TWI391401B - 人類化之抗-因子d抗體及其用途 - Google Patents
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Classifications
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Description
補體系統在清除免疫複合物及對傳染性試劑、外源抗原、經病毒侵染細胞及腫瘤細胞之免疫應答中起主要作用。然而,補體亦參與病理性炎症及自身免疫疾病。因此,抑制補體級聯系統之過度或不受控活化可向患有該等疾病及病況之患者提供臨床效益。
補體系統涵蓋兩種不同活化途徑,稱為經典途徑及旁路途徑(V.M.Holers,InClinical Immunology:Principles and Practice
,ed.R.R.Rich,Mosby Press;1996,363-391)。經典途徑係通常藉由形成抗原-抗體複合物激活之鈣/鎂-依賴性級聯系統。旁路途徑係藉由在特定易感表面(例如酵母及細菌之細胞壁多糖及特定生物聚合物質)上沈積及活化C3激活之鎂-依賴性級聯系統。補體途徑之活化產生補體蛋白之生物活性片段,例如C3a、C4a及C5a過敏毒素以及C5b-9膜攻擊複合物(MAC),該等片段介導炎症活性,包括白血球趨化現象、巨噬細胞、嗜中性粒細胞、血小板、肥大細胞及內皮細胞之活化、血管滲透性、細胞溶解及組織損害。
因子D係活化旁路補體途徑必需之高度特異性絲胺酸蛋白酶。其斷裂結合至C3b之因子B生成C3b/Bb酶,該酵素為旁路途徑C3/C5轉移酶之活性組份。因子D可能為適宜抑制目標,因為在人類中其血漿濃度極低(1.8微克/毫升)且已顯示其為活化旁路補體途徑之限制酵素(P.H.Lesavre及H.J.Mller-Eberhard.J.Exp.Med
.,1978;148:1498-1510;J.E.Volanakis等人,New Eng.J.Med
.,1985;312:395-401)。
已顯示減量調節補體活化在動物模型及活體外研究中對治療若干疾病症候有效,例如全身性紅斑狼瘡及腎小球腎炎(Y.Wang等人,Proc.Natl.Acad.Sci
.;1996,93:8563-8568)、類風濕性關節炎(Y.Wang等人,Proc.Natl.Acad.Sci
.,1995;92:8955-8959)、心肺分流術及血液透析(C.S.Rinder,J.Clin.Invest
.,1995;96:1564-1572)、器官移植中之超急性排異反應(T.J.Kroshus等人,Transplantation
,1995;60:1194-1202)、心肌梗塞(J.W.Homeister等人,J.Immunol
.,1993;150:1055-1064;H.F.Weisman等人,Science,1990;249:146-151)、再灌注損傷(E.A.Amsterdam等人,Am.J.Physiol
.,1995;268:H448-H457)及成人呼吸窘迫症候群(R.Rabinovici等人,J.Immunol
.,1992;149:1744-1750)。此外,其他炎症性病況及自身免疫/免疫性複雜疾病亦與補體活化密切相關(V.M.Holers,ibid.,B.P.Morgan.Eur.J.Clin.Invest
.,1994:24:219-228),包括熱損傷、嚴重哮喘、過敏性休克、腸道炎症、蕁麻疹、血管性水腫、血管炎、多發性硬化症、重症肌無力、膜性增生性腎小球腎炎、及Sjgren氏症候群。
補體介導病症領域需要抗體治療法且本發明之人類化抗體提供可用於滿足該需求之高親和力抗體。
概括而言,本發明係關於包含鼠類抗體166-32之重鏈及輕鏈可變結構域序列之抗體,其為能抑制因子D相關生物活性之抗體。舉例而言,在18微克/毫升之濃度下(在血液中與約1.5倍莫耳濃度之人類因子D等效;抗-因子D抗體與因子D之莫耳比約為1.5:1),可觀察到該抗體顯著抑制旁路補體活性(參見例如美國專利第6,956,107號)。
本發明亦係關於鼠類MAb 166-32之人類化抗體。本發明包括該等抗體可變重鏈及輕鏈之胺基酸序列及其對應核酸序列。本發明另一實施例包括該等抗體之CDR序列。
本發明另一實施例包括包含本發明抗體之組合物。本發明另一實施例提供包含本發明抗體序列之細胞系及載體。本發明一態樣包括製備及使用本發明抗體及組合物之方法。
本發明另一實施例係關於該等人類化抗體之用途,其用於製備用於治療與過度或不受控補體活化相關之病症之藥物或組合物。其包括心肺分流手術期間之補體活化;在急性心肌梗塞、動脈瘤、中風、出血性休克、擠壓傷、多器官功能衰竭、低血量性休克、腸內缺血或導致缺血之其他事件發生後,由於缺血-再灌注導致之補體活化。已顯示補體活化亦與炎症性病況相關,例如嚴重燒傷、內毒素血症、敗血性休克、成人呼吸窘迫症候群、血液透析;過敏性休克、嚴重哮喘、血管性水腫、Crohn氏病、鐮狀細胞貧血症、鏈球菌感染後腎炎及胰腺炎。該等病症可能為不良藥物反應、藥物過敏、IL-2誘導血管滲漏症候群或放射攝影造影劑過敏症之結果。其亦包括自身免疫性疾病,例如全身性紅斑狼瘡、重症肌無力、類風濕性關節炎、阿茲海默氏症(Alzheimer's disease)及多發性硬化症。補體活化亦與移植排異相關。補體活化亦與眼部疾病相關,例如年齡相關性黃斑變性、糖尿病性視網膜病。
整篇本申請案中所用術語應理解為具有所屬領域技術人員習知之一般及典型意義。然而,申請者期望下列術語具有如下所定義之特定定義。
就抗體鏈多肽序列而言,短語"實質上相同"可理解為與參照多肽序列相比抗體鏈顯示至少70%、或80%、或90%或95%之序列一致性。就核酸序列而言該術語可理解為與參照核酸序列相比核苷酸序列顯示至少約85%、或90%、或95%或97%之序列一致性。
術語"一致性"或"同源性"應理解為意指在比對序列並引入空位(若需要)以達成整個序列之最高百分比一致性後,候選序列中與擬比較對照序列之殘基相同之胺基酸殘基百分比,其中不將任何保守取代視為序列一致性之一部分。N-或C-末端延伸或插入均不應理解為降低一致性或同源性。用於比對之方法及計算機程序在業內眾所周知。可使用序列分析軟件量測序列一致性。
術語"抗體"係以最廣泛含義使用,且具體地涵蓋單株抗體(包括全長單株抗體)、多株抗體及多特異性抗體(例如雙特異性抗體)。抗體(Ab)及免疫球蛋白(Ig)係具有相同結構特徵之糖蛋白。儘管抗體對特定靶顯示結合特異性,但免疫球蛋白既包括抗體亦包括其他缺乏靶特異性之抗體樣分子。天然抗體及免疫球蛋白通常為約150,000道爾頓之異四倍體糖蛋白,由兩條相同輕(L)鏈及兩條相同重(H)鏈組成。每一重鏈在一端均具有一可變結構域(VH
),後接多個恆定結構域。每一輕鏈在一端均具有一可變結構域(VL
)且在其另一端具有一恆定結構域。
本文所用"抗-人類因子D抗體"意指以此一方式特異性結合至人類因子D以抑制或實質上減弱補體活化之抗體。
在抗體可變結構域之情況下術語"可變"意指下述事實:各抗體可變結構域某些部分之序列極為不同,且該術語用於每一特定抗體對其特定靶之結合及特異性。然而,在抗體可變區域中可變性並非均勻分佈。其集中於在輕鏈及重鏈可變結構域中均存在之三個區段中,該等區段稱為互補決定區(CDR),亦稱為高可變區(HVR)。可變結構域中保守程度更高之部分稱為骨架(FR)。天然重鏈及輕鏈之可變結構域各自包括4個主要採用β-折疊構型藉由三個CDR連接之FR區,其形成環連接,且在某些情況下形成部分β-折疊結構。每一鏈中之CDR皆藉由FR區緊密結合在一起且與其它鏈CDR共同促進抗體靶結合位點之形成(參見Kabat等人)。除非另有說明,本文所用免疫球蛋白胺基酸殘基編號係根據Kabat等人之免疫球蛋白胺基酸殘基編號系統加以實施(Sequences of Proteins of Immunological Interest,National Institute of Health,Bethesda,Md.1987)。
本文所用術語"高可變區"、"HVR"或"HV"意指抗體可變結構域中序列高度可變及/或結構上形成所定義環之區域。一般而言,抗體包含六個高可變區;三個在VH中(H1、H2、H3)及三個在VL中(L1、L2、L3)。本文使用且涵蓋多個高可變區之描述。Kabat互補性決定區(CDR)係基於序列可變性且使用最為廣泛(Kabat等人,Sequences of Proteins of Immunological Interest,
5th Ed.Public Health Service,National Institutes of Health,Bethesda,MD.(1991))。而Chothia指結構環之位置(Chothia及Lesk J.Mol.Biol.196:901-917(1987))。AbM高可變區代表Kabat之CDR與Chothia之結構環之間的折衷方案且用於Oxford Molecular之AbM抗體建模軟件中。"接觸"高可變區係基於對可獲得複雜晶體結構之分析。來自每個該等高可變區之殘基係如下所述。
高可變區可包括下述"經延伸高可變區":VL中之24-36或24-34(L1)、46-56或50-56(L2)及89-97(L3)及VH中之26-35(H1)、50-65或49-65(H2)及93-102、94-102或95-102(H3)。對於每個該等定義根據Kabat等人(見上文)將可變結構域殘基編號。
"骨架"或"FR"殘基係除本文所定義之高可變區殘基或CDR殘基以外之彼等可變結構域殘基。
術語"如於Kabat中編號之可變結構域殘基"或"如於Kabat中編號之胺基酸位點"及其變型意指用於在Kabat等人,Sequences of Proteins of Immunological Interest,5th Ed.Public Health Service,National Institutes of Health,Bethesda,MD.(1991)中所彙編抗體之重鏈可變結構域或輕鏈可變結構域之編號系統。使用該編號系統,實際線性胺基酸序列可包含更少或額外之對應於可變結構域FR或CDR之縮短或插入之胺基酸。舉例而言,重鏈可變結構域可包含在H2之殘基52後之單胺基酸插入(根據Kabat編號之殘基52a)及重鏈FR殘基82後之插入殘基(例如根據Kabat編號之殘基82a、82b及82c等)。可藉由用"標準"Kabat經編號序列比對抗體序列之同源區域來確定給定抗體殘基之Kabat編號。
通常在涉及可變結構域中殘基(大致為輕鏈中殘基1-107及重鏈中殘基1-113)時使用Kabat編號系統(例如Kabat等人,Sequences of Immunological Interest.5th Ed.Public Health Service,National Institutes of Health,Bethesda,Md.(1991))。通常在涉及免疫球蛋白重鏈恆定區中殘基時使用"EU編號系統"或"EU索引"(例如在上文Kabat等人之文獻中所報告之EU索引;重鏈恆定結構域之絞鏈區大概為重鏈殘基216-230(EU編號))。"如於Kabat中之EU索引"係指人類IgG1 EU抗體之殘基編號。除非本文另外說明,否則所提及的抗體可變結構域殘基編號意指使用Kabat編號系統之殘基編號。除非本文另外說明,否則所提及的抗體恆定結構域殘基編號意指使用EU編號系統之殘基編號(例如參見美國臨時專利申請案第60/640,323號,EU編號圖)。
術語"抗體片段"係指全長抗體之一部分,通常指靶結合區或可變區。抗體片段之實例包括Fab、Fab'、F(ab')2
及Fv片段。短語抗體之"功能片段或類似物"係指具有與全長抗體相同定性生物活性之化合物。舉例而言,抗-人類因子D抗體之功能片段或類似物係可以此一方式結合至因子D以防止或實質上減弱補體活化之功能片段或類似物。就抗體而言,本文所用"功能片段"意指Fv、F(ab)及F(ab')2
片段。"Fv"片段係包含完整靶識別及結合位點之最小抗體片段。此區域係由一個重鏈可變結構域與一個輕鏈可變結構域呈非共價緊密結合之二聚體(VH
-VL
二聚體)組成。各可變結構域之三個CDR係以該構型相互作用以在VH
-VL
二聚體表面上界定靶結合位點。該六個CDR共同賦予抗體以靶結合特異性。然而,甚至單可變結構域(或僅包含三個靶特異性CDR之半Fv)亦能識別並結合靶。"單鏈Fv"或"sFv"抗體片段包含抗體之VH
及VL
結構域,其中該等結構域係以單多肽鏈形式存在。一般而言,Fv多肽另外包含位於VH
及VL
結構域之間之多肽連接體,其使sFv能形成所期望靶結合結構。
Fab片段包含輕鏈之恆定結構域及重鏈之第一恆定結構域(CH1)。Fab'片段因在重鏈CH1結構域之羧基末端增加了若干殘基而與Fab片段不同,該等殘基包括來自抗體鉸鏈區之一或多個半胱胺酸。F(ab')片段係藉由F(ab')2
