retransfusion at a dose of i · ν.10 units / kg, and then administered 1 hour after retransfusion Dosage of 5 units / kg. Adjust the blood draw for the reduction of the starting blood volume so that the MAP (mean arterial pressure) can be between 40 and 50 mm Hg and the C0 (cardiac output) is reduced by 50-70% . About 50 ml / kg is usually drawn for this and stored until re-transfusion. Defective shrinkage is maintained for 2-3 hours and controlled in this way to keep its line beyond no more than 5 to 7mE Q. At the end of this shock period, re-transfusion of blood collected previously is started. This period lasts 4 hours. Ringer's solution was additionally administered to supplement re-transfusion. The humanized antibody Hu D r e g 5 5 or an equivalent volume of saline was used as a blank group 'and administered intravenously 15 minutes after the start of retransfusion. The anti-L-selectin antibody was administered at a dose of 2 mg / kg. At the end of the re-blood transfusion, the animal woke up from anesthesia and returned to the threshold for observation. At 24 hours, 48 hours, and 72 hours, low-level anesthesia was induced, and detection variables were registered and blood was drawn. This paper size applies to Chinese National Standard (CNS) A4 (210X 297 mm) ^ 19-520289 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (Π) No death, sacrifice and post-mortem. The primary endpoints of the study were death, survival, and organ damage to the lungs. In the first experiment, three control animals were treated with a blank solution, and two were given HuD I · g 5 5 humanized antibodies. Of the three control animals, two died at 38 and 41 hours before the end of the three-day observation period, while two animals treated with anti-L-selectin survived. In the animals treated with antibodies, the degree of organ damage expressed by lung wet weight was almost normal (normal value 7-8 g / kg BW), while it was comparable in all three control animals treated with the blank group. Increase (Figure 1). This is due to the infiltration of fluids after osmotic disorders. In surviving animals, the cardiovascular variable C02 & MAP (Figures 2 and 3) was better than the control animals at 24 hours. The dying control animals also had a negative arterial baseline excess (BE), showing a chaotic acid-base balance (Figure 4). The increase in leukocytes (increased white blood cells) observed in control animals was not seen in antibody animals (Figure 5). Example 2 Use of anti-L-selectin antibodies to reduce post-traumatic mortality The experiment reported in Example 1 was continued and expanded to include 28 baboons, arbitrarily assigned to two experimental groups performed as described in Example 1 one. Baboons received 2 ml / kg of anti-L-selectin antibody, i.v., or a suitable blank volume-dose as a control group, which was injected 15 minutes after the start of reperfusion after the hemorrhage period. The primary endpoint of the study's statistical analysis was mortality and survival at the end of the 3-day observation period. Use Fisher's to confirm that the paper size is in accordance with Chinese National Standard (CNS) A4 specification (210X 297mm) (Please read the precautions on the back before filling out this page) Order-20-520289 A7 B7 V. Description of the invention (18) Field test Mortality analysis was performed, and log-rank-survival analysis was performed before the trial. Report unilateral P values (reduce mortality or prolong survival by active treatment). Only when the estimated statistical probability (P) < 0.05 is the non-useful hypothesis rejected. Anti-L-selectin antibody reduced mortality in the control group, from 10 of 14 baboons (= 70%) (ρ < 0.05) to 3 of the active treatment group (= 2 1%) It has statistical significance. In addition, the survival time in the anti-L-selectin group was extended to 64.4 hours, while the animals in the control group died earlier (P < 0.05), with an average of 42 hours. This difference is statistically significant. Condensed results ζ (please read the notes on the back before filling this page)

