TWI585104B - 基於vl和vhh可變區衍生物的高親和力抗聚集抗體 - Google Patents
基於vl和vhh可變區衍生物的高親和力抗聚集抗體 Download PDFInfo
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Description
本發明是涉及抗體,具體說,是涉及一種基於VL和VHH可變區衍生物的高親和力抗聚集抗體,屬於生物醫藥技術領域。
抗體為可溶性血液糖蛋白或組織液糖蛋白,也稱免疫球蛋白(Ig),其在脊椎動物體液免疫中發揮著關鍵的作用。抗體由B細胞在回應各種結構的外來生化物質(抗原)時生成。由於抗體對特定抗原具有高的特異性和親和力,而且針對無限數目的抗原譜均可生成其抗體,所以抗體及其衍生物成為基礎醫學研究及應用醫學研究中最重要試劑中的一類。
經典抗體[1,2]是包含兩個相同重(H)鏈(即:一個重鏈可變區─VH區,三個重鏈恆定區─CH1區、CH2區和CH3區,以及一個位於CH1區和CH2區之間的鉸鏈區)和兩個相同輕(L)鏈(即:輕鏈可變區─VL區和輕鏈恆定區─CL區)的大多體蛋白質(IgG約150KDa)。上述各鏈由非共價鍵和共價鍵(二硫鍵)連接為一個四鏈分子。木瓜蛋白酶可將抗體分子分解為Fab(抗原結合片段)和Fc(可結晶片段)片段。由此可見,該分子通過一個區段(Fab)定義其抗原相關特異性,而由另一個區段(Fc)執行其消除抗原的效應功能[3,4]。H鏈的CH1區和CH2區之間由鉸鏈區隔開,該鉸鏈區確保了Fab片段的可動性以及IgG分子與暴露於細胞上的Ig效應受體之間的相互作用。CH2區包含介導細胞活化
(ADCC和ADCP)的Fcγ受體的結合區域以及補體系統分子(CDC)的結合區域。此外,CH2區還包含一個位點,該位點是所有免疫球蛋白同種型用於連接糖類的連接點。CH3區幾乎完全決定了IgG二聚體的穩定性,並可與細胞表面上的FcRn受體相互作用,從而確定了抗體的藥代動力學特性以及其在體內的代謝和分佈。重鏈可變區(VH)和輕鏈可變區(VL)各自的互補決定區(CDR)可結合形成抗原結合片段,同時,各可變區與恆定區的骨架區並不直接參與抗原識別。經典抗體的最小Fab衍生物為一單鏈構建體,在該構建體中,各輕重鏈的可變區與一接頭序列(scFv)相連接。
在駱駝科動物(駱駝、大羊駝、小羊駝)的血液中已發現大量具有簡化結構的特定非經典抗體,該發現極具價值[5]。此類抗體(重鏈抗體,HCAb)是由二聚體形式的單個截短重鏈(無CH1區)構成,不含任何輕鏈。HCAb的抗原結合片段僅由單個重鏈可變區(VHH)形成,該VHH通過鉸鏈區連接至Fc區。VHH更常稱作單區抗體,“納體”,“微型抗體”,或“奈米抗體”。除了大小較小(12~15KDa)之外,與經典IgG抗體相比,此類單區結構的分離物還呈現出許多優點,即:聚集、化學及熱穩定性。VHH抗體可在細菌和酵母細胞中成功克隆及表達。由於上述特性,此類抗體的研發方向有治療方向(Ablynx公司),以及實驗室和工業色譜方向(CaptureSelect親和力產品)。
含單條Ig重鏈二聚體的重鏈抗體首次發現於駱駝科各代表性動物血清免疫球蛋白的電泳分析中[5]。HCAb的相對比例(占所有IgG的比例)從大羊駝和小羊駝的約15~25%變化至駱駝的約60~80%[6]。
據推測,非經典HCAb(至少對駱駝科而言如此)源自於經典抗體基因的較近期進化。對於HCAb和經典抗體而言,CH2和CH3兩
個重鏈恆定區高度保守。HCAb不具有與經典抗體的第一恆定區CH1相對應的區域。單峰駱駝基因組含有由約50個VH生成基因以及40個VHH生成基因組成的基因簇,其後跟隨有D區段和J區段的多個基因以及恆定區(Cμ、Cγ、Cε及Cα)的編碼基因。顯然,Cγ基因中的某一些用於形成HCAb(突變導致CH1區的缺失),而其他用於生成經典抗體(保留CH1區)。D區段和J區段的相同基因可隨機連接一個VH基因或一個VHH基因。這表明VH基因和VHH基因位於同一基因位點[7~10]。