胃蛋白酶消化產物之鉸鏈半胱胺酸處之二硫鍵斷裂而生成。抗體片段之其他化學偶聯已為所屬領域技術人員所習知。
本文所用術語"單株抗體"係指自實質上同源之抗體群獲得之抗體,即除可能存在極少量天然發生之突變外,構成該群體之各個抗體均相同。單株抗體具有針對單個靶位點之高度特異性。此外,與通常包括針對不同決定子(抗原決定部位)之不同抗體之習用(多株)抗體製劑相反,每一單株抗體僅針對靶上之單個決定子。除其特異性外,單株抗體之優勢在於其可藉由雜交瘤培養加以合成,而不受其他免疫球蛋白污染。修飾詞"單株"意指抗體特徵係自實質上同源之抗體群獲得,且不應理解為需要藉由任一特定方法來生產該抗體。舉例而言,可使用熟知技術自噬菌體抗體文庫分離得到用於本發明之單株抗體。根據本發明使用之親代單株抗體可藉由Kohler及Milstein首先闡述之雜交瘤方法(Nature 256,495(1975))加以製備,或可藉由重組方法加以製備。
非人類(例如鼠類)抗體之"人類化"形式係嵌合免疫球蛋白、免疫球蛋白鏈或其片段(例如Fv、Fab、Fab'、F(ab')2
或抗體之其他靶結合子序列),其包含得自非人類免疫球蛋白之最小序列。一般而言,人類化抗體可包含實質上所有至少一個且通常兩個可變結構域,其中所有或實質上所有CDR區對應於非人類免疫球蛋之彼等,且所有或實質上所有FR區為人類免疫球蛋白共有序列之彼等。人類化抗體亦可包含至少部分免疫球蛋白恆定區(Fc)(通常為所選人類免疫球蛋白模板之恆定區)。
用於人類化非人類抗體之方法為業內所熟知。一般而言,人類化抗體具有自非人類來源引入其之一或多個胺基酸殘基。該等非人類胺基酸殘基通常稱為"引入"殘基,其通常取自"引入"可變結構域。基本上可按照Winter及合作者之方法藉由用嚙齒目動物之CDR序列取代人類抗體之對應序列來實施人類化[Jones等人,Nature
,321
:522-525(1986);Riechmann等人,Nature
,332
:323-327(1988);Verhoeyen等人,Science
,239
:1534-1536(1988)]。因此,該等"人類化"抗體為嵌合抗體(美國專利第4,816,567號),其中實質上少於一個完整人類可變結構域之部分已由來自非人類物種之對應序列所替代。實際情況下,人類化抗體通常為人類抗體,其中某些CDR殘基及可能某些FR殘基係由來自嚙齒目動物抗體中類似位點之殘基取代。
當意欲將抗體用於人類治療用途時,在某些情況下選擇將用於製備人類化抗體之人類可變結構域(輕鏈及重鏈二者)對降低抗原性及/或HAMA應答(人類抗-小鼠抗體)可能很重要。降低或消除HAMA應答通常係臨床研發適宜治療試劑之重要態樣。參見例如Khaxzaeli等人,J.Natl.Cancer Inst.(1988),80:937;Jaffers等人,Transplantation(1986),41:572;Shawler等人,J.Immunol.(1985),135:1530;Sears等人,J.Biol.Response Mod.(1984),3:138;Miller等人,Blood(1983),62:988;Hakimi等人J.Immunol.(1991),147:1352;Reichmann等人,Nature(1988),332:323;Junghans等人,Cancer Res.(1990),50:1495。如本文所述,本發明提供經人類化以降低或消除HAMA應答之抗體。可使用業內習知之常規方法另外獲得該等抗體之變型體,下文進一步闡述某些該等方法。根據所謂"最佳擬合"方法,針對已知人類可變結構域序列之完整文庫篩選嚙齒目動物抗體之可變結構域序列。人類V結構域序列經鑑別與嚙齒自動物之V結構域序列最接近且人類化抗體接受其內之人類骨架區(FR)(Sims等人,J.Immunol
.151:2296(1993);Chothia等人,J.Mol.Biol
.196:901(1987))。另一方法使用得自輕鏈或重鏈特定亞型之所有人類抗體共有序列之特定骨架區。相同骨架可用於若干不同人類化抗體(Carter等人,Proc.Natl.Acad.Sci
.USA
,89:4285(1992);Presta等人,J.Immunol
.151:2623(1993))。
舉例而言,來自本文所述抗體之胺基酸序列可作為起始(親代)序列用於骨架多樣化及/或高可變序列。本文中將與起始高可變序列連接之所選擇骨架序列稱為受體人類骨架。受體人類骨架可來自或衍生自人類免疫球蛋白(其VL及/或VH區),同時亦可來自或衍生自人類共有骨架序列,因為在人類患者中已顯示該等骨架具有最小或不具有免疫原性。用於本文目的之"受體人類骨架"係包含衍生自人類免疫球蛋白骨架或來自人類共有骨架之VL或VH骨架之胺基酸序列之骨架。"衍生自"人類免疫球蛋白骨架或人類共有骨架之受體人類骨架可包含與其相同之胺基酸序列或可包含既有胺基酸序列變化。倘若存在既有胺基酸變化,較佳存在不超過5個且較佳4個或更少,或3個或更少之既有胺基酸變化。在一實施例中,VH受體人類骨架之序列與VH人類免疫球蛋白骨架序列或人類共有骨架序列相同。在一實施例中,VL受體人類骨架序列與VL人類免疫球蛋白骨架序列或人類共有骨架序列相同。"人類共有骨架"係代表在所選擇人類免疫球蛋白VL或VH骨架序列中存在最普遍之胺基酸殘基之骨架。一般而言,所選擇人類免疫球蛋白VL或VH序列係來自可變結構域序列亞型。一般而言,該序列亞型係如Kabat等人所述之亞型。在一實施例中,對VL而言該亞型係如Kabat等人所述之亞型I。在一實施例中,對VH而言該亞型係如Kabat等人所述之亞型III。
倘若受體係衍生自人類免疫球蛋白,視情況可藉由將供體骨架序列與人類骨架序列集合中之不同人類骨架序列比對而基於其與供體骨架序列之同源性選擇一人類骨架序列,且選擇同源性最高之骨架序列作為受體。受體人類骨架可來自或衍生自公開數據庫中可獲得之人類抗體種系序列。
在一實施例中,本文中人類共有骨架係來自或衍生自VH亞型VII及/或VL亞型I共有骨架序列。
在一實施例中,用於生成抗-因子D抗體之人類骨架模板可包括來自包含用於VH鏈之VI-4.1b+(VH7族)及JH4d之組合(圖3)及/或用於VL鏈之DPK4(VI族)及JK2之組合(圖4)之模板之骨架序列。
因此,VH受體人類骨架可包括一個、兩個、三個或所有下列骨架序列:包含QX1
QLVQSGX2
ELKKPGASVKVSCKAS(SEQ ID NO:27之胺基酸1-25)之FR1,其中X1
係I或V,X2
係P或S;包含WVX3
QAPGQGLE(SEQ ID NO:27之胺基酸36-46)之FR2,其中X3
係K或R;包含RFVFSLDTSVSTAYLQISSLKAEDTAX4
YYCX5
R(SEQ ID NO:27之胺基酸67-98)之FR3,其中X4
係T或V,X5
係E或A;包含WGQGTLVTVSS(SEQ ID NO:8之胺基酸105-115或SEQ ID NO:27之胺基酸105-115)之FR4。
VH共有骨架之實例包括:減去Kabat CDR的人類VH亞型I共有骨架(SEQ ID NO:28);減去經延伸高可變區的人類VH亞型I共有骨架(SEQ ID NOs:29-31);減去Kabat CDR的人類VH亞型II共有骨架(SEQ ID NO:32);減去經延伸高可變區的人類VH亞型II共有骨架(SEQ ID NOs:33-35);人類VH亞型III共有骨架最小Kabat CDR(SEQ ID NO:36);減去經延伸高可變區的人類VH亞型III共有骨架(SEQ ID NOs:37-39);減去Kabat CDR的人類VH亞型VII共有骨架(SEQ ID NO:55);人類VH亞型VII共有骨架最小經延伸高可變區(SEQ ID NOs:56-58);減去Kabat CDR的人類VH受體骨架(SEQ ID NO:40);減去經延伸高可變區的人類VH受體骨架(SEQ ID NOs:41-42);減去Kabat CDR的人類VH受體2骨架(SEQ ID NO:43);或減去經延伸高可變區的人類VH受體2骨架(SEQ ID NOs:44-45)。
在一實施例中,VH受體人類骨架包括一個、兩個、三個或所有下列骨架序列:包含QVQLVQSGPELKKPGASVKVSCKAS(SEQ ID NO:8之胺基酸1-25)之FR1,包含WVRQAPGQGLE(SEQ ID NO:8之胺基酸36-46)之FR2,包含RFVFSLDTSVSTAYLQISSLKAEDTAVYYCER(SEQ ID NO:8之胺基酸67-98),RFVFSLDTSVSTAYLQISSLKAEDTAVYYCE(SEQ ID NO:8之胺基酸67-97),RFVFSLDTSVSTAYLQISSLKAEDTAVYYC(SEQ ID NO:8之胺基酸67-96),RFVFSLDTSVSTAYLQISSLKAEDTAVYYCS(SEQ ID NO:51),或RFVFSLDTSVSTAYLQISSLKAEDTAVYYCSR(SEQ ID NO:52)之FR3,包含WGQGTLVTVSS(SEQ ID NO:8之胺基酸105-115或SEQ ID NO:27之胺基酸105-115)之FR4。
VL受體人類骨架可包括一個、兩個、三個或所有下列骨架序列:包含DIQX6
TQSPSSLSX7
SVGDRVTITC(SEQ ID NO:26之胺基酸1-23)之FR1,其中X6
係V或M,X7
係M或A;包含WYQQKPGKX8
PKLLIX9
(SEQ ID NO:26之胺基酸35-49)之FR2,其中X8
係P或V,X9
係S或Y;包含GVPSRFSX10
SGSGX11
DFTLTISSLQPEDVATYYC(SEQ ID NO:26之胺基酸57-88)之FR3,其中X10
係S或G,X11
係A或T;包含FGQGTKX12
EIK(SEQ ID NO:54)之FR4,其中X12
係V或L。
VL共有骨架之實例包括:人類VL亞型I共有骨架(SEQ ID NO:47);人類VL亞型II共有骨架(SEQ ID NO:48);人類VL亞型III共有骨架(SEQ ID NO:49);或人類VL亞型IV共有骨架(SEQ ID NO:50)。
在一實施例中,VL受體人類骨架可包括一個、兩個、三個或所有下列骨架序列:包含DIQVTQSPSSLSASVGDRVTITC(SEQ ID NO:7之胺基酸1-23)之FR1,包含WYQQKPGKVPKLLIS(SEQ ID NO:7之胺基酸35-49)之FR2,包含GVPSRFSGSGSGTDFTLTISSLQPEDVATYYC(SEQ ID NO:7之胺基酸57-88)之FR3,包含FGQGTKLEIK(SEQ ID NO:7之胺基酸98-107)、或FGQGTKVEIK(SEQ ID NO:53)之FR4。
受體序列可與選自人類免疫球蛋白或人類共有骨架之人類骨架序列相同,同時本發明涵蓋受體序列可包含相對人類免疫球蛋白序列或人類共有骨架序列之既有胺基酸取代。該等既有取代較佳為最低限度;通常為4個、3個、2個或1個僅相對人類免疫球蛋白序列或共有骨架序列不同之胺基酸。
將非人類抗體之高可變區殘基納入VL及/或VH受體人類骨架中。舉例而言,可納入對應於Kabat CDR殘基、Chothia高可變環殘基、Abm殘基及/或接觸殘基之殘基。視情況,可納入下列經延伸高可變區殘基:24-34(L1)、50-56(L2)及89-97(L3)、26-35(H1)、50-65或49-65(H2)及93-102、94-102或95-102(H3)。
本發明一態樣提供包含至少1個、2個、3個、4個、5個或6個選自下述各項之HVR之抗體:(a)包含選自SEQ ID NO:13、SEQ ID NO:23及SEQ ID NO:25之胺基酸序列之HVR-H1;(b)包含SEQ ID NO:14之胺基酸序列之HVR-H2;(c)包含選自SEQ ID NO:15及SEQ ID NO:20之胺基酸序列之HVR-H3;(d)包含SEQ ID NO:16之胺基酸序列之HVR-L1;(e)包含選自SEQ ID NO:17、SEQ ID NO:21及SEQ ID NO:24之胺基酸序列之HVR-L2;及(f)包含選自SEQ ID NO:18、SEQ ID NO:22及SEQ ID NO:19之胺基酸序列之HVR-L3。
本發明一態樣提供包含至少1個、2個、3個、4個、5個或6個選自下列各項之HVR之抗-因子D抗體:(a)包含與選自SEQ ID NO:13、SEQ ID NO:23及SEQ ID NO:25之胺基酸序列序列一致性為至少90%、91%、92%、93%、94%、95%、96%、97%、98%或99%之胺基酸序列之HVR-H1;(b)包含與SEQ ID NO:14之胺基酸序列序列一致性為至少90%、91%、92%、93%、94%、95%、96%、97%、98%或99%之胺基酸序列之HVR-H2;(c)包含與選自SEQ ID NO:15及SEQ ID NO:20之胺基酸序列序列一致性為至少90%、91%、92%、93%、94%、95%、96%、97%、98%或99%之胺基酸序列之HVR-H3;(d)包含與SEQ ID NO:16之胺基酸序列序列一致性為至少90%、91%、92%、93%、94%、95%、96%、97%、98%或99%之胺基酸序列之HVR-L1;(e)包含與選自SEQ ID NO:17、SEQ ID NO:21及SEQ ID NO:24之胺基酸序列序列一致性為至少90%、91%、92%、93%、94%、95%、96%、97%、98%或99%之胺基酸
