TWI356062B - Therapeutic peptides and method - Google Patents
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- TWI356062B TWI356062B TW094116511A TW94116511A TWI356062B TW I356062 B TWI356062 B TW I356062B TW 094116511 A TW094116511 A TW 094116511A TW 94116511 A TW94116511 A TW 94116511A TW I356062 B TWI356062 B TW I356062B
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Description
1356062 九、發明說明: 【發明所屬之技術領域】 ’本發明係關於 白質及胜肽及其 本發明係關於免疫學領域。更特定言之 發炎及含TREM-1蛋白質之特定序列的蛋 療疾病(如敗血症及 功能等價物(本文指TREM-1胜肽)在 敗血性休克)中之用途。 敗血症是構成特別護理資源之重要消耗且一直是特別護 理方面中之經常存在的問題。據估計每年在美國及歐洲 % 400 〇()()與· _間之患者羅患此病。在支持性及抗菌治療 兩者中雖然有改善但是發病率及死亡率仍报高。非複雜敗 血症至彼等患有敗血性休克及多器官功能障礙之患者中的 死亡率在40%至80%間變化。現在更加瞭解該等病症之發病 機理。對免疫、發炎及血液介體之複雜網絡之更多瞭解可 允許合理及新穎治療之發展。 【先前技術】
在感染後,先天及認知免疫反應在形成特異性及複雜性 之連續相中發展,最後導致傳染劑清除及體内平衡重建。 先天免疫反應用作防衛之第一條線,且其經活化諸如類鐸 受體(toll-like receptor,TLR)(1、2)之模式識別受體藉由各 種病原體相關之微生物模式(PAMP)(3)而引發。活化TLR引 起諸如TNF-α及IL-Ιβ之細胞激素的大量釋放,其在如敗金 症之嚴重感染情況下可促成組織損傷及致命休克(4、5)。 TNF-a及IL-1 β之拮抗劑出現在本文中作為敗血症之可能令 人感興趣之洽療劑,但遺憾的是其在臨床試驗中顯示功效 101968.doc 1356062 有限(6-8)。這可能是由於該等細胞激素是清除感染所必需 且其移除將使致命細菌生長之事實(9-11)。 另一尤其涉及感染反應之受體(在骨髓細胞-1上表現之引 發受體(TREM-1))為最近發現之受體家族TREM家族(表現 於嗜中性白血球及單核細胞一子集之表面上)的成員。 TREM受體籍由關聯銜接分子DAP12活化骨髓細胞。已報導 嚙合TREM-1以引發促發炎細胞激素在微生物產物存在下 之合成。
表現於骨髓細胞上之引發受體(TREM· 1)係最近發現之細 胞表面分子,其已在人類及小鼠科動物分葉核嗜中性白血 球及成熟單核細胞中識別(12)。其屬於免疫球蛋白總科且在 稱為DAP 12之銜接蛋白質幫助下活化下游訊號路徑 (12-15)。Bouchon及合作者已表明TREM-1之表現在自感染 患者之細胞培養及組織樣品中於諸如綠膿桿菌
(Pseudomonas aeruginosa)或金黃素葡萄球菌(Staphylococcus aureus)存在下在嗜中性白血球及單核細胞上很大程度向上 調節(16)。在顯著對比中,TREM-1在患有免疫錯合物引起 之非感染發炎性疾病(諸如牛皮癬、潰瘍性結腸炎或脈管炎) 之患者樣品中沒有被上調節。(16)此外,當將TREM-1結合 至其配位體時,存在LPS之合成效應及促發炎細胞激素 TNF-α及GM-CSF之擴大合成,連同IL-10生成之抑制(17)。 在LPS引發敗血性休克之小鼠科模型中,阻塞TREM-1訊號. 保護該等動物免遭死亡,進一步強調該分子之決定性角色 (13, 16)。 101968.doc 1356062 最近研究證實TREM-1在感染之發炎性反應中起關鍵作 用(參見 BOUCHON 等人(2000) J. Immunol. 164:4991-4995)。在 人類中對細菌及真菌感染而在骨髓細胞上增加TREM-1表 現。類似地,在小鼠中引發脂多糖(LPS)休克與TREM-1之 表現增加有關《此外,以可溶性TREM-1/Ig稠合蛋白質做 "誘捕"受體治療小鼠,保護小鼠免遭LPS或E.coli引起之死 亡。
名為"186 Secreted Proteins"之美國6,420,526主張含有至 少30個人類TREM-1之鄰近胺基酸之TREM-1的非特異及非 例示性經分離斷片。未提供關於該等片段之生物資料。 如US2003165875A中所述,人類IgGl恆定區及小鼠 TREM-1或人THEM· 1之細胞外區域間之稠合蛋白質顯示於 小鼠中與内毒素血症相抵之效應。
發明者驚奇地發現自TREM-1蛋白質衍生之特定胜肽能 夠作TREM-1蛋白質之拮抗劑且因而具有在治療敗血症及 敗血性休克中之應用》該等發明者進一步證實同樣的胜肽 亦調節活體内感染引發之促發炎級聯,從而抑制敗血症動 物模型之過度反應及死亡。 先前該等發明者已識別TREM-1之可溶形式(sTREM-Ι)且 觀測自敗血性休克患者而非對照組之血清樣品中之顯著含 量。本文亦描述該等發明者已證實其在調變敗血症期間發 炎中之假定作用(參見Gibot等人(2004) Ann. Intern. Med.. 141(1):9-15及 Gibot 等人(2004) N. Engl. J. Med. 350(5):451-8)。 本文描述該等發明者顯示TREM-1 (sTREM-1)之可溶形式 101968.doc 1356062 在小鼠感染進攻期間釋放在周圍血液中。該等發明者亦證 實單核細胞為sTREM的主要源,且顯示模擬treM- 1之細胞 外區域部分之合成胜肽可藉由活體外活化單核細胞來調節 細胞激素生成。
本文描述該等發明者觀測TREM-1在活體外經LPS以及在 涉及敗血性休克實驗模型之動物金清中活化之單核細胞分 泌。在活體外及活體内,模仿sTREM-1之短期高度保存區 域之合成胜肽經人類單核細胞削弱細胞激素生成並保護敗 血性動物免受過度反應及死亡。該等胜肽不僅在預防亦在 下調節促發炎細胞激素之有害效應中有效。該等資料證實 經TREM-1胜肽之TREM-1活體内調變是治療感染性疾病 (例如敗血症或敗血性休克)或治療類似敗血症病症之有價 值之治療工具。 【發明内容】
因此’本發明提供治療感染性疾病(尤其敗血症或敗血性 休克)或治療類似敗血症病症之方法及組合物。 如本文描述,該等發明者已確定合併自"CDR2"及"CDR3” 之序列的TREM-1蛋白質細胞外部分之數種胜肽(見表丨)令 人驚奇地具有類似於之前描述敗血症模型中IgG1恆定區及 TREM-1之細胞外區域間之稍合蛋白質相似的活性。該等胜 肽亦具有高於該蛋白質之優勢,尤其在製造費用方面。 因此’本發明提供包含一或多種自TREM-1蛋白質之 CDR2或CDR3衍生之序列的多胜肽。該多胜肽較佳包含少 於30個該TREM-1蛋白質之鄰近胺基酸。 101968.doc 1356062 如表1所示,該等胜肽或多胜肽之實例含有或包含 (如)15-25種來自TREM-1蛋白質之胺基酸(”AA··)胜肽,且含 '有或包含經自蛋白質天然序列側接之受體之CDR區域(3-6 - AA)的所有或部分,只要類CDR區域之功能沒喪失該蛋白質 之長度可變化。該等胜肽係衍生自如表2(人)及表3(小鼠) 之TREM-1受體蛋白質胺基酸序列。 表1顯示自小鼠TREM-1 "mPX" (NCBI參考序列(RefSeq) NP—067381)或人類 TREM-1 "hPX”(NCBI參考序列(RefSeq) ^ NP_06 1113)衍生之胜肽。加下劃線之胺基酸跨越人類 TREM-1 互補決定區(CDR),如 Radaev 等人 2003 Structure (Camb.) 11 (12),1527-1535 (2003)所描述。 表2顯示人類胺基酸序列NP_061113。加下劃線之胺基酸
跨越人類TREM-1互補決定區(CDR) 2 (RPSKNS; [SEQ ID NO:20])及 3 (QPPKE [SEQ ID NO:21]),如 Radaev 等人 2003
Structure (Camb·) 11 (12),1527-1535 (2003)所猫述。
表3顯示小鼠TREM-1胺基酸序列NP_067381。加下劃線之 胺基酸跨越小鼠TREM-1互補決定區(CDR) 2 (RPFTRP; [SEQ ID NO:22])及 3 (HPPND; [SEQ ID NO:23])。 表1包括來自人及小鼠TREM-1 CDR 2及CDR 3之序列的胜肽
hCDR2 mPl (67-89): [SEQEDNO:3] hPl (67-89): [SEQ ID NO: 16] LVVTORPFTRPSEVHMGKFTLKH LACTERPSKNSHPVOVGRIILED 101968.doc -10- 1356062
hCDR3 mP2 (114-136): [SEQ ID NO:4] VIYHPPNDPWLFHPVRLWTKG mP4 (103-123) : [SEQ ID NO:6] LOVTDSGLYRCVIYHPPNDPV mP5 (103-119): [SEQ ID NO:7] LQVTDSGLYRCVIYHPP hP2 (114-136) : [SEQ Π) NO:17] VIY〇PPKEPHMLFDRIRLWTKG hP4 (103-123): [SEQ ID NO:18] LOVEDSGLYOCVIYOPPKEPH hP5 (103-119) : [SEQ ID NO:19] LQVEDSGLYQCVIYOPP 表2人類TREM-1胺基酸序列NP_061113 1 MRKTRLWGLL WMLFVSELRA ATKLTEEKYE LKEGQTLDVK CDYTLEKFAS SQKAWQIIRD 61 GEMPKTLACT ERPSKNSHPV Q VGRIILED Y HDHGLLRVRM VNLQ VEDSGL YQCVIYQPPK 121 EPHMLFDRIR LVVTKGFSGT PGSNENSTQN VYKIPPTTTK ALCPLYTSPR TVTQAPPKST 181 ADVSTPDSEINLTNVTDIIR VPVFNIVILL· AGGFLSKSLV FS VLFAVTLR SFVP [SEQIDNO:!] 表3小鼠TREM-1胺基酸序列NP_0673 81 1 MRKAGLWGLL CVFFVSEVKA AIVLEEERYD LVEGQTLTVK CPFNIMKYAN SQKAWQRLPD 61 GKEPLTLVVT ORPFTRPSEV HMGKFTLKHD PSEAMLQVQM TDLQVTDSGL YRCVIYHPPN 121 DPVVLFHPVR LVVTKGSSDV FTPVIIPITR LTERPILITT KYSPSDTTTT RSLPKPTAVV 181 SSPGLGVTIINGTDADSVST SSVTISVICG LLSKSLVFIILFIVTKRTFG [SEQ ID NO:2] 因此,本發明提供經分離或重組製備之多胜肽或胜肽, 其包含或基本由自TREM-1蛋白質之CDR2或CDR3或者該 等多胜肽之片段、同源物、衍生物、稠合蛋白質或變異體(如 本文界定)之序列組成,其在這裏本文"本發明之多胜肽或 胜肽''或"TREM-1胜肽或TREM-1多胜肽",較佳該等實體包 101968.doc -11 - 1356062
含小於3_TR购蛋白質之鄰近胺基酸,例如表2或表3所 :般在本發明之多胜狀或蛋白質或者其片段、同源物、 街生物或變異體欲使用(例如治療)特殊物種時,則自該物種 之TREM-i蛋白質胺基酸序列(或者若不知該序列時,自類 似物種)選擇TREM-1蛋白質之CDR2或CDR3序列。例如用 於治療人類疾病(尤其敗血症、敗血性休克或類似敗血症病 症)本發明之多胜肽或蛋白質將包含一或多種包含所有或 部分來自人類TREM-1蛋白質之CDR24CDR3的序列。 此外,本發明提供包含一胺基酸序列之經分離多胜肽或 蛋白質’該胺基酸序列至少約60%、70%、75%、8〇%、85%、 、95%或 98%與胺基酸序列 SEQIDN〇:2〇、21、22、23 或其片段、同源物、衍生物或變異體相同。本發明亦提供 包含一胺基酸序列之經分離或重組製備之胜肽、多胜肽或 蛋白質’其包含或基本由至少約3、4、5、6、7、8、9、10、 11、 12、 13、 14、 15、 16、 17、 18、 19、 20、 21、 22、 23、 24、25、26、27、28或29或更多TREM-1蛋白質之鄰近胺基 酸組成’該TREM-1蛋白質之3個或更多鄰近胺基酸係衍生 自序列 SEQ ID NO:20、21、22、23(換言之,代表 TREM-1 蛋白質之所有或部分CDR2或CDR3存在於該胜肽、多胜肽 或蛋白質中的序列)或其片段、同源物、衍生物或變異體。 在較佳實施例中,該等胜肽、多胜肽或蛋白質或其片段、 同源物、衍生物或變異體具有TREM-1全長蛋白質之生物活 性,諸如抗原性、免疫原性、引發促發炎向化性激動素及 細胞激素、調動細胞溶質Ca2+、蛋白質酪胺酸磷酸化、介 101968.doc -12· 1356062 個胺基酸可為 HPP、PPN、PND、RPF、PFT、FTR或 TRP。 該等多胜肽可包含序列HPP、HPPN、HPPND或RPFTRP。 在特定實施例中,本發明之多胜肽為或包含SEQ ID No. 7, 其揭示於 Gibot 等人(2004) J Exp Med 200, 1419-1426。 在特定實施例中本發明之多胜肽不是也不包含SEQ ID No. 7 ° 在特定實施例中本發明之多胜肽為或包含選自SEQ ID Nos. 3、4及6之序列。
在特定實施例中本發明之多胜肽為或包含選自SEQ ID Nos. 16、17、18及 19之序列。 在特定實施例中本發明之多胜肽包含自CDR2衍生之序 列。 在特定實施例中本發明之多胜肽包含自CDR3衍生之序 列。
吾人提供本發明之多胜肽或胜肽用於治療,尤其治療敗 血症、敗血性休克及類似敗血症病症,且用於製造治療敗 血症、敗血性休克及類似敗血症病症之藥物中。此外提供 含有本發明多胜肽或胜肽之組合物及醫藥組合物,及使用 本發明之多胜肽或胜肽治療敗血症、敗血性休克及類似敗 血症病症之方法。此外吾人提供本發明之多胜肽或胜肽用 於治療以在敗血症、敗血性休克及類似敗血症病症中重建 血液動力學參數,且用於製造治療敗金症、敗A性休克及. 類似敗血症病症中異常血液動力學參數之藥物中。 術語”觸發表現於骨髓細胞上之受體”或"TREM”指一組 101968.doc -14· 1356062 活化受體,其選擇性表現於不同類型骨髓細胞上,諸如肥 大細胞、單核細胞、巨噬細胞、樹突狀細胞(DC)及嗜中性 白血球’且其可在免疫及發炎性反應中具有支配性作用。 TREM主要為在其細胞外區域中含Ig形折疊之跨膜糖蛋 白’且因此屬於Ig_SF。該等受體含有短細胞内區域,但缺 乏訊號介體停靠基元且需要銜接蛋白質(諸如DApi2)用於 細胞活化。 本文所用術語||骨髓細胞"指一組骨髓衍生之細胞譜系, % 包括粒細胞(嗜中性白血球、嗜伊紅血球及嗜鹼白血球)、單 核細胞、巨噬細胞及肥大細胞。此外亦包括骨髓源之周邊 血液樹突狀細胞及在合適培養條件下自單核細胞活體外衍 生之樹突狀細胞及巨噬細胞。