非經典抗體的可變區(VHH)和經典抗體的可變區(VH)具有非常相似的組織結構,正如人IgG3子類的VH區與駱駝科動物的VH和VHH區具有很高的同源性。在上述兩種情況中,可變區均包含圍繞於三個高度可變互補決定區(CDR)周側的四個保守骨架區FR。此外,在上述兩種情況中,免疫球蛋白可變區的典型三維結構均由兩個β層形成,其中的一個β層包含四個胺基酸序列,另一個β層包含五個胺基酸序列[11,12]。上述結構的三個CDR在可變區的一側形成一簇,在該處,所述CDR參與抗原識別並位於β結構的連接環上。然而,上述兩種情況之間存在複數個涉及單區VHH功能性的重要區別,因此,VHH的CDR1和CDR3獲得顯著增大。VHH互補決定區通常在兩個片段(通常在CDR1和CDR3,較少情況下在CDR2和CDR3)中同時含有半胱氨酸殘基。關於VHH晶體結構的研究表明:上述半胱氨酸殘基形成二硫鍵,從而為此類抗體的上述環形結構提供額外穩定性[12]。VHH的最顯著特徵在於:在其第二骨架區內,有四個親水性胺基酸殘基取代疏水性胺基酸殘基(根據Kabat編號,分別為Val37Phe(37位上苯丙氨酸對纈氨酸的取代),Gly44Glu(44位上谷氨酸對甘氨酸的取代),Leu45Arg(45位上精氨酸對亮氨酸的取代),Trp47Gly(47位上甘氨酸對色氨酸的取代)[13])。對於VH區而
言,此骨架區高度保守,富含疏水性胺基酸殘基,且在與輕鏈可變區VL的連接中發揮必不可少的作用。VHH區在此方面差異巨大:親水性胺基酸對疏水性胺基酸的取代使得VHH與VL之間的結合變得不可能。上述取代同樣可以解釋VHH(奈米抗體)以重組蛋白質形式存在時的高溶解性[14]。
HCAb與經典抗體的所有可能的互補位(抗體的抗原結合部分)之間似乎可能存在顯著差異。由於這兩種抗體類型共存於同一生物體之內,因此可認為該兩者之間為彼此互補而非競爭關係。例如,在針對完全相同的動物進行免疫時,關於抗原物質的各種表位,上述兩種抗體類型可以平行生成或單獨生成或以不同比例並行生成的事實已被多次報導。儘管有推測認為,與經典的雙區抗體相比,單區抗體的可能互補位種類較少,但許多發表出版物已明確表明,針對相當多抗原的最為全面的各種表位均能獲得HCAb[15]。顯然,此方面的原因在於上述增大的CDR1和CDR3區。還應注意的是,VHH具有可能是在免疫時的抗體親和力成熟過程中積累的極其大量(與經典抗體的可變區相比)的體細胞超突變[16]。X射線繞射分析表明:VHH的抗原結合環區可形成經典可變區通常無法形成的結構[12,16]。對於經典抗體的VH和VL區而言,所有六個CDR對於抗原結合的貢獻度幾乎相同;然而,對於VHH而言,通常情況下,CDR3對於互補位的形成最為重要。業已表明,VHH(而非VH或VL)的CDR3能夠形成極其長的指狀結構,該結構可深入至抗原結構中,從而尤為重要的是,可對酶的活性位點進行檢測[12]。正是因為VHH抗原結合區具有小的尺寸以及可形成通常無法形成的新互補位的能力,所以能夠制得可對經典抗體無法處理的表位進行識別的HCAb(例如,可生產出對酶具有有效抑制作用的抗體)[17]。
與經典IgG抗體相比,由於單區VHH具有高度的唯一特異
性,在生物體內的消除速度較快,因此對其治療用途有時造成了限制。現今已有數種用於改善VHH結構藥代動力學的方法,包括與PEG的化學偶聯以及與清除降低介導多肽(例如半衰期長達三周的HSA或Fc融合蛋白)的共價結合[18,19,20]。此外,通過重組技術將可與人體血液內的上述成分(HSA及IgG)進行高親和力非共價相互作用的小肽結合至VHH上的方法已獲得成功應用[21]。然而,此類方法的技術效果和免疫原性仍然存在問題,而且其在臨床或早期研究階段中的使用可行性仍處在研究階段。
另外,在將抗體用做藥物製劑方面的最大限制在於其聚集和化學穩定性、親和力以及免疫原性。由於大多數單克隆抗體來源於鼠類抗體,因此在人體中頻繁使用此類抗體將引起針對抗體治療的免疫應答(例如,過敏反應)。此類型的免疫應答最終至少導致缺乏療效,在最壞情況下還可導致潛在過敏反應。另一方面,聚集或化學不穩定的治療性抗體不但會降低該藥物產品的經時治療特性,還可能增加其在對人類患者給藥時的免疫原性。
綜上所述,開發具有改善的功能特性及治療特性(與先前已知抗體相比較),尤其是具有提高的聚集性、化學及熱穩定性和改善的親和力,且同時易於工業規模化獲得的基於VHH的抗體是非常重要的。
以下提供與含VHH區的各種抗體構建體相關的資訊。
專利申請PCT/EP2008/066368描述了一種包含與Fc片段連接的多個單獨可變區的抗體。
其中,納體可用作具有Fc片段的可變區,而所述Fc片段來源於IgE類抗體。所述的可變區和Fc片段可通過位於鉸鏈區內的接頭相連接。
專利申請US 2009/0202979公開了一種包含直接連接至人類抗體恆定區的完整或部分VHH抗體的抗體。
此外,胺基酸取代可影響抗體的物化及生物特性是公知的。
例如,專利申請US20110028348描述了一種在35、45、47、93~100以及100a位引入胺基酸取代以提高所獲抗體親水性的重鏈可變區。