、1T 死亡率 存活時間(小時) 抗一 L -選擇素抗體 3/14" 64·4土 4·7+ 空白一對照組 10/14 42·4土 5· 7 經濟部中央標準局員工消費合作社印製 平均土平均的標準偏差; η = 14(每組); *,ρ<0 · 05利用Fisher’s確實試驗; +,P < 0 · 0 5利用對數一排列—試驗。 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) -21 - 520289 A7 __B7 五、發明説明(19) 觀察期爲7 2小時。 這些數據顯示,將由於出血性-創傷休克造成絕血-再 灌注傷害之狒狒,投予抗- L -選擇素之早期處理可顯著 地延長存活時間及減低死亡率,此與空白一對照組比較而 言。 ' 實例3 使用抗一 L 一選擇素抗體以減少體外而液循環後之器官傷 研究拮抗L -選擇素之人化抗體,較好是 H u D r e g 5 5,在體外血液循環後減少器官傷害之 保護作用,此種狀況爲在心臟手術中心肺機器長時期操作 後常會發生的。 經濟部中央標準局員工消費合作社印製 (請先閱讀背面之注意事項再填寫本頁) 至於模式,可於狒狒中經由心肺機器操作達數小時而 引起嚴重的肺傷害,此機器係可在心臟停止後接管肺及心 臟之功能。一旦關掉機器,重新開始心臟之泵送作用,並 再開始內源的循環及呼吸作用,活化的白血球會大量浸潤 至肺循環中造成肺部嚴重傷害。存在於肺循環中之白血球 可局部釋出高濃度之毒性介體,其造成血管內皮之傷害且 接下來滲透性增加。於此過程中,流體由血管空間流過到 肺胞內(最小的肺部肺胞),造成流體在肺部之聚集。此 破壞肺中氣體之交換,因此開始依賴人口呼吸。當氟體交 換嚴重地增加時氧需求增加,且此由於肺胞一內皮障壁之 本紙張尺度適用中國國家標隼(CNS ) A4規格(2Κ)Χ 297公釐) 一 22 - 520289 A7 B7____ 五、發明説明(20) 纖維增殖性轉形作用將更形惡化。因此’在特別嚴重的例 子中,呼吸道內吸入之氧氣濃度將由尋常的約2 0%增加 至約1 0 0%。然而,在此例子中,供應純氧並不足以維 持血液中動脈氧濃度或氧部份壓力在適度之水平下。 纖維增殖性轉形作用過程及肺水腫造成肺動脈壓力之 增加,其係與肺相連如此造成右心室之緊張。若這些反應 進一步累積最後會由於心肺衰竭而死亡。 經濟部中央標準局員工消費合作社印製 (請先閲讀背面之注意事項再填寫本頁) 令體重(BW)在1 8及2 2公斤間之成年狒狒於3 個月檢疫後進行研究。經禁食的動物以氯胺酮(6 - 8毫 克/公斤)使鎮靜,插管,再接上CP A P呼吸器(2 5 ±2%的吸氣02濃度)。以1 一 3毫升/公斤/小時之 戊巴比妥維持麻醉。動物可自主呼吸。再經由右頸靜脈推 Swan Ganz導管至肺動脈內。抽血及偵測血壓用之導管綁 至右臂動脈。用於輸血,醫療及採血之導管則引入左臂靜 脈內。膀胱插管以測出尿產量。爲使流體平衡,動物接受 5毫升/公斤/小時之林格氏液。動物血液溫度由紅外燈 之助維持在37°C。進行血液氣體分析(P〇2,PC02 ,PH,BE,HC03-),且決定血液動力學變數( MAP,RAP,PAP,C〇,HR)。利用呼吸率( RR)及最末呼出之CO2來決定肺功能。重覆採血以偵 測白血球細胞之數目(W B C )。 於實驗開始之初打開胸腔(胸腔切開術),再備妥靜 脈腔及大動脈。之後,首先是靜脈腔繼以大動脈接上套管 ,如此來自靜脈腔之血液可流入心肺機器,再回至大動脈 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) - 23 - 520289 A7 B7 五、發明説明(21) 。心肺機中之蠕動泵承擔起心臟之泵送功能,並確保維持 循環所需之壓力梯度。以膜和氧作用達成氧之交換及二氧 化碳之結合。將血液肝素化,如此管道及血管均不會阻塞 。血液經由管道系統再回至大動脈,逆經由正常血管系統 分佈於體內。 心肺機器接管心及肺之功能。心臟停止而機器在操作 中,如此操作之外科醫生可在心臟瓣膜上工作(插入人工 物)。 經濟部中央標準局員工消費合作社印製 (請先閱讀背面之注意事項再填寫本頁) 在4小時之體外循環末了前1 5分鐘,將2毫克/公 斤HuD r e g 5 5或空白組相同體積劑量直接投予至 心肺機系統內。於體外循環末了後動物再觀察4小時。重 覆如前之偵測,於體外循環之前,之中及之後進行。特別 要記錄動脈血中氣體及酸鹼平衡之變數,心血管變數如平 均動脈血壓,右動脈壓,肺動脈壓,心輸出量及心博速率 ,肺功能(如最末呼出之C 0 2 ),並抽血以進行血液學 ,臨床化學(如腎及肝功能)及生化分析。此外,也測出 尿量(腎功能)。再者,也決定肺中滲透性失調症之變數 。於實驗末了動物犧牲及驗屍,並進行組織學檢查以決定 各種器官及系統傷害程度,如心,肺,肝,腎,腸, CNS,血液等。預期以HuDr eg 55處理之動物 可較以空白處理組持續較少的器官傷害。 序列表 (1 ) 一般資料 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) 一 24 - 520289 A7 B7 五、發明説明(22) (i )申請人 (A )名字:Martin, Ulrich, et al. (i i )發明名稱:用於受創傷後防止多數器官衰竭及 用於體外血液循環後防止急性器官損傷之抗選擇素抗體。 (i i i )序列數目:4 (i v )通訊住址: , (A ) Felfe & Lynch Attn: Norman D. Hanson (B ) 805 Third Avenue (C ) New York (D ) New York (E ) U. S. A. (F ) 10022 (v )電腦可讀型式: (A) 媒體型式:3,5"電腦磁碟 (B )電腦:I B M p C可相容 經濟部中央標準局員工消費合作社印製 (請先閱讀背面之注意事項再填寫本頁) (C)操作系統:PC—DOS/MS—DOS (D )軟體:A S C I I (v i )目前申請資料 (A )申請編號:欲指定 (B) 20-DeC - 95 (C )分類:5 3 0 (v i i )先前申請資料: (A) 申請編號:EP 95 1 1 2 8 9 5.8 (B) 立檔日期:17 — Aug — 1995 本紙張尺度適用中國國家標準(CNS )八4規格(210 X 297公釐) 520289 • A 7 B7 五、發明説明(23) (A) 申請編號:EP 95 114 969.9 (B) 立檔日期·· 19 一 Sep-1995 (A) 申請編號·· US 08 5 7 8 9 5 3 (B) 立檔曰期:27 — Dec — 1995 (viii)法律事務代理資料 (A )名稱:H a n s ο η , N 〇 r m a n D · (B)註冊號:30,946 (C )參考 / 索引號:BOER 1 0 5 9 -PFF/NDH (i x )電傳資料 (A) 電話:(212) 688 - 92 00 (B) 傳真:(212) 838 - 3884 (2 ) S E Q ID N〇:l 資料 (i )序列特性 經濟部中央標準局員工消費合作社印製 (請先閱讀背面之注意事項再填寫本頁) (A)長度:654鹼基對 (B )型式:核酸 (C )股性:雙股 (D )拓撲學:線型 (ii)分子型式:cDNA (i X )特色, 1T mortality, survival time (hours) anti-L-selectin antibody 3/14 " 64 · 4 土 4 · 7 + blank control group 10/14 42 · 4 土 5 · 7 Staff Consumer Cooperatives, Central Bureau of Standards, Ministry of Economic Affairs Standard deviation of printed average soil average; η = 14 (per group); *, ρ < 0 · 05 using Fisher's exact test; +, P < 0 · 0 5 using logarithmic one permutation-test. This paper size applies to China National Standard (CNS) A4 specification (210X 297 mm) -21-520289 A7 __B7 V. Description of the invention (19) The observation period is 72 hours. These data show that early treatment with anti-L-selectin for baboons with hemorrhagic-traumatic shock caused by hemorrhagic-traumatic shock can significantly prolong survival and reduce mortality, compared with the blank control group In terms of. '' Example 3 Use of anti-L-selectin antibodies to reduce organ damage after in vitro and liquid circulation studies Humanized antibodies against L-selectin, preferably Hu D reg 5 5, reduce organ damage after extracorporeal blood circulation Protective effect, this kind of situation often occurs after long-term operation of the lung machine in the heart surgery center. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) As for the mode, it can be operated for several hours in a baboon via a heart-lung machine, which can cause serious lung injury. Take over lung and heart functions after stopping. Once the machine is turned off, the pumping action of the heart is resumed, and the endogenous circulation and breathing action is resumed. Activated white blood cells will infiltrate the pulmonary circulation in large quantities and cause serious lung injury. The white blood cells present in the pulmonary circulation can locally release high concentrations of toxic mediators, which cause damage to the vascular endothelium and subsequent increase in permeability. During this process, fluid flows from the vascular space into the lung cells (the smallest lung cell), causing the fluid to accumulate in the lungs. This disrupts the exchange of gas in the lungs and therefore begins to depend on the population to breathe. Oxygen demand increases when fluoride exchange is severely increased, and because of the paper size of the lung cell-endothelial barrier, the Chinese National Standard (CNS) A4 (2K) x 297 mm is applicable.