本文所定義術語"敗血症、敗血性休克"或"敗血症或敗血 性休克"指全身性發炎反應症候群(SIRS)之子群。術語,,敗血 症"通常在懷疑或證實感染時保留給SIRS。生理學變量之模 式已顯示在嚴重病患者中對一定範圍内身體損傷有反應, 該等身體損傷包括:外傷、燒傷、胰腺炎及感染。該等反 應包括發炎反應、白血球增多或嚴重白血球減少、過高熱 或體溫過低、心動過速及呼吸過速,且統稱為術語全身性 發炎反應症候群(SIRS)。此定義強調無論感染之存在,發 炎過程在該等條件下之重要性。在器官灌注明顯不足時敗 血症被進一步分級為嚴重敗血症,明顯徵兆係藉由諸如低 氧血、尿過少、乳酸酸血症或經改變腦功能之器官功能障 礙。”敗血性休克"通常為與低血壓併發之嚴重敗血症,在 101968.doc •15- 1356062
人類中定義為不管適當流體復甦小於90 mmHg之心臟收縮 血壓。敗血症及SIRS可由於失調之器官灌注及以氧氣處理 與兩種或兩種以上器官衰竭併發,稱為多重器官衰竭 (MOF)。除了感染之全身性效應外,全身性發炎反應亦可 發生在嚴重發炎條件下,諸如胰腺炎及燒傷。發炎反應徵 兆之出現係不好隨外傷損傷定義》在加強護理單元中,革 蘭氏陰性細菌涉及50至60%敗血症病例,其革蘭氏陽性細 菌占病例之進一步35至40%。病例之剩餘部分係歸因於真 菌、病毒及原生動物之不常見起因。
本文所用術語"類似敗血症病症"指彼等狀態,其中患者 患有類似於敗血症或敗血性休克之症狀,但感染劑不是如 下列情況之敗血症病例中所見發炎性介體類似級聯及/或 血液動力學參數改變的主要或初始原因,例如在患有急性 或慢性肝衰竭之患者中(參見Wasmuth HE等人J Hepatol. 2005 Feb; 42(2):195-201),在心搏停止後之復甦後病例中(參 見 Adrie C 等人 Curr Opin Crit Care. 2004 Jun; 10(3):208-12),在 癌症化療後治療類似敗血症病症中(參見Tsuj i E等人Int J Cancer. 2003 Nov 1; 107(2):303-8),在經歷含重組TNF-α人工 發熱隔離肢體灌注療法或類似治療之患者中(參見 Zwaveling JH 等人 Crit Care Med. 1996 May; 24(5):765-70)或嬰 兒中之類似敗金症疾病(參見Griffin MP等人Pediatr Res. 2003 Jun; 53(6):920-6)。 本文所用術語"與敗血症、敗血性休克或類似敗血症病症 相抵之活性π指分子(如胜肽、多胜肽或工程抗體)治療敗血 101968.doc -16- 1356062 程式、計分=50、詞長=3執行以獲得與本發明之NIP2b、 NIP2cL及NIP2cS蛋白質分子同源之胺基酸序列。為獲得有 間隙之校準用於比較目的,可如Altschul等人,(1997) Nucleic Acids Res. 25(17):3389-3402 描述使用'Gapped BLAST。當使用BLAST及GappedBLAST程式時,可使用各 程式之默認參數(如XBLAST及NBLAST)。參見 http://www.ncbi.nlm.nih.gov。
術語"蛋白質"及"多胜肽”在本文互換使用。本文使用術語 "胜肽"指兩個或兩個以上胺基酸或胺基酸類似物(包括非天 然產生胺基酸)之鏈,相鄰胺基酸藉由胜肽(-NHCO-)鍵連 接。因此,本發明之胜肽包括寡胜肽、多胜肽、蛋白質、 擬態胜肽(mimetope)及擬胜肽。技術中已知製備擬態胜肽及 擬胜肽之方法。
術語"擬態胜肽”及"擬胜肽”在本文互換使用。化合物X之 "擬態胜肽"指其中X之功能活性必需之X化學結構被其它模 仿X構形之化學結構置換的化合物。擬胜肽之實例包括其中 胜肽主鏈經一或多個苯幷二氮呼分子(參見如,James,G.L. 等人(1993) Science 260:1937-1942)及"顛倒(retro-inverso)" 胜肽(參見美國專利No. 4,522,752至Sisto)取代之胜肽化合 物。術語"擬態胜肽"及"擬胜肽"亦指構形上及功能上用作含 胜肽化合物中特定胺基酸之取代基而不反而嚴重妨礙該胜 肽功能之部分(而非天然產生胺基酸)。胺基酸模擬劑之實例 包括D-胺基酸。可使用習知胜肽合成程式製備以一或多種 D-胺基酸取代之胜肽。額外取代包括具有含官能基之可變 10l968.doc •19· 1356062 術語”天然產生胺基酸"包括任意20個胺基酸殘基,該等 胺基酸殘基通常包含生命系統中多數多胜肽、纖維蛋白質 * 中發現之少數胺基酸(如4-羥基脯胺酸、5-羥基離胺酸、-N- • .甲基離胺酸、3-曱基組胺酸、鎖鏈素、異鎖鏈素)及蛋白質 中未發現之天然產生胺基酸(如·丙胺酸、-胺基丁酸、高半 胱胺酸、高絲胺酸、瓜胺酸、鳥胺酸、刀豆胺酸、今可豆 胺酸及-氰基丙胺酸)0 術語"天然產生胺基酸之側鏈”欲包括式I中R代表之任意 ^ 天然產生胺基酸之側鏈。熟習此項技術者應瞭解式I之結構 欲涵蓋諸如脯胺酸之胺基酸,其中側鏈為環或雜環結構(如 在捕中R基團及胺基構成五員雜環)。類似地,以上式I 之化合物欲涵蓋諸如脯胺酸之胺基酸,其中在式I中(如) 及R4構成雜環。
本文所用術語”同源物”指具有公共生物活性(包括抗原性/ 免疫原性及發炎調節活性)及/或結構區域且具有本文描述 之足夠胺基酸的一系列胜肽或多胜肽之任意成員。該等同 源物可來自相同或不同種類之動物。 本文所用術語"變異體"指給定胜肽之天然產生對偶基因 變化或者給定胜肽或蛋白質(其中一或多個經胺基酸取 代、加成或刪除修飾之胺基酸殘基)之重組製備變化。 本文所用術語”衍生物"指給定胜肽或蛋白質之變化,該 胜肽或蛋白質另外改質(意即)經任何類型分子(較佳具有生 物活性)共價連接至該胜肽或蛋白質,包括非天然產生胺基 酸0 101968.doc -21 - 1356062 動物種類,較佳來自哺乳動物,更佳來自齧齒動物,諸如 小鼠及鼠,且最佳來自人類。它們較佳呈現TREM-1之至少 一種結構及/或功能特徵,且較佳能夠治療敗血症、敗血性 休克或類似敗血症病症’例如藉由作為TREM-1受體活性之 抬抗劑。該等修飾包括胺基酸取代、刪除及/或嵌入。胺基 酸修飾可藉由該技術中已知之任何方法製備且各種方法對 熟習此項技術者是可得且常規的。
此外,在製造胺基酸取代時,通常待取代之胺基酸殘基 可為保守胺基酸取代(意即"保守取代"),例如極性殘基以極 性殘基取代’親水性殘基以親水殘基取代,疏水性殘基以 疏水性殘基取代,正電荷殘基以正電荷殘基取代,或負電 荷殘基以負電荷殘基取代β而且通常待修飾之胺基酸殘基 並非經物種高度或完全保留及/或保持自其衍生之該胜肽 及/或蛋白質生物活性是關鍵的。
本發明之胜肽可以任意方便之方法直接合成。通常存在 之反應基(如胺基、硫醇及/或羧基)將在全部合成期間受保 遵。本發明之胜肽部分(如彼等其中包含之胺基酸為遺傳編 碼之胺基酸的胜肽)能夠熟習此項技術者熟知之表現系統 在原核及真核宿主中表現。亦已熟知(如)微生物表現之胜肽 的隔離及純化方法。為本發明之該等胜肽編碼之聚核苷酸 進一步構成本發明之態樣。本文使用”聚核苷酸”指脫氧核 苷酸或核糖核酸之聚合物,以單獨片段形式或做更大結構 之組份’如表現載體,諸如質粒。本發明之聚核苷酸序列 包括DNA、RNA及cDNA序列。由於基因編碼之簡化,當然 I01968.doc -23-
DZ 聚㈣酸能夠為根據本發明之特定胜肽编碼。當 ;!、,宿主用於表現胜肽,用某些步驟以自經表現之抗 細囷胜肽保護該宿主县 疋必而的。該等技術在此項技術中已 知且包括使用細菌菌種,該細菌菌種對經表現之胜狀或以 “或兩端部分表現稍合胜肽(其使根據本發明之胜肽的抗 囷活性)有抵抗性。在後面之情況τ,可在收集後^解胜狀 、製&活&胜狀。右該胜肽併人化學修飾,那麼經表現胜 肽之活性/歡性會低,且其僅藉由合成後化學修飾調變。 a此外’本發明亦涵蓋本發明多胜肽之衍生物。例如(但不 是限制方式),衍生物可包括經下列修飾之胜肽或蛋白質, 如藉由糖基化、乙酿化、聚乙二醇化、鱗酸化、酿胺化、 錯由已知保護/阻斷基團衍生、解蛋白裂解、連接至細胞配 位體或其它蛋白質等。多種化學修飾之任一種可藉由已知 技術進行,包括(但不限於)特定化學裂解、乙醯化、甲醯化 等。此外,該衍生物可含有一或多個非經典胺基酸。熟習 此項技術者要;主忍各種修御胜肽以增加效能、延長活性及/ 或增加半衰期之方法。在一實施例(w〇 〇21〇195)中,藉由 經醯胺鍵與至少一個構形剛性取代基偶合,在胜肽之N端、 胜肽之C端,或沿胜肽鏈之游離胺基或羧基製得該修飾。有 類似效果之其它胜肽修飾實例描述於(例如)W〇 2004029081 ' WO 03086444 ' WO 03049684 > WO 0145746 ' WO 0103723及 WO 9101743。 本發明進一步提供包含本發明胜肽或多胜肽或模擬本發 明胜肽或多胜肽活性之抗體。該等抗體包括(但不限於):多 101968.doc • 24· 1356062 株、單株、雙專一性、多專一性、人類、人化、嵌合抗體、 單鏈抗體、Fab片段、F(ab')2片段、連接二硫化物之Fvs及 含有VL或VH區域或者甚至特定結合至本發明多胜肽之互 補決定區(CDR)的片段。在另一實施例中,亦可使用該項技 術中已知之各種噬菌體顯示法產生抗體。亦可使用該項技 術中已知方法使用重組產生Fab, Fab'及F(ab')2片段之技 術,該等方法諸如彼等描述於PCT公開案WO 92/22324;
Mullinax 等人,BioTechniques,12(6):864-869, 1992 ;及 Sawai 等人,1995,AJRI 34:26-34 ;及 Better 等人,1988,Science 240:1041-1043 (該等案之全文各以引用的方式併入本文中) 中之方法。可用於產生單鏈Fvs及抗體之技術實例包括彼等 描述於美國專利Nos. 4,946,778及5,25 8,498 ; Huston等人, 1991,Methods in Enzymology 203:46-88 ; Shu等人,1993,?1:〇。· Natl· Acad. Sci. USA 90:7995-7999 ;及 Skerra 等人,1988,
Science 240:1038-1040中之技術。為某些用途,包括活體内 使用抗體於人類中及活體外偵測檢定,使用嵌合、人化或 人類抗體是較佳的。嵌合抗體為其中抗體之不同部分係自 不同動物種類衍生之分子,諸如具有自鼠科動物單株抗體 衍生之可變區域及自人類免疫球蛋白衍生之恆定區域的抗 體。製造嵌合抗體之方法在此項技術中已知。參見如, Morrison, 1985, Science 229:1202 ; Oi 等人,1986, BioTechniques 4:214 ; Gillies等人,1989,J. Immunol. Methods 125:191-202、 美國專利>1〇3.5,807,715;4,816,567;及4,816,397;該等案 之全文以引用的方式併入本文中。人化抗體為來自結合所 101968.doc -25- 1356062
需抗原之非人類物種抗體的抗體分子,該抗原具有一或多 個來自非人類物種之互補決定區(CDR)及來自人類免疫球 蛋白之構架區,或在本發明情況下具有一或多個自TREM-1 蛋白質衍生之CDR。如該項技術中已知,人類構架區中構 架殘基可以來自CDR施體抗體之相應殘基取代以改變(較 佳改良)抗原結合。該等框架取代係藉由如該項技術中習知 方法識別,如藉由模仿CDR於框架殘基間之相互作用以識 別對抗原結合及序列比較重要之框架殘基,以識別特殊位 置之不尋常框架殘基。參見如,Queen等人,美國專利No. 5,585,089 ; Riechmann等人,1988, Nature 332:323,1988, 該等案之全文以引用的方式併入本文中。可使用多種該項 技術中已知方法人化抗體,該等方法包括(例如)CDR接枝 (EP 239,400; PCT公開案 WO 91/09967;美國專利Nos· 5,225,539; 5,530,101 及 5,585,089)、鑲面或再塗層(EP
592,106; EP 5 19,596; Padlan, 1991, Molecular Immunology, 28(4/5):489-498; Studnicka等人,1994, Protein Engineering, 7(6):805-814: Roguska等人,1994, Proc Natl. Acad. Sci. USA 91:969-973,及 chain shuffling (美國專利 No_ 5,565,332),所 有該等案之全文以引用的方式併入本文中。
完全人類抗體尤其為治療性治療人類患者所需》可藉由 各種該項技術中已知方法(包括上述噬菌體顯示法)使用自 人類免疫球蛋白序列衍生之抗體庫製備人類抗體。參見美 國專利 Nos_ 4,444,887 及 4,716,111 ;及 PCT 公開案 WO 98/46645; WO 98/50433; WO 98/24893; WO 98/16654; WO 101968.doc -26- 1356062 96/34096; WO 96/33735 ;及 WO 91/10741,該等案之全文各 以引用的方式併入本文中。亦可使用基因改造小鼠製造人 類抗體(參見 Lonberg 及 Huszar (1995),Int. Rev. Immunol· 13:65-93)。為詳細描述製造人類抗體及人類單株抗體之該 技術及製造該等抗體之方案,參見如,PCT公開案WO 98/24893; WO 92/01047; WO 96/34096; WO 96/33735 ;歐洲 專利 No. 0 598 877;美國專利 Nos. 5,413,923; 5,625,126; 5,633,425; 5,569,825; 5,661,016; 5,545,806; 5,814,318;
5,885,793; 5,9 16,771及5,939,598 ;該等案之全文以引用的 方式併入本文中。此外,可雇傭諸如Abgenix,Inc. (Freemont,
CA),Medarex (NJ)及 Genpharm (San Jose, CA)之公司以使 用類似上述技術提供相對所選抗原導向之人類抗體。可使 用提及為”引導選擇"之技術產生識別所選抗原決定基之完 全人類抗體。在該方法中使用選擇之非人類單株抗體(如小 鼠抗體)以引導選擇識別相同抗原決定基之完全人類抗體 (Jespers等人,1988, Bio/technology 12:899-903)。稍合或共 軛於異源多胜肽抗體可在該項技術中習知之免疫檢定或純 化方法中(如親合性層析法)使用。參見如,PCT公開案號 WO 93/21232; EP 439,095 ; Naramura等人,1994, Immunol· Lett. 39:9卜99 ;美國專利 5,474,981 ; Gillies等人,1992 Proc.