如今,已開發出通過對已分離單區VHH及VH的結構進行優化而降低其免疫原性並提高其聚集穩定性的方法。
Vincke等[22]已發現:將特徵胺基酸中49位上的谷氨酸取代為甘氨酸,50位上的精氨酸取代為亮氨酸後,可獲得穩定性更高但可溶性降低的新的區域。此外,將骨架區FR-2內42位上的苯丙氨酸取代為纈氨酸,52位上的甘氨酸/丙氨酸取代為色氨酸可引起H3環的重新定向,從而使得解離常數增加6~10倍(6.85×10-3 1/s),因此對抗體與抗原的親和力至關重要。將42位上的苯丙氨酸取代為纈氨酸可降低所獲得抗體的穩定性。將VH序列中49位上的甘氨酸以及50位上的亮氨酸取代後可降低所述區域的穩定性,而將VHH中49位上的谷氨酸以及50位上的精氨酸人源化後可獲得高穩定性的可變區。
研究人員[23]已分辨出多個使人重鏈可變區(VH)在相應輕鏈不存在時也可穩定存在的突變及序列位點。所述研究人員採用組合噬菌體展示文庫以及常規生物物理方法分析了整個原有輕鏈連接部位以及第三互補決定區(CDR3)。與自主行為取決於所述疏水性的原有輕鏈連接部位與CDR3之間的相互作用的駱駝科動物重鏈抗體的單聚體形式可變區(V(H)H區)不同,所述文獻的作者們發現,許多體外演化出的V(H)區的穩定性基本上與所述CDR3序列無關,相反地,其穩定性源自於通過
使結構相容性親水殘基取代外露的疏水殘基而使原有輕鏈連接部位親水性獲得增加的突變。上述改造區域可通過重組方式以高收率表達,在高濃度下主要以單聚體形式存在,以可逆方式解折疊,而且具有甚至比典型駱駝科動物V(H)H區更高的熱穩定性。由於多數上述致穩突變較少見於天然V(H)和V(H)H區,因此無法通過研究天然序列和結構進行預測。結果表明,可使用區別於在駱駝科動物V(H)H區所發現的非天然突變衍生出結構特性超出天然V(H)區的自主V(H)區。從上述文獻可知,在可中和經典VHH構象的遮蔽效應的短HCDR3區存在的情況下,將VH特徵胺基酸中47位元上的色氨酸取代為甘氨酸,37位上的酪氨酸取代為纈氨酸,4位上的谷氨酸取代為44位上的甘氨酸,45位上的精氨酸取代為亮氨酸後,可使分離出的VHH區重新生成與VJ區相結合的能力[24]。多項研究已證實,經典IgG結構治療性抗體的聚集穩定性的增強與其免疫原性的降低之間存在關係,而且Hermeling等人在其2004年發表的綜述[25]中對此進行了總結。如今,尚未發現既含有VHH區,但同時與全長人IgG內的輕鏈可變區連結的抗體。因此,需要開發一種穩定性和親和力更高、表達性能良好且免疫原性較低的全新抗體形式。
此外,此前尚未有與開發具有如下特徵的分子的方法相關的描述:易於獲取;具有更高聚集穩定性;具有更高親和力;在哺乳動物細胞培養物中具有高表達水準。
如上所述,本發明首次描述了一種因含有可與全長人IgG的輕鏈可變區結合的VHH衍生物而形成與原生抗體類似(因此,具有低免疫原性)但卻具有更高聚集穩定性和親和力且具有治療性單克隆抗體結構的構建體的抗體。
本發明提出一種具有更高親和力和更高聚集穩定性的人源化單克隆抗體,優選為IgG類型抗體,其中,其可變區是VHH衍生物與輕鏈VL可變區的結合。
作為一種實施方式,所述的VHH衍生物可包含44X245X3位上的胺基酸取代,其中,X2=G(甘氨酸)、A(丙氨酸)、V(纈氨酸)、S(絲氨酸)、T(蘇氨酸);X3=A、V、T、H(組氨酸);或其組合(44和45表示胺基酸取代位置)。下文中,胺基酸取代位置採用Kabat編號方案(http://www.bioinf.org.uk/abs/)進行表示。
作為另一實施方式,所述的VHH衍生物與含有分離自免疫動物的初始VHHIgG抗體相比,具有更高的聚集穩定性,所述免疫動物可源自駱駝科。
作為另一實施方式,所述的VHH衍生物具有分離自駱駝科免疫動物的抗體重鏈可變區和含有在任何位置上的額外人典型胺基酸取代,除了在44和45位上的如下取代之外:a)44X2,其中,X2=G、A、V、S、T;b)45X3,其中,X3=A、V、T、H;或其組合。
作為另一實施方式,所述的VHH衍生物具有分離自駱駝科未免疫動物的抗體重鏈可變區和含有在任何位置上的額外人典型胺基酸取代,除了在44和45位上的如下取代之外::a)44X2,其中,X2=G、A、V、S、T;b)45X3,其中,X3=A、V、T、H;或其組合。
作為另一實施方式,所述的輕鏈VL可變區是人抗體的衍生物,優選為哺乳類動物抗體的人源化片段。
作為另一實施方式,其中的VHH衍生物包含位於44位(Kabat編號方案)上的半胱氨酸,其中的輕鏈VL可變區含有位於100位(Kabat編號方案)上的半胱氨酸。