-22-520289 A7 B7____ V. Description of the invention (20) The fibroproliferative transformation effect will be worsened. Therefore, in a particularly severe case, the concentration of oxygen inhaled in the respiratory tract will increase from about 20% to about 100%. However, in this example, the supply of pure oxygen is not sufficient to maintain arterial oxygen concentration or partial pressure of oxygen at a moderate level. Fibroproliferative transformation and pulmonary edema increase pulmonary artery pressure, which is connected to the lungs and thus causes tension in the right ventricle. If these reactions accumulate, they will eventually die from cardiopulmonary failure. Printed by the Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling this page). Make adult baboons with body weight (BW) between 18 and 22 kg to conduct research after 3 months of quarantine. The fasted animals were sedated with ketamine (6-8 mg / kg), intubated, and connected to a CP AP respirator (2 5 ± 2% inspiratory 02 concentration). Anesthesia was maintained with pentobarbital at 1 to 3 ml / kg / hour. Animals can breathe spontaneously. Then push the Swan Ganz catheter through the right jugular vein into the pulmonary artery. A catheter for drawing blood and detecting blood pressure was tied to the right arm artery. For transfusion, medical and blood collection catheters are introduced into the left vein. The bladder was intubated to measure urine output. To equilibrate the fluid, animals received 5 ml / kg / hour Ringer's solution. Animal blood temperature was maintained at 37 ° C with the help of infrared lamps. Blood gas analysis (P02, PC02, PH, BE, HC03-) was performed, and hemodynamic variables (MAP, RAP, PAP, Co, HR) were determined. Respiratory rate (RR) and the last exhaled CO2 are used to determine lung function. Blood was collected repeatedly to detect the number of white blood cells (W B C). The thorax was opened at the beginning of the experiment (thoracotomy), and the veins and aorta were prepared. After that, the venous cavity was first connected with the aorta with a cannula, so that blood from the venous cavity could flow into the cardiopulmonary machine, and then return to the aorta. 520289 A7 B7 5. Description of the invention (21). The peristaltic pump in the heart-lung machine performs the pumping function of the heart and ensures the pressure gradient required to maintain circulation. The exchange of oxygen and the combination of carbon dioxide are achieved by the action of membrane and oxygen. The blood is heparinized so that the pipes and blood vessels are not blocked. The blood returns to the aorta through the piping system and is distributed in the body through the normal vascular system. Cardiopulmonary machines take over the functions of the heart and lungs. The heart stops and the machine is in operation, so that the surgeon can work on the heart valve (insertion of an artificial object). Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page). 15 minutes before the end of the extracorporeal circulation for 4 hours, dose 2 mg / kg HuD reg 5 5 or the same volume of the blank group Directly into the heart-lung machine system. Animals were observed for an additional 4 hours after the end of extracorporeal circulation. Repeat the previous test, before, during and after extracorporeal circulation. In particular, the variables of gas and acid-base balance in arterial blood, cardiovascular variables such as mean arterial blood pressure, right arterial pressure, pulmonary arterial pressure, cardiac output and heart rate, and pulmonary function (such as the last exhaled C 0 2), and Blood is drawn for hematology, clinical chemistry (such as kidney and liver function) and biochemical analysis. In addition, urine volume (renal function) was also measured. Furthermore, it also determines the variables of osmotic disorders in the lungs. Animals were sacrificed and necropsied at the end of the experiment, and histological examinations were performed to determine the degree of damage to various organs and systems, such as heart, lung, liver, kidney, intestine, CNS, blood, etc. Animals treated with HuDr eg 55 are expected to sustain less organ damage than the blank treatment group. Sequence Listing (1) General Information This paper size applies to Chinese National Standard (CNS) A4 specifications (210X297 mm)-24-520289 A7 B7 V. Description of invention (22) (i) Applicant (A) Name: Martin, Ulrich , et al. (ii) Invention name: anti-selectin antibody for preventing most organ failure after trauma and for preventing acute organ damage after extracorporeal blood circulation. (iii) Number of sequences: 4 (iv) Address: (A) Felfe & Lynch Attn: Norman D. Hanson (B) 805 Third Avenue (C) New York (D) New York (E) USA (F) 10022 (v) Computer readable type: (A) Media type: 3, 5 " Computer disk (B) Computer: IBM p C Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Compatible Economy (Please read the note on the back first) Please fill in this page again for matters) (C) Operating system: PC—DOS / MS—DOS (D) Software: ASCII (vi) Current application information (A) Application number: To specify (B) 20-DeC-95 (C) Category: 5 3 0 (vii) Previous application materials: (A) Application number: EP 95 1 1 2 8 9 5.8 (B) Date of filing: 17 — Aug — 1995 This paper size applies to Chinese National Standard (CNS) 8 4 Specifications (210 X 297 mm) 520289 • A 7 B7 V. Description of the Invention (23) (A) Application No .: EP 95 114 969.9 (B) Date of incorporation ·· 19-Sep-1995 (A) Application No. ·· US 08 5 7 8 9 5 3 (B) Date of filing: 27 — Dec — 1995 (viii) Legal affairs agency information (A) Name: Hans ο η, N 〇rman D · (B) Registration number: 30 , 946 (C) Reference / Index: BOER 1 0 5 9 -PFF / NDH (ix) Telex (A) Telephone: (212) 688-92 00 (B) Fax: (212) 838-3884 (2 ) SEQ ID NO: l Information (i) Sequence characteristics Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) (A) Length: 654 base pairs (B) Type: Nucleic acid (C) strand: double strand (D) topology: linear (ii) molecular type: cDNA (i X)