Natl. Acad· Sci· USA 89:1428-1432 ;及 Fell等人,1991,J.
Immunol. 146:2446-2452,該等案之全文以弓I用的方式併入 本文中。 ’ 在另一態樣中,本發明係提供用以鑑定可鍵結本發明多 101968.doc -27- 1356062 胜肽之化合物或配位體或調節本發明多胜肽活性之化合物 或配位體之方法。該方法包含測定在試驗化合物有或無存 在時多胜肽之生物活性及鑑定會改變(增加或降低)該多胜 .肽生物活性之試驗化合物。 在一個實施例中,本發明提供一種包含一生物活性分子 及本發明多胜肽一或多個區域或其片段之稠合蛋白質。明 確言之’本發明係提供包含重組方式稠合或化學方式與本 發明多胜肽一或多個區域或其片段之共軛(包括共價及非 共價共軛二者)的稠合蛋白質。 本發明進一步涵蓋其中本發明多胜肽或其片段係以重組 桐合或化學共軛至(包括共價及非共價共軛二者)異源多胜 肽(意即無關之多胜狀或其部分,較佳該多胜肽之至少1〇、 至少20、至少30、至少40、至少50、至少60、至少70、至 少80、至少90或至少1〇〇個胺基酸)以產生稠合蛋白質的稠 合蛋白質。該稠合作用不一定是直接的,而可藉由連接子 序列產生。 在一個貫例中,稠合蛋白質中的本發明多胜肽或其片段 可稠合至衍生自各種類型免疫球蛋白。例如,本發明多胜 肽可稠合至人類IgGl或IgM分子之恆定區域(如鉸鏈、CH2 及 CH3 區域),(例如 Hudson & Souriauso (2003) Nature
Medicine 9(1): 129-134所描述)’如此可使稠合多胜肽或其 片段在活體内更加可溶且穩定。藉由聚乙二醇化(即稠合至 聚乙二醇)亦可延長抗體片段之短暫半衰期(參見Le〇ng, S.R.等人(2001) Cytokine 16:106-119)。在該稠合之一個實例中 101968.doc -28- 1356062 (描述於WO 01 83525中),Fc區域係與生物活性胜肽稠合β 藉由將Fc區域以共價方式連結至所選胜肽之至少一個胺基 " 酸上可製造出醫藥學上活性化合物。連接至媒劑上可增加 .胜肽之半衰期,否則其在活體内會很快降解。 或者,可使用非經典可選蛋白質支架(例如參見Nygren &
Skerra (2004) J Immunol Methods 290 (1-2):3-28 或 WO 03049684)以併入(且複製功能)本發明之胜肽,例如藉由將 自TREM-1 CDR2或CDR3衍生之胜肽序列嵌入蛋白質框架 % 以支撐與CDR2或CDR3在固定空間排列上具有結構/功能相 似性之構形可變環圈。 該等稍合蛋白質或基於支架之蛋白質可用作免疫原以製 造識別本發明之多胜肽或其片段之特定抗體。在另一較佳 實施例中,可將該等稠合蛋白質或基於支架之蛋白質投藥 至患者以抑制活體内配位體與其受體間之相互作用。該相 互作用抑制將阻斷或抑制涉及敗血症及敗血性休克之細胞 反應。
在一態樣中’稠合蛋白質包含在N端稠合至異源訊號序列 之本發明多胜肽。可購得各種訊號序列。例如,可購得蜂 毒素及人類胎盤驗性填酸驗之分泌序列(§tratagene; La Jolla ’ CA)為真核異源訊號序列。作為原核異源訊號序列之 實例’可列出phoA分泌序列(Sambrook等人 ,supra ;及 Current Protocols in Molecular Biology,1992,Ausubel等 人 ’ eds” John Wiley & Sons)及蛋白 a分泌序列(Pharmacia Biotech; Piscataway,NJ)。另一實例為桿狀病毒套膜蛋白之 101968.doc -29- 1356062 gp67分泌序列(Current Protocols in Molecular Biology,1992, Au.subel等人,eds.,John Wiley & Sons)。 在另一實施例中,本發明之多胜肽可稠合至標籤序列, 如六組胺酸胜肽,諸如pQE載體中提供之標籤(QIAGEN,
Inc” 9259 Eton Avenue, Chatsworth, CA,91311),其中很多 可購得。如 Gentz等人 ’ 1989,Proc. Natl. Acad. Sci. USA 86:821-824中描述’舉例而言’六組胺酸提供稠合蛋白質之 方便純化。蛋白質標籤之其它實例為紅血球凝聚素"HA"標 臧’其相應於自流行性感冒紅血球凝聚素蛋白質衍生之抗 原決定基(Wilson等人’ 1984,Cell 37:767),以及"旗標',標 斌(Knappik等人 ’ 1994,Biotechniques 17(4):754-761)。該 等標籤尤其有用於純化重組製造之本發明之多胜肽。 稍合蛋白質可藉由標準重組DN A技術或藉由蛋白質合成 技術(如藉由使用胜肽合成器)製造。例如,為稠合蛋白質編 碼之核酸分子可藉由習知技術合成,包括自動DNa合成 器。或者,基因片段之PCR放大可使用引起兩個連續基因 片段(其可隨後被黏接並重新放大以產生嵌合基因序列)間 之補充突出物的錨定引子來進行(參見如,Current卩⑺⑺⑶匕 in Molecular Bi〇logy, 1992, Ausubel等人,他,J〇hn π — & Sons)。為稠合蛋白質編碼之核苷酸序列可被嵌入合適表 現載體,意即含有轉錄及翻譯嵌入蛋白質·編碼序列所必需 元素之載體。已知各種宿主-載體系統及選擇系統。在一特 定實施例中,稠合蛋白質之表現係藉由固有性啟動子調 節。在另一實施例中,稠合蛋白質之表現係藉由可誘導促 101968.doc •30· 1356062 進J調節》依照該等實施例,促進劑可為組織特定促進劑。 含有為蛋白質編碼之基因嵌入之表現載體可藉由三種常用 法識別.(a)核酸雜交’(b)存在或不存在"標記"基因功 :’及⑷表現嵌入序列。在第一種方法中,可藉由核酸雜 交使用包含與為稠合蛋白質編碼之嵌入基因同源之序列的 探針偵測表現載體中為稠合蛋白質編碼之基因的存在。在 第二種方法中,可基於存在或不存在特定"標記"基因功能 (如胸苷激酶活性、抗抗生素性、轉化顯型、桿狀病毒中包 零含體形式等)識別並選擇重組載體/宿主系統,該等特定"標 记基因功能係由嵌入載體中為稠合蛋白質編碼之核苷酸 序列引起。例如,若為稠合蛋白質編碼之核苷酸序列嵌入 載體之標記基因序列内,則含有為稠合蛋白質編碼之基因 的重組體可藉由不存在標記基因功能識別。在第三種方法 中,重組表現載體可藉由檢定由重組體表現之基因產物(意 即稠合蛋白質)來識別。該等檢定可基於(例如)活體外檢定 ^ 系統中稠合蛋白質之物理或功能特性,如與抗稠合蛋白質 抗體結合。對於重組蛋白質之長期高產量生成,穩定表現 是較佳的。例如,可設計穩定表現稠合蛋白質之細胞株。 不使用3有剞本病毒源之表現載體,可以藉由合適表現控 制元素(如促進劑、強化子、序列、轉錄終止子、多聚腺嘌 呤位置等)控制之DNA以及選擇之標記轉變宿主細胞❶隨著 引入外來DNA,設計之細胞可在富集培養基中生長丨_2天, 且然後轉變為所選培養基。重組質粒中所選標記賦予對該 選擇之抗性且使細胞穩定結合質粒至其染色體並生長以形 101968.doc -31· 1356062 (尤其合適之診斷法,參見wo 2004081233,Gib〇t等人(2_
Ann Intem Med. 及 Gibot 等人(2004) N Engl J 福.35〇(5):45 i·8)來確定羅患敗血症或敗血性休克之患 者。本文描述之㈣劑(例如)可用於治療罹患諸如彼等前述 之發展疾病之患者^發日月之方法適用於哺乳動物,如人 類、非人類靈長類、綿羊、豬、牛、馬、山羊、狗、截及 齧齒動物’諸如小鼠及大鼠。通常本發明之方法係用於人 類患者。 此外,本發明提供包含本發明之多胜肽或模擬本發明多 胜肽之其抗體或片段的醫藥組合物。本發明之胜肽、多胜 肽及抗體(本文亦稱為”活性化合物,,)可併入適於投藥之醫 藥組合物。該等組合物通常包含胜狀、蛋白質&抗體及醫 藥學上可接受之載劑。 本文使用術語"醫藥學上可接受之稀釋劑、載劑或賦形劑" 意欲包括與醫藥上投藥相容之任何及所有溶劑、分散培養 基、塗層、抗細菌及抗真菌劑、等張及吸收延遲劑及類似 物。在該技術中已熟知該等培養基及試劑作醫藥學活性物 質之用途。除了任何與活性化合物不相容之任何習知培養 基或试劑的範圍,涵蓋其在組合物中之用途。補充活性化 合物亦可併入該等組合物。 本發明包括製備含有本發明胜肽或多胜肽之醫藥組合 物。該等組合物可進一步包括額外活性劑。因而,本發明 進一步包括藉由調配醫藥學上可接受之載劑與本發明之胜 肽或多胜肽及一或多種額外活性化合物製備醫藥組合物的 •101968.doc -33· 1356062 方法。 將本發明之醫藥組合物調配為與投藥之預想途徑相容。 投藥途徑包括非經腸,如靜脈内、皮内、皮下、經皮(局部)、 經黏膜、關節内、腹膜内及胸膜内,以及口服、吸入及直 腸投藥。用於非經腸、皮内或皮下應用之溶液或懸浮液可 包括下列組份:無菌稀釋液,諸如注射用水、生理食鹽水 浴液、不揮發油、聚乙二酵、甘油、丙二醇或其它合成溶 劑’抗細菌劑,諸如苄醇、對羥基苯甲酸甲酯;抗氧化劑, 諸如抗壞血酸或亞硫酸氫鈉;螯合劑,諸如乙二胺四乙酸; 緩衝液,諸如乙酸鹽、檸檬酸鹽或磷酸鹽,以及用於調節 張力之6式劑,諸如氣化鈉或右旋糖。pH值可以酸或鹼調節, 諸如鹽酸或氫氧油。非經腸製劑可封人安瓶、拋棄式注 射器或玻璃或塑料制多劑量小瓶。 適於主射用途之醫藥組合物包括無菌水溶液(可溶於水 時)或分散液及用於臨時製備無菌可注射溶液或分散液之 無菌粉末。對於靜脈内投藥,合適載劑包括生理鹽水、抑 菌水 Cremophor EL™ (BASF; parsippany,NJ)或磷酸鹽緩 衝生理食鹽水叫在所有情況下,該組合物必須無:且 應為易注射程度之流體並存在注射器。其在製造及儲存條 件下必須是穩定的且必須可與諸如細菌及真菌之微生物之 污染行為相抵而保存。載劑可為含有(例如)水、乙醇、多元 醇(例如甘油、丙二醇及液體聚乙二酵及類似物)之溶劑或分 散培養基及其合適混合物。保持適當流動性可(例如)藉由使 用諸如Μ脂之塗層’在分散液情況下藉由保持所練子 101968.doc •34· 1356062 尺寸’及藉由使用界面活㈣卜防止微生物行為可藉由各 種抗細菌及抗真菌劑達成,例如對氧苯甲酸醋、氯丁醇、 苯齡、抗壞血酸、硫柳采及類似物。在很多情況下,較佳 在組合物中包括等張劑’例如糖、多元醇(諸如甘露醇、山 梨糖醇)、氯化鈉。可藉由在組合物中包括延遲吸收試劑(例 如單硬脂酸铭及明膠)達到注射組合物之延長吸吹。 製備無菌注射溶液可藉由將所需量之活性化合物(如多 胜肽或抗體)在合適溶劑中併入以上列舉成份之一… (如需要)之合適溶劑接著過渡殺@。通常,製備分散液係藉 由將該活性化合物併人含有基本分散液培養基及所需來自 以上列舉之其它成份的無菌媒劑。在製備無菌注射溶液之 無菌粉末的情況下,較佳製備方法為真空乾燥及束乾,其 獲得活性成份粉末加上任意額外需要之來自其前無菌過渡 溶液之成份。 口服組合物通常包括惰性稀釋劑或可食用載劑。其可封 入明膠膠囊或壓縮成㈣卜為σ服治療投藥目%,可將賦 形劑併入活性化合物並以錠劑、口含錠或膠囊形式使用。 醫藥相容黏合劑及/或佐劑材料可包括作為組合物之部 分。錠劑、藥丸、膠囊、口含錠及類似物可含有任意下列 成份或相似性質之化合物:黏合劑’諸如微晶纖維素、黃 蓍膠或明膠;賦形劑,諸如澱粉或乳糖;分裂劑,諸如褐 藻酸、澱粉羥基乙酸鈉或玉米澱粉;潤滑劑,諸如硬脂酸 鎖或氫化植物油(Sterotes);助流劑’諸如膠狀二氧化石夕; 甜味劑,諸如蔗糖或糖精;或調味劑,諸如胡椒薄荷 '水 101968.doc •35- 1356062 楊酸甲@旨或燈味調味劑。 為吸入投藥’可以氣溶膠噴射形式自含有合適推進劑(如 氣體’諸如二氧化碳)或喷霧器之加壓容器或分散器傳送該 等化合物。 全身性投藥亦可為經黏膜或經皮方式。對於經黏膜或經 皮技藥’在調配時使用適於待滲透障壁之滲透劑。該等滲 透劑通常在此項技術中已知,且包括(例如對於經黏膜投藥) 凊办劑、膽汁鹽及梭鏈抱酸衍生物。可藉由使用鼻噴霧或 ® 栓劑完成經黏膜投藥。對於經皮投藥,如此項技術中通常 所知,將/舌性化合物調配為油膏、藥膏、凝膠或乳霜。該 等化合物亦可以栓劑(如習知栓劑基質’諸如可可油及其它 甘油醋)或保持灌腸劑形式製備以用於直腸傳遞。 在一實施例中,以保護化合物免受自身快速消除之載劑 製備活性化合物,諸如受控釋放調配物,包括植入體及封 入微膠囊傳遞系統。可使用可生物降解、可生物相容聚合 物,諸如乙烯醋酸乙烯酯、聚酸酐、聚乙醇酸、膠原蛋白、 聚原酸酯及聚乳酸。製備該等調配物之方法對熟習此項技 術者顯而易見。該等物質亦可自Alza c〇rp〇rati〇r^ N〇va
Pharmaceuticals,Inc.購得。亦可使用脂質懸浮液(包括目標 為經感染細胞之脂質,含對病毒抗原的單株抗體)作醫藥學 上可接受之載劑。可根據熟習此項技術者已知之方法製備 該等物質,例如美國專利N〇. 4,522,811所描述。 以單位劑型調配口服或非經腸組合物以利於投藥及劑量 均尤其有利。本文使用單位劑型指對於待治療之患者適 101968.doc • 36 · 1356062 合作單位劑量之物理離散單位;各單位含有計算用來產生 有關所需醫藥載劑之所需治療效果的活性化合物預定量。 本發明單位劑型之說明書受控制並直接依賴於活性化合物 之獨特特徵及待達成之特定治療效果以及化合治療個體之 該活性化合物之技術中固有的限制。 如本文界定,治療有效量之蛋白質或多胜肽(意即有效劑 量)介於約0.001至30 mg/kg體重、較佳約〇.〇1至25 mg/kg體 重、更佳約〇·1至20mg/kg體重及甚至更佳約iiiomg/kg, • 2 至 9 mg/kg ’ 3 至 8 mg/kg,4 至 7 mg/kg,或 5 至 6 mg/kg體重 之範圍内。 對於抗體’較佳劑量為體重之0.1 mg/kg至1〇〇 mg/kg(通 常10 mg/kg至20 mg/kg)。若抗體要在腦中起作用,那麼5〇 mg/kg至100 mg/kg之劑量通常合適。通常部分人類抗體及 完全人類抗體在人體中比其它抗體具有更長半衰期。因此 低劑直及低頻率投藥常常是可能的。可使用諸如脂質化之 修飾以穩定抗體並增強攝取及組織滲透(如,進入腦中)。脂 籲 質化抗體之方法描述於Cruikshank等人,1997,J. Acquired