作為另一實施方式,所述抗體是屬於以下任一同種型:IgG1、IgG2、IgG3或IgG4。
作為另一實施方式,所述抗體包含作為IgG的一部分的非原生的修飾Fc。
作為另一實施方式,所述抗體具有如下聚集穩定性:當使用濃度高於10mg/mL且在4℃下儲存六個月以上後,溶液中聚集物含量的增加量不超過初始含量的5%。
作為另一實施方式,所述抗體具有如下聚集穩定性:當使用濃度高於10mg/mL且在37℃下儲存兩周以上後,溶液中聚集物含量的增加量不超過初始含量的5%。
作為另一實施方式,所述抗體具有如下聚集穩定性:當使用濃度高於10mg/mL且在42℃下儲存48小時以上後,溶液中聚集物含量的增加量不超過初始含量的5%。
作為另一實施方式,所述抗體具有如下聚集穩定性:當使用濃度高於10mg/mL且在50℃下儲存6小時以上後,溶液中聚集物含量的增加量不超過初始含量的5%。
作為一種實施方式,所述抗體的解離常數KD10-9M。
作為另一實施方式,所述抗體的抗體-抗原相互作用的動力
學結合常數kon105 1/ms。
作為又一實施方式,所述抗體的抗體-抗原相互作用的動力學解離常數dis10-4 1/s。
此外,本發明提出一種抗體片段,所述抗體片段可以為輕鏈,重鏈,所述輕鏈和/或重鏈的可變區,所述可變區為抗體序列的一部分,所述抗體序列包括生物特異性抗體變體。
作為另一實施方式,所述抗體片段為輕鏈,重鏈,所述輕鏈和/或重鏈的可變區,所述可變區為Fab的一部分。
作為另一實施方式,所述抗體片段可以為輕鏈,重鏈,所述輕鏈和/或重鏈的可變區,所述可變區為scFv的一部分。
此外,本發明提出一種生產本發明抗體的方法,所述抗體的生產方法可包括選自下述的階段:本領域所熟知的定向誘變、展示方法、遺傳工程、生物化學及高性能生物技術方法,可包括在駱駝科動物抗體VHH區不同位置上進行定向誘變的方法。
此外,本發明提供一種編碼了本發明抗體或其片段的DNA構建體,以及一種包括一個或多個本發明DNA構建體的表達載體。
此外,本發明提出一種包括所述表達載體或DNA構建體的細胞系。
此外,本發明提出一種人源化單克隆抗體或其片段的生產方法,該方法涉及將所述細胞系在足以獲得所述抗體或其片段的條件下培養於培養基中,然後對所獲得的抗體或其活性片段進行分離純化。
此外,本發明還提出一種包括所述表達載體的宿主細胞。
此外,本發明還提出一種人源化單克隆抗體或其片段的生產方法,該方法涉及將所述宿主細胞在足以獲得所述抗體或其片段的條件
下培養於培養基中,然後對所獲得的抗體或其活性片段進行分離純化。
此外,本發明提出一種含有抗體或其片段的藥物組合物,該抗體或其片段與一種或多種藥學上適用的賦形劑、稀釋劑或載體聯用。專用生物技術指導性資料(如文獻[25])描述了組合物獲取技術的細節。
本發明的另一實施方式涉及一種與人IL-17A特異性結合的活性分子內的抗體或其片段,其中,所述抗體或其片段包含:a)一種含有HCDR1、HCDR2和HCDR3三個超變區的駱駝科動物的重鏈可變區VHH衍生物;其中:HCDR1包含SEQ ID NO.1所示的胺基酸序列:G-T-F-A-T-X32-X33-X34-X35(根據Kabat指數編號),其中:X32是選自S,N,K,R,E,W,Q,D,A,V和F的胺基酸;X33是選自P和S的胺基酸;X34是選自M和I的胺基酸;X35是選自G,N,S,A,L,I,R,V和Q的胺基酸;HCDR2包含SEQ ID NO.2所示的胺基酸序列:X50-I-X52-X52a-S-G-X55-D-R-I-Y-A-D-S-V-K-G,其中:X50是選自A,G和L的胺基酸;X52是選自S,D和E的胺基酸;X52a是選自P和A的胺基酸;X55是選自G,S,T,L,R,D,E,K,A和W的胺基酸;HCDR3包含SEQ ID NO.3所示的胺基酸序列:C-A-X94-X95-X96-X97-F-X99-X100-X100a-X100b-X100c-X100d-X100e-X100f-D-Y-D-S,其中:X94是選自K,S,T,V,D和G的胺基酸;X95是選自R和K的胺基酸;
X96是選自G,R,Y,H,D,W和K的胺基酸;X97是選自R,A,V,S,L和H的胺基酸;X99是選自D,E,G,A,R,V,K和Q的胺基酸;X100是選自G,S和N的胺基酸;X100a是選自G,T,P,V,R,N和K的胺基酸;X100b是選自V,S,T,L,Y,A,H,G和I的胺基酸;X100c是選自Y,W和S的胺基酸;X100d是選自R,V,L,Y,A,W,K,G,Q和I的胺基酸;X100e是選自T,L,A和S的胺基酸;X100f是選自T,L,G,P,N,A,Q,F,I和D的胺基酸;以及b)一種人抗體的輕鏈VL可變區或人源化抗體的輕鏈可變區。