(A) 名稱/索引:CDS (B) 位置:1,,654 (xi)序列說明:SEQ ID Ν Ο : 1 本紙張尺度適用中國國家標準(CNS ) Α4規格(210Χ 297公釐) 一 26 - 520289 A7 ___B7 五、發明説明(Μ) 4 4 4 2 9 1 ο 4 2 6(A) Name / Index: CDS (B) Position: 1,654 (xi) Sequence description: SEQ ID Ν Ο: 1 This paper size applies to China National Standard (CNS) A4 specification (210 × 297 mm)-26- 520289 A7 ___B7 V. Description of the Invention (Μ) 4 4 4 2 9 1 ο 4 2 6

GAC ATT CAG ATG ACC CAA TCT CCG AGC TCT TTG TCT GCG TCT GTA GGGGAC ATT CAG ATG ACC CAA TCT CCG AGC TCT TTG TCT GCG TCT GTA GGG

Asp 工le Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15Asp Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15

GAT AGG GTC ACT ATC ACC TGC AAG GCC AGC CAA AGT GTT GAT TAT GATGAT AGG GTC ACT ATC ACC TGC AAG GCC AGC CAA AGT GTT GAT TAT GAT

Asp Arg Val Thr lie Thr Cys Lys Ala Ser Gin Ser Val Asp Tyr Asp 20 25 30Asp Arg Val Thr lie Thr Cys Lys Ala Ser Gin Ser Val Asp Tyr Asp 20 25 30

GGT GAT AGT TAT ATG AAC TGG TAC CAA CAG AAA CCA GGA AAG GCA CCCGGT GAT AGT TAT ATG AAC TGG TAC CAA CAG AAA CCA GGA AAG GCA CCC

Gly Asp Ser Tyr Met Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro 35 40 45Gly Asp Ser Tyr Met Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro 35 40 45

AAG CTT CTC ATC TAT GCT GCA TCC AAC CTA GAA TCT GGT ATC CCA TCCAAG CTT CTC ATC TAT GCT GCA TCC AAC CTA GAA TCT GGT ATC CCA TCC

Lys Leu Leu 工le Tyr Ala Ala Ser Asn Leu Glu Ser Gly lie Pro Ser 50 55 60Lys Leu Leu Engineer Tyr Ala Ala Ser Asn Leu Glu Ser Gly lie Pro Ser 50 55 60

AGG TTT AGT GGC AGT GGG TCT GGG ACA GAC TTC ACC CTC ACC ATC TCTAGG TTT AGT GGC AGT GGG TCT GGG ACA GAC TTC ACC CTC ACC ATC TCT

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser 65 70 75 80Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser 65 70 75 80

TCT CTG CAG CCG GAG GAT TTC GCA ACC TAT TAC TGT CAG CAA AGT AATTCT CTG CAG CCG GAG GAT TTC GCA ACC TAT TAC TGT CAG CAA AGT AAT

Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Asn 85 90 95Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Asn 85 90 95

GAA GAT CCG TGG ACG TTC GGT CAA GGC ACC AAG GTG GAA ATC AAA CGAGAA GAT CCG TGG ACG TTC GGT CAA GGC ACC AAG GTG GAA ATC AAA CGA

Glu Asp Pro Trp Thr Phe Gly Gin Gly Thr Lys Val Glu 工le Lys Arg 100 105 110 ACT GTG GCT GCA CCA TCT GTC TTC ATC TTC CCG CCA TCT GAT GAG CAG 384 一 Thr Val Ala Ala Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu Gin I 115 120 125 、、、 部· ^ TTG AAA TCT GGA ACT GCC TCT GTT GTG TGC CTG CTG AAT AAC TTC TAT 43 2 標 Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr f 130 135 140 局 員 CCC AGA GAG GCC AAA GTA CAG TGG AAG GTG GAT AAC GCC CTC CAA TCG 480 ' 費 Pro Arg Glu Ala Lys Val Gin Trp Lys Val Asp Asn Ala Leu Gin Ser 合 145 150 155 160 作 社 印 製 本紙張尺度適用中國國家標率(CNS ) A4規格(210X297公釐) -27 - 520289 A7 B7 五、發明説明(25) GGT AAC TCC CAG GAG AGT GTC ACA GAG CAG GAC AGC AAG GAC AGC ACC 528 Gly Asn Ser Gin Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr 165 170 175 TAC AGC CTC AGC AGC ACC CTG ACG CTG AGC AAA GCA GAC TAG GAG AAA 576 Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys 180 .185 190 CAC AAA GTC TAC GCC TGC GAA GTC ACC CAT CAG GGC CTG AGC TCG CCC 624 His Lys Val Tyr Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro 195 200 205 GTC ACA AAG AGC TTC AAC AGG GGA GAG TGT 654 Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 (請先閱讀背面之注意事項再填寫本頁)Glu Asp Pro Trp Thr Phe Gly Gin Gly Thr Lys Val Glu Le Lys Arg 100 105 110 ACT GTG GCT GCA GCA CCA TCT GTC TTC ATC TTC CCG CCA TCT GAT GAG CAG 384-Thr Val Ala Ala Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu Gin I 115 120 125 、,,, and Ministry ^ TTG AAA TCT GGA ACT GCC TCT GTT GTG TGC CTG CTG AAT AAC TTC TAT 43 2 Standard Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr f 130 135 140 Bureaux CCC AGA GAG GCC AAA GTA CAG TGG AAG GTG GAT AAC GCC CTC CAA TCG 480 'Fee Pro Arg Glu Ala Lys Val Gin Trp Lys Val Asp Asn Ala Leu Gin Ser 145 150 155 160 Standards apply to China National Standards (CNS) A4 specifications (210X297 mm) -27-520289 A7 B7 V. Description of invention (25) GGT AAC TCC CAG GAG AGT GTC ACA GAG CAG GAC AGC AAG GAC AGC ACC 528 Gly Asn Ser Gin Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr 165 170 175 TAC AGC CTC AGC AGC ACC CTG ACG CTG AGC AAA GCA GAC TAG GAG AAA 576 Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys 180. 185 190 CAC AAA GTC TAC GCC TGC GAA GTC ACC CAT CAG GGC CTG AGC TCG CCC 624 His Lys Val Tyr Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro 195 200 205 GTC ACA AAG AGC TTC AAC AGG GGA GAG TGT 654 Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 (Please read the notes on the back before filling this page)

經濟部中央標準局員工消費合作社印製 (2 ) S E Q ID N0:2 資料 (i )序列特性 (A )長度:2 1 8 (B )型式:胺基酸 (C )股性:單股 (D )拓撲學:線型 (i i)分子型式:蛋白質 (xi)序列描述:SEQ ID NO: 2 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) M9 - 28 - 520289 經濟部中央標準局員工消費合作,社印製 A7 B7 五、發明説明(26)Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (2) SEQ ID N0: 2 Data (i) Sequence characteristics (A) Length: 2 1 8 (B) Type: Amino acid (C) Share property: Single share (D ) Topology: Linear (ii) Molecular type: Protein (xi) Sequence description: SEQ ID NO: 2 This paper size applies to Chinese National Standard (CNS) A4 (210X 297 mm) M9-28-520289 Central Standard of the Ministry of Economic Affairs Bureau's consumer cooperation, printed by the company A7 B7 V. Invention description (26)

Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 l〇 15Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 l〇 15

Asp Arg Val Thr lie Thr Cys Lys Ala Ser Gin Ser Val Asp Tyr Asp 20 25 30 'Asp Arg Val Thr lie Thr Cys Lys Ala Ser Gin Ser Val Asp Tyr Asp 20 25 30 '

Gly Asp Ser Tyr Met Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro 35 40 45Gly Asp Ser Tyr Met Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro 35 40 45

Lys Leu Leu lie Tyr Ala Ala Ser Asn Leu Glu Ser Gly lie Pro Ser 50 55 60Lys Leu Leu lie Tyr Ala Ala Ser Asn Leu Glu Ser Gly lie Pro Ser 50 55 60

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser 65 70 75 80Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser 65 70 75 80

Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Asn 85 90 95Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Asn 85 90 95

Glu Asp Pro Trp Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg 100 105 110Glu Asp Pro Trp Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg 100 105 110

Thr Val Ala Ala Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu Gin 115 120 125Thr Val Ala Ala Pro Ser Val Phe lie Phe Pro Pro Asp Glu Gin 115 120 125

Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr 130 135 140Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr 130 135 140

Pro Arg Glu Ala Lys Val Gin Trp Lys Val Asp Asn Ala Leu Gin Ser 145 150 155 160Pro Arg Glu Ala Lys Val Gin Trp Lys Val Asp Asn Ala Leu Gin Ser 145 150 155 160

Gly Asn Ser Gin Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr 165 170 175Gly Asn Ser Gin Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr 165 170 175

Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys 180 185 190Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys 180 185 190

His Lys Val Tyr Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro 195 200 205His Lys Val Tyr Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro 195 200 205

Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 本紙張尺度適用中國國家標準(CNS ) M規格(210X297公釐) (請先閲讀背面之注意事項再填寫本頁)Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 This paper size is applicable to Chinese National Standard (CNS) M specification (210X297 mm) (Please read the precautions on the back before filling this page)

-29 - 520289 A7 B7 五、發明説明(27)-29-520289 A7 B7 V. Description of Invention (27)

E S 2 /{V 序 \Jy \1/ Nly XI/ A B c D .1 ( /IN ( ( iE S 2 / (V sequence \ Jy \ 1 / Nly XI / A B c D .1 (/ IN ((i

XX

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X AX A

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X 特度式性撲子色稱置色稱置列 Q 列長型股拓分特名位特名位序 性X special style flutter color call color call Q line long stock extension special name special name order

料資 3 〇 N D 3 酸股線: 1 核雙:式 ...... 學型 對基鹼 9 2Material 3 〇 N D 3 acid strand: 1 nuclear double: formula ...... type of base 9 2

A N D 型 C S D C引索 9 2 3 (請先閱讀背面之注意事項再填寫本頁) 弓索 肽 t a m Q E S明說A N D Type C S D C Index 9 2 3 (Please read the notes on the back before filling this page) Bowstring peptide t a m Q E S

DD

3 ο N 經 濟 部 中 梢 Μ j、 工 消 費 合 作 社 印 製 GAA GTG CAA CTG GTG GAG TCT GGG GGA GGC TTA GTG CAG CCT GGA GGA 483 ο N The Ministry of Economic Affairs, the Ministry of Economic Affairs, printed by the Consumer Cooperative Agency GAA GTG CAA CTG GTG GAG TCT GGG GGA GGC TTA GTG CAG CCT GGA GGA 48

Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15 AGC TTG AGA CTC TCC TGT GCA GCC TCT GGA TTC ACT TTC AGT ACC TAT 96Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15 AGC TTG AGA CTC TCC TGT GCA GCC TCT GGA TTC ACT TTC AGT ACC TAT 96

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr 20 25 30 本紙張尺度適用中國國家標準(CNS ) A4規格(210x297公釐) -30 - 520289 A7 B7 五、發明説明(28) GCC ATG TCT TGG GTT CGC CAG GCT CCA GGG AAG GGA CTC GAG TGG GTC 144Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr 20 25 30 This paper size applies to Chinese National Standard (CNS) A4 size (210x297 mm) -30-520289 A7 B7 V. Description of the invention (28) GCC ATG TCT TGG GTT CGC CAG GCT CCA GGG AAG GGA CTC GAG TGG GTC 144

Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 請 先 丨閣 i讀 之 注 意 事 項 再 填 寫 本 頁 35 40 45 GCA TCC ATT AGT ACT GGT GGT AGC ACC TAC TAT CCA GAC AGT GTG AAG 192Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Please read the notes and fill in this page 35 40 45 GCA TCC ATT AGT ACT GGT GGT AGC ACC TAC TAT CCA GAC AGT GTG AAG 192

Ala Ser lie Ser Thr Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val Lys 50 55 60 GGC CGA TTC ACC ATC TCC AGA GAT AAT GCC AAG AAC ACC CTG TAC CTG 24 0Ala Ser lie Ser Thr Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val Lys 50 55 60 GGC CGA TTC ACC ATC TCC AGA GAT AAT GCC AAG AAC ACC CTG TAC CTG 24 0

Gly Arg Phe Thr 工le Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu 65 70 75 80 CAA ATG AAT TCT CTG AGG GCT GAG GAC ACG GCC GTG TAT TAC TGT GCA 288Gly Arg Phe Thr Engineering Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu 65 70 75 80 CAA ATG AAT TCT CTG AGG GCT GAG GAC ACG GCC GTG TAT TAC TGT GCA 288

Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys A'la 85 90 95 * AGA GAC TAT GAC GGG TAT TTT GAC TAC TGG GGC CAA GGC ACC CTG GTC 33 6Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys A'la 85 90 95 * AGA GAC TAT GAC GGG TAT TTT GAC TAC TGG GGC CAA GGC ACC CTG GTC 33 6

Arg Asp Tyr Asp Gly Tyr Phe Asp Tyr Trp Gly Gin Gly Thr Leu Val 100 105 110 ACA GTC TCC TCA GCT TCC ACC AAG GGC CCA TCC GTC TTC CCC CTG GCG 384Arg Asp Tyr Asp Gly Tyr Phe Asp Tyr Trp Gly Gin Gly Thr Leu Val 100 105 110 ACA GTC TCC TCA GCT TCC ACC AAG GGC CCA TCC GTC TTC CCC CTG GCG 384

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala 115 120 125 CCC TGC TCC AGG AGC ACC TCC GAG AGC ACA GCC GCC CTG GGC TGC CTG 432Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala 115 120 125 CCC TGC TCC AGG AGC ACC TCC GAG AGC ACA GCC GCC CTG GGC TGC CTG 432

Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu 130 135 140 GTC AAG GAC TAC TTC CCC GAA CCG GTG ACG GTG TCG TGG AAC TCA GGC 480Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu 130 135 140 GTC AAG GAC TAC TTC CCC GAA CCG GTG ACG GTG TCG TGG AAC TCA GGC 480

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly 145 150 155 160 經濟部中央標準局員工消費合作社印裳 GCC CTG ACC AGC GGC GTG CAC ACC TTC CCG GCT GTC CTA CAG TCC TCA 528Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly 145 150 155 160 Employee Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Yin GCC CTG ACC AGC GGC GTG CAC ACC TTC CCG GCT GTC CTA CAG TCC TCA 528

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gin Ser Ser 165 170 175 GGA CTC TAC TCC CTC AGC AGC GTG GTG ACC GTG CCC TCC AGC AGC TTG 576 Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu 180 185 190 本紙張尺度適用中國國家標準(CNS ) A4規格(21〇x29?公釐) ~ 31 - 520289 A7 B7五、發明説明(29) GGC ACG AAG ACC TAC ACC TGC AAC GTA GAT CAC AAG CCC AGC AAC ACC Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr 195 200 205 AAG GTG GAC AAG AGA GTT GAG TCC AAA TAT GGT CCC CCA TGC CCA TCA Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser 210 215 220 TGC CCA GCA CCT GAG TTC CTG GGG GGA CCA TCA GTC TTC CTG TTC CCC Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro 225 230 235 240 CCA AAA CCC AAG GAC ACT CTC ATG ATC TCC CGG ACC CCT GAG GTC ACG Pro Lys Pro Lys Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr 245 250 255 TGC GTG GTG GTG GAC GTG AGC CAG GAA GAC CCC GAG GTC CAG TTC AAC Cys Val Val Val Asp Val Ser Gin Glu Asp Pro Glu Val Gin Phe Asn 260 265 270 TGG TAC GTG GAT GGC GTG GAG GTG CAT AAT GCC AAG ACA AAG CCG CGG Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 275 280 285 GAG GAG CAG TTC AAC AGC ACG TAC CGT GTG GTC AGC GTC CTC ACC GTC Glu Glu Gin Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 290 295 300 CTG CAC CAG GAC TGG CTG AAC GGC AAG GAG TAC AAG TGC AAG GTC TCC Leu His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 305 310 315 320 AAC AAA GGC CTC CCG TCC TCC ATC GAG AAA ACC ATC TCC AAA GCC AAA Asn Lys Gly Leu Pro Ser Ser lie Glu Lys Thr lie Ser Lys Ala Lys 325 330 335 GGG CAG CCC CGA GAG CCA CAG GTG TAC ACC CTG CCC CCA TCC CAG GAG Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Gin Glu 340 345 350 GAG ATG ACC AAG AAC CAG GTC AGC CTG ACC TGC CTG GTC AAA GGC TTC Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe 355 360 365 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) (請先閱讀背面之注意事項再填寫本頁) 訂 912 960 « 1008 1056 1104 520289 A7 B7 五、發明説明(3〇) TAC CCC AGC GAC ATC GCC GTG GAG TGG GAG AGC AAT GGG CAG CCG GAG Tyr Pro Ser Asp 工le Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu 370 375 380 AAC AAC TAC AAG ACC ACG CCT CCC GTG CTG GAC TCC GAC GGC TCC TTC Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 385 390 395 400 TTC CTC TAC AGC AGG CTA ACC GTG GAC AAG AGC AGG TGG CAG GAG GGG Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gin Glu Gly 405 410 415 1152 7 請 先 閱 讀 背 1200 面 之 注 意 事 項 1248 再Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gin Ser Ser 165 170 175 GGA CTC TAC TCC CTC AGC AGC GTG GTG ACC GTG CCC TCC AGC AGC TTG 576 Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu 180 185 190 This paper size applies to Chinese National Standard (CNS) A4 size (21 × 29? Mm) ~ 31-520289 A7 B7 V. Description of invention (29) GGC ACG AAG ACC TAC ACC TGC AAC GTA GAT CAC AAG CCC AGC AAC ACC Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr 195 200 205 AAG GTG GAC AAG AGA GTT GAG TCC AAA TAT GGT CCC CCA TGC CCA TCA Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser 210 215 220 TGC CCA GCA CCT GAG TTC CTG GGG GGA CCA TCA GTC TTC CTG TTC CCC Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro 225 230 235 240 CCA AAA CCC AAG GAC ACT CTC ATG ATC TCC CGG ACC CCT GAG GTC ACG Pro Lys Pro Lys Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr 245 250 255 TGC GTG GTG GAC GTG AGC CAG GAA GAC CCC GAG GTC CAG TTC AAC Cys Val Val Val Asp Val Ser G in Glu Asp Pro Glu Val Gin Phe Asn 260 265 270 TGG TAC GTG GAT GGC GTG GAG GTG CAT AAT GCC AAG ACA AAG CCG CGG Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 275 280 285 GAG GAG CAG TTC AAC AGC ACG TAC CGT GTG GTC AGC GTC CTC ACC GTC Glu Glu Gin Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 290 295 300 CTG CAC CAG GAC TGG CTG AAC GGC AAG GAG TAC AAG TGC AAG GTC TCC Leu His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 305 310 315 320 AAC AAA GGC CTC CCG TCC TCC ATC GAG AAA ACC ATC TCC AAA GCC AAA Asn Lys Gly Leu Pro Ser Ser lie Glu Lys Thr lie Ser Lys Ala Lys 325 330 335 GGG CAG CCC CGA GAG CCA CAG GTG TAC ACC CTG CCC CCA TCC CAG GAG Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Gin Glu 340 345 350 GAG ATG ACC AAG AAC CAG GTC AGC CTG ACC TGC CTG GTC AAA GGC TTC Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe 355 360 365 This paper size applies to China National Standard (CNS) A4 specifications (210X 297 mm) (Please read the notes on the back first Refill this page) Order 912 960 «1008 1056 1104 520289 A7 B7 V. Description of the invention (3〇) TAC CCC AGC GAC ATC GCC GTG GAG TGG GAG AGC AAT GGG CAG CCG GAG Tyr Pro Ser Asp Worker Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu 370 375 380 AAC AAC TAC AAG ACC ACG CCT CCC GTG CTG GAC TCC GAC GGC TCC TTC Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 385 390 395 400 TTC CTC TAC AGC AGG CTA ACC GTG GAC AAG AGC AGG TGG CAG GAG GGG Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gin Glu Gly 405 410 415 1152 7 Please read the precautions on the back 1200 and 1248 before