序列之HVR-L2;及(f)包含與選自SEQ ID NO:18、SEQ ID NO:22及SEQ ID NO:19之胺基酸序列序列一致性為至少90%、91%、92%、93%、94%、95%、96%、97%、98%或99%之胺基酸序列之HVR-L3。在某些實施例中,含有序列一致性為至少90%、91%、92%、93%、94%、95%、96%、97%、98%或99%之胺基酸序列之HVR包含相對參照序列之取代、插入或缺失,但包含該胺基酸序列之抗體保留結合因子D之能力。在某些實施例中,該參照序列中可取代、插入或缺失總計1至10個胺基酸,參照序列係選自由下列各項組成之群:SEQ ID NO:13、SEQ ID NO:25、SEQ ID NO:14、SEQ ID NO:15、SEQ ID NO:20、SEQ ID NO:16、SEQ ID NO:17、SEQ ID NO:21、SEQ ID NO:23、SEQ ID NO:18、SEQ ID NO:22及SEQ ID NO:24。在某些實施例中,本發明提供包含至少1個、2個、3個、4個、5個或6個選自下列各項之HVR之抗體:(a)包含選自SEQ ID NO:13、SEQ ID NO:23及SEQ ID NO:25之胺基酸序列之HVR-H1;(b)包含SEQ ID NO:14之胺基酸序列之HVR-H2;(c)包含選自SEQ ID NO:15及SEQ ID NO:20之胺基酸序列之HVR-H3;(d)包含SEQ ID NO:16之胺基酸序列之HVR-L1;(e)包含選自SEQ ID NO:17、SEQ ID NO:21及SEQ ID NO:24之胺基酸序列之HVR-L2;及(f)包含選自SEQ ID NO:18、SEQ ID NO:22及SEQ ID NO:19之胺基酸序列之HVR-L3。
本發明一態樣提供包含選自SEQ ID NO:6、SEQ ID NO:8、SEQ ID NO:10、SEQ ID NO:12之重鏈可變結構域之抗體。本發明一態樣提供包含選自SEQ ID NO:5、SEQ ID NO:7、SEQ ID NO:9及SEQ ID NO:11之輕鏈可變結構域之抗體。本發明一態樣提供包含含有SEQ ID NO:6之重鏈可變結構域之抗體。本發明一態樣提供包含含有SEQ ID NO:5之輕鏈可變結構域之抗體。本發明一態樣提供包含含有SEQ ID NO:6之重鏈可變結構域及含有SEQ ID NO:5之輕鏈可變結構域之抗體。本發明一態樣提供包含含有SEQ ID NO:8之重鏈可變結構域之抗體。本發明一態樣提供包含含有SEQ ID NO:7之輕鏈可變結構域之抗體。本發明一態樣提供包含含有SEQ ID NO:8之重鏈可變結構域及含有SEQ ID NO:7之輕鏈可變結構域之抗體。本發明一態樣提供包含含有SEQ ID NO:10之重鏈可變結構域之抗體。本發明一態樣提供包含含有SEQ ID NO:9之輕鏈可變結構域之抗體。本發明一態樣提供包含含有SEQ ID NO:10之重鏈可變結構域及含有SEQ ID NO:9之輕鏈可變結構域之抗體。本發明一態樣提供包含含有SEQ ID NO:12之重鏈可變結構域之抗體。本發明一態樣提供包含含有SEQ ID NO:11之輕鏈可變結構域之抗體。本發明一態樣提供包含含有SEQ ID NO:12之重鏈可變結構域及含有SEQ ID NO:11之輕鏈可變結構域之抗體。
本發明一態樣提供包含一重鏈可變結構域之抗-因子D抗體,該重鏈可變結構域包含與選自由SEQ ID NO:6、8、10及12組成之群之胺基酸序列序列一致性為至少90%、91%、92%、93%、94%、95%、96%、97%、98%或99%之胺基酸序列。在某些實施例中,序列一致性為至少90%、91%、92%、93%、94%、95%、96%、97%、98%或99%之胺基酸序列包含相對參照序列之取代、插入或缺失,但包含該胺基酸序列之抗體保留結合至因子D之能力。在某些實施例中,選自由SEQ ID NO:6、8、10或12組成之群之序列中可取代、插入或缺失總計1至10個胺基酸。在某些實施例中,該等取代、插入或缺失存在於HVR以外之區域(即在FR中)。在某些實施例中,抗-因子D抗體包含含有選自由SEQ ID NO:6、8、10或12組成之群之胺基酸序列之重鏈可變結構域。
在某些實施例中,本發明提供包含一輕鏈可變結構域之抗-因子D抗體,該輕鏈可選結構域包含與選自由SEQ ID NO:5、7、9及11組成之群之胺基酸序列序列一致性為至少90%、91%、92%、93%、94%、95%、96%、97%、98%或99%之胺基酸序列。在某些實施例中,序列一致性為至少90%、91%、92%、93%、94%、95%、96%、97%、98%或99%之胺基酸序列包含相對參照序列之取代、插入或缺失,但包含該胺基酸序列之抗體保留結合至因子D之能力。在某些實施例中,選自由SEQ ID NO:5、7、9或11組成之群之序列中可取代、插入或缺失總計1至10個胺基酸。在某些實施例中,該等取代、插入或缺失存在於HVR以外之區域(即在FR中)。在某些實施例中,抗-因子D抗體包含含有選自由SEQ ID NO:5、7、9或11組成之群之胺基酸序列之輕鏈可變結構域。
抗-因子D抗體可包含任何適宜骨架可變結構域序列,前提條件係抗體保留結合至因子D之能力。舉例而言,在某些實施例中,本發明抗-因子D抗體包含為VI.4.1 b+與JH4d組合(參見圖3)之重鏈可變結構域骨架序列。在某些實施例中,本發明抗-因子D抗體包含人類亞型VII重鏈骨架共有序列。在某些實施例中,抗-因子D抗體包含重鏈可變結構域骨架序列,其包括:包含SEQ ID NO:8之胺基酸1-25之FR1、包含SEQ ID NO:8之胺基酸36-46之FR2、包含SEQ ID NO:8之胺基酸67-98之FR3及包含SEQ ID NO:8之胺基酸105-115之FR4。在該等抗體之一實施例中,重鏈可變結構域序列包括在40及/或88位(Kabat編號)之取代。在該等抗體之一實施例中,40位係半胱胺酸(C)或丙胺酸(A)及/或88位係半胱胺酸(C)或丙胺酸(A)。在某些實施例中,本發明之抗-因子D抗體包含為DPK4與JK2組合(參見圖4)之輕鏈可變結構域骨架序列。在某些實施例中,本發明抗-因子D抗體包含人類I(I)輕鏈骨架共有序列。在某些實施例中,本發明抗-因子D抗體包含一輕鏈可變結構域骨架序列,其包括:包含SEQ ID NO:7之胺基酸1-23之FR1、包含SEQ ID NO:7之胺基酸35-49之FR2、包含SEQ ID NO:7之胺基酸57-88之FR3及包含SEQ ID NO:7之胺基酸98-107之FR4。在該等抗體之一實施例中,輕鏈可變骨架序列在15、43及/或104位(Kabat編號)包含一或多個取代。在該等抗體之一實施例中,15位係半胱胺酸(C)或纈胺酸(V),43位係半胱胺酸(C)或丙胺酸(A)及/或104位係纈胺酸(V)或亮胺酸(L)。
此外,抗-因子D抗體可包含任何適宜恆定結構域序列,前提條件係該抗體保留結合因子D之能力。舉例而言,在某些實施例中,本發明抗-因子D抗體包含至少部分重鏈恆定結構域。在一實施例中,本發明抗-因子D抗體包含α、δ、ε、γ或μ重鏈之一或其組合之重鏈恆定結構域。端視其重鏈(CH
)恆定結構域之胺基酸序列,可將免疫球蛋白分配為不同種類或同型物。免疫球蛋白分五類:IgA、IgD、IgE、IgG及IgM,其重鏈分別命名為α、δ、ε、γ及μ。基於CH
序列及功能之相對較小差異可將γ及α類進一步分為亞類,例如人類表現下列亞類:IgG1、IgG2、IgG3、IgG4、IgA1及IgA2。在一實施例中,本發明抗-因子D抗體包含一重鏈恆定結構域,其在導致對效應子功能(例如鍵結親和力)之所期望效應之胺基酸位點含有取代。在一實施例中,本發明抗-因子D抗體包含一重鏈恆定結構域,其在不導致效應子作用效應(例如鍵結親和力)之胺基酸位點含有取代。在一實施例中,本發明抗-因子D抗體包含IgG型(例如IgG1、IgG2、IgG3或IgG4)重鏈恆定結構域且在114位(Kabat編號;相當於EU編號之118位)、168位(Kabat編號;相當於EU編號之172位)、172位(Kabat編號;相當於EU編號之176位)及/或228位(EU編號)另外包含取代。在一實施例中,本發明抗-因子D抗體包含IgG型(例如IgG1、IgG2、IgG3或IgG4)重鏈恆定結構域且在114位另外含有取代(其中114位係半胱胺酸(C)或丙胺酸(A),168位係半胱胺酸(C)或丙胺酸(A),172位係半胱胺酸(C)或丙胺酸(A)及/或228位係脯胺酸(P)、精胺酸(R)或絲胺酸(S))。此外,舉例而言,在某些實施例中,本發明抗-因子D抗體包含至少部分輕鏈恆定結構域。在一實施例中,可基於其恆定結構域之胺基酸序列將來自任何脊椎動物物種之輕鏈分配為稱為及γ
之兩種截然不同類型之一,而本發明抗-因子D抗體包含或γ
輕鏈之一或其組合之輕鏈恆定結構域。在一實施例中,本發明抗-因子D抗體包含一輕鏈恆定結構域,其在導致對效應子功能(例如鍵結親和力)之所期望效應之胺基酸位點含有取代。在一實施例中,本發明抗-因子D抗體包含一輕鏈恆定結構域,其在不導致對效應子功能(例如鍵結親和力)之效應之胺基酸位點含有取代。在一實施例中,本發明抗-因子D抗體包含型輕鏈恆定結構域且在110、144、146及/或 168位(Kabat編號)另外含有取代。在一實施例中,本發明抗-因子D抗體包含型輕鏈恆定結構域且在110位(其中110係半胱胺酸(C)或纈胺酸(V))、144位(其中144係半胱胺酸(C)或丙胺酸(A))、146位(其中146係異亮胺酸(I)或纈胺酸(V))及/或168位(其中168係半胱胺酸(C)或絲胺酸(S))另外含有取代。
本發明一態樣提供與下列抗體競爭之抗體:鼠類抗體166-32及/或人類化抗-因子D抗體純系#56、#111、#250或#416,及/或包含人類化抗-因子D抗體純系#56、#111、#250或#416之可變結構域或HVR序列之抗體。亦提供與下列抗體所結合抗原決定部位相同之抗體:如鼠類抗體166-32及/或人類化抗-因子D抗體純系#56、#111、#250或#416,及/或包含人類化抗-因子D抗體純系#56、#111、#250或#416之可變結構域或HVR序列之抗體。
在一實施例中,本發明提供抗-因子D抗體,其中該抗體對因子D之單價親和力(例如呈Fab片段形式之抗體對因子D之親和力)更低,例如較嵌合抗體之單價親和力(例如呈Fab片段形式之嵌合抗體對因子D之親和力)低至少1倍或2倍,且其包含、包括或基本上包括SEQ ID NO:2之輕鏈可變結構域及SEQ ID NO:1之重鏈可變結構域。
在一實施例中,本發明提供抗-因子D抗體,其中該抗體對因子D之二價親和力(例如呈IgG形式之抗體對因子D之親和力)更低,例如較嵌合抗體之二價親和力(例如呈IgG形式之嵌合抗體對因子D之親和力)低至少1倍或2倍,且其包含、包括或基本上包括SEQ ID NO:2之輕鏈可變結構域及SEQ ID NO:1之重鏈可變結構域。
在另一實施例中,本發明提供抗-因子D抗體,其中該抗體對因子D之單價親和力(例如呈Fab片段之抗體對因子D之親和力)更高,例如較嵌合抗體之單價親和力(例如呈Fab片段之嵌合抗體對因子D之親和力)高至少1倍或2倍,且其包含、包括或基本上包括SEQ ID NO:2之輕鏈可變結構域及SEQ ID NO:1之重鏈可變結構域。
在另一實施例中,本發明提供抗-因子D抗體,其中該抗體對因子D之二價親和力(例如呈IgG之抗體對因子D之親和力)更高,例如較嵌合抗體之二價親和力(例如呈IgG之嵌合抗體對因子D之親和力)高至少1倍或2倍,且其包含、包括或基本上包括SEQ ID NO:2之輕鏈可變結構域及SEQ ID NO:1之重鏈可變結構域。
在另一實施例中,本發明提供抗-因子D抗體,其中以其單價形式存在之該抗體對因子D之親和力(例如該呈Fab片段之抗體對因子D之親和力)為1.0 nM(1.0x10-9
M)或更高。在另一實施例中,本發明提供抗-因子D抗體,其中以其單價形式存在之該抗體對因子D之親和力(例如該呈Fab片段之抗體對因子D之親和力)為0.5 nM(0.5x10-9
M)或更高。在另一實施例中,本發明提供抗-因子D抗體,其中以其單價形式存在之該抗體對因子D之親和力(例如該呈Fab片段之抗體對因子D之親和力)為1.0 pM(1.0x10-12