作為一種替代實施方式,所述的與人IL-17A特異性結合的抗體或其片段包含:a)一種含有HCDR1、HCDR2和HCDR3三個超變區的重鏈可變區VHH衍生物,其中:HCDR1包含SEQ ID NO.4所示的胺基酸序列:G-T-F-A-T-S-P-M-G;HCDR2包含SEQ ID NO.5所示的胺基酸序列:A-I-S-P-S-G-G-D-R-I-Y-A-D-S-V-K-G;HCDR3包含SEQ ID NO.6所示的胺基酸序列:C-A-V-R-R-R-F-D-G-T-S-Y-Y-T-G-D-Y-D-S;以及b)一種人抗體的輕鏈VL可變區或人源化抗體的輕鏈可變區。
作為一種替代實施方式,所述的與人IL-17A特異性結合的抗體或其片段包含:a)一種含有SEQ ID NO.7所示胺基酸序列:
的重鏈可變區VHH衍生物;以及b)一種人抗體的輕鏈VL可變區或人源化抗體的輕鏈可變區。
作為一種替代實施方式,所述的與人IL-17A特異性結合的抗體或其片段包含VHH衍生物,其中的可變區包含與SEQ ID NO.7至少90%相同的胺基酸序列。
作為一種替代實施方式,所述的與人IL-17A特異性結合的抗體或其片段包含:a)含有SEQ ID NO.7所示胺基酸序列的VHH衍生物;以及b)含有SEQ ID NO.8所示胺基酸序列:
的人抗體的輕鏈VL可變區。
作為一種替代實施方式,所述的與人IL-17A特異性結合的抗體或其片段包含VHH衍生物及人抗體的輕鏈VL可變區,所述的可變區包含與SEQ ID NO.8至少90%相同的胺基酸序列。
作為一種替代實施方式,所述的與人IL-17A特異性結合的抗體或其片段包含SEQ ID NO.9所示胺基酸序列:
的重鏈以及包含SEQ ID NO.10所示胺基酸序列:
的人抗體輕鏈VL可變區。
作為另一實施方式,所述的與人IL-17A特異性結合的抗體包含重鏈和輕鏈,所述的各鏈含有分別與SEQ ID NO.9和/或SEQ ID NO.10至少90%相同的胺基酸序列。
作為一種替代實施方式,所述的與人IL-17A特異性結合的抗體與人IL-17A的結合親和力的特徵參數KD10-10M。
作為另一實施方式,所述的與人IL-17A特異性結合的抗體與人IL-17A的動力學結合常數kon105 1/ms。
作為另一實施方式,所述的與人IL-17A特異性結合的抗體與人IL-17A的動力學解離常數dis10-5 1/s。
作為一種實施方式,所述的與人IL-17A特異性結合的抗體對人IL-17A的活性抑制率均50%。
作為一種實施方式,所述的與人IL-17A特異性結合的抗體產自哺乳動物,酵母或細菌細胞。
作為一種實施方式,所述的與人IL-17A特異性結合的抗體的Fc區含有一個或多個額外胺基酸取代,與具有天然Fc的抗體相比較,所述取代提高了抗體的物理化學和藥代動力學特性,且同時不導致抗體與IL-17A結合能力的損失。
本發明一種實施方式涉及一種DNA構建體,該DNA構建體編碼了與人IL-17A特異性結合的抗體。
此外,本發明還涉及一種包含一個或多個DNA構建體的表達載體,所述DNA構建體編碼了與人IL-17A特異性結合的抗體。
此外,本發明還涉及一種宿主細胞,該細胞包括載體,該載體用於獲得與人IL-17A特異性結合的抗體。
此外,本發明還涉及一種用於生產與人IL-17A特異性結合的抗體的方法,其特徵在於,將含有DNA構建體的宿主細胞在適於獲得所述抗體或其片段的條件下培養於培養基中,並進而對所述抗體或其活性片段進行分離純化。
此外,本發明還涉及一種藥物組合物,該藥物組合物包含與人IL-17A特異性結合的抗體,以及一種或多種藥學上適用的賦形劑、稀釋劑或載體。所述組合物進一步可包含選自TNF-α抑制劑的活性藥物成分,所述組合物可用於治療IL-17A介導的疾病或失調。由IL-17A介導的疾病或失調選自:風濕性關節炎、骨關節炎、青少年慢性關節炎、膿毒性關節炎、萊姆關節炎(Lyme arthritis)、牛皮癬關節炎、反應性關節