Immune Deficiency Syndromes 及人類 Retrovirology 14:193 中ο 醫藥組合物可連同投藥說明書包括於容器、包裝或分配 器中。 本發明進一步提供含有本發明胜肽或多胜肽或者模擬本 發明多胜肽之其抗體或片段之套組,較佳具有用於(例如) 治療敗血症、敗血性休克或類似敗血症病症之說明。 101968.doc •37- 1356062 本發明提供識別(或篩選)模擬本發明多胜肽或對(例如) 本發明多胜肽活性具有刺激或抑制效應之調節劑,意即候 選或測試化合物或試劑(如胜肽、擬胜肽、小分子或其它藥 物)。本發明尤其k供篩選化合物或組合物以治療敗血症' 敗血性休克或類似敗血症病症之方法,該方法包含:提供 TREM- 1胜肽,將盲腸結紮及穿孔模型之動物與^ ^ 肽接觸(或使用本文描述或該技術中已知之其它檢定);測定 是否在敗血症中存在調變,例如其中存活率增加指示 ® TREM-1胜肽可用來治療敗血症、敗血性休克或類似敗血症 病症* 本發明進一步關於藉由上述篩選檢定識別之新穎試劑及 其用於如此描述治療之用途。 本說明書中引用之所有公開案(包括但不限於專利及專 利申請案)係以引用的方式全部併入本文中,該引用的程度 就如同已特定地及個別地將各個公開案之完全陳述以引用 的方式併入一般β ® 本發明各態樣之較佳特徵可適用於各個態樣,已作必要 的修正(mutatis mutandis)。 【實施方式】 本發明現參照下列非限制性實例、參照圖形描述,其中: 實例1 : TREM-1胜肽保護小鼠免受敗血性休克之死亡 合成符合下列標準之TREM-1胜肽:i)在人類及小鼠 TREM-1間之最高同源性及與TREM_2之最低同源性。ϋ)跨 越TREM-1之互補決定區(CDR)之胜肽。根據公開之TREM-1 101968.doc •38- 1356062 晶體結構,且與抗體類似,該等殘基可能涉及同源配位體 辨識(Radaev 等人(2003) Structure (Camb). Dec; 11(12):1527-35 & Kelker 等人(2004) J Mol Biol. Sep 24; 342(4):1237-48)(參 見圖1)。一個胜肽(PI)係在CDR2區域中設計,且三個胜肽 (P2、P4及P5)在CDR3區域中設計。第四個胜肽(P3)在連接 V型免疫球蛋白類(Ig)區域(Ig-V)至跨膜區域之頸部區域。 由於TREM-1及TREM-2間之高序列同源性而沒有在CDR1 區域中設計胜肽。
因此,自 Protein and Peptide Chemistry Facility, Institute of Biochemistry, University of Lausanne定購且合成並純化 下列TREM-1蛋白質之胜肽: Ρ1 (CDR2 67-89) LVVTQRPFTRPSEVHMGKFTLKH [SEQ ID NO:3] Ρ2 (CDR3 114-136) VIYHPPNDPVVLFHPVRLVVTKG [SEQIDNO:4] Ρ3 (頸部區域168-184) TTTRSLPKPTAVVSSPG [SEQIDNO:5] Ρ4 (CDR3 103-123) LQVTDSGLYRCVIYHPPNDPV [SEQ ID NO:6] Ρ5 (CDR3 103-119): LQVTDSGLYRCVIYHPP [SEQEDNO:7], Plsc* (P1混雜序列) LTPKHGQRSTHVTKFRVFEPVML [SEQIDNO-.8] P5sc* (p5 混雜序列) TDSRCVIGLYHPPLQVY *此為對照組胜肽且確實不具保護作用 [SEQIDNO:9]
在本實例之實驗中,投予所指示之200 μΐ體積之溶液莫耳 濃度之胜肽。為評定TREM1-胜肽保護小鼠不受LPS誘發内 毒素血症之能力,發明者在致命劑量脂多醣(LPS)前1小時 投予胜肽PI、Ρ2、Ρ3及Ρ5 (3 00 μΜ)(圖2)。隨時間監控致命 ’!·生並與接受單獨媒劑之對照組注射之動物比較。與丨0。/〇之 10l968.doc •39· 1356062 對照組小鼠相比,P5注射給予最大保護,有9〇%之動物在 LPS注射後仍存活7天(p<〇 〇〇1)。與1〇%之對照組小鼠相比 60%之P1處理小鼠及50%之P2處理小鼠自内毒素血症存活 (分別為p<0.01及ρ<〇.〇5)β有趣的是,所有P3處理小鼠在Lps 注射後4天内死亡。該等結果顯示含有對應於假定配位體結 合位置(CDR2及CDR3)之TREM-1之細胞外部分序列的胜肽 可保護小鼠不受致命休克之害。, 為研究TREM· 1胜肽處理是否能延遲直至投予匕”後,發 • 明者在LPS注射後4小時注射胜肽。只有在P1情況下,此延 遲處理給予對致命劑量LPS之重要保護(圖3)。與60%在LPS 前1 h處理之小鼠及1 〇%以單獨媒劑處理之小鼠相比,8〇0/。 在LPS後4小時注射P1之小鼠自内毒素血症存活(分別為 ρ<0·001及ρ<0·01)»因此,P1甚至在内毒素血症發作後注射 都是有效的。一個星期沒有發生後期死亡,表明ρ丨不僅延 遲LPS致命發作,且亦提供持久保護^ Ρ1投藥在6〇〇 μΜ投 藥時給予最大保護(80%) (ρ<0.01) ’且保護水平在3〇〇 μΜ時 籲 降至50% (ρ<〇·〇5)且在150 μΜ時進一步降至30%(與20%對 照組小鼠相比),指示Ρ1之劑量依賴效果(圖4)。然後發明者 研究在"CLP”模型中Ρ1是否保護不受敗血性休克(盲腸結紮 及穿孔廣泛用於敗血症之實驗模型)。在CLP後5及24小時以 兩劑量P1處理之小鼠與對照組小鼠相比保護免受死亡 (p=0.0791) ’儘管統計上區別不明顯。與5°/。以P3胜肽處理. 之小鼠相比’ 40%在LPS後5天注射P1之小鼠存活。在lps 後10天,處理之小鼠仍然活著,表明P1不僅延遲死亡,且 101968.doc • 40· 1356062 亦提供持久保護(圖5)。 實例2 : TREM-1胜肽P1抑制結合可溶性小鼠TREM-1/IgG 至TREM-1配位體陽性細胞 在CLP中測試之TREM-1衍生胜肽中,胜肽PI、P2及卩5證 實保護活性。可能之作用機制可為TREM-1衍生之胜肽干預 TREM-1/TREM-1配位體相互作用之能力。為瞭解決該問 題,發明者在TREM-1配位體陽性細胞上執行競爭實驗:自 CLP處理小鼠之PEC(腹膜滲出細胞)。 • 使來自患有盲腸結紮及穿孔(CLP)誘發腹膜炎之小鼠之 腹膜滲出細胞(PEC)或周邊血液細胞在以可溶性小鼠 TREM-1/IgGl嵌合體或以對照IgGl培育後經受流式細胞儀 分析。然後使用FITC染色之抗人類IgGl (Jackson Laboratory, Bar Harbor, USA)顯示結合。以PE共辆之郎GR1或抗Ly-6G (BD Bioscience,Milano,Italy)雙重染色細胞。藉由在加入 mTREM-1-IgGl前於冰上以指示濃度之胜肽預培育細胞45 分鐘執行以TREM-1胜肽之競爭。為增加靈敏性亦使用四聚 ® TREM-1/IgGl執行某些染色,該四聚TREM-1/IgGl如下生 成:對於各染色樣品,於室溫黑暗中,在PBS/BSA 0.5%緩 衝液中以4:1莫耳比使對照IgGl與蛋白質A Alexa 488共軛 (Molecular Probes, Brussels,Belgium)錯合 30 分鐘。將額外 人類IgGl(10 pg)加入該溶液以完全阻斷蛋白質A抗體之非 特異性結合。 如圖6所示’,自mTREM-1之CDR2區域衍生之P1胜狀以及 跨越CDR3區域之P2及P5胜肽以劑量獨立方式抑制TREM-1 101968.doc -41 - 1356062 與其配位體之相互作用。相反自連接類似IgG部分至跨膜區 域之TREM-丨頸部區域衍生之P3胜肽是無效的。 實例3 :對鼠科敗血症中藉由TREM-1胜肽P5調節發炎性反 應之額外研究 方法 自周邊血液製備單核細胞
從實驗室員工中5個健康自願者收集10 mL周邊血液樣品 於 EDTA-K上。經於 RPMI (Life Technologies, Grand Island, NY) 體積比稀釋後,於室溫經Ficoll梯度(Amersham Pharmacia, Uppsala, Sweden)離心血液30分鐘以分離PBMC。洗務並計數 在梯度上回故之細胞。為去掉淋巴細胞懸浮液,然後以 5xl06/mL濃度將細胞植入24孔平底組織培養盤(Corning, Corning, NY)且使其在37°C經2小時黏附。去除所得淋巴細 胞懸浮液,且將黏附單核細胞於37 °C下在以10% FCS (Invitrogen,Cergy, France)補充之完全培養基中(RPMI 1640,0.1 mM 丙酮酸鈉、2 mM盤尼西林(Penicillin)、50 pg/mL Streptomycin; Life Technologies)保持於 5〇/〇 C〇2‘l·亙溫 箱中。 TREM-1胜肽 使用Gen-Bank中人類TREM-1序列、登記號#八卩287008及 小鼠TREM-1序列#AF241219 ,化學合成胜肽"P5" (LQVTDSGLYRCVIYHPP; [SEQ ID NO:7])呈 C端醯胺化胜 肽(Pepscan Systems, Lelystad,The Netherlands)。獲得正嫁 之胜肽產率大於99%且量測質量為1961 Da,而計算質量為 101968.doc • 42- 1356062 1962 Da,且在製備純化後是均勻的,此由質譜及分析逆相 高效液相層析法證實。相似合成含有與P5相同胺基酸但為 不同序列順序之胜肽"P5sc" (TDSRCVIGLYHPPLQVY; [SEQ ID NO:9])並用作"對照組胜肽"。 活體外刺激單核細胞
為 了活化,在E.coli LPS (0111:B4,1 pg/mL,Sigma-Aldrich, La Verpillidre,France)存在下培養單核細胞。藉由錐藍排除法 (trypan blue exclusion)及藉由量測乳酸鹽脫氫酶釋放評定 細胞生存能力。在某些實驗中,以TNF-a (5至100 ng/mL, R&D Systems, Lille, France)、IL-Ιβ (5至 100 ng/mL,R&D
Systems)、rIFN-γ (up至 100 U/mL, R&D Systems)、rIL-10 (5 00 U/ml,R&D Systems)或高達 100 ng/mL之 P5 或對照組胜 肽的組合給出該刺激。 為了經由TREM-1活化單核細胞,如下加入抗TREM-1激 動劑單選殖抗體(R&D Systems):平底盤每孔以10 pg/mL抗 TREM-1預塗布。在磷酸鹽緩衝生理食鹽水(PBS)中徹底洗 ® 滌後,如上相似濃度加入單核細胞懸浮液。在蛋白酶抑制 劑(PMSF and Protease Cocktail Inhibitor; Invitrogen)存在下 執行某些實驗。根據根據製造商(BD Biosciences,San Diego, USA)推薦之ELISA檢定不含細胞之清液之TNF-α及IL-Ιβ生 成。為解決單核細胞中P5對NF-κΒ活性之效果,執行基於 ELISA之檢定(BD Mercury™ Transfactor Kit,BD Biosciences)。 在 E.coli LPS (0111:B4,1 pg/mL),及/或激動劑抗 TREM-1 單選殖抗體(10 pg/mL)及/或P5(100 ng/mL)存在下培養單核 101968.doc • 43· 1356062 細胞24小時。然後製備全細胞萃取物並根據製造商之推薦 測定NF-κΒ p50及p65含量。重複三次執行所有實驗且資料 以平均值(SEM)來表示。 鑑定並定量sTREM-1釋放量
如上述培養初級單核細胞。於37°C以E.coli LPS (0111:B4, 1 g/mL)處理該等細胞24小時。經細胞調節之培養基利用抗-TREM-1單選殖抗體(R&D Systems)進行西方墨點法,以證 實可經抗-TREM-1辨識之27 kDa物質的存在。如別處報導 (18)利用反射掃描儀及Quantity One Quantitation Software (Bio-Rad,Cergy,France)藉由評定免疫點法上紋帶之光學 密度量測可溶性TREM-1含量。藉由參考純化TREM-1產生 之標準曲線比較該等樣品之光學密度測定各樣品之可溶性 TREM-1濃度。所有的測量進行重複三次。此技術之靈敏度 可使得sTREM-Ι含量偵測低至5 pg/mL。
TREM-1 RT-PCR
使用TRIzol試劑(Invitrogen)從培養在LPS下之初級單核 細胞中萃取總 mRNA,並使用 Superscript RT II (Invitrogen) 進行逆轉錄作用以產生cDNA。然後用於所有反應之 RT-PCR 條件為 94°C,30 s/65°C,30 s/68°C,1 分鐘,進行 30 個循環。以 2.5 mM MgCl2, 0·2 mM dNTP,2.0 U Taq聚合酶 及 20 pM 5'及 3'寡核普酸引子(Proligos, Paris, France)進行 增幅作用。 所用5'及3’引子對之序列如下: 對於 TREM-1(17) 101968.doc -44- 1356062 TTGTCTCAGAACTCCGAGCTGC; [SEQ ID NO:1〇] 及 GAGACATCGGCAGTTGACTTGG; [SEQ ID NO:ll] 對於 TREM-lsv(19) GGACGGAGAGATGCCCAAGACC; [SEQ ID NO:12] 及
ACCAGCCAGGAGAATGACAATG; [SEQ ID NO:13] 對於β-肌動朊(用作家管增幅子) GGACGACATGGAGAAGATCTGG; [SEQ ID NO:14] 及 ATAGTAATGTCACGCACGATTTCC; [SEQ ID NO:15] PCR產物在瓊脂糖凝膠上進行電泳,並以溴化乙錠染色 顯像。 LPS誘發之小鼠内毒素血症