M)或更高。在另一實施例中,本發明提供抗-因子D抗體,其中以其單價形式存在之該抗體對因子D之親和力(例如該呈Fab片段之抗體對因子D之親和力)為0.5 pM(0.5x10-12
M)或更高。
在另一實施例中,本發明提供抗-因子D抗體,其中以其二價形式存在之該抗體對因子D之親和力(例如該呈IgG之抗體對因子D之親和力)為1.0 nM(1.0x10-9
M)或更高。在另一實施例中,本發明提供抗-因子D抗體,其中以其二價形式存在之該抗體對因子D之親和力(例如該呈IgG之抗體對因子D之親和力)為0.5 nM(0.5x10-9
M)或更高。在另一實施例中,本發明提供抗-因子D抗體,其中以其二價形式存在之該抗體對因子D之親和力(例如該呈IgG之抗體對因子D之親和力)為1.0 pM(1.0x10-12
M)或更高。在另一實施例中,本發明提供抗-因子D抗體,其中以其二價形式存在之該抗體對因子D之親和力(例如該呈IgG之抗體對因子D之親和力)為0.5 pM(0.5x10-12
M)或更高。
在另一實施例中,本發明提供抗-因子D抗體,其中以其單價形式存在之該抗體對因子D之親和力(例如該呈Fab片段之抗體對因子D之親和力)介於0.5 mM(0.5x10-6
M)及0.5 pM(0.5x10-12
M)之間。在另一實施例中,本發明提供抗-因子D抗體,其中以其單價形式存在之該抗體對因子D之親和力(例如該呈Fab片段之抗體對因子D之親和力)介於15 nM(15x10-9
M)及0.1 nM(0.1x10-9
M)之間。在另一實施例中,本發明提供抗-因子D抗體,其中以其單價形式存在之該抗體對因子D之親和力(例如該呈Fab片段之抗體對因子D之親和力)介於5.5 nM(5.5x10-9
M)及1 nM(1x10-9
M)之間。在另一實施例中,本發明提供抗-因子D抗體,其中以其單價形式存在之該抗體對因子D之親和力(例如該呈Fab片段之抗體對因子D之親和力)介於0.5 pM(0.5x10-12
M)及2 pM(2x10-12
M)之間。
在另一實施例中,本發明提供抗-因子D抗體,其中以其二價形式存在之該抗體對因子D之親和力(例如該呈IgG之抗體對因子D之親和力)介於0.5 mM(0.5x10-6
M)及0.5 pM(0.5x10-12
M)之間。在另一實施例中,本發明提供抗-因子D抗體,其中以其二價形式存在之該抗體對因子D之親和力(例如該呈IgG之抗體對因子D之親和力)介於10 nM(10x10-9
M)及0.05 nM(0.05x10-9
M)之間。在另一實施例中,本發明提供抗-因子D抗體,其中以其二價形式存在之該抗體對因子D之親和力(例如該呈IgG之抗體對因子D之親和力)介於5.5 nM(5.5x10-9
M)及1 nM(1x10-9
M)之間。在另一實施例中,本發明提供抗-因子D抗體,其中以其二價形式存在之該抗體對因子D之親和力(例如該呈IgG之抗體對因子D之親和力)介於0.5 pM(0.5x10-12
M)及2 pM(2x10-12
M)之間。
在另一實施例中,本發明提供抗-因子D抗體,其中以其單價形式存在之該抗體對因子D之親和力(例如該呈Fab片段之抗體對因子D之親和力)為約3.7 nM(3.7x10-9
M)。在另一實施例中,本發明提供抗-因子D抗體,其中以其單價形式存在之該抗體對因子D之親和力(例如該呈Fab片段之抗體對因子D之親和力)為約3.3 nM(3.3x10-9
M)。在另一實施例中,本發明提供抗-因子D抗體,其中以其單價形式存在之該抗體對因子D之親和力(例如該呈Fab片段之抗體對因子D之親和力)為約5.1 nM(5.1x10-9
M)。在另一實施例中,本發明提供抗-因子D抗體,其中以其單價形式存在之該抗體對因子D之親和力(例如該呈Fab片段之抗體對因子D之親和力)為約2.7 nM(2.7x10-9
M)。在另一實施例中,本發明提供抗-因子D抗體,其中以其單價形式存在之該抗體對因子D之親和力(例如該呈Fab片段之抗體對因子D之親和力)為約1.4 nM(1.4x10-9
M)。在另一實施例中,本發明提供抗-因子D抗體,其中以其單價形式存在之該抗體對因子D之親和力(例如該呈Fab片段之抗體對因子D之親和力)為約1.4 pM(1.4x10-12
M)。在另一實施例中,本發明提供抗-因子D抗體,其中以其二價形式存在之該抗體對因子D之親和力(例如該呈IgG之抗體對因子D之親和力)為約1.1 pM(1.1x10-12
M)。在另一實施例中,本發明提供抗-因子D抗體,其中以其單價形式存在之該抗體對因子D之親和力(例如該呈Fab片段之抗體對因子D之親和力)為約0.19 nM(0.19x10-9
M)。在另一實施例中,本發明提供抗-因子D抗體,其中以其二價形式存在之該抗體對因子D之親和力(例如該呈IgG之抗體對因子D之親和力)為約0.08 nM(0.08x10-9
M)。在另一實施例中,本發明提供抗-因子D抗體,其中以其單價形式存在之該抗體對因子D之親和力(例如該呈Fab片段之抗體對因子D之親和力)為約12.3 nM(12.3x10-9
M)。在另一實施例中,本發明提供抗-因子D抗體,其中以其二價形式存在之該抗體對因子D之親和力(例如該呈IgG之抗體對因子D之親和力)為約9.0 nM(9.0x10-9
M)。
在另一實施例中,本發明提供抗-因子D抗體,其中以其單價形式存在之該抗體對因子D之親和力(例如該呈Fab片段之抗體對因子D之親和力)為約1.4 pM(1.4x10-12
M)+/- 0.5。在另一實施例中,本發明提供抗-因子D抗體,其中以其二價形式存在之該抗體對因子D之親和力(例如該呈IgG之抗體對因子D之親和力)為約1.1 pM(1.1x10-12
M)+/- 0.6。在另一實施例中,本發明提供抗-因子D抗體,其中以其單價形式存在之該抗體對因子D之親和力(例如該呈Fab片段之抗體對因子D之親和力)為約0.19 nM(0.19x10-9
M)+/- .01。在另一實施例中,本發明提供抗-因子D抗體,其中以其二價形式存在之該抗體對因子D之親和力(例如該呈IgG之抗體對因子D之親和力)為約0.08 nM(0.08x10-9
M)+/- 0.01。在另一實施例中,本發明提供抗-因子D抗體,其中以其單價形式存在之該抗體對因子D之親和力(例如該呈Fab片段之抗體對因子D之親和力)為約12.3 nM(12.3x10-9
M)+/- 2。在另一實施例中,本發明提供抗-因子D抗體,其中以其二價形式存在之該抗體對因子D之親和力(例如該呈IgG之抗體對因子D之親和力)為約9.0 nM(9.0x10-9
M)+/- 1。
在另一實施例中,抗-因子D抗體可能以其單價形式具有約3.7 nM(3.7x10-9
M)+/- 2之對因子D之親和力(例如該呈Fab片段之抗體對因子D之親和力)。在另一實施例中,抗-因子D抗體可能以其單價形式具有約3.3 nM(3.3x10-9
M)+/- 2之對因子D之親和力(例如該呈Fab片段之抗體對因子D之親和力)。在另一實施例中,抗-因子D抗體可能以其單價形式具有約5.1 nM(5.1x10-9
M)+/- 2之對因子D之親和力(例如該呈Fab片段之抗體對因子D之親和力)。在另一實施例中,抗-因子D抗體可能以其單價形式具有約2.7 nM(2.7x10-9
M)+/- 2之對因子D之親和力(例如該呈Fab片段之抗體對因子D之親和力)。在另一實施例中,抗-因子D抗體可能以其單價形式具有約1.4 nM(1.4x10-9
M)+/- 2之對因子D之親和力(例如該呈Fab片段之抗體對因子D之親和力)。在另一實施例中,抗-因子D抗體可能以其單價形式具有約1.4 pM(1.4x10-12
M)+/- 2對因子D之親和力(例如該呈Fab片段之抗體對因子D之親和力)。在另一實施例中,抗-因子D抗體可能以其二價形式具有約1.1 pM(1.1x10-12
M)+/- 2之對因子D之親和力(例如該呈IgG之抗體對因子D之親和力)。在另一實施例中,抗-因子D抗體可能以其單價形式具有約0.19 nM(0.19x10-9
M)+/- 2之對因子D之親和力(例如該呈Fab片段之抗體對因子D之親和力)。在另一實施例中,抗-因子D抗體可能以其二價形式具有約0.08 nM(0.08x10-9
M)+/- 2之對因子D之親和力(例如該呈IgG之抗體對因子D之親和力)。在另一實施例中,抗-因子D抗體可能以其單價形式具有約12.3 nM(12.3x10-9
M)+/- 2之對因子D之親和力(例如該呈Fab片段之抗體對因子D之親和力)。在另一實施例中,抗-因子D抗體可能以其二價形式具有約9.0 nM(9.0x10-9
M)+/- 2之對因子D之親和力(例如該呈IgG之抗體對因子D之親和力)。
業內已明確,配體與其受體之鍵結親和力可藉由各種分析方法中任一種加以確定且可以各種定量數值加以表現。因此,在一實施例中,鍵結親和力係以Kd值表現且反映固有鍵結親和力(例如具有最小化抗體親抗原性效應)。通常且較佳地,在無細胞或含細胞環境中於活體外量測鍵結親和力。正如本文更詳細之闡述,可將鍵結親和力之倍數差異以人類化抗體(例如為Fab形式)之單價鍵結親和力數值與參照/比較抗體(例如為Fab形式)(例如具有供體高可變區序列之鼠類抗體)之單價鍵結親和力數值之比來定量,其中鍵結親和力數值係在類似分析條件下測定。因此,在一實施例中,鍵結親和力之倍數差異係以以Fab形式存在之人類化抗體與該參照/比較Fab抗體之Kd值之比加以測定。舉例而言,在一實施例中,若本發明抗體(A)之親和力較參照抗體(M)之親和力"低3倍",且若A之Kd值為3x,M之Kd值將為1x,則A之Kd值與M之Kd值之比將為3:1。反之,在一實施例中,若本發明抗體(C)之親和力較參照抗體(R)之親和力"高3倍",則若C之Kd值為1x,R之Kd值將為3x,且C之Kd值與R之Kd值之比將為1:3。可使用業內習知各種分析方法中任一種(包括本文所述之彼等)來達成鍵結親和力之量測,包括(例如)Biacore、放射免疫測定法(RIA)及ELISA。
此外,本發明抗體之Kd值可端視所使用具體分析條件而變化。舉例而言,在一實施例中,可以一分析方法達成鍵結親和力之量測,其中固定Fab或抗體而量測配體(即因子D)之鍵結,或者固定Fab或抗體之配體(即因子D)而量測Fab或抗體之鍵結。在一實施例中,可以一分析方法達成鍵結親和力之量測,其中再生條件可包括(1)pH 1.5下之10 mM甘油或4 M MgCl2
,及(2)pH介於pH 1.0及pH 7.5之間,包括pH 1.5、pH 5.0、pH 6.0及pH 7.2。在一實施例中,可以一分析方法達成鍵結親和力之量測,其中鍵結條件可包括(1)PBS或HEPES-緩衝鹽溶液及(2)Tween-20,及0.1% Tween-20。在一實施例中,可以一分析方法達成鍵結親和力之量測,其中配體(即因子D)來源可來自市售來源。在一實施例中,可以一分析方法達成鍵結親和力之量測,其中(1)固定Fab或抗體而量測配體(即因子D)之鍵結,(2)再生條件包括pH 7.2下之4 M MgCl2
及(3)鍵結條件包括pH 7.2下含有0.1% Tween-20之HEPES-緩衝鹽溶液。在一實施例中,可以一分析方法達成鍵結親和力之量測,其中(1)固定配體(即因子D)而量測Fab或抗體之鍵結,(2)再生條件包括pH 1.5下之10 mM甘油,及(3)鍵結條件包括PBS緩衝液。
術語"細胞"、"細胞系"及"細胞培養物"包括子代。亦應瞭解,所有子代之DNA含量可能因特意或無意突變而不精確相同。可包括最初轉化細胞篩選中具有相同功能或生物學性質之變異子代。本發明所用"宿主細胞"通常為原核宿主或真核宿主。
術語"載體"意指一DNA構築體,其包含以可操作方式連接至能影響適宜宿主中DNA表現之適宜控制序列之DNA序列。該等控制序列包括影響轉錄之啟動子、控制該轉錄之可選操縱子序列、編碼適宜mRNA核糖體結合位點之序列,及控制轉錄及轉譯終止之序列。載體可為質粒、噬菌體顆粒、或僅為潛在基因組插入體。一旦經轉化至適宜宿主中,該載體可獨立於宿主基因組複製且發揮功能,或在某些情況下可自身整合至基因組中。在本說明書中,由於質粒為載體之最常用形式,有時"質粒"與"載體"可互換使用。然而,本發明意欲涵蓋可起相同作用之其他載體形式,且該等載體形式為或將為業內所習知。
本文所用詞"標記"係指可與分子或蛋白質(例如抗體)直接或間接偶聯之可檢測化合物或組合物。該標記自身為可檢測(例如,放射性同位素標記或螢光標記)或在酵素標記情況下能催化可檢測底物化合物或組合物之化學變化。
本文所用"固相"係指本發明抗體可黏附其上之非水性基質。本文所涵蓋之固相實例包括部分或完全由玻璃(例如受控孔隙玻璃)、多糖(例如瓊脂糖)、聚丙烯醯胺、聚苯乙烯、聚乙烯醇及矽酮形成之彼等。在特定實施例中,端視環境,固相可包括分析盤孔;在其他實施例中其可為純化管柱(例如親和層析管柱)。