炎、脊柱關節病、系統性紅斑狼瘡、克羅恩氏病(Crohn’s disease)、潰瘍性結腸炎、炎性腸病、胰島素依賴型糖尿病、甲狀腺炎、哮喘、過敏性病症、牛皮癬、皮炎、系統性硬化症、移植物抗宿主病、移植排斥、與器官移植有關的急性或慢性免疫疾病、肉狀瘤病、動脈粥樣硬化、彌散性血管內凝血、川崎病(Kawasaki disease)、格雷夫斯病(Graves’ disease)、腎病綜合症、慢性疲勞綜合症、壞死性血管炎(Wegener's disease)、過敏性紫癜(Henoch-Schonlein purpura)、伴有腎損害的顯微鏡下多血管炎、慢性活動性肝炎、葡萄膜炎、感染性休克、中毒性休克綜合症、膿毒症綜合症、惡病質、感染、入侵、獲得性免疫缺陷綜合症、急性橫貫性脊髓炎、亨廷頓舞蹈病(Huntington chorea)、帕金森病(Parkinson disease)、阿爾茨海默病(Alzheimer disease)、中風、原發性膽汁性肝硬化、溶血性貧血、惡性腫瘤、心力衰竭、心肌梗塞、艾迪生病(Addison disease)、多腺性自身免疫綜合症I型或II型,施密特氏綜合症(Schmidt's syndrome)、急性呼吸窘迫綜合症、脫髮、斑形脫髮、血清反應陰性關節病、關節病、萊特爾氏綜合症(Reiter's syndrome)、牛皮癬性關節病、與潰瘍性結腸炎有關的關節病、腸病性滑膜炎、與衣原體有關的關節病、脊椎關節病、動脈粥樣硬化病、特異反應性過敏、自身免疫性大皰病、天皰瘡、落葉狀天皰瘡、類天皰瘡、線狀IgA疾病、自身免疫性溶血性貧血、Coombs陽性溶血性貧血、獲得性惡性貧血、青少年惡性貧血、肌痛性腦脊髓炎、慢性疲勞綜合症、慢性活動性肝炎症、顱巨細胞動脈炎、原發性硬化性肝炎、隱源性自身免疫性肝炎、愛滋病、愛滋病相關疾病、乙肝、丙肝、常見變異型免疫缺陷病、擴張型心肌病、女性不育、卵巢功能不全、過早卵巢衰竭、肺纖維化、隱源性致纖維化性肺泡炎、炎症後間質性肺病、間質性肺炎、與間質性肺病相關的結締組織病、與間質性肺病相關的混合性結締組織
病、與間質性肺病相關的系統性硬皮病、與間質性肺病相關的類風濕性關節炎、與肺病相關的系統性紅斑狼瘡、與肺病相關的皮肌炎、與肺病相關的多發性肌炎、與肺病相關的乾燥綜合症、與肺病相關的強直性脊椎炎、彌漫性肺血管炎、與肺病相關的血鐵質、藥物引起的間質性肺病、纖維化、輻射誘導的纖維化、閉塞性細支氣管炎、慢性嗜酸細胞性肺炎、伴有淋巴細胞浸潤的肺疾病、感染後間質性肺病變、痛風性關節炎、自身免疫性肝炎、I型自身免疫肝炎、II型自身免疫性肝炎、自身免疫性低血糖症、伴有角質肥厚的B型胰島素抵抗、甲狀旁腺機能減退、急性移植相關的免疫疾病、慢性移植相關的免疫疾病、骨關節病、原發性硬化性膽管炎、I型牛皮癬、II型牛皮癬、特發性白細胞減少症、自身免疫性嗜中性白血球減少症、NOS-腎疾病、腎小球性腎炎、顯微鏡腎下多血管炎、萊姆病(Lyme disease)、盤狀紅斑狼瘡、先天性的NOS男性不育、抗精子免疫、多發性硬化、交感性眼炎、結締組織病繼發的肺動脈高壓症、肺出血腎炎綜合症、結節性多動脈炎的肺表現、急性風濕熱、類風濕性脊椎炎、史提爾氏病(Still's disease)、系統性硬皮病、乾燥綜合症(Sjogren's Syndrome)、關節炎、自身免疫性血小板減少症、特發性血小板減少症、自身免疫性甲狀腺病、甲狀腺機能亢進、自身免疫性甲狀腺機能減退、萎縮性自身免疫性甲狀腺機能減退、原發性粘液水腫、晶狀體抗原性葡萄膜炎、原發性血管炎、白癜風、急性肝病、慢性肝病、酒精性肝硬化、酒精誘導的肝損傷、膽汁鬱積、特質性肝疾病,藥物誘導的肝炎、非酒精性脂肪性肝炎、過敏症、哮喘、B組鏈球菌感染(group B streptococcal infection,GBS)、精神障礙、Th1-或Th2-介導的疾病、急性或慢性疼痛、惡性腫瘤(如:肺癌、乳腺癌、胃癌、膀胱癌、結腸直腸癌、胰腺癌、卵巢癌、前列腺癌或造血系統惡性腫瘤)、無β脂蛋白血症、手足發紺、急性或慢性感染、急
性或慢性侵染、急性白血病、急性淋巴細胞白血病、急性骨髓性白血病、急性或慢性細菌感染、急性胰腺炎、急性腎衰竭、腺癌、心房異位、AIDS癡呆綜合症、酒精誘導的肝炎、過敏性結膜炎、過敏性接觸性皮炎、過敏性鼻炎、同種異體移植排斥、α-I抗胰蛋白酶缺乏症、側向肌萎縮性硬化症、貧血、心絞痛、前角細胞變性、抗-CD3治療、抗磷脂綜合症、抗受體的過敏反應、主動脈瘤、外周動脈瘤、主動脈夾層、高動脈壓、冠狀動脈硬化、動靜脈瘺、共濟失調、恆定或陣發性心房纖維性顫動、心房撲動、房室阻斷、B-細胞淋巴瘤、骨移植排斥、骨髓移植排斥、束支傳導阻滯、伯基特淋巴瘤(Burkitt lymphoma)、燒傷、心律失常、心肌頓抑綜合症、心臟腫瘤、心肌病、對旁路的炎性應答、軟骨移植排斥、腦皮層變性、小腦病症、混亂或多灶性房性心動過速、化療所致疾病、慢性粒細胞性白血病、慢性酒精成癮、慢性炎性疾病、慢性淋巴白血病、慢性阻塞性肺病、慢性水楊酸鹽中毒、結腸直腸癌、充血性心臟衰竭、結膜炎、接觸性皮炎、肺心病、冠狀動脈疾病、克雅氏病(Creutzfeldt-Jakob