由當地倫理委員會批准後,隨機將雄性Balb/C小氣(2〇至. 23 g)分組,並在LPS攻毒前或後以與P5 (5〇〇 μι生理食踏水) 或對照組載體組合之E.coli LPS處理。在某些實驗中, -Li 〇 注射後一小時腹膜内投予5 pg抗TREM-1單選殖抗體。每 及 時檢查小鼠之生存能力,或定期犧牲動物。灰清樣〇 q 臟刺穿收集並以ELISA (BD Biosciences)分析| 了Νρ IL-Ιβ,並以免疫點分析其sTREM-Ι含量。 CLP多微生物敗血症模型 用腹膜内投藥0.2 mL無菌不含發熱原之鹽水士 丁疋見他命 (ketamine)及甲苯嗟嗪(xylazine)麻療 Male Baib/c小 鼠(7至9 101968.doc -45- 1356062 週’ 20至23 g)。藉由1.0 cm腹部中線切口曝露盲腸並使其 經受末梢一半結紮接著以G21針穿兩個小孔。自該等小孔排 出少量大便以保證通暢β將盲腸放入腹膜腔且腹部切口於 兩層中閉合。手術後以0.5 ml生理食鹽水溶液注射所有小鼠 用於流體復蘇且皮下注射每12 h 1.25 mg(意即50 Mg/g)伊米 配能(Imipenem) 〇將動物隨機分組且以生理食鹽水(n=14)、 對照組胜肽(n=14,100 μβ)或於H0(n=18)、H+4(n=i8)或 H+24(n=18)單獨注射之P5(l〇〇 gg)處理。最後一組小鼠 (n=18)於H+4、H+8及H+24重複注射P5 (100μβ)處理。將所 有處理稀釋至500 μΐ生理食鹽水且腹膜内投藥。發明者接著 尋求測定各種劑量Ρ5之效果。為此目的,在CLP後於Η0以 單獨注射生理食鹽水或10 、2〇 、50 gg、1〇〇叩或2〇〇 pg之P5處理小鼠(每組η=ι 5)並監控存活率。在clp後24小時 於麻醉下每組殺死額外五個動物以測定細菌數量及細胞激 素含量。實驗2 mL RPMI 1640 (Life Technologies)獲得腹膜 灌洗流體且藉由心臟穿孔收集血液。血清中TNF_a& IL- J p 之濃度藉由ELISA (BD Biosciences)測定。為估計細闺數 量,將血液及腹膜灌洗流體以系列對數稀釋植入以5%綿羊 企瓊脂盤補充之胰蛋白大豆中。植入後於37〇c有氧培育胰 蛋白大豆瓊脂盤24小時’且無氧培育48小時,結果表示為 每ml血液之CFU及腹膜灌洗之每小鼠之cfu。 統計分析 血清sTREM-1及細胞激素含量表示為平均值(±sd)。藉由 比較存活率曲線使用Log-Rank測試評定P5相抵LPS致命性 101968.doc -46- 之保護。所有統計分析以Statview軟體(Abacus Concepts, Berkeley CA)完成且雙側(two-tailed) P<0.05被認為是重要 的。 結果 在以E.coli LPS刺激後自培養之人類單核細胞釋放可溶 形式之TREM-1 為識別活體内sTREM-Ι之潛在釋放,發明者以LPS刺激人 類單核細胞並藉由SDS-PAGE分析該調節之培養培養基。 LPS刺激以時間依賴之方式誘導27-kDa蛋白質出現(圖 7A)。西方墨點法揭示該蛋白質由單選殖抗體控制與 TREM- 1之細胞外區域相抵而辨識(圖7 A) 〇在誘導sTREM-1 存在於調節培養基中之LPS濃度未使細胞存活能力受影 響,表明TREM-1釋放不是因為細胞死亡。類似地,以蛋白 酶抑制劑處理單核細胞不影響TREM-1釋放(圖7A)。 TREM-1 mRNA含量經LPS處理而增加(圖7B),而TREM-lsv mRNA含量仍無法偵測。這表明TREM-1釋放可能與基因之 增加轉錄有關且與TREM-lsv表現無關。 以 TNF-a (5 至 100 ng/mL)或 IL-Ιβ (5 至 100 ng/mL)刺激單 核細胞16小時以細胞激素劑量獨立之方式誘導很小之 TREM-1釋放。釋放即使在濃度高達100 U/mL時,以IFN-γ 刺激也不誘導TREM-1。 藉由P5減少初炎性細胞激素之LPS相關釋放 在以LPS培養單核細胞之清液中發現了重要TNF-cc及 IL-Ιβ生成。對於以TREM-1 mAb及LPS兩者培養之細胞 101968.doc -47- 1356062
TNF-α及IL-Ιβ生成與彼等以mAb或LPS單獨培養之細胞相 比甚至更高(圖8A)。當培養基以P5或IL-10補充時初炎性細 胞激素之誘導釋放在LPS刺激後相當低。P5降低(以濃度獨 立之方式)自以LPS或以LPS及mAb培養細胞之TNF-α及 IL-Ιβ產生且同時增加sTREM-Ι自LPS培養細胞之釋放。對 照組胜肽對細胞激素或sTREM-1釋放沒有呈現作用(未顯 示資料)。驚人對比的是,IL-10完全抑制TREM-1及初炎性 細胞激素之釋放(圖8A)。LPS及TREM-1 mAb兩者誘導單核 細胞性NF-κΒ p50及p65之強活化,且LPS及TREM-1 mAb之 組合投藥導致協同效果》P5抑制藉由嚙合TREM-1誘導之 NF-κΒ活化但不改變LPS之效果(圖8B)。 增加LPS處理之小鼠之血清sTREM-1含量 為測定小鼠中内毒素血症期間是否全身性釋放 sTREM-卜發明者LPS投藥後量測血清sTREM-l含量。血清 sTREM-Ι在投藥LD5〇劑量之LPS後1小時易於偵測且在LPS 處理後4至6小時可保持於頂點穩定水平(圖9)。
TREM-1胜肽"P5”保護内毒素血症小鼠免受致命 在致命劑量(LD1()())LPS後60分鐘由單劑量P5處理之小鼠 被以劑量獨立方式預防其免受死亡(圖10A)。為了研究P5處 理是否可延遲直至投藥LPS後,發明者在LPS注射後4或6小 時開始注射P5。此高達4小時之延遲處理給予相抵LD1()0劑 量LPS之重要保護(圖10B)。一個星期沒有發生完全死亡, 表明P5不僅延遲LPS致命性發作,其亦提供持久保護。對照 組小鼠都在死亡前顯示無精打采、豎毛及腹瀉。對比之下, 101968.doc -48- 1356062 P5處理之小鼠較好保持了整潔及活性,無腹瀉且活潑。為 闡明P5保護小鼠免受LPS致命之機制,發明者在2及4小時測 定内毒素血症小鼠之TNF-ct、IL-1 β及sTREM-1之血清含 .量。與對照組相比,由100 pg之P5預處理降低細胞計算含 量30%且增加sTREM-Ι含量2倍,如表4中顯示。 表4.内毒素血症小鼠中TNF-α、IL-ip及sTREM-Ι之血清濃度 TNF-a (ng/mL) IL-lp(ng/mL) sTREM-1 (ng/mL) H2 H4 H2 H4 H2 H4 對照組 3.3 土 1.0 0.4 士 0.1 0.3 土 0.1 1.5±0·2 249±48 139士 8 • P5(100pg) 2.4 土 0.5 0.1 土 0.1 0.2 士 0.1 0.9±0.2 475±37 243±28 嚙合TREM-1對小鼠是致命的 為進一步強調TREM-1嚙合在LPS調節之死亡中之作用, 以組合投藥LD5〇劑量LPS之激動劑抗TREM-1 mAb處理小 鼠。此誘導死亡率自50%顯著增加至100% (圖10C)。 P5保護小鼠免受CLP誘導之致命 為研究P5在更相關敗血性休克模型中之作用,發明者執 行了 CLP實驗(圖11A)。對照組包含以生理食鹽水或以對照 # 組胜肽注射之小鼠。在該多微生物敗血症模型中,P5仍甚 至在晚至敗血症發作後24小時投藥時仍給予相抵致命性之 重大保護。有趣的是,重複注射P5對存活率具有更有利之 效果(P<0.01)。存在P5對存活率(圖11B)及細胞激素生成之 劑量反應效果。P5對細菌清除沒有效果(圖12)。 101968.doc -49- 1356062 表5. CLP後24小時TNF-α、IL-Ιβ及sTREM-l之血清濃度 對照組胜肽 TNF-a (pg/mL) 105±12 IL-Ιβ (pg/mL) 841±204 sTREM-1 (ng/mL) 52±3 對照組生理食鹽水 118土 8 792土198 35 土 5 P5 10 110±11 356±62 43 士 8 Ρ5 20 pg 89±10 324±58 58 士 8 P5 50 pg 24±6 57±11 93 土 10 P5 100 pg 20±3 31 士3 118±12 P5 200 pg 21±7 37±8 158±13 敗血症例示自對嚴重感染之有害或損壞宿主反應的複雜 臨床症候群。敗血症在開始時發展,對全身性感染之合適 0 宿主反應變擴大,且然後被不良調節(4、5)。曝露於LPS之 嗜中性白血球及單核細胞/巨噬細胞(例如)被活化並釋放諸 如TNF-α及IL-Ιβ之促發炎細胞激素。廣泛認為該等細胞激 素之過度產生貢獻了敗血症患者中所見之多種器官壞死 (20-23)。 TREM- 1為最近識別之分子,其涉及單核細胞活化及發炎 性反應(12、14)。其屬於相關活化下游訊號事件之NK細胞 受體之家族。PNN及單核細胞/巨噬細胞上TREM-1之表現顯 φ 示是由LPS所誘導(16、17)。 如本文描述,發明者證實在以E.coli LPS刺激後自培養之 人類單核細胞釋放可溶形式之TREM-1。該可溶形式亦可在 早至LPS攻毒後1小時在内毒素血症小鼠之血清中偵測。這 與對感染之先天免疫響應之極早相中涉及TREM-1是一致 的。沒有很明確地闡明釋放sTREM-1之機制,但是其似乎 與TREM-1基因之增加轉錄有關。然而,儘管以蛋白酶抑制 .劑混合液培育不改變sTREM-Ι釋放,但是不能完全排除表 101968.doc -50- 1356062 面TREM-1自膜之分裂。有趣的是,以諸如TNF-α、IL-Ιβ或 IFN-γ之促發炎細胞激素刺激人類單核細胞誘導極小 sTREM-l釋放直至加入LPS作共刺激物。可選mRNA TREM-1接合變異體(TREM-lsv)之表現被偵測於單核細胞 中,其可以牛分枝桿菌(Mycobacterium bovis) BCG之細胞 壁部分而不是LPS刺激(25)而翻譯成可溶受體(18)。這在該 •研究中被證實為i)LPS不增加單核細胞中mRNA TREM-1 sv 含量,及ii)只有27-kDa蛋白質經LPS刺激釋放而不是 ® 17.5-kDa變異體。 儘管其天然配位體還未被識別(13、14),在單核細胞上以 促效劑單選殖抗體嚙合TREM-1導致促發炎細胞激素生成 之進一步增強,而P5以濃度獨依賴之方式誘導該等綜合體 之降低,且IL-10完全使其抑制。 促發炎細胞激素及尤其TNF-α被認為是有害的,但它們仍 亦對敗血症具有有利效果(5),如患損害TNF-α反應(9-11) 之動物中腹膜炎之致命問題所顯示。此外,在臨床試驗中, ® 抑制TNF-α增加死亡率(8)。最終TNF-ct在清除感染中之作用 已由以下發現所強調:敗血症為以TNF-α拮抗劑治療之類風 濕性關節炎患者中之常見併發症(26)。 P5調變細胞激素生成之機制尚不清楚。P5包含互補決定 區(CDR)-3及TREM-1之細胞外區域之'F,β束。後者含有調 節二聚作用之酪胺酸殘基。Radaev等人假定TREM-1以其 CDR等價之環圈區域俘獲其配位體(27)。因此P5可削減 TREM-1二聚及/或與TREM-1之天然配位體競爭。此外,P5 101968.doc •51 · 調節之sTREM-1釋放自單核細胞之增加防止膜TREM-1之 嚙合,如TNF-α系統中,sTREM-Ι用作誘餌受體(28、29)。 活化轉錄因子NF-κΒ是在曝露於諸如LPS之細菌刺激物 後單核細胞發炎細胞激素生成中之關鍵步驟(30, 31)。在各 種NF-KB/Rel二聚體中,p65/p50雜二聚體是單核細胞中LPS 誘導NF-κΒ之原型形式(32)。P5破壞嚙合TREM-1誘導之 p65/p50NF-KB過度活化。這可至少部分解釋P5對細胞激素 生成及保護不受致命性之效果,此處所示之效果在LPS誘導 敗血性休克前一小時或甚至在其後高達4小時注射胜肽時 會發生。 内毒素血症實驗上達成較為容易,但不完全適於再生人 類敗血症,而LPS誘導之多微生物敗血症為更加複雜卻更佳 之模型,包括使用流體復蘇及抗體。因此後者亦可用於此 研究,且即使晚至在敗血症發作後24小時投藥,其證實P5 提供之劑量依賴保護。然而P5之有利效果與增強之細菌清 除無關。 使用免疫調節療法中之一個困難為預測敗血症發展是不 可能的,且因此接受彼等治療之患者常常已經患有良好形 成之敗血症(6)。由於P5看來即使在敗血症發作後注射是有 效的,.因而其可構成現實之治療(24、33)。 相比之下,由激動劑抗TREM-1單選殖抗體嚙合TREM-1 調節LPS攻毒小鼠中死亡率之引人注目之增加:此進一步強 調TREM-1嚙合在敗血性休克期間之有害效果。 實驗敗血性休克僅部分再生人類敗血症,事實上,吾組 101968.doc -52· 1356062 最近表不sTREM-1之重大含量在含敗血症患者之重症患者 血清中釋放(34),在存活患者中觀測到最高含量。這與我們 的實驗發現是一致的,該等發現表明越重要之TreM- 1釋 放’結果越有利,且因此支持(至少理論上)可溶性TrEm胜 肽作為發作後敗血症治療之潛在價值。 TREM-1看來在感染觸發之即刻免疫反應中是關鍵參與 者。在感染之早期相中,由於由微生物產物嚙合模式辨識 受體’嗜中性白血球及單核細胞引起發炎性反應。同時微 參 生物產物誘導上調節及sTREM-1釋放。經辨識未知配位 體’ TREM-1活化將該等發炎性反應放大之訊號路徑’特別 是在單核細胞/巨噬細胞中。調節TREM-1訊號降低(儘管無 完全抑制)細胞激素生成且保護敗血性動物免受高反應性 及死亡。以諸如P5之胜肽調節TREM-1嚙合可為治療敗血症 之合適治療工具’尤其因為其似乎即使在感染侵襲隨後之 敗血症發作後還是活性的。 實例4 :以P1及P5處理之LPS處理及敗血性大鼠的i液動力 ®學研究 藉由執行鼠中LPS及CLP (盲腸結紮及穿孔)實驗研究 TREM-1胜狀在敗血性休克之進一步模型中之作用。 材料及方法 LPS誘發之内毒素血症 將動物隨機分組(η=10·20)並以與TREM-1或混雜胜肽腹 膜内組合之埃希氏大腸桿菌(Escherichia coli) LPS (0111:B4,Sigma-Aldrich,Lyon, France)處理。 101968.doc -53- 1356062 CLP多微生物敗血症模型 該程式已詳細描述於別處(參見Mansart,Α·等人Shock 19:3 8-44 (2003))。簡言之,大鼠(每組n=6-10)藉由腹膜内投 藥克他命(150 mg/kg)麻醉。藉由3.0 cm腹部中線切口曝露 盲腸並使其經受末梢一半結紮接著以G21針穿兩個小孔。自 該等小孔排出少量大便以保證通暢。將盲腸放入腹膜腔且 腹部切口於兩層中閉合。