在本文中用於選殖或表現載體中DNA之適宜宿主細胞係原核細胞、酵母細胞或高等真核細胞。適用於此目的之原核生物包括格蘭氏(Gram)陰性菌及格蘭氏陽性菌二者,例如腸細菌,例如大腸桿菌(E.coli)、腸桿菌(Enterobacter)、歐文氏菌(Erwinia)、克雷白氏桿菌(Klebsiella)、變形菌(Proteus)、沙門氏菌(Salmonella)、黏質沙雷氏菌(Serratia)及志賀氏桿菌(Shigella),以及桿菌(Bacilli)、假單胞菌(Pseudomonas)及鏈黴菌(Streptomyces)。一較佳大腸桿菌株宿主為大腸桿菌294(ATCC 31,446),但其他菌株例如大腸桿菌B、大腸桿菌X1776(ATCC 31,537)及大腸桿菌W3110(ATCC 27,325)亦適合。該等實例為例示性而非限制性。
除原核生物外,諸如絲狀真菌或酵母等真核微生物亦為抗體編碼載體之適宜選殖或表現宿主。在低等真核微生物宿主中最常使用釀酒酵母(Saccharomyces cerevisiae)。然而,多種其他屬、種及菌株通常亦可得到且可用於本發明中,例如,稷酒裂殖酵母菌(Schizosaccharomyces pombe);克魯維酵母屬(Kluyveromyces);念珠菌屬(Candida);木黴屬(Trichoderma);粗糙鏈孢黴(Neurospora crassa);及絲狀真菌,例如脈孢菌(Neurospora)、青黴菌(Penicillium)、彎頸黴(Tolypocladium)以及麯黴(aspergillus)宿主,例如構巢麴菌(A.nidulans)及黑曲黴菌(A.niger)。
適用於表現糖基化抗體之宿主細胞衍生自多細胞生物。原則上,可使用來自脊椎動物或無脊椎動物培養物之任何高等真核細胞培養物。無脊椎動物細胞之實例包括植物細胞及昆蟲細胞,Luckow等人,Bio/Technology 6,47-55(1988);Miller等人,Genetic Engineering,Setlow等人,eds.Vol.8,第277-279頁(Plenam publishing 1986);Mseda等人,Nature 315,592-594(1985)。已鑑別出大量杆狀病毒株及變體及來自宿主(例如草地黏蟲(Spodoptera frugiperda)(毛蟲)、伊蚊(Aedes)(蚊子)、黑腹果蠅(Drosophila melanogaster)(果蠅)及家蠶(Bombyx mori))之對應許可性昆蟲宿主細胞。多種轉染用病毒株可自公開途徑獲得,例如,苜蓿銀紋夜蛾(Autographa californica)NPV之L-1變體及家蠶NPV之Bm-5株,且根據本發明該等病毒可用作本文中之病毒,尤其用於草地黏蟲細胞之轉染。此外,棉花、玉米、馬鈴薯、大豆、矮牽牛、西紅柿及煙草之植物細胞培養物亦可用作宿主。
在培養(組織培養)中培養脊椎動物細胞及增殖脊椎動物細胞已成為常規程序。參見Tissue Culture,Academic Press,Kruse及Patterson,eds.(1973)。有用哺乳動物宿主細胞系之實例為猴腎臟細胞;人類胚胎腎臟細胞系;幼倉鼠腎臟細胞;中國倉鼠卵巢細胞/-DHFR(CHO,Urlaub等人,Proc.Natl.Acad.Sci.USA 77:4216(1980));小鼠sertoli細胞;人類子宮頸癌細胞(HELA);犬腎臟細胞;人類肺細胞;人類肝臟細胞;小鼠乳腺癌細胞;及NS0細胞。
將宿主細胞用上述用於產生抗體之載體轉化,且在習用營養培養基中培養,該營養培養基經修飾為適用於誘導啟動子、選擇轉化體、或擴增編碼期望序列之基因。
用於產生本發明抗體變體之宿主細胞可在各種培養基中加以培養。市售培養基例如Ham's F10(Sigma)、最低必需培養基(MEM,Sigma)、RPMI-1640(Sigma)、及達爾伯克氏改良伊格爾氏培養基(Dulbecco's Modified Eagle's Medium)(DMEM,Sigma)皆適用於培養宿主細胞。另外,在Ham等人,Meth.Enzymol.58:44(1979)、Barnes等人,Anal.Biochem.102:255(1980)、美國專利第4,767,704號;第4,657,866號;第4,560,655號;第5,122,469號;第5,712,163號;或第6,048,728號中任一所述培養基皆可用作宿主細胞培養基。若需要,任一該等培養基中皆可補充有激素及/或其他生長因子(例如胰島素、鐵傳遞蛋白、或表皮生長因子)、鹽(例如X-氯化物,其中X為鈉、鈣、鎂;及磷酸鹽)、緩衝液(例如HEPES)、核苷酸(例如腺苷及胸苷)、抗生素(例如GENTAMYCIN.TM.藥物)、痕量元素(定義為通常以微莫耳級終濃度存在之無機化合物)、以及葡萄糖或等效能量來源。亦可以所屬領域技術人員熟知之適當濃度引入任一其他所需補充物。培養條件,例如溫度、pH及諸如此類,係先前所選表現用宿主細胞所用條件,且對所屬領域技術人員係顯而易見。
使用重組技術時,抗體可在細胞內、在細胞周質間隙中產生,或直接分泌至培養基中。若抗體變體係在細胞內產生,作為第一步驟,可藉由(例如)離心或超濾去除微粒碎屑(宿主細胞或經溶解片段)。Carter等人,Bio/Technology 10:163-167(1992)闡述用於分離分泌至大腸桿菌細胞周質間隙之抗體之程序。簡言之,在乙酸鈉(pH 3.5)、EDTA及苯基甲基磺醯基氟化物(PMSF)存在下經約30分鐘將胞漿解凍。可藉由離心去除細胞碎屑。倘若抗體變體分泌至培養基中,通常首先使用市售蛋白質濃縮過濾器(例如Amicon或Millipore Pellicon超濾設備)濃縮取自該等表現系統之上清液。在任一前述步驟中皆可引入蛋白酶抑制劑(例如PMSF)以抑制蛋白質水解,且可引入抗生素以防止外來污染物生長。
自細胞製備之抗體組合物可使用(例如)羥基磷灰石層析法、凝膠電泳法、透析法及親和層析法加以純化,其中親和層析法為較佳純化技術。蛋白質A作為親和配體之適宜性取決於抗體變體中所含任一免疫球蛋白Fc結構域之種類及同種型。蛋白質A可用於純化基於人類IgG1、IgG2或IgG4重鏈之抗體(Lindmark等人,J.Immunol Meth.62:1-13(1983))。蛋白質G經推薦用於所有小鼠同種型及用於人類IgG3(Guss等人,EMBO J.5:1567-1575(1986))。親和配體所附著基質最經常為瓊脂糖,但亦可利用其他基質。物理性質穩定之基質(例如受控孔隙玻璃或聚(苯乙烯二乙烯基)苯)可達成較瓊脂糖更快之流速及更短之處理時間。在抗體變體包含CH3結構域時,可使用Bakerbond ABXTM樹脂(J.T.Baker,Phillipsburg,N.J.)實施純化。視待回收抗體變體而定,亦可使用其他蛋白質純化技術,例如,離子交換管柱之分級分離、乙醇沉澱法、反相HPLC、矽膠層析法、肝素層析法、使用陰離子或陽離子交換樹脂(例如聚天冬胺酸管柱)之SEPHAROSETM
層析法、層析聚焦法、SDS-PAGE及硫酸銨沉澱法。
在任一初步純化步驟後,可使用pH介於約2.5-4.5之間之洗脫緩衝液對包含目標抗體變體與污染物之混合物實施低pH疏水作用層析,較佳係在低鹽濃度(例如,自約0-0.25 M鹽)下實施。
多肽或抗體之治療調配物可藉由將具有期望純度之多肽與業內常用之可選"醫藥上可接受"載劑、賦形劑或穩定劑(其皆稱為"賦形劑")混合而製備為凍乾調配物或水溶液形式儲存。舉例而言,緩衝劑、穩定劑、防腐劑、等滲劑、非離子型去污劑、抗氧化劑及其他各種添加劑。(參見Remington's Pharmaceutical Sciences,第16版,A.Osol,Ed.(1980))。該等添加劑在所採用劑量與濃度下必須對接受者無毒。
緩衝劑有助於將pH保持於接近生理條件之範圍內。其較佳係以約2 mM至約50 mM之濃度存在。適用於本發明之緩衝劑包括有機酸及無機酸兩者及其鹽,例如檸檬酸鹽緩衝液(例如,檸檬酸單鈉-檸檬酸二鈉混合物、檸檬酸-檸檬酸三鈉混合物、檸檬酸-檸檬酸單鈉混合物等),琥珀酸鹽緩衝液(例如,琥珀酸-琥珀酸單鈉混合物、琥珀酸-氫氧化鈉混合物、琥珀酸-琥珀酸二鈉混合物等),酒石酸鹽緩衝液(例如,酒石酸-酒石酸鈉混合物、酒石酸-酒石酸鉀混合物、酒石酸-氫氧化鈉混合物等),富馬酸鹽緩衝液(例如,富馬酸-富馬酸單鈉混合物等),富馬酸鹽緩衝液(例如,富馬酸-富馬酸單鈉混合物、富馬酸-富馬酸二鈉混合物、富馬酸單鈉-富馬酸二鈉混合物等),葡萄糖酸鹽緩衝液(例如,葡萄糖酸-葡萄糖酸鈉混合物、葡萄糖酸-氫氧化鈉混合物、葡萄糖酸-葡萄糖酸鉀混合物等),草酸鹽緩衝液(例如,草酸-草酸鈉混合物、草酸-氫氧化鈉混合物、草酸-草酸鉀混合物等),乳酸鹽緩衝液(例如,乳酸-乳酸鈉混合物、乳酸-氫氧化鈉混合物、乳酸-乳酸鉀混合物等)及乙酸鹽緩衝液(例如,乙酸-乙酸鈉混合物、乙酸-氫氧化鈉混合物等)。另外,可能提及磷酸鹽緩衝液、組胺酸緩衝液及三甲胺鹽,例如Tris。
可添加防腐劑以延遲微生物生長,且其可以0.2%-1%(w/v)之量添加。適用於本發明之防腐劑包括苯酚、苄醇、間-苯甲酚、對羥基苯甲酸甲酯、對羥基苯甲酸丙酯、十八烷基二甲基苄基氯化銨、苯紮鹵銨(例如,苯紮氯銨、苯紮溴銨、苯紮碘銨)、氯化六甲雙銨、對羥基苯甲酸烷基酯(例如對羥基苯甲酸甲酯或對羥基苯甲酸丙酯)、兒茶酚、間苯二酚、環己醇及3-戊醇。
亦可添加有時稱為"穩定劑"之等滲劑,以確保本發明液體組合物之等滲性,且其包括多羥基糖醇,較佳為三羥基或更多羥基糖醇,例如甘油、赤蘚醇、阿糖醇、木糖醇、山梨糖醇及甘露醇。
穩定劑係指一大類賦形劑,其功能可自填充劑至可溶解治療性試劑或有助於防止變性或防止黏附至容器壁之添加劑。典型穩定劑可為多羥基糖醇(如上文所列舉);胺基酸,例如精胺酸、賴胺酸、甘胺酸、穀胺醯胺、天冬醯胺、組胺酸、丙胺酸、鳥胺酸、L-亮胺酸、2-苯丙胺酸、穀胺酸、蘇胺酸等;有機糖或糖醇,例如乳糖、海藻糖、水蘇糖、甘露醇、山梨糖醇、木糖醇、核糖醇、肌醇、衛矛醇、甘油及類似物,包括環多醇,例如環己六醇;聚乙二醇;胺基酸聚合物;含硫還原劑,例如脲、谷胱甘肽、硫辛酸、巰基乙酸鈉、硫代甘油、α
-單硫代甘油及硫代硫酸鈉;低分子量多肽(即<10殘基);蛋白質,例如人血清白蛋白、牛血清白蛋白、明膠或免疫球蛋白;親水性聚合物,例如聚乙烯吡咯烷酮單糖,例如木糖、甘露糖、果糖、葡萄糖;二糖,例如乳糖、麥芽糖、蔗糖;以及三糖,例如棉子糖;多糖,例如葡聚糖。穩定劑可以0.1-10,000重量份數/重量份數活性蛋白質之量存在。
可添加非離子型表面活性劑或去污劑(亦稱作"潤濕劑")以促進溶解治療性試劑以及保護治療性蛋白質不因攪動發生聚集作用,其亦容許調配物暴露於受應力作用之剪切面下而不引起蛋白質變性。適宜非離子型表面活性劑包括聚山梨醇酯(20、80等)、泊洛沙姆(polyoxamers)(184、188等)、Pluronic.RTM.聚醇、聚氧乙烯脫水山梨糖醇單醚(Tween.RTM.-20、Tween.RTM.-80等)。非離子型表面活性劑可以自約0.05毫克/毫升至約1.0毫克/毫升且較佳約0.07毫克/毫升至約0.2毫克/毫升之量存在。
其他各種賦形劑包括填充劑(例如澱粉)、鼇合劑(例如EDTA)、抗氧化劑(例如抗壞血酸、甲硫胺酸、維生素E)及共溶劑。若需要本文調配物亦可含有一種以上用於所治療特定適應症之活性化合物,較佳包含具有彼此無不利影響之互補活性之彼等。舉例而言,人們可期望另外提供免疫抑制劑。該等分子適合以對欲達成目的有效之量以組合形式存在。亦可將活性成份分別裝入藉由(例如)凝聚技術或藉由界面聚合製備之微膠囊(例如羥甲基纖維素或明膠微膠囊及聚(甲基丙烯酸甲酯)微膠囊)中、膠體藥物輸送系統(例如脂質體、白蛋白微球體、微滴乳液、奈米顆粒及奈米膠囊)中或粗滴乳液中。該等技術揭示於Remington's Pharmaceutical Sciences(第16版,A.Osol,Ed.(1980))中。
所用活體內投與用調配物必須無菌。此可(例如)藉由經由無菌濾膜過濾容易地達成。可製備緩釋製劑。緩釋製劑之適宜實例包括含抗體變體固態疏水聚合物之半滲透性基質,該等基質呈成形物件形式,例如薄膜或微膠囊。緩釋基質之實例包括聚酯、水凝膠(例如聚(甲基丙烯酸-2-羥乙基酯)或聚(乙烯基醇))、聚交酯(美國專利第3,773,919號)、L-穀胺酸與L-穀胺酸乙酯之共聚物、不可降解乙烯-乙酸乙烯酯、可降解乳酸-乙醇酸共聚物,例如LUPRON DEPOTTM
(由乳酸-乙醇酸共聚物及乙酸亮丙瑞林(leuprolide acetate)組成之可注射微球體)以及聚-D-(-)-3-羥基丁酸。儘管諸如乙烯-乙酸乙烯酯及乳酸-乙醇酸等聚合物可使分子持續釋放超過100天,但某些水凝膠釋放蛋白質時間較短。當已裝入膠囊抗體長時間留於體內時,暴露於37℃潮濕環境中可使其變性或聚集而導致生物活性缺失且可能改變免疫原性。端視所涉及機制可設計合理策略以保持穩定性。舉例而言,若發現聚集機制係經由硫代-二硫化物互換形成分子間S--S鍵,則可藉由修飾巰基殘基、自酸性溶液凍乾、控制水分含量、使用適宜添加劑及形成特定聚合物基質組合物來達成穩定性。