Disease)、培養陰性的膿毒症、囊性纖維化、細胞因數療法誘導的疾病、拳擊運動員的腦病、脫髓鞘病、登革出血熱(dengue hemorrhagic fever)、皮炎、皮膚病、多尿症、糖尿病、糖尿病相關的動脈粥樣硬化血管疾病、彌漫性雷維小體疾病(diffuse Lewy body disease)、充血性擴張型心肌病、基底神經節疾病、中年唐氏綜合症(Down's syndrome in middle age)、中樞神經系統多巴胺阻滯劑誘導的運動障礙、藥物敏感性、濕疹、腦脊髓炎、心內膜炎、內分泌病、會厭炎、EB病毒感染(Epstein-Barr viral infection)、紅痛病、錐體外系病症、小腦病症、家族性嗜血細胞性淋巴組織細胞增生症、胎兒胸腺移植排斥、弗裡德希氏共濟失調(Friedreich's ataxia)、外周動脈疾病、真菌敗血症、產氣性蜂窩組織炎、胃潰瘍、腎小球性腎炎、任何器官或組
織的移植排斥、革蘭氏陰性膿毒症、革蘭氏陽性膿毒症、由細胞內生物體引起的肉芽腫、毛細胞白血病、哈-施病(Hallervorden-Spatz disease)、橋本甲狀腺炎(Hashimoto's thyroiditis)、枯草熱、心臟移植排斥、血色病、血液透析、溶血性尿毒綜合症、血栓性血小板減少性紫癜、出血、甲型肝炎、束支心律失常、HIV感染、HIV神經病、霍奇金病(Hodgkin disease)、運動機能亢進性運動疾病、過敏反應、過敏性相關的肺炎、高血壓、運動機能減退的運動障礙、下丘腦-垂體-腎上腺軸的檢查、特發性艾迪生氏病(idiopathic Addison's disease)、特發性肺纖維化、抗體介導的細胞毒性、衰弱、嬰兒肌肉萎縮、主動脈炎症、流感病毒A、暴露於電離輻射、虹膜睫狀體炎、葡萄膜炎、視神經炎、局部缺血、再灌注誘導的疾病、缺血性中風、幼年型類風濕性關節炎、幼年型脊髓性肌萎縮、卡波濟氏肉瘤(Kaposi's sarcoma)、腎移植排斥、軍團桿菌病、利什曼病、麻風病、皮質脊髓束損傷、脂肪水腫、肝臟移植排斥、淋巴水腫、瘧疾、惡性淋巴瘤、惡性組織細胞病、惡性黑色素瘤、腦膜炎、腦膜炎球菌血症、代謝疾病、特發性疾病、偏頭痛、多系統線粒體疾病、混合性結締組織病、單克隆丙種球蛋白病、多發性骨髓瘤、多系統變性症、重症肌無力、細胞內鳥結核分枝桿菌、結核分枝桿菌、骨髓增生異常綜合症、心肌梗塞、心肌缺血性疾病、鼻咽癌、新生兒慢性肺疾病、腎炎、腎病、神經退行性疾病、神經源性肌萎縮、嗜中性粒細胞減少性發熱、非何傑金氏淋巴瘤(non-Hodgkin’s lymphoma)、腹部主動脈分支閉塞、動脈阻塞性疾病、OKT3治療、睾丸炎、附睾炎、輸精管吻合術、器官腫大、骨質疏鬆症、胰腺移植排斥、胰腺癌、副腫瘤性疾病、腫瘤相關的高鈣血症、甲狀旁腺移植排斥、盆腔炎症性疾病、常年性鼻炎、心包疾病、周邊動脈粥樣硬化疾病、外周血管疾病、腹膜炎、惡性貧、卡氏肺囊蟲肺炎、POEMS綜合
症、灌注後綜合症、泵頭綜合症、心臟切開後梗塞後綜合症、子癇前期、進行性核上性麻痹、原發性肺動脈高血壓、放射療法、雷諾氏現象或疾病(Raynaud's phenomenon or disease)、雷諾氏病(Raynoud's disease)、雷弗素姆病(Refsum's disease)、常規窄QRS心動過速、腎血管性高血壓、再灌注損傷、限制性心肌病、肉瘤、硬皮病、老年性舞蹈症、路易體癡呆(Dementia with Lewy bodies)、血清反應陰性關節炎、休克、鐮狀細胞病、皮膚同種異體移植排斥、皮膚變化、小腸移植排斥、實體瘤、特異性心律失常、脊髓性共濟失調、脊髓小腦退化、鏈狀球菌肌炎、小腦結構損傷、亞急性硬化性全腦炎、暈厥、心血管梅毒、全身性過敏反應、綜合全身炎症反應綜合症、全身型幼年類風濕性關節炎、毛細管擴張、血栓閉塞性脈管炎、血小板減少症、外傷、出血、III型超敏反應、IV型超敏反應、不穩定心絞痛、尿毒癥、尿膿毒病、蕁麻疹、心臟瓣膜病、靜脈曲張、血管炎、靜脈疾病、靜脈血栓形成、心室纖維性顫動、病毒感染、真菌感染、病毒性腦炎、無菌性腦膜炎、病毒嗜血細胞綜合症、韋尼克-科爾薩科夫綜合症(Wernicke-Korsakoff syndrome)、威爾遜氏病(Wilson's disease)、任何器官或組織的異種移植排斥、急性冠狀動脈綜合症、急性特發性多神經炎、急性炎症性脫髓鞘性多發性神經病、急性缺血、成人斯蒂爾病(adult-onset Stills disease)、斑形脫髮、過敏性反應、抗磷脂抗體綜合症、再生障礙性貧血、冠狀動脈硬化、特應性濕疹、特應性皮炎、自身免疫皮炎、與鏈球菌感染相關的自身免疫性疾病、自身免疫性腸病、自身免疫性聽力喪失、自身免疫性淋巴細胞增生綜合症、自身免疫性心肌炎、自身免疫性卵巢早衰、瞼炎、支氣管擴張、大皰性類天皰瘡、心血管疾病、災難性抗磷脂綜合症、乳糜瀉、頸椎病、慢性缺血、疤痕性類天皰瘡、多發性硬化、結膜炎、兒童期發作的精神病症、慢性阻塞性肺病、淚