手術後以50 mL/kg之生理食鹽水 溶液皮下注射所有小鼠用·於流體復蘇。然後如上注射 TREM-1或混雜胜肽》 大鼠中血液動力學量測 LPS注射後立即以及在CLP後16小時使用別處描述之程 式記錄動脈BP(心臟收縮、心臟舒張及平均)、心率、腹部 大動脈血流及腸系膜企流(參見Mansart, A.等人Shock 19:38-44 (2003))。簡言之,以PE-50管道插入左頸動脈及左 頸靜脈。藉由壓力傳感器及放大記錄系統(ΙΟΧ EMKA Technologies,Paris, France)連續監控動脈BP。血管周探針 (Transonic Systems,Ithaca, NY)包覆上腹部大動脈及腸系 膜動脈,以藉由流量計(Transonic Systems)監控其各自流 動。最後量測之後(LPS實驗期間第4小時及CLP後第24小 時)’藉由靜脈内過量劑量之戊硫代巴比妥鈉(sodium thiopental)犧牲動物。 生物量測 自左頸動脈連續提取血液。在自動血液氣體分析器(ABl 735,Radiometer, Copenhagen,Denmark)上執行動脈乳酸鹽 10l968.doc -54· 1356062 濃度及血液氣體分析》根據製造商推薦藉由ELIS A測試 (Biosource,Nivelles,Belgium)測定血漿中 TNF-α及 IL-Ιβ之 濃度。使用 Griess反應(R&D Systems, Abingdon, UK)量測硝 酸鹽/亞硝酸鹽之血漿濃度。 統計分析 結果表示為平均土SD。使用學生測試執行組間比較。所 有統計分析以Statview軟體(Abacus Concepts, CA)完成且雙 側P<0.05被認為是重要的。 結果 内毒素血症模型 在LPS投藥後,對照動物(混雜胜肽處理之大鼠)中動脈 壓、大動脈及腸系膜血流快速下降而其心率仍未變化(表 6)。在TREM-1胜肽處理之動物中動脈壓及大動脈血流之下 降延遲直至第二小時,彼時具有比對照動物顯著更高值。 在P1及P5處理之小組之間沒有區別。相比之下,該等兩胜 肽沒有一個對腸系膜血流之下降有任何效果(表6)。 動脈pH值隨時間保持恆定直至Lps注射後第四小時,而 其僅在對照組中嚴重下降(表6)。對照動物中在第三小時後 存在之顯著動脈乳酸鹽含量上升被TREM· 1胜肽消除(表 )對於pH值、動脈碳酸氫鹽及乳酸鹽濃度,在η及μ之 間沒有區別。 如預期’ TNF-α血漿濃度之峰值由Lps在注射後3〇分鐘與 1 J、時之間誘發’接著其後是逐漸下降(圖i3a)。Η胜狀注 射對該生成無效果,而P5減小TNF_a生成〜3〇%。 101968.doc •55· 1356062 P1延遲IL-Ιβ峰直至LPS注射後第三小時,但沒有削弱。 相比之下,P5強烈降低IL-Ιβ釋放(圖13B)。 在對照組及P1處理之動物中中亞硝酸鹽/硝酸鹽濃度在 LPS投藥後快速上升,但經P5處理仍穩定(圖14)。 表6. LPS誘發之内毒素血症期間血液動力學參數 心率 MAP 大動脈血流 腸系膜血流 pH 乳酸鹽 (bpm) (mmHg) (mL/分鐘) (mL/分鐘) (mmol/L) 對照組 H0 486±13 123±21 45±7 13·6±3·4 7.31±0·03 3·3±0.8 H1 522±16 103±25 25±8a 9·6±3·3 7·28±0.03 4.2±0.3 H2 516±13 98±23 12±5a’b 8.0±3.7 7.29±0.03 5·9±0.6 H3 490±20 78 土 8 a,b 8±3 a,b 5.8±1·1 7.26±0.01 7.9±1.8a’b H4 510士18 67士 9a,b 6土 la’b 4.1±0.8 7.03±0.10a’b 11.5±0.7a,b P1 H0 464士 25 116±10 49士11 12·0±3.7 7·32±0·04 2.7 士 0.1 H1 492±26 119士14 39士12a 10.5±1.7 7.29±0.04 4.9士1.1 H2 492士 26 113±21 26±14a 7.7±2.7 7.30±0.01 5.0 士 0.9 H3 480±30 97±29a 22±8a 5.0±1.0 7.26±0.06 5.7±0.7a H4 480±20 92±7a 16±6a 4·8±0·9 7.26±0.08a 7.9 士 1.7a P5 H0 474士49 115土16 48±9 12.8±6·4 7.33 土 0.04 3.4±1.5 H1 498±26 99 士 22 32±8 11.4 土 2.7 7.28±0.06 5.4 土 1.4 H2 510±42 101±18 23±4b 9·2±1.9 7.32±0.07 5·5±1.6 H3 517±62 93±21b 20±7b 6.0±0.8 7.29±0.11 5.9±1.7b H4 510±26 89±10b 15±6b 5.0±1·0 7.28 土 0.12b 7.4±1.8b
ap<0.05 P1對比對照組 bp<0.05 P5對比對照組 CLP模型
由於本發明者模型之嚴重性為其在CLP完成後16至20小 時最高,該等發明者選擇在第16小時研究動物。重要的是, 在該時間以前沒有死亡。儘管所有動物被流體復甦,沒有 一個接受抗生素以嚴格考慮胜肽之作用。 隨時間在對照組動物中存在動脈壓之明顯下降,且藉由 H24心臟收縮、心臟舒張及平均動脈壓分別為58±7 mmHg.、 25±4 mmHg及38±2 mmHg。該下降幾乎完全以P1或P5治療 消除,H16及H24之間沒有顯著區別(圖15)。P1及P5治療之 101968.doc •56- 1356062 鼠之間沒有區別。 TREM-1胜肽亦防止對照組動物t發現之大動脈及腸系 膜血流下降(表7)。在P5治療下對腸系膜血流改變之保護效 應甚至更高。血流之相對保存與增加之心率無關,因為後 者在對照組動物中甚至更慢(表7)。 由P1胜肽削弱,且幾乎由P5消除對照組大鼠中發展之進 行性新陳代謝酸中毒。對於動脈乳酸鹽上升發現同樣保護 性傾向,P5具有更明顯效果(表/7)。 表7. CLP多微生物敗血症模型期間血液動力學及選擇之生 物化學參數 心跳率 大動脈血流腸系膜血流 pH值 碳酸氫鹽 乳酸鹽 (bpm) (mL/分鐘) (mL/分鐘) (mmol/L) (mmol/L) 對照組 H16 516±44a’b 38±10 10.6±3.0b 7.31±0.07b 16.9±2.7 4.7±1.5b H20 543±35a’b 19±lla’b 4.3±1.5b 7.23±0.05a,b 12.0±5.6a,b 8.5±1.4a,b H24 480±20 14±9a,b 2.5±0.7b 7.17±0.01a’b 10.3±3.3a 10.8±1.9a>b P1 H16 462±16a 41±12 13.5±7.2 7.32±0.04 16.8 土 4.4 4.9 土 0.4 H20 480±30a 28±17a 5.3±3.0C 7.31±0.18a 16.0±5.4b 5.3±l.la,c H24 420士30 22±16a 4.5±2.1c 7.24±0.06a’c 11.2±0.8C 6.8 士 0.9a’c P5 H16 460±17b 41士14 15.3±3.5b 7.35 士 0.01b 18.6±2.0 3_3±0.4b H20 500±17b 31±5b 11.0±6.9b>c 7.34±0.01b 18.0±0.9a 3.6±0.9b'c H24 510±20 28±8b 8.5±3.5b>c 7.36±0.01b>c 17.1±0.9a>c 4.9±l.lb>c ap<0.05 P1對比對照組 # bp<0.05 P5對比對照組 cp<0.05 P5對比 P1 P1及P5均誘導TNF-ct生成下降,P5再一次具有更強的效 果。在H20,血漿TNF-α在P5處理下幾乎不可偵測,而其在 其它動物組中.保持上升(圖16)。 亞硝酸鹽/硝酸鹽濃度在對照組動物中上升但在兩 TREM-1胜肽處理之組中仍處在低水平(圖17)。 因此在敗血性大鼠中發現P5及P1對血液動力學之保護作 101968.doc -57- 1356062 用。與心率無關’保持動脈壓及血流。此外,調變TREM-1 訊號降低(儘管不是完全地)細胞激素生成且保護敗血性動 物免受高反應性。細胞激素生成未被完全抑制之事實是關 .鍵點。事實上’儘管吾人認為諸如TNF - α之發炎性細胞激素 是有害的,但是其亦在敗企症中起有益效應,這係由患損 壞TNF-α反應之動物中腹膜炎模型之致命組織所強調。 敗血性休克期間發現之iNOS活化導致大量NO生成,其部 分解釋了某些周邊脈管病症(特別是血管擴張及低血壓在 心肌自身,多數NO行為由負責生成CGMP (其對收縮損壞細 胞溶質鈣之效果)之可溶性鳥苷酸環化酶活化來調節。環狀 GMP亦能夠刺激某些填酸二酷酶活性。細胞内cAMP含量之 隨後下降可解釋Ν Ο削弱β腎上腺素能刺激效果之能力。因 而保持動脈壓可部分由NO生成減少來解釋,其由trem- 1 胜肽處理之動物中低血漿亞硝酸鹽/硝酸鹽濃度反映。 發炎性細胞激素生成之降低可部分解釋對血流顯著之效 應。事實上,儘管心肌抑制之潛在細胞激素調節劑之清單 很長’但是TNF-a及IL-Ιβ已顯示是良好候選者。該等兩後 者細胞激素抑制活體外和體外(ex vivo)心肌收縮。此外自 人類敗血性血清中和或移除TNF-a或IL-Ιβ部分消除[活體 外及活體内]心肌抑制效應。儘管P1&P5在内毒素血症期間 對血流及動脈壓具有相同作用,但是其對細胞激素生成之 作用不同,P1對血漿TNF-α及IL-Ιβ濃度只有輕微效果。因 而TREM-1胜肽之保護作用僅部分與其細胞激素釋放之作 用相關’或涉及多餘的路徑。 101968.doc -58- 1356062 在大鼠之實驗性敗血性休克期間藉由使用小合成胜肽調 變TREM-1路徑對血液動力學參數具有有益效果,同時存在 發炎性細胞激素生成之削弱。 簡而言之,該等資料顯示TREM-1胜肽1)有效保護受實驗 動物免受敗血症相關血液動力退化;2)削弱乳酸酸中毒發 展;3)調變諸如TNF-α及IL-Ιβ之促發炎細胞激素之生成, 及4)降低氧化氮之產生。因此TREM-1胜肽潛在地有用於恢 復患有敗血症、敗血性休克或類似敗血症病症之患者中之 ® 血液動力學參數。 參考文獻 1. Aderem,A及R.J. Ulevitch,R.J. 2000. Toll-like receptors in the induction of the innate immune response. Nature 406:782-786。 2. Thoma-Uszynski, S., S. Stenger, O. Takeuchi, M.T. Ochoa, P.A. Engele, P.A. Sieling, P.F. Barnes, M. Rollinghoff, P.L. Bolcskei及 M. Wagner. 2001. Induction of direct antimicrobial
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19. Gingras,M.C·,H. Lapillonne及J.F· Margolin. 2001. TREM-1, MDL-1 及DAP 12 expression is associated with a mature stage of myeloid development. Mol. Immunol. 38:817-24 e 20. Dinarello, C.A. 1997. Proinflammatory and anti-inflammatory cytokines as mediators in the pathogenesis of septic shock. Chest 112 (suppl):S21-9 0 21. Bone, R.C., R.A Balk, F.B. Cerra, R.P. Dellinger, W.A. Knauss, R.M. Schein及W.J. Sibbald.1992. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies 101968.doc -61 - 1356062 in sepsis. The ACCP/SCCM Consensus Conference Committee. American in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest 101:1644-55 o 22. Warren, H.S. 1997. Strategies for the treatment of sepsis. N. Engl. J. Med. 336:952-3 ° 23. Stone, R. 1994. Search for sepsis drugs goes on despite past failures. Science 264:365-7 o 24. Cohen, J. 2001. TREM-1 in sepsis. Lancet 358:776-8。 25. Begun, N.A., K. Ishii, M. Kurita-Taniguchi, M. Tanabe, M. Kobayashi, Y. Moriwaki, M. Matsumoto, Y. Fukumori, I. Azuma, K. ToyoshimaAT. Seya. 2004. Mycobacterium bovis BCG cell wall-specific differentially expressed genes identified by differential display and cDNA substraction in human macrophages. Infect.Immun. 12:937-48 o 26. Keane, J., S. Gershon, R.P. Wise, E. Mirabile-Levens, J. Kasznica, W.D. Schwieterman,J.N· Siegel 及 M.M. Braun.