AAT GTC TTC TCA TGC TCC GTG ATG CAT GAG GCT CTG CAC AAC CAC TAC 1296 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 420 425 430 ACA CAG AAG AGC CTC TCC CTG TCT CTG GGT AAA Thr Gin Lys Ser Leu Ser Leu Ser Leu Gly Lys 435 440 1329 訂 經濟部中央標準局員工消費合作社印裝 (2 ) S E Q ID NO:4 資料 (i )序列特性: (A )長度:4 4 3 (B )型式:胺基酸 (C )股性:雙股 (D )拓撲學:線型 (ii)分子型式··蛋白質 (X i )序列說明:s E Q ID Ν Ο : 4 本紙張尺度適用中國國家標準(CNS ) A4規格(297公釐〉 MW. -33 - 520289 A7 B7 五、發明説明(31)AAT GTC TTC TCA TCA TGC TCC GTG ATG CAT GAG GCT CTG CAC AAC CAC TAC 1296 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 420 425 430 ACA CAG AAG AGC CTC TCC CTG TCT CTG GGT AAA Thr Gin Lys Ser Leu Ser Leu Ser Leu Gly Lys 435 440 1329 Order printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (2) SEQ ID NO: 4 Data (i) Sequence characteristics: (A) Length: 4 4 3 (B) Type: Amino acid (C) strand property: double strand (D) topology: linear (ii) molecular type · protein (X i) sequence description: s EQ ID Ν Ο: 4 This paper size applies to Chinese National Standards (CNS) A4 specifications (297 mm> MW. -33-520289 A7 B7 V. Description of the invention (31)

Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15Glu Val Gin Leu Val Glu Ser Gly Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15

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

20 25 30 I20 25 30 I

Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ala Ser 工le Ser Thr Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val Lys 50 55 60Ala Ser Gong Ser Thr Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val Lys 50 55 60

Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu 65 70 75 80Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu 65 70 75 80

Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala ; 85 90 95 iGin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala; 85 90 95 i

Arg Asp Tyr Asp Gly Tyr Phe Asp Tyr Trp Gly Gin Gly Thr Leu Val 100 105 110Arg Asp Tyr Asp Gly Tyr Phe Asp Tyr Trp Gly Gin Gly Thr Leu Val 100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala 115 120 125 、Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala 115 120 125,

Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu 130 135 140Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu 130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly 145 150 155 160 經濟部中央標準局員工消費合作社印製 (請先閲讀背面之注意事項再填寫本頁)Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly 145 150 155 160 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (Please read the notes on the back before filling out this page)

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gin Ser Ser 165 170 175Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gin Ser Ser 165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu 180 185 190Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu 180 185 190

Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr 195 200 205Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr 195 200 205

Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser 210 215 220 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) 一 34 - 經濟部中央標準局員工消費合作社印製 520289 A7 B7 五、發明説明(32)Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser 210 215 220 This paper size applies to the Chinese National Standard (CNS) A4 size (210X 297 mm)-34-Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 520289 A7 B7 V. Description of the invention (32)

Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro 225 230 235 240Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro 225 230 235 240

Pro Lys Pro Lys Asp Thr Leu Met 工le Ser Arg Thr Pro Glu Val Thr 245 250 255Pro Lys Pro Lys Asp Thr Leu Met Engineer Ser Arg Thr Pro Glu Val Thr 245 250 255

Cys Val Val Val Asp Val Ser Gin Glu Asp Pro Glu Val Gin Phe Asn 260 265 270Cys Val Val Val Asp Val Ser Gin Glu Asp Pro Glu Val Gin Phe Asn 260 265 270

Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 275 280 285Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 275 280 285

Glu Glu Gin Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 290 295 300Glu Glu Gin Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 290 295 300

Leu His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 305 310 315 320Leu His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 305 310 315 320

Asn Lys Gly Leu Pro Ser Ser lie Glu Lys Thr lie Ser Lys Ala Lys 325 330 335Asn Lys Gly Leu Pro Ser Ser lie Glu Lys Thr lie Ser Lys Ala Lys 325 330 335

Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Gin Glu 340 345 350Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Gin Glu 340 345 350

Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Ph^ 355 360 365Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Ph ^ 355 360 365

Tyr Pro Ser Asp 工le Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu 370 375 380Tyr Pro Ser Asp Tool Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu 370 375 380

Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 385 390 395 400Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 385 390 395 400

Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gin Glu Gly 405 410 415Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gin Glu Gly 405 410 415

Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 420 425 430Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 420 425 430

Thr Gin Lys Ser Leu Ser Leu Ser Leu Gly Lys 435 440 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) (請先閱讀背面之注意事項再填寫本頁)Thr Gin Lys Ser Leu Ser Leu Ser Leu Gly Lys 435 440 This paper size is applicable to China National Standard (CNS) A4 size (210X 297 mm) (Please read the precautions on the back before filling this page)

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Claims (1)