在特定病症或病況治療中治療性多肽、抗體或其片段之有效量可取決於病症或病況之性質且可藉由標準臨床技術來確定。可能時,人們可期望在人體測試前測定劑量反應曲線及本發明醫藥組合物,首先在活體外測定,然後在有用動物模型系統中測定。
在一較佳實施例中,藉由皮下注射投與治療性多肽、抗體或其片段之水溶液。每一劑量可係自約0.5微克至約50微克/公斤體重,或更佳為自約3微克至約30微克/公斤體重。
端視各種臨床因素(包括疾病類型、疾病嚴重程度及患者對治療性試劑之敏感性),皮下投與之給藥方案可自每月一次至每日一次變化。
本發明人類化抗體可用於診斷分析中,例如用於檢測相關靶在特定細胞、組織或血清中之表現。對於診斷性應用,抗體變體通常用可檢測部分加以標記。可利用多種標籤。定量螢光變化之技術係如上文所述。化學發光底物可藉由化學反應以電子方式加以激活,隨後其發射可量測(例如使用化學發光計)光線或向螢光受體提供能量。酵素標記之實例包括螢光素酶(例如,螢火蟲螢光素酶及細菌螢光素酶;美國專利第4,737,456號)、螢光素、2,3-二氫化二氮雜萘二酮、蘋果酸脫氫酶、脲酶、過氧化物酶,例如辣根過氧化物酶(HRPO)、鹼性磷酸酶、β-半乳糖苷酶、葡萄糖澱粉酶、溶菌酶、糖氧化酶(例如,葡萄糖氧化酶、半乳糖氧化酶及葡萄糖-6-磷酸脫氫酶)、雜環氧化酶(例如尿酸酶及黃嘌呤氧化酶)、乳過氧化物酶、微過氧化物酶及諸如此類。O'Sullivan等人,Methods for the Preparation of Enzyme-Antibody Conjugates for Use in Enzyme Immunoassay,in Methods in Enzym(Ed.J.Langone & H.Van Vunakis),Academic press,New York,73:147-166(1981)中闡述將酵素偶聯至抗體之技術。
有時,標記間接與抗體變體偶聯。所屬領域技術人員可瞭解達成此目的之多種技術。舉例而言,抗體變體可與生物素偶聯,且上文所述三大類標記中任一種皆可與抗生物素蛋白偶聯,或反之亦然。生物素可選擇性結合至抗生物素蛋白,且因此標記可以此間接方式與抗體變體偶聯。或者,為使標記與抗體變體間接偶聯,可使抗體變體與小型半抗原(例如二葡萄糖酸鹽)偶聯且使上述不同類型標記之一與抗-半抗原抗體變體(例如,抗-二葡萄糖酸鹽抗體)偶聯。由此,可達成標記與抗體變體之間接偶聯。
在本發明另一實施例中,抗體變體不需標記,且可使用結合至抗體變體之經標記抗體檢測其存在。
本發明抗體可用於任一已知分析方法中,例如競爭性結合分析法、直接及間接三明治分析法及免疫沉澱分析法。Zola,Monoclonal Antibodies:A Manual of Techniques,第147-158頁(CRC Press公司1987)。
競爭性結合分析依賴經標記標準品與測試樣品競爭與有限量抗體變體結合之能力。測試樣品中靶數量與結合至抗體之標準品數量成反比。為有利於測定已結合標準品數量,通常在競爭之前或之後使抗體不溶解。因此,可方便地將結合至抗體之標準品及測試樣品與保持未結合狀態之標準品及測試樣品分離。
三明治分析涉及使用兩種抗體,每一種能結合至不同免疫原部分或抗原決定部位或待檢測蛋白質。在三明治分析中,由固定在固態支持體上之第一抗體結合待分析測試樣品,且隨後使第二抗體結合至該測試樣品上,由此形成不可溶之三部分複合物。參見(例如)美國專利第4,376,110號。第二抗體自身可用可檢測部分標記(直接三明治分析)或可使用經可檢測部分標記之抗-免疫球蛋白抗體加以量測(間接三明治分析)。舉例而言,一類三明治分析為ELISA分析,在該情況下可檢測部分為酵素。
例如對於免疫組織化學而言,腫瘤樣品可為新鮮或冷凍的,或可經包埋於石蠟中且用一防腐劑(例如福爾馬林)加以固定。
抗體亦可用於活體內診斷分析。一般而言,將抗體變體用放射性核苷酸(例如,.sup.111 In、.sup.99 Tc,、sup.14 C、.sup.131 I、.sup.3 H、.sup.32 P或.sup.35 S)標記,以使得可用免疫閃爍照相法定位腫瘤。舉例而言,本發明高親和性抗-IgE抗體可用於檢測存在於(例如)哮喘患者肺內之IgE數量。
本發明抗體可以試劑盒形式提供,即預定數量試劑與實施診斷分析之說明書之成套組合。倘若以酵素標記抗體變體,試劑盒可包含酵素所需底物及輔因子(例如提供可檢測發色團或螢光團之底物前體)。此外,可包含其他添加劑,例如穩定劑、緩衝液(例如封阻緩衝液或溶解緩衝液)及諸如此類。各種試劑之相對數量可大幅變化以提供實質上使分析敏感度最佳化之該等試劑溶液濃度。具體而言,試劑可以包含賦形劑之乾燥粉末形式(通常經凍乾)提供,該等賦形劑溶解後可提供具有適宜濃度之試劑溶液。
本發明涵蓋本發明抗體可用於治療哺乳動物。舉例而言,在一實施例中,將抗體投與至非人類哺乳動物以獲得臨床前數據。待治療例示性非人類哺乳動物包括非人類靈長類動物、犬、貓、嚙齒目動物及其他可實施臨床前研究之哺乳動物。可用該等哺乳動物建立將用抗體治療之疾病之動物模型,或可將其用於研究目標抗體之毒性。在每一該等實施例中,皆可對哺乳動物實施劑量遞增研究。
可藉由任一適宜方式投與抗體或多肽,包括非經腸、皮下、腹膜腔內、肺內及鼻內,且若期望,對於局部免疫抑制治療,可採用病灶內方式投與。非經腸輸注包括肌內、靜脈內、動脈內、腹膜腔內或皮下投與。此外,抗體變體適合藉由脈衝輸注方式投與,尤其以抗體變體之遞減劑量投與。較佳藉由注射給與劑量,最佳藉由靜脈內或皮下注射給與,此部分地取決於投與時間長短。
對於預防或治療疾病,抗體或多肽之適宜劑量可取決於:待治療疾病類型、疾病嚴重程度及病程、投與抗體變體之目的係預防抑或治療、先前治療、患者臨床史及對抗體之應答,以及主治醫師之決定。
端視疾病類型及嚴重程度,不論係(例如)藉由一次或多次分開投與抑或藉由連續輸注投與,向患者投與之抗體初始候選劑量為約0.1毫克/公斤至150毫克/公斤(例如0.1-20毫克/公斤)。端視上述因素,通常日劑量可為約1毫克/公斤至100毫克/公斤或更高。對於在數天或更長時間內重複投與,端視病況,治療應持續至疾病症狀發生所期望抑制為止。然而,可使用其他劑量方案。該治療進度可容易地藉由習用技術及分析方法加以監測。WO 94/04188揭示一例示性劑量方案。
抗體組合物可以與良好醫療實踐一致之方式加以調配、確定劑量及投與。在此情況下所考慮因素包括:所治療具體病症、所治療具體哺乳動物、個體患者之臨床病況、病症起因、試劑之輸送位點、投與方法、投與時間安排及醫務人員熟知之其他因素。待投與抗體之"治療有效量"可藉由該等因素來決定,且為預防、改善或治療疾病或病症所需之最小量。抗體無需但視情況用一或多種當前用於預防或治療所討論病症之試劑調配。該等其他試劑之有效量取決於抗體在調配物中含量、病症或治療類型及上文所討論之其他因素。通常以與上文所用相同之劑量及投與途徑使用該等試劑或以約1至99%之上文所用劑量使用該等試劑。
將因子D識別為其靶之本發明抗體可用於治療補體介導病症。該等病症係與補體之過度或不受控活化相關。其包括:心肺分流手術期間之補體活化;在急性心肌梗塞、動脈瘤、中風、出血性休克、擠壓傷、多器官功能衰竭、低血量性休克及腸內缺血發生後,由於缺血-再灌注導致之補體活化。該等病症亦可包括具有炎症性病況之疾病或病況,例如嚴重燒傷、內毒素血症、敗血性休克、成人呼吸窘迫症候群、血液透析;過敏性休克、嚴重哮喘、血管性水腫、Crohn氏病、鐮狀細胞貧血症、鏈球菌感染後腎炎及胰腺炎。該等病症可能為不良藥物反應、藥物過敏、IL-2誘導血管滲漏症候群或放射攝影對比介導過敏症之結果。其亦包括自身免疫性疾病,例如全身性紅斑狼瘡、重症肌無力、類風濕性關節炎、阿茲海默氏症(Alzheimer's disease)及多發性硬化症。補體活化亦與移植排異相關。最近已顯示補體活化與眼部疾病(例如年齡相關性黃斑變性、糖尿病性視網膜病)間具有強相關性。
提供下列實例以舉例說明而非加以限制。
將鼠類mAb 166-32之重鏈可變區(VH
)及輕鏈可變區(VL
)之序列與在公共文庫中可獲得之人類抗體種系序列相比較。當選定一如上文步驟1中所述模板時使用多個標準,包括全長、骨架中相似CDR位置、總同源性、CDR尺寸等。同時考慮所有該等標準提供最佳人類模板之選擇結果,如在圖3及4中所示之166-32 MAb重鏈及輕鏈序列與各自人類模板序列間之序列比對中所示。
在此情況下,使用一個以上之人類骨架模板來設計此抗體。針對VH
鏈所選人類模板為VI-4.1b+(7-04.1基因座)(存取# X62110)(VH7族)與JH4d之組合(參見圖3)。針對VL
鏈所選人類模板為DPK4(VK I族)與JK2之組合(參見圖4)。
一旦選定模板,藉由DNA合成及重疊PCR來構建Fab文庫。該文庫係由用所選各自人類模板合成之MAb 166-32 CDR組成。使編碼部分VH
及VL
序列之重疊核苷酸經合成介於約63至約76個核苷酸之間,其中18至21個核苷酸重疊。構建表現抵抗因子D抗原之人類化Fab文庫之載體,且將其轉化入E.coli DH10B中然後塗佈於XL-1B菌苔上。
根據尺寸(獨立純係數量)及多樣性(突變分佈)來評估文庫品質。經測序之20種純系中約14種具有輕鏈及重鏈二者之雙插入。骨架中擺動突變係均勻分佈。
在標準PCR條件下使用包含骨架區FR1特定序列及退火至前導序列(基因III)末端之懸垂序列之生物素化正向引物及來自保守恆定區(Ck
或CH1)之反向引物來實施VL
及VH
基因之PCR擴增。藉由瓊脂糖凝膠電泳或藉由市售PCR純化試劑盒純化PCR產物以去除未經納入之生物素化引物及非特異性PCR產物。
捕獲過濾轉印法係用於初次篩選。實際篩選尺寸較理論文庫尺寸大3倍以上。藉由單點ELISA分析法進一步篩選候選文庫。藉由使用基於Fab濃縮之因子D之直接抗原滴定來確定最佳結合者。
捕獲轉印篩選
使用捕獲過濾轉印分析法根據Fab與因子D之結合以達成初次篩選。塗佈高滴定度噬菌體並在37℃下培養(約6-8小時)直至使用。將山羊抗-人類κ
在10毫升PBST中稀釋至10微克/毫升;根據標準噬菌斑轉印程序製備用於轉印噬菌斑之硝酸纖維素濾膜,然後在振盪器上將其浸沒於10毫升封阻緩衝液中2小時。用PBST將濾膜沖洗3次。將該等濾膜施用於噬菌斑菌苔且在室溫下培養約15-24小時。然後自試驗盤移出該等濾膜且用TBST沖洗3次。
將因子D(50微克/毫升)在PBST中稀釋至0.1微克/毫升且向每片濾膜上添加4毫升。在振盪器上將該等濾膜在溶液中於室溫下培養2小時,之後沖洗3次,每次5分鐘。以4毫升/濾膜之體積添加經稀釋166-222-HRP(用PBST稀釋至1:10,000)並在振盪器上將該等濾膜培養1小時。將該等濾膜沖洗4次。乾燥該等濾膜後將其浸沒於TMB底物中,之後將其浸沒於水中以終止反應。鑒定陽性純系。
使用單點ELISA分析實施第二次篩選。使用山羊抗-人類Fab(1:12,000,50微升/孔)塗佈Immulon II盤且在室溫下過夜。第二天用盤洗滌器將該盤洗滌4次。以100微升/孔之體積添加封阻緩衝液且在室溫下將該盤培養1小時。然後將該盤洗滌4次。
以50微升/孔之體積添加待篩選之各Fab(來自15毫升細胞周質製劑或上清液)且在室溫下培養1小時。將該盤洗滌4次之後以50微升/孔添加0.01微克/毫升之生物素化因子D。在室溫下將該盤培養1小時然後洗滌4次。添加StreptAvidin-HRP(1:10,000,溶於PBST中)且在室溫下培養1小時。將該盤洗滌5次然後藉由以50微升/孔添加TMB底物使其顯色。在顯色良好時(10-45分鐘)添加50微升體積之終止緩衝液並在450奈米處讀取該盤。
對與人類因子D具有良好鍵結親和力之16種人類化純系實施測序(參見表1)。其中,輕鏈中之2位(100%人類)及49位(100%小鼠)及重鏈中之93位(100%小鼠)係高度保守,此表明該等位點在維持抗體結合能力中起重要作用。
藉由BIAcore分析及溶血抑制分析來評估純系#56。BIAcore分析顯示對人類因子D純系#56具有與嵌合166-32Fab類似之親和力(參見表4)。溶血抑制分析顯示純系#56稍微較166-32 Fab有效(參見圖6)。純系# 56輕鏈骨架中包含兩種鼠類殘基而重鏈骨架中包含4種鼠類殘基。(參見表1)。基於該等結果實施進一步優化。
藉由BIAcore分析表徵純系#111及#114(參見表4)。同樣藉由溶血抑制分析表徵純系#104、#111、#114及#130(參見圖6)。如溶血抑制分析所示(圖7),該等純系具有較嵌合166-32更強之親和力,且在抑制旁路途徑中較嵌合Fab更有效。純系#111輕鏈中具有與純系# 56相同之二鼠類殘基(4及49位)。其在重鏈97位亦包含如在純系#56中所發現之保守鼠類殘基。在純系#111之輕鏈及重鏈CDR3二者中皆具有一有益突變。自所篩選二獨立文庫(人類化文庫及人類化/CDR3最優化文庫)中我們發現,最佳純系具有相似共有殘基。