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Crystal structure of the human myeloid cell activating receptor TREM-1. Structure 11:1527-35 0 28. Lantz,M.,U. Gullberg及E. Nilsson. 1990. Characterization in vitro of a human tumor necrosis factor binding protein. A soluble form of tumor necrosis factor receptor. J. Clin. Invest. 86:1396-1401。 101968.doc •62· 1356062 29. van Zee, K.J., T. Kohno及E. Fischer· 1992. Tumor necrosis soluble receptors circulate during experimental and clinical inflammation and can protect against excessive tumor necrosis .factor a in vitro and in vivo. Proc. Natl. Acad. Sci. USA 89:4845-4853 。 30. Collart,Μ.A·, P. Baeuerle及P. Vassalli. 1990· Regulation of tumor necrosis factor alpha transcription in macrophages. Involvement of four NFkB motifs and constitutive and inducible form of NFkB. Mol. Cell Biol. 10:1498-506。
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Characterization of a functional NFkB site in the human IL-Ιβ promoter: evidence for a positive autoregulatory loop. Mol. Cell Biol. 13:6231-40。 32. Urban,M.B·,R. Schreck及P.A. Baeuerle. 1991. NFkB contacts DNA by a heterodimer of the p50 and p65 subunit. EMBO J. 10:1817-25 。 33. Lolis,E.及R. Bucala. 2003. Therapeutic approaches to innate
immunity: severe sepsis and septic shock. Nat. Rev. Drug. Discov. 2:635-45。 34. Gibot, S., M.N. Kolopp-Sarda, M.C. Bene, A. Cravoisy, B. Levy, G. Faure 及 P.E. Bollaert. 2004. Plasma level of a triggering receptor expressed on myeloid cells-1: its diagnostic accuracy in patients with suspected sepsis. Ann. Intern. Med. 141:9-15。 【圖式簡單說明】 圖1A顯示TREM-1及TREM-2家族成員之序列比對。人類 101968.doc -63- 1356062 TREM-1以小鼠trem]及人類及小鼠TREM_2使用 CLUSTAL W.之1.74版比對。二級結構分配對應於公開人類 TREM_1結構(箭頭為β束且圓柱體為α螺旋)(Radaev等人 (2003) Structure (Camb). Dec; 11(12):1527-35)。涉及同-雜 二聚物形成之殘基在黑色背景上顯示為白色。為V型ig折疊 守值之半胱胺酸制二硫化物鍵為粗體。間隙以(-)指示,同 一殘基以(*),相似以(:或·)。人類及小鼠TREM1序列間相 似性之延長區域顯示於灰色背景上之方框。本文實例中使 用之TREM-1胜肽序列以下劃線指示。 圖1B顯示公開TREM-1同二聚結構之連續剖面圖(Kelker 等人(2004) J Mol Biol. Sep 24; 342(4):1237-48)。包含抗體 等價互補決定區(CDR)之假定結合位置為紅色。 圖2顯示投藥TREM-1胜肽(LPS前1小時)減少内毒素血症 誘發之死亡。BALB/c小鼠(每組1〇隻)被腹膜内注射2〇〇 LPS。在LPS前1小時腹膜内注射TREM-1胜肽Ρ卜Ρ2、Ρ3或 P5(每小鼠200 μΐ之300 μΜ溶液)。監控小鼠之生存能力一天 兩次達7天。由Logrank測試執行統計分析。來自對照組小 鼠之資料代表來自同樣條件下執行之兩個獨立實驗之累積 存活率曲線。 圖3顯示TREM-1胜肽P1能夠在LPS後4小時注射時有效減 少内毒素血症誘發之死亡^ BALB/c小鼠(每組10隻)經腹膜 内注射200 pg LPS。在LPS前1小時或後4小時腹膜内注射 TREM-1胜肽P1,每小鼠200 μΐ之300 μΜ溶液。監控小氣之 生存能力一天兩次達7天》由Logrank測試執行統計分析。 101968.doc -64 - 1356062 來自對照組小鼠之資料代表來自同樣條件下執行之兩個獨 立實驗之累積存活率曲線。 圖4顯示投藥TREM-1胜肽(LPS後4小時)減少内毒素血症 誘發之死亡。BALB/c小鼠(每組10隻)經腹膜内注射200 pg LPS。在LPS後4小時腹膜内注射P1胜肽,每小鼠200 μΐ之 150、300 及 600 μΜ(點),或者 Ρ3,每小鼠 200 μΐ 之 600 μΜ 溶液(滿正方形)。監控小鼠之生存能力一天兩次達7天。由 Logrank測試執行統計分析。 圖5顯示TREM-1胜肽P1保護不受盲腸結紮及穿孔 (CLP)。如材料及方法中描述在C57BL/6小鼠中(每組15隻) 誘導CLP。CLP誘導後5及24小時腹膜内注射P1胜肽(空點) 或P3胜肽(滿正方形)(每小鼠200 μΐ之600 μΜ溶液)。監控小 鼠之生存能力一天兩次達7天。由Logrank測試執行統計分 析。
圖6顯示PI,P2及P5胜肽(但不是P3胜肽)抑制可溶 TREM-1/IgGl結合至TREM-1配位體陽性腹膜滲出細胞。顯 示在每小鼠200 μΐ之500 μΜ溶液(細線)、每小鼠100 μΐ之500 μΜ溶液(點線)或不存在胜肽時(粗線)螢光測定分析含200 ng小鼠TREM- Ι/hIgGl之腹膜渗出細胞。灰色直方圖代表以 人類IgGl免疫染色作對照。 圖7A顯示在以含及不含蛋白酶抑制劑之LPS刺激後自培 養之單核細胞釋放sTREM-Ι。LPS刺激誘導有抗TREM-1 mAb (嵌入物)特定識別之27-kD蛋白質出現。藉由反射免疫 點量測經調節之培養培養基中sTREM-1含量。資料顯示為 101968.doc -65 - 1356062 平均土SD(n=3)。 圖7B顯示單核細胞中TREM-1 mRNA之表現。如所示以 LPS (1 pg/mL)刺激培養之單核細胞0、1及16小時。1小時内 LPS誘導 TREM-1 mRNA產生。
圖8A自培養之單核細胞釋放細胞激素及sTREM-1。為細 胞活化,在24孔平底組織培養盤中於LPS (1 pg/mL)存在下 培養初級單核細胞。在某些實驗中組合P5 (10至100 ng/mL)、對照組胜肽(10 至 100 ng/mL)或 rIL-10(500 U/mL) 來提供該刺激。為經由TREM-1活化單核細胞,如所示加入 激動劑抗TREM-1 mAb(10 pg/mL)。藉由ELISA或免疫點對 於製造TNF-α、IL-Ιβ及sTREM-Ι分析無細胞之清液。所有 實驗執行三次且資料以平均值(SEM)來表示。 A:培養基 b:P5 10 ng/mL c:抗 TREM-1
d:LPS
e:LPS + 抗 TREM-1 f:LPS + P5 10 ng/mL g:LPS + P5 50 ng/mL h:LPS + P5 100 ng/mL I:LPS + IL10 圖8B顯示P5對NFkB活化之效果。如指示在E.coli LPS (0111:B4,1 pg/mL)、抗 TREM-1 mAb (10 pg/mL)及 /或 P5 (100 ng/mL)存在下培養單核細胞24小時,且使用基於 101968.doc -66- ELISA之檢定測定NFkB p50及p65含量。重複三次執行實 驗,且資料以平均光學密度(SEM)來表示。 圖9顯示經LPS處理小鼠之血清中sTREM-Ι之積聚。 以LPS (LD50,腹膜内)處理雄性Balb/C小鼠(20至23 g)。 藉由免疫點檢定血清之sTREM-Ι。血清sTREM-Ι在LPS投藥 後1小時易於偵測且保持在一穩定水平4至6小時。 圖10A顯示小鼠中P5預處理保護免受LPS之致命性。將雄 性Balb/C小鼠(20至23 g)隨機分組(每組10隻小鼠)並以 LD10()之LPS處理。在LPS前60分鐘投予P5(50 pg或100 μβ) 或對照組載體。 圖10Β顯示小鼠中Ρ5之延遲投藥保護LPS之致命性。將雄 性Balb/C小鼠(20至23 g)隨機分組(每組8隻小鼠)並以LD100 之LPS處理。如指示在LPS後4或6小時投予P5 (75 pg)或對 照組載體。 圖10C顯示投予激動劑TREM-1 mAb對小鼠是致命的。將 雄性Balb/C小鼠(20至23 g)隨機分組(每組8隻小鼠)並如指 示以LD5〇之LPS +對照組載體、LD5〇之LPS +抗TREM-1 mAb (5 pg)或LD1G()之LPS +對照組載體之組合處理。在LPS注射 後1小時投予對照組載體及抗TREM-1 mAb。 圖11A顯示P5部分保護小鼠不受CLP誘發致命。將雄性 Balb/C小鼠(20至23 g)隨機分組並以生理食鹽水(n=l4)或對 照組胜肽(n=14,100 pg)或以於 HO (n=18)、H+4 (n=18)或. H+24 (n=18)以單個感染之P5 (100 gg)處理。將最後一組小 鼠(n=18)於H+4、H+8及H+24以重複注射P5 (100 pg)處理。 101968.doc -67- 1356062 .圖11B顯示P5對存活率之劑量效應。在cLp後於H〇以單注 射生理食鹽水或10 、20 pg、50 pg、1〇〇叫或2〇〇 之 ρ5處理小鼠(每組η=ΐ5)並監控存活率。 圖丨2顯示在CLP期間Ρ5對細菌數量無效果。在CLP後24 小時麻醉下殺死小鼠(每組5隻)。測定腹膜灌洗流體及血液 .中細菌數量,且結果表示為每〇1[血液之CFU及腹膜灌洗之 每小鼠之CFU » * 圖13顯示投藥LPS (15 mg/kg)後大鼠中TNF-α及IL-Ιβ血 • 漿濃度發展。 P<〇.〇5 P5處理對比對照組動物 P<0.0S P5處理對比P1處理動物 圖U顯示投藥LPS(15 mg/kg)後大鼠中亞硝酸鹽/硝酸鹽 濃度發展。 * P<〇.〇5 P5處理對比對照組動物及?1處理動物 圖^顯示盲腸結紮及穿孔誘發之腹膜炎期間大鼠中平均 動脈壓發展。 # P<0‘〇S對比對照組動物 圖丨6顯示盲腸結紮及穿孔誘發之腹膜炎期間鼠中TNF_a 金聚濃度發展。 * Ρ<0·〇5 P5處理對比對照組動物 Ρ<0·〇5 Ρ1處理對比對照組動物 $Ρ<〇·〇5 Ρ5對比Ρ1處理動物 圖17顯示盲腸結紮及穿孔誘發之腹膜炎期間鼠中亞硝酸 鹽/硝酸鹽濃度發展。 ρ<0·〇5 Ρ5及Ρ1處理動物對比對照組動物 101968.doc -68 - 1356062 序列清單
<110> BioXellSpA
Universite Henri Poincare - Nancy 1
Faure, Gilbert
Gibot, Sebastien
Panina, Paola
Passini, Nadia <μ〇>治療性胜肽及方法 / <130> BXL-P037 <140> 094116511 <141> 2005-05-20 <150> GB 0426146.7 <151> 2004-1N29 <160> 23 - <170>專利版本3.1 <210> 1 <211> 234 <212> PRT <213>現代智人 <400> 1
Met Arg Lys Thr Arg Leu Trp Gly Leu Leu Trp Met Leu Phe Val Ser 1 5 10 、 15
Glu Leu Arg Ala Ala Thr Lys Leu Thr Glu Glu Lys Tyr Glu Leu Lys ; 20 25- 30 - 丨、 ' -.