520289 A8 B8 C8 D8 六、申請專利範圍 附件一(A ) (請先閲讀背面之注意事項再填寫本頁) 第8 5 1 1 2 85 8號專利申請案 中文申請專利範圍修正本 民國91年12月;2日修正 1 一*種用於治療多重創傷事件之藥學組成物,其中 含有治療有效劑量的抗-選擇素抗體,並組合藥學上可接 受之載劑。 2 ·如申請專利範圍第1項之藥學組成物,其中該抗 一選擇素抗體是抗- L 一選擇素抗體。 3 ·如申請專利範圍第1項之藥學組成物,其中該抗 一選擇素抗體是抗一 E -選擇素抗體。 4 ·如申請專利範圍第1項之藥學組成物,其中該抗 -選擇素抗體是抗一 P -選擇素抗體。 5 ·如申請專利範圍第1項之藥學組成物,其中含有 每公斤體重1 . 0 — 10毫克的抗一選擇素抗體。 經濟部智慧財產局員工消費合作社印製 6 ·如申請專利範圍第1項之藥學組成物,其於多重. 創傷事件後〇 . 5 — 8小時投藥。 7 ·如申請專利範圍第6項之藥學組成物,其於多重 創傷事件後0 · 5 - 4小時投藥。 8 ·如申請專利範圍第5項之藥學組成物,其在6及 7 2小時間隔間投藥。 9 ·如申請專利範圍第8項之藥學組成物,其在6及 3 6小時間隔間投藥。 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) 一 1 - 520289 A8 B8 C8 D8 六、申請專利範圍 (請先閱讀背面之注意事項再填寫本頁) 1 〇 ·如申請專利範圍第1項之藥學組成物,其於多 重創傷事件後高達1 0天時投藥,且投藥之劑量及時間由 先前劑量投藥後6 - 2 4小時間隔下病人血清或血漿中抗 一選擇素抗體之濃度來決定,其中當, (a )該抗-選擇素抗體濃度低於病患血清或血漿每 毫升1 0微克時,投予至少如前一劑高之劑量,可高至最 大1 0毫克/公斤劑量,或是當, (b )該抗-選擇素抗體濃度介於病人血清或血漿每 毫升1 0微克及5 0微克之間時,投予先前劑量一半之劑 量,或是當, (c )該抗-選擇素抗體的濃度大於病人血清或血漿 每毫升5 0微克時,則不投予抗-選擇素抗體及藥學上可 接受的載劑,並依據(a )及(b )步驟進一步追踪病人 的血清或血漿。 1 1 ·如申請專利範圍第1項之藥學組成物,其中的 抗-選擇素抗體爲人化的抗體。 1 2 ·如申請專利範圍第1 1項之藥學組成物,其中. 經濟部智慧財產局員工消費合作社印製 的人化抗體是抗一 L 一選擇素抗體HuD r e g 5 5或 \ H u D r eg 200。 1 3 · —種可減少多重創傷後器官衰竭發生率可能性 之藥學組成物,其中包括治療有效劑量之至少一種抗選擇 素抗體,並組合藥學上可接受之載劑。 1 4 ·如申請專利範圍第1 3項之藥學組成物,其中 的抗-選擇素抗體是人化的。 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) 一 2 - 520289 A8 B8 C8 D8 六、申請專利範圍 1 5 .如申請專利範圍第1 3項之藥學組成物,其中 該抗-選擇素抗體是抗一 L 一選擇素抗體。 1 6 .如申請專利範圍第1 3項之藥學組成物,其中 該抗-選擇素抗體是抗一 P -選擇素抗體。 1 7 .如申請專利範圍第1 3項之藥學組成物,其中 該抗-選擇素抗體是抗一 L 一選擇素抗體。 1 8 .如申請專利範圍第1 3項之藥學組成物,其中 的抗—L 一選擇素抗體是Dr eg 55或HuDr eg 5 5° 1 9 ·如申請專利範圍第1 3項之藥學組成物,其中 該器官衰竭是多數器官衰竭。 (請先閲讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) -3 -520289 A8 B8 C8 D8 VI. Scope of Patent Application Annex I (A) (Please read the notes on the back before filling out this page) No. 8 5 1 1 2 85 Chinese Patent Application Scope Amendment 12 Month; 2nd amendment 1 * A pharmaceutical composition for treating multiple traumatic events, which contains a therapeutically effective dose of an anti-selectin antibody and a pharmaceutically acceptable carrier. 2. The pharmaceutical composition according to item 1 of the application, wherein the anti-selectin antibody is an anti-L-selectin antibody. 3. The pharmaceutical composition according to item 1 of the patent application scope, wherein the anti-selectin antibody is an anti-E-selectin antibody. 4. The pharmaceutical composition according to item 1 of the application, wherein the anti-selectin antibody is an anti-P-selectin antibody. 5. The pharmaceutical composition according to item 1 of the patent application scope, which contains 1.0 to 10 mg of anti-selectin antibody per kilogram of body weight. Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 6 · If the pharmaceutical composition in the scope of patent application No. 1 is applied, it is administered 0.5 to 8 hours after the multiple traumatic event. 7. The pharmaceutical composition according to item 6 of the patent application, which is administered 0.5 to 4 hours after a multiple trauma event. 8. The pharmaceutical composition according to item 5 of the patent application, which is administered at intervals of 6 and 72 hours. 9. The pharmaceutical composition according to item 8 of the patent application, which is administered at intervals of 6 and 36 hours. This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 1-520289 A8 B8 C8 D8 VI. Scope of patent application (please read the notes on the back before filling this page) 1 〇 · If the scope of patent application The pharmaceutical composition of item 1 is administered up to 10 days after a multiple trauma event, and the dosage and time of the administration are from the previous dose of anti-selectin antibody in the serum or plasma of the patient at an interval of 6 to 24 hours after the previous dose. The concentration is determined, wherein when (a) the concentration of the anti-selectin antibody is lower than 10 micrograms per milliliter of the patient's serum or plasma, the dose is at least as high as the previous dose, and can be as high as 10 mg / The dose in kilograms, or when (b) the anti-selectin antibody concentration is between 10 micrograms and 50 micrograms per milliliter of the patient's serum or plasma, half the previous dose is administered, or when, (c ) When the concentration of the anti-selectin antibody is greater than 50 micrograms per milliliter of the patient's serum or plasma, the anti-selectin antibody and the pharmaceutically acceptable carrier are not administered, and further according to steps (a) and (b) Track patient's serum or blood . 1 1 · The pharmaceutical composition according to item 1 of the application, wherein the anti-selectin antibody is a humanized antibody. 1 2 · The pharmaceutical composition according to item 11 of the scope of patent application, where the humanized antibody printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs is an anti-L-selectin antibody HuD reg 5 5 or \ Hu D r eg 200. 1 3-A pharmaceutical composition that reduces the likelihood of the occurrence of multiple post-traumatic organ failure, comprising a therapeutically effective dose of at least one anti-selectin antibody in combination with a pharmaceutically acceptable carrier. 1 4 · The pharmaceutical composition according to item 13 of the application, wherein the anti-selectin antibody is humanized. This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) 1 2-520289 A8 B8 C8 D8 VI. Application scope of patents 15. For the pharmaceutical composition No. 13 of the scope of patent application, where the anti- Selectin antibodies are anti-L-selectin antibodies. 16. The pharmaceutical composition according to item 13 of the application, wherein the anti-selectin antibody is an anti-P-selectin antibody. 17. The pharmaceutical composition according to item 13 of the patent application scope, wherein the anti-selectin antibody is an anti-L-selectin antibody. 18. The pharmaceutical composition according to item 13 of the patent application, wherein the anti-L-selectin antibody is Dr eg 55 or HuDr eg 5 5 ° 1 9. The pharmaceutical composition according to item 13 of the patent application Among them, the organ failure is most organ failure. (Please read the precautions on the back before filling out this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs This paper applies the Chinese National Standard (CNS) A4 specification (210X297 mm) -3-
TW85112858A 1995-08-17 1996-10-21 Anti-selectin antibodies for prevention of multiple organ failure after polytrauma and for prevention of acute organ damage after extracorporeal blood circulation TW520289B (en)

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