為進一步最佳化純系#111之親和力,藉由將單突變同時引入CDR-H1及CDR-L2中來構建抗體文庫。簡言之,使用定點誘變技術藉由使編碼單突變之寡居核苷酸退火至純系#111模板來構建該等文庫。對與人類因子D具有極高親和力之總計24種純系實施測序。24種純系中,鑒定出若干多餘有益突變。選擇純系#250、#315、#345及#416用於BIAcore分析(參見表4)。BIAcore數據顯示對人類因子D該等純系具有較起始純系#111更高之親和力。同樣在溶血抑制分析(參見圖6)及旁路途徑抑制(圖7)中測試純系#250、#315、#348及#416。
使用溶血抑制分析及BIAcore分析來測定人類化純系之生物功能(參見下文實例6)。根據下述程序實施溶血分析。用Coulter Counter對以約1:2x104
稀釋度存於20毫升鹽水(0.9% NaCl)中之20微升以1:20稀釋之兔紅血球(RRBC)(0.5毫升+9.5毫升GVB/Mg-EGTA緩衝液)實施計數。然後將細胞濃度調節至約2-5x104
細胞/毫升。各盤接受約500x106
/盤之RRBC或約1毫升RRBC/盤(500x106
/2-5 x104
)。
將細胞稀釋於6毫升GVB/Mg-EGTA緩衝液/盤中,藉由在4℃下以1360 rpm旋轉4分鐘將其混合並洗滌3次。將RRBC沉澱物懸浮於3毫升GVB/Mg-EGTA緩衝液/盤中且將其保存在冰上。
在臨用前將來自-80℃冷凍機之人類血清解凍。在GVB/Mg-EGTA緩衝液(5毫升/盤(最終濃度為10%))中將血清稀釋至20%血清濃度且將其保存在冰上。
將樣品在5-6℃下振盪30秒然後在37℃下振盪40分鐘。使樣品振盪冷卻至5-6℃然後在4℃下以2,000 rpm離心3分鐘。將約80微升上清液轉移至96孔平底盤中且使用標準盤讀數器在590奈米處讀取OD值。如下所述計算百分比抑制率:%抑制率={[(S-SB)-(U-SB)]/(S-SB)}x100%。(U=樣品1、2或3(分別在表3之第1、2或3列)。
固定化
-使用胺偶聯法將人類因子D(Advanced Research Inc,0.1毫克/毫升)直接固定至CM5芯片(BiaCore)上。該程序概述如下:(1)以5微升/分鐘恒流(PBS)。(2)注射35微升EDC/NHS(1:l)。(3)注射35微升存於乙酸緩衝液(pH 4.5)中之人類因子D。(4)藉由注射35微升鯨蠟醇胺來封閉經活化基團。(5)藉由5微升pH 1.5之10 mM甘胺酸清洗表面。配體(人類因子D)之固定化程度為約1,000 RU。使用α-人類因子D(huDi,40微升,31.5微克/毫升)進行測試,得到約900 RU的相對應答。
動力學分析
-將所有抗-人類因子D之Fab稀釋於PBS緩衝液中。在高採集速率下用40微升注射脈衝以一系列濃度製備各樣品:12.5 nM、25 nM、50 nM、75 nM、100 nM、125 nM及150 nM。藉由施用pH 1.5之10 mM甘胺酸之5微升脈衝來完成再生。藉由在准一級動力學條件下使用BIAvaluation 3.0版將Fab結合跡線擬合至1:1結合模型來獲得動力學參數。結果列示於下表2中。藉由總體擬合程序獲取所有數據。
所屬領域之技術人員僅使用常規實驗即可識別或能確定本文所述本發明具體實施例之許多等效方案。下述申請專利範圍意欲涵蓋該等等效方案。
圖1A及1B展示鼠類MAb 166-32可變重鏈(圖1A)及可變輕鏈(圖1B)之胺基酸序列。
圖2A及2B展示鼠類MAb 166-32可變重鏈(圖2A)及可變輕鏈(圖2B)之核酸序列。
圖3展示鼠類MAb 166-32輕鏈之比較。
圖4展示鼠類MAb 166-32重鏈之比較。
圖5展示人類化抗體純系#56、#111、# 250及#416各自可變重鏈及可變輕鏈之胺基酸序列。
圖6展示人類化抗體Fab純系#56、#111、# 250及#416之溶血分析結果。
圖7展示人類化抗體Fab純系#56、#111、# 250及#416對旁路補體活性之抑制。
圖8A-B(可變重鏈(VH)共有骨架)及圖9A-B(可變輕鏈(VL)共有骨架)以下列序列標識符展示可用於實施本發明之例示性受體人類共有骨架序列:(圖8A-B)減去Kabat CDR的人類VH亞型I共有骨架(SEQ ID NO:28)、減去經延伸高可變區的人類VH亞型I共有骨架(SEQ ID NOs:29-31)、減去Kabat CDR的人類VH亞型II共有骨架(SEQ ID NO:32)、減去經延伸高可變區的人類VH亞型II共有骨架(SEQ ID NOs:33-35)、減去Kabat CDR的人類VH亞型III共有骨架(SEQ ID NO:36)、減去經延伸高可變區的人類VH亞型III共有骨架(SEQ ID NOs:37-39)、減去Kabat CDR的人類VH亞型VII共有骨(SEQ ID NO:55)、減去經延伸高可變區的人類VH亞型VII共有骨架(SEQ ID NOs:56-58)、減去Kabat CDR人類VH受體骨架(SEQ ID NO:40)、減去經延伸高可變區的人類VH受體骨架(SEQ ID NOs:41-42)、減去Kabat CDR的人類VH受體2骨架(SEQ ID NO:43)及減去經延伸高可變區的人類VH受體2骨架(SEQ ID NOs:44-46)以及(圖9A-B)人類VL亞型I共有骨架(SEQ ID NO:47)、人類VL亞型共有骨架(SEQ ID NO:48)、人類亞型III共有骨架(SEQID NO:49)及人類亞型IV共有骨架(SEQ ID NO:50)。
<110> 美商建南德克公司<120> 人類化抗-因子D抗體及其用途<130> P4028R1 <140> 096141085 <141> 2007-10-31 <150> US 60/856.505 <151> 2006-11-02 <160> 58 <170> PatentIn vcrsion 3.4 <210> 1 <211> 115 <212> PRT <213> 人工的<220> <223> MAB166-32之可變重鏈結構域<400> 1<210> 2 <211> 107 <212> PRT <213> 人工的<220> <223> MAB166-32之可變輕鏈結構域<400> 2 <210> 3 <211> 345 <212> DNA <213> 人工的<220> <223> MAB166-32之可變重鏈結構域<400> 3<210> 4 <211> 321 <212> DNA <213> 人工的<220> <223> MAB166-32之可變輕鏈結構域<400> 4<210> 5 <211> 107 <212> PRT <213> 人工的<220> <223> 人類化純系#56之可變輕鏈結構域<400> 5<210> 6 <211> 115 <212> PRT <213> 人工的<220> <223> 人類化純系#56之可變重鏈結構域<400> 6<210> 7 <211> 107 <212> PRT <213> 人工的<220> <223> 人類化純系#111之可變輕鏈結構域<400> 7<210> 8 <211> 115 <212> PRT <213> 人工的<220> <223> 人類化純系#111之可變重鏈結構域<400> 8 <210> 9 <211> 107 <212> PRT <213> 人工的<220> <223> 人類化純系#250之可變輕鏈結構域<400> 9<210> 10 <211> 115 <212> PRT <213> 人工的<220> <223> 人類化純系#250之可變重鏈結構域<400> 10 <210> 11 <211> 107 <212> PRT <213> 人工的<220> <223> 人類化純系#416之可變輕鏈結構域<400> 11<210> 12 <211> 115 <212> PRT <213> 人工的<220> <223> 人類化純系#416之可變重鏈結構域<400> 12 <210> 13 <211> 10 <212> PRT <213> 人工的<220> <223> MAB166-32之CDR-H1 <400> 13<210> 14 <211> 19 <212> PRT <213> 人工的<220> <223> MAB166-32之CDR-H2 <400> 14<210> 15 <211> 6 <212> PRT <213> 人工的<220> <223> MAB166-32之CDR-H3 <400> 15<210> 16 <211> 11 <212> PRT <213> 人工的<220> <223> MAB166-32之CDR-L1 <400> 16<210> 17 <211> 7 <212> PRT <213> 人工的<220> <223> MAB166-32之CDR-L2 <400> 17<210> 18 <211> 9 <212> PRT <213> 人工的<220> <223> MAB166-32之CDR-L3 <400> 18<210> 19 <211> 9 <212> PRT <213> 人工的<220> <223> 人類化純系#111之CDR-L3 <400> 19<210> 20 <211> 6 <212> PRT <213> 人工的<220> <223> 人類化純系#111之CDR-H3 <400> 20<210> 21 <211> 7 <212> PRT <213> 人工的<220> <223> 人類化純系#250之CDR-L2 <400> 21<210> 22 <211> 9 <212> PRT <213> 人工的<220> <223> 人類化純系#250之CDR-L3 <400> 22<210> 23 <211> 10 <212> PRT <213> 人工的<220> <223> 人類化純系#250之CDR-H1 <400> 23<210> 24 <211> 7 <212> PRT <213> 人工的<220> <223> 人類化純系#416之CDR-L2 <400> 24<210> 25 <211> 10 <212> PRT <213> 人工的<220> <223> 人類化純系#416之CDR-H1 <400> 25<210> 26 <211> 107 <212> PRT <213> 人工的<220> <223> 人類化純系之可變輕鏈複合物<220> <221> misc_featurc <222> (4)..(4) <223> Xaa可為任一天然存在之胺基酸<220> <221> misc_feature <222> (13)..(13) <223> Xaa可為任一天然存在之胺基酸<220> <221> misc_featurc <222> (43)..(43) <223> Xaa可為任一天然存在之胺基酸<220> <221> misc_feature <222> (49)..(49) <223> Xaa可為任一天然存在之胺基酸<220> <22l> misc_feature <222> (64)..(64) <223> Xaa可為任一天然存在之胺基酸<220> <221> misc_feature <222> (69)..(69) <223> Xaa可為任一天然存在之胺基酸<400> 26<210> 27 <211> 115 <212> PRT <213> 人工的<220> <223> 人類化純系之可變重鏈複合物<220> <221> misc_feature <222> (2)..(2) <223> Xaa可為任一天然存在之胺基酸<220> <221> misc_feature <222> (9)..(9) <223> Xaa可為任一天然存在之胺基酸<220> <221> misc_feature <222> (38)..(38) <223> Xaa可為任一天然存在之胺基酸<220> <221> misc_feature <222> (93)..(93) <223> Xaa可為任一天然存在之胺基酸<220> <221> misc_feature <222> (97)..