Glu Gly Gin Thr Leu Asp Val Lys Cys Asp Tyr Thr Leu Glu Lys Phe 35 40 45
Ala Ser Ser Gin Lys Ala Trp Gin lie lie Arg Asp Gly Glu Met Pro 50 55 60
Lys Thr Leu Al'a Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val 65 70 75 80
Gin Val Gly Arg lie lie Leu Glu Asp Tyr His Asp His Gly Leu Leu 85 90 95
Arg Val Arg Met Val Asn Leu Gin Val Glu Asp Ser Gly Leu Tyr Gin 100 105 110
Cys Val lie Tyr Gin Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg e 115 120 125 lie Arg Leu Val Val Thr Lys Gly Phe Ser Gly Thr Pro Gly Ser Asn 130 135 140
Glu Asn Ser Thr Gin Asn Val Tyr Lys lie Pro Pro Thr Thr Thr Lys 145 150 155 160
Ala Leu Cys Pro Leu Tyr Thr Ser Pro Arg Thr Val Thr Gin Ala Pro 165 170 175 101968.doc 1356062
Pro Lys Ser Thr Ala Asp Val Ser Thr Pro Asp Ser Glu lie Asn Leu 180 185 190
Thr Asn Val Thr Asp lie lie Arg Val Pro Val Phe Asn lie Val lie 195 200 205
Leu Leu Ala Gly Gly Phe Leu Ser Lys Ser Leu Val Phe Ser Val Leu 210 215 220
Phe Ala Val Thr Leu Arg Ser Phe Val Pro 225 230 <210> 2 <211> 230 <212、 PRT <213 >鼠科動物 <400> 2
Met Arg Lys Ala Gly Leu Trp Gly Leu Leu Cys Val Phe Phe Val Ser IS 10 15
Glu Val Lys Ala Ala lie Val Leu Glu Glu Glu Arg Tyr Asp Leu Val 20 25 30
Glu Gly Gin Thr Leu Thr Val Lys Cys Pro Phe Asn lie Met Lys Tyr 35 40 45
Ala Asn Ser Gin Lys Ala Trp Gin Arg Leu Pro Asp Gly Lys Glu Pro 50 55 60
Leu Thr Leu Val Val Thr Gin Arg Pro Phe Thr Arg Pro Ser Glu Val 65 70 75 80
His Met Gly Lys Phe Thr Leu Lys His Asp Pro Ser Glu Ala Met Leu 85 90 95
Gin Val Gin Met Thr Asp Leu Gin Val Thr Asp Ser Gly Leu Tyr Arg 100 105 110
Cys Val lie Tyr His Pro Pro Asn Asp Pro Val Val Leu Phe His Pro 115 120 125
Val Arg Leu Val Val Thr Lys Gly Ser Ser Asp Val Phe Thr Pro Val 130 135 140 lie lie Pro lie Thr Arg Leu Thr Glu Arg Pro lie Leu lie Thr Thr 145 150 155 160
Lys Tyr Ser Pro Ser Asp Thr Thr Thr Thr Arg Ser Leu Pro Lys Pro 165 170 175
Thr Ala Val Val Ser Ser Pro Gly Leu Gly Val Thr lie lie Asn Gly 180 185 190
Thr Asp Ala Asp Ser Val Ser Thr Ser Ser Val Thr lie Ser Val lie 195 200 205
Cys Gly Leu Leu Ser Lys Ser Leu Val Phe lie lie Leu Phe lie Val 210 215 220 101968.doc 1356062
Thr Lys Arg Thr Phe Gly 225 230 <210> 3 <211> 23 <212> PRT <213〉尉斗動物 <400> 3
Leu Val Val Thr Gin Arg Pro Phe Thr Arg Pro Ser Glu Val His Met 1 5 10 15
Gly Lys Phe Thr Leu Lys His 20 > > > > 0 12 3 1111 2 2 2 2 < V V < 4 23
PRT 鼠科動物 <400> 4
Val lie Tyr His Pro Pro Asn Asp Pro Val Val Leu Phe His Pro Val 15 10 15
Arg Leu Val Val Thr Lys Gly 20 <210> 5 <211> 17 <212> PRT <213〉謝動物 <400> 5
Thr Thr Thr Arg Ser Leu Pro Lys Pro Thr Ala Val Val Ser Ser Pro 15 10 15
Gly <210> 6 <211> 21 <212> PRT <213〉鼠科動物 <400> 6
Leu Gin Val Thr Asp Ser Gly Leu Tyr Arg Cys Val lie Tyr His Pro 15 10 15
Pro Asn Asp Pro Val 20 <210> 7 <211> 17 <212> PRT <213 >鼠科動物 <400> 7 101968.doc 1356062
Leu Gin Val Thr Asp Ser Gly Leu Tyr Arg Cys Val He Tyr His Pro 1 5 10 15 Pro <210> 8 <211> 23 <212> PRT <213>人造 <400> 8 Leu Thr Pro Lys His Gly Gin Arg Ser Thr His Val Thr Lys Phe Arg 15 10 15 Val Phe Glu Pro Val Met Leu 20
<210> <211> <212> <213>
9 17 PRT 人造 <400> 9
Thr Asp Ser Arg Cys Val lie Gly Leu Tyr His Pro Pro Leu Gin Val 15 10 15 Tyr <210> 10 <211> 22 <212> DNA <213 >人造 <400> 10 ttgtctcaga actccgagct gc <210> 11 •<211> 22 <212> DNA <213>人造 <400> 11 gagacatcgg cagttgactt gg <210> 12 <211> 22 <212> DNA <213>人造 <400> 12 ggacggagag atgcccaaga cc <210> 13 <211> 22 <212> DNA <213 >人造 <400> 13 22 22 101968.doc -4- 22 1356062 accagccagg agaatgacaa tg 22 <210> 14 <211> 22 <212> DNA <213>人造 <400> 14 ggacgacatg gagaagatct gg <210> 15 <211> 24 <212> DNA <213〉人造 <400> 15 atagtaatgt cacgcacgat ttcc 22 24
<210> 16 <211> 23 <212> PRT <213〉現代智人 <400> 16
Leu Ala Cys Thr Glu Arg Pro Ser Lys Asn Ser His Pro Val Gin Val 15 10 15 Gly Arg lie lie Leu Glu Asp 20 <210> 17 <211> 23 <212> PRT <213 >現代智人 <400> 17
Val lie Tyr Gin Pro Pro Lys Glu Pro His Met Leu Phe Asp Arg lie 15 10 15 Arg Leu Val Val Thr Lys Gly 20 <210> 18 <211> 21 <212> PRT <213>現代智人 <400> 18
Leu Gin Val Glu Asp Ser Gly Leu Tyr Gin Cys Val lie Tyr Gin Pro 15 10 15 Pro Lys Glu Pro His 20 <210> 19 <211> 17 <212> PRT <213〉現代智人 101968.doc 1356062 <400> 19
Leu Gin Val Glu Asp Ser Gly Leu Tyr Gin Cys Val lie Tyr Gin Pro 1 5 10 15
Pro <210> <211> <212> <213> 20 6 PRT現代智人 <400> 20
Arg Pro Ser Lys Asn Ser 1 5 <210> <211> <212> <213> 21 5 PRT現代智人 <400> 21
Gin Pro Pro Lys Glu 1 5 <210> <211> <212> <213> 22 6 PRT鼠科動物 <400> 22
Arg Pro Phe Thr Arg Pro 1 5 <210> <211> <212> <213> 23 5 PRT鼠科動物 <400> 23
His Pro Pro Asn Asp 1 5 101968.doc
Claims (1)
- 申請專利範圍: 第094116511號專利申請案 巾文申誚專利範轉換本(100 ψΤϋΤ一種多胜肽或其衍生物’其可作為如SEQ ID NO: 1所定義 之TREM-1蛋白質拮抗劑,包含SEQ ID NO:20之胺基酸序 列或SEQIDNO:21之至少3個胺基酸,其中: (a)該多胜肽由下列所組成: ⑴來自SEQ ID NO: 1之IS至29個胺基酸連續序列;或 (ii)來自SEQ ID ΝΟ:1之15至29個胺基酸連續序列, 其中一胺基酸係經另一胺基酸保守取代; (b)由與SEQIDNOs:16、17、18或19具有至少80%之序 列相同性之胺基酸序列所組成之多胜肽; 且其中(a)或(b)多胜肽之衍生物係藉由已知保護/阻斷 基團進行糖基化、乙酿化、聚乙二醇化、麟酸化、酿胺 化或衍生化所修飾。 2. 如請求項1之多胜肽或其衍生物,其由下列所組成: ⑴來自SEQ ID NO: 1之15至29個胺基酸連續序列;或 (ii)來自SEQ ID ΝΟ:1之15至29個胺基酸連續序列,其 中一胺基酸係經另一胺基酸保守取代; 且其中⑴或(ii)多胜肽之衍生物係藉由已知保護/阻斷 基團進行糖基化、乙醯化、聚乙二醇化、磷酸化、醯胺 化或衍生化所修飾。 3. 如請求項1之多胜肽或其衍生物,其中該多胜肽係由與 SEQ ID NOs:16、17、18或19具有至少80%之序列相同性 之胺基酸序列所組成; 101968-1001018.doc 1356062 且其中多胜肽之衍生物係藉由已知保護/阻斷基團進行 糖基化、乙醯化、聚乙二醇化、磷酸化、醯胺化或衍生 化所修飾。 4. 如請求項3之多胜肽或其衍生物,其中該多胜肽係由與 SEQ ID NO: 19具有至少80%之序列相同性之胺基酸序列 所組成》 5. 如請求項3之多胜肽或其衍生物,其中該多胜肽係由與 SEQ ID NOs:16、17、18或19具有至少80%之序列相同性 _ 之胺基酸序列所組成,且其與該等序列之差異僅為保守 鲁 修飾。 6. 如請求項4之多胜肽或其衍生物,其中該多胜肽係由與 SEQ ID NO: 19具有至少80%之序列相同性之胺基酸序列 所组成,且其與該序列之差異僅為保守修飾。 7·如請求項1或2之多胜肽或其衍生物,其中該多胜肽係由 來自SEQ ID ΝΟ:1之15至29個胺基酸連續序列所組成。 8·如請求項1之多胜肽或其衍生物,其包含來自SEQ ID NO:21之至少3個胺基酸,其中該來自SEQ ID NO:21之至 鲁 少3個胺基酸為qpp、qppk或QPPKE。 9. 如請求項5之多胜肽或其衍生物,其中該多胜肽係由具有 SEQ ID NOs: 16、17、18或19之序列之胺基酸序列所組成。 10. —種多胜肽或其衍生物,其可作為如SEQ ID NO:2所定義 之TREM-1蛋白質拮抗劑,包含SEQIDNO:22之胺基酸序 列或SEQ ID NO:23之至少3個胺基酸,其中: (a)該多胜肽由下列所組成: 101968-1001018.doc 1356062 (i) 來自SEQIDNO:2之15至29個胺基酸連續序列;或 (ii) 來自SEQ ID NO:2之15至29個胺基酸連續序列,其 中一胺基酸係經另一胺基酸保守取代; 或 (b)由與SEQ ID NOs:3、4、6或7具有至少80%之序列相 同性之胺基酸序列所組成之多胜肽; 且其中(a)或(b)多胜肽之衍生物係藉由已知保護/阻斷 基團進行糖基化、乙醯化、聚乙二醇化、磷酸化、醯胺 化或衍生化所修飾。 11. 如請求項10之多胜肽或其衍生物,其中該多胜肽由下列 所組成: (0來自SEQIDNO:2之15至29個胺基酸連續序列;或 (ii)來自SEQ ID NO:2之15至29個胺基酸連續序列,其 中一胺基酸係經另一胺基酸保守取代; 且其中(i)或(ii)多胜肽之衍生物係藉由已知保護/阻斷 基團進行糖基化、乙醯化、聚乙二醇化、磷酸化、醯胺 化或衍生化所修飾。 12. 如請求項10之多胜肽或其衍生物,其中該多胜肽係由與 SEQ ID NOs:3、4、6或7具有至少80%之序列相同性之胺 基酸序列所組成; 且其中多胜肽之衍生物係藉由已知保護/阻斷基團進行 糖基化、乙醯化、聚乙二醇化、填酸化、酿胺化或衍生 化所修飾。 13·如請求項⑺或丨丨之多胜肽或其衍生物’其中該多胜肽係 101968-1001018.doc 1356062 由來自SEQID NO:2之15至29個胺基酸連續序列所組成。 14. 如請求項1〇之多胜肽或其衍生物,其包含來自seq id NO:23之至少3個胺基酸,其中該來自SEQ ID NO:23之至 少3個胺基酸為HPP、HPPN或HPPND。 15. 如請求項1或10之多胜肽或其衍生物,其特徵在於具有治 療敗血症及敗血性休克之能力。 如請求項1或1〇之多胜肽或其衍生物,其係用於治療。 17. 如請求項1或10之多胜肽或其衍生物,其係用於敗血症及 敗血性休克之治療。 18, 一種多胜肽,其為由下列所組成之稠合蛋白:如請求項1 至13中任一項之多胜肽或其衍生物,及選自下列所組成 $群之異質性多胜肽:衍生自免疫球蛋白 < 序列、非傳 ,另類蛋白赁支絮·、:稍合ί至韻多胜肽或其衡生物之 異源訊號序歹ί及標籤序列V 、 H 一種經分離聚核:y:酸’其能夠編碼如請求項1至16中任一 項之多胜肽或其衍生物。 20. —種載體,其包含如請求項丨9之聚核苷酸。 21. —種醫藥組合物,其包含如請求項1至16中任一項之多胜 狀或其衍生物》 22. —種如請求項1至16中任一項之多胜肽之用途’其係用於 製造治療敗血症或敗血性休克之藥物。 101968-1001018.doc
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- 2005-05-20 PL PL05752687T patent/PL1817337T3/pl unknown
- 2005-05-20 EP EP05752687A patent/EP1817337B1/en active Active
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- 2005-05-20 WO PCT/EP2005/052338 patent/WO2006056492A1/en active Application Filing
- 2005-11-21 CN CNA200510104693XA patent/CN1817901A/zh active Pending
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Also Published As
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GB0426146D0 (en) | 2004-12-29 |
IL183165A0 (en) | 2007-09-20 |
DE602005026157D1 (de) | 2011-03-10 |
JP5599382B2 (ja) | 2014-10-01 |
US20120015867A1 (en) | 2012-01-19 |
ZA200703782B (en) | 2010-07-28 |
TW200616657A (en) | 2006-06-01 |
JP4951213B2 (ja) | 2012-06-13 |
US20160193288A1 (en) | 2016-07-07 |
EP1817337A1 (en) | 2007-08-15 |
IL183165A (en) | 2014-07-31 |
BRPI0518675A2 (pt) | 2008-12-02 |
CN1817901A (zh) | 2006-08-16 |
US8013116B2 (en) | 2011-09-06 |
GB0709406D0 (en) | 2007-06-27 |
GB2433936A (en) | 2007-07-11 |
EP1817337B1 (en) | 2011-01-26 |
JP2006149365A (ja) | 2006-06-15 |
ATE496942T1 (de) | 2011-02-15 |
US20200254058A1 (en) | 2020-08-13 |
WO2006056492A1 (en) | 2006-06-01 |
PL1817337T3 (pl) | 2011-10-31 |
ES2360184T3 (es) | 2011-06-01 |
US20090253632A1 (en) | 2009-10-08 |
GB2433936B (en) | 2010-06-23 |
JP2012082206A (ja) | 2012-04-26 |
JP2015006180A (ja) | 2015-01-15 |
US9273111B2 (en) | 2016-03-01 |
US10603357B2 (en) | 2020-03-31 |
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