(97) <223> Xaa可為任一天然存在之胺基酸<400> 27<210> 28 <211> 87 <212> PRT <213> 人工的<220> <223> 序列係合成的<400> 28<210> 29 <211> 81 <212> PRT <213> 人工的<220> <223> 序列係合成的<400> 29<210> 30 <211> 80 <212> PRT <213> 人工的<220> <223> 序列係合成的<400> 30<210> 31 <211> 79 <212> PRT <213> 人工的<220> <223> 序列係合成的<400> 31 <210> 32 <211> 87 <212> PRT <213> 人工的<220> <223> 序列係合成的<400> 32<210> 33 <211> 81 <212> PRT <213> 人工的<220> <223> 序列係合成的<400> 33 <210> 34 <211> 80 <212> PRT <213> 人工的<220> <223> 序列係合成的<400> 34<210> 35 <211> 79 <212> PRT <213> 人工的<220> <223> 序列係合成的<400> 35<210> 36 <211> 87 <212> PRT <213> 人工的<220> <223> 序列係合成的<400> 36<210> 37 <211> 81 <212> PRT <213> 人工的<220> <223> 序列係合成的<400> 37<210> 38 <211> 80 <212> PRT <213> 人工的<220> <223> 序列係合成的<400> 38 <210> 39 <211> 79 <212> PRT <213> 人工的<220> <223> 序列係合成的<400> 39<210> 40 <211> 87 <212> PRT <213> 人工的<220> <223> 序列係合成的<400> 40 <210> 41 <211> 81 <212> PRT <213> 人工的<220> <223> 序列係合成的<400> 41<210> 42 <211> 80 <212> PRT <213> 人工的<220> <223> 序列係合成的<400> 42<210> 43 <211> 87 <212> PRT <213> 人工的<220> <223> 序列係合成的<400> 43<210> 44 <211> 81 <212> PRT <213> 人工的<220> <223> 序列係合成的<400> 44<210> 45 <211> 80 <212> PRT <213> 人工的<220> <223> 序列係合成的<400> 45 <210> 46 <211> 79 <212> PRT <213> 人工的<220> <223> 序列係合成的<400> 46<210> 47 <211> 80 <212> PRT <213> 人工的<220> <223> 序列係合成的<400> 47 <210> 48 <211> 80 <212> PRT <213> 人工的<220> <223> 序列係合成的<400> 48<210> 49 <211> 80 <212> PRT <213> 人工的<220> <223> 序列係合成的<400> 49<210> 50 <211> 80 <212> PRT <213> 人工的<220> <223> 序列係合成的<400> 50 <210> 51 <211> 31 <212> PRT <213> 人工的<220> <223> 序列係合成的<400> 51<210> 52 <211> 32 <212> PRT <213> 人工的<220> <223> 序列係合成的<400> 52<210> 53 <211> 10 <212> PRT <213> 人工的<220> <223> 序列係合成的<400> 53<210> 54 <211> 10 <212> PRT <213> 人工的<220> <223> 序列係合成的<220> <221> misc_feature <222> (7)..(7) <223> Xaa可為任一天然存在之胺基酸<400> 54<210> 55 <211> 87 <212> PRT <213> 人工的<220> <223> 序列係合成的<400> 55<210> 56 <211> 81 <212> PRT <213> 人工的<220> <223> 序列係合成的<400> 56 <210> 57 <211> 80 <212> PRT <213> 人工的<220> <223> 序列係合成的<400> 57<210> 58 <211> 79 <212> PRT <213> 人工的<220> <223> 序列係合成的<400> 58
(無元件符號說明)
Claims (37)
- 一種抗-因子D抗體或其抗體片段,其中該抗體具有包含下述各項之可變輕鏈:具有SEQ ID NO:16之序列之CDR-L1;具有SEQ ID NO:17、21或24之序列之CDR-L2,及具有SEQ ID NO:18、19或22之序列之CDR-L3;及具有包含下述各項之可變重鏈:具有SEQ ID NO:13、23或25之序列之CDR-H1;具有SEQ ID NO:14之序列之CDR-H2;及具有SEQ ID NO:15或20之序列之CDR-H3;其限制條件為,該抗體或片段不包含SEQ ID NO:1之重鏈可變結構域胺基酸序列及SEQ ID NO:2之輕鏈可變結構域胺基酸序列。
- 如請求項1之抗-因子D抗體或片段,其中該抗體具有包含下述各項之可變輕鏈:具有SEQ ID NO:16之序列之CDR-L1;具有SEQ ID NO:21或24之序列之CDR-L2,及具有SEQ ID NO:18、19或22之序列之CDR-L3;及具有包含下述各項之可變重鏈:具有SEQ ID NO:13、23或25之序列之CDR-H1;具有SEQ ID NO:14之序列之CDR-H2;及具有SEQ ID NO:15或20之序列之CDR-H3。
- 如請求項1之抗-因子D抗體或片段,其中該抗體具有包含下述各項之可變輕鏈:具有SEQ ID NO:16之序列之CDR-L1;具有SEQ ID NO:17、21或24之序列之CDR-L2,及具有SEQ ID NO:19或22之序列之CDR-L3;及具有包含下述各項之可變重鏈:具有SEQ ID NO:13、23或25之序列之CDR-H1;具有SEQ ID NO:14之序列之CDR- H2;及具有SEQ ID NO:15或20之序列之CDR-H3。
- 如請求項1之抗-因子D抗體或片段,其中該抗體具有包含下述各項之可變輕鏈:具有SEQ ID NO:16之序列之CDR-L1;具有SEQ ID NO:17、21或24之序列之CDR-L2,及具有SEQ ID NO:18、19或22之序列之CDR-L3;及具有包含下述各項之可變重鏈:具有SEQ ID NO:23或25之序列之CDR-H1;具有SEQ ID NO:14之序列之CDR-H2;及具有SEQ ID NO:15或20之序列之CDR-H3。
- 如請求項1之抗-因子D抗體或片段,其中該抗體具有包含下述各項之可變輕鏈:具有SEQ ID NO:16之序列之CDR-L1;具有SEQ ID NO:17、21或24之序列之CDR-L2,及具有SEQ ID NO:18、19或22之序列之CDR-L3;及具有包含下述各項之可變重鏈:具有SEQ ID NO:13、23或25之序列之CDR-H1;具有SEQ ID NO:14之序列之CDR-H2;及具有SEQ ID NO:20之序列之CDR-H3。
- 如請求項1之抗-因子D抗體或片段,其中該抗體包含SEQ ID NO:6、SEQ ID NO:8、SEQ ID NO:10或SEQ ID NO:12之重鏈可變結構域胺基酸序列。
- 如請求項6之抗-因子D抗體或片段,其中該抗體包含SEQ ID NO:8之重鏈可變結構域胺基酸序列。
- 如請求項1之抗-因子D抗體或片段,其中該抗體包含SEQ ID NO:5、SEQ ID NO:7、SEQ ID NO:9或SEQ ID NO:11之輕鏈可變結構域胺基酸序列。
- 如請求項8之抗-因子D抗體或片段,其中該抗體包含SEQ ID NO:7之輕鏈可變結構域胺基酸序列。
- 如請求項9之抗-因子D抗體或片段,其中SEQ ID NO:7之104位之胺基酸殘基為纈胺酸或亮胺酸。
- 一種抗-因子D抗體或其抗體片段,其中該抗體包含SEQ ID NO:6、SEQ ID NO:8、SEQ ID NO:10或SEQ ID NO:12之重鏈可變結構域胺基酸序列及SEQ ID NO:5、SEQ ID NO:7、SEQ ID NO:9或SEQ ID NO:11之輕鏈可變結構域胺基酸序列。
- 如請求項11之抗-因子D抗體或片段,其中SEQ ID NO:7之104位之胺基酸殘基為纈胺酸或亮胺酸。
- 如請求項11之抗-因子D抗體或片段,其中該抗體包含SEQ ID NO:5之可變結構域序列及SEQ ID NO:6之可變結構域序列。
- 如請求項11之抗-因子D抗體或片段,其中該抗體包含SEQ ID NO:7之可變結構域序列及SEQ ID NO:8之可變結構域序列。
- 如請求項14之抗-因子D抗體或片段,其中SEQ ID NO:7之104位之胺基酸殘基為纈胺酸或亮胺酸。
- 如請求項11之抗-因子D抗體或片段,其中該抗體包含SEQ ID NO:9之可變結構域序列及SEQ ID NO:10之可變結構域序列。
- 如請求項11之抗-因子D抗體或片段,其中該抗體包含SEQ ID NO:11之可變結構域序列及SEQ ID NO:12之可變結構域序列。
- 如請求項1之抗-因子D抗體或片段,其中該抗體包含一多肽,其包含下述胺基酸序列:QX1 QLVQSGX2 E LKKPGASVKV SCKASGYTFT SYGMNWVX3 QA PGQGLEWMGW INTYTGETTYADDFKGRFVF SLDTSVSTAY LQISSLKAED TAX4 YYCX5 REG GVNNWGQGTL VTVSS(SEQ ID NO:27),其中X1 係I或V,X2 係P或S,X3 係K或R,X4 係T或V,且X5 係E或A。
- 如請求項1之抗-因子D抗體或片段,其中該抗體包含一多肽,其包含下述胺基酸序列:DIQX6 TQSPSSLSX7 SVGDRVTITCITSTDIDDDMNWYQQKPGKX8 PKLLIX9 DGNTLRPGVPSRFSX10 SGSGX11 DFTLTISSLQPEDVATYYCLQSDSLPYTFGQGTKLEIK(SEQ ID NO:26),其中X6 係V或M,X7 係M或A,X8 係P或V,X9 係S或Y,X10 係S或G,且X11 係A或T。
- 如請求項19之抗-因子D抗體或片段,其中SEQ ID NO:26之104位之胺基酸殘基係纈胺酸或亮胺酸。
- 如請求項18之抗-因子D抗體或片段,其中該抗體進一步包含含有SEQ ID NO:26之胺基酸序列之多肽,其中X6 係V或M,X7 係M或A,X8 係P或V,X9 係S或Y,X10 係S或G,且X11 係A或T。
- 如請求項21之抗-因子D抗體或片段,其中SEQ ID NO:26之104位之胺基酸殘基係纈胺酸或亮胺酸。
- 一種抗-因子D抗體或其抗體片段,其中該抗體具有包含下述各項之可變輕鏈:具有SEQ ID NO:16之序列之CDR-L1;具有SEQ ID NO:17之序列之CDR-L2,及具有SEQ ID NO:19之序列之CDR-L3;及具有包含下述各項之可變重鏈:具有SEQ ID NO:13之序列之CDR-H1;具有SEQ ID NO:14之序列之CDR-H2;及具有SEQ ID NO:20之序列之CDR-H3。
- 一種抗-因子D抗體或其抗體片段,其中該抗體包含具有SEQ ID NO:7之胺基酸序列之輕鏈可變結構域序列及具有SEQ ID NO:8之胺基酸序列之重鏈可變結構域序列。
- 如請求項24之抗-因子D抗體或片段,其中SEQ ID NO:7之104位之胺基酸殘基係纈胺酸或亮胺酸。
- 如請求項1至21中任一項之抗-因子D抗體或片段,其中該抗體為人類化抗體。
- 一種如請求項1至25中任一項之抗-因子D抗體之可變結構域。
- 一種經分離核酸,其編碼如請求項1至25中任一項之抗-因子D抗體或片段。
- 一種經分離核酸,其編碼如請求項27之可變結構域。
- 一種載體,其包含如請求項28或29之核酸。
- 一種宿主細胞,其包含如請求項30之載體。
- 一種組合物,其包含如請求項1至25中任一項之抗-因子D抗體或片段。
- 一種組合物,其包含如請求項27之可變結構域。
- 一種如請求項32或33之組合物之用途,其用於製造用於治療補體介導病症之藥物。
- 如請求項34之用途,其中該病症係眼部疾病。
- 如請求項35之用途,其中該眼部疾病係年齡相關性黃斑變性或糖尿病性視網膜病。
- 一種製備抗-因子D抗體或其抗體片段或抗-因子D抗體之可變結構域之方法,其包含培養如請求項31之宿主細胞。
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EP (4) | EP3466971A1 (zh) |
JP (6) | JP2010508819A (zh) |
KR (6) | KR101645144B1 (zh) |
CN (7) | CN105085682A (zh) |
AR (2) | AR063760A1 (zh) |
AU (1) | AU2007313685C1 (zh) |
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