囊炎、皮肌炎、糖尿病性視網膜病、椎間盤突出、椎間盤脫出、藥物誘發的免疫性溶血性貧血、心內膜炎、子宮內膜異位症、眼內炎、鞏膜外層炎、紅斑多形物、嚴重紅斑多形物、妊娠期類天皰瘡、吉蘭-巴雷綜合症(Guillain-Barre syndrome,GBS)、枯草熱、休斯綜合症(Hughes syndrome)、特發性帕金森病、特發性間質性肺炎、IgE介導的變態反應、自身免疫性溶血性貧血、包涵體肌炎、傳染性眼部炎性疾病、炎性脫髓鞘病、炎症性心臟病、炎症性腎病、先天性肺纖維化、常見間質性肺炎、虹膜炎、角膜炎、乾燥性角結膜炎、庫斯毛爾病(Kussmaul-Meier病)、蘭德裡麻痹(Landry palsy)、朗格漢斯細胞組織細胞增生症(Langerhans' cell histiocytosis)、大理石狀皮膚病、黃斑變性、顯微鏡下多血管炎、Bechterew病、運動神經元疾病、粘膜類天皰瘡、多發性器官衰竭、重症肌無力、脊髓發育不良綜合症、心肌炎、神經根病症、神經病、非A型肝炎、非B型肝炎、視神經炎、骨質溶解症、卵巢癌、JIA少關節型、外周動脈閉塞性疾病、周圍性血管疾病、周圍動脈疾病、靜脈炎、多發性結節性動脈炎、多軟骨炎、風濕性多肌痛、白發病、多關節型幼年特發性關節炎、多發性內分泌缺陷、多肌炎、風濕性多肌痛、泵後綜合症、原發性帕金森氏綜合症、前列腺癌、直腸癌、造血系統惡性腫瘤(如:白血病、淋巴瘤)、前列腺炎、單純紅細胞再生障礙性貧血、原發性腎上腺機能不足、復發性視神經脊髓炎、心瓣手術後的再狹窄、風濕性心臟病、滑膜炎、痤瘡、膿皰病、股肥大、骨炎、硬皮病、繼發性澱粉樣變性、休克肺、鞏膜炎、坐骨神經痛、繼發性腎上腺機能不足、矽相關的結締組織病、Sneddon-Wilkison病、強直性脊柱炎、Stevens-Johnson綜合症、全身炎症反應綜合症、顱動脈炎、弓形體鼻炎、中毒性表皮壞死松解症、橫貫性脊髓炎、腫瘤壞死因數受體相關的週期性綜合症、I型變態反應、II型糖尿病、蕁麻疹、常
見間質性肺炎、血管炎、春季結膜炎、病毒性視網膜炎、Vogt-Koyanagi-Harada綜合症、濕性黃斑變性、傷口癒合相關的關節病、耶爾森氏菌屬相關的關節病、沙門氏菌相關的關節病。
本發明還涉及一種包含與人IL-17A特異性結合的抗體的藥物組合物,該藥物組合物可以治療有效量給藥以用於治療IL-17A介導的疾病或失調。
本發明還涉及一種使用與人IL-17A特異性結合的抗體治療IL-17A介導的疾病或失調的方法,所述治療方法還可涉及TNF-α抑制劑的給藥。
其他用於闡明本發明的實施例旨不在於將本發明局限於這些實施例本身。
本申請的描述包括所引用的所有資訊來源。
術語定義
除非另有說明,本申請中所使用的“單克隆抗體”涉及從大羊駝獲得的抗體,嵌合抗體,人源化抗體,或全人源抗體。本發明單克隆抗體的生產可使用例如重組技術,噬菌體展示技術,合成技術,或者這些技術與本領域所熟知的其他技術的組合。
“單克隆抗體”是指例如從任何真核克隆、原核克隆或噬菌體克隆等單個拷貝或克隆獲得,而非從其生產技術獲得的抗體。“單克隆抗體”可以為完整抗體(具有完全或全長Fc區),實際上的完整抗體,包含抗原結合區的抗體部分或片段(例如:源自大羊駝抗體、嵌合抗體、人源化抗體或人抗體的Fab片段、Fab'片段或F(ab')2片段)。“Fab”片段包含輕鏈可變區和輕鏈恆定區,以及重鏈可變區和第一重鏈恆定區(CH1)。“F(ab')2”抗體片段包含由C端區域內的鉸接半胱氨酸殘基主要以共價方式結合的
一對Fab片段。抗體片段之間的其它化學鍵亦為習知技術所熟知。
此外,本申請中使用的“單克隆抗體”可以為單鏈Fv,該單鏈Fv可通過將VHH和VL的編碼DNA與接頭序列相結合的方式獲得。只要蛋白質具有特定性結合至靶體或優選結合至靶體(例如表位或抗原)的能力,其均由“抗體”一詞所涵蓋。抗體既可糖基化,也可不糖基化,這均屬於本發明的範圍內。
本申請中所使用的“衍生物”或抗體“變體”一詞是指在親本抗體序列中增加、刪除和/或取代一個或多個胺基酸殘基後產生的異於親本序列的胺基酸序列所對應的分子。在優選實施方式中,抗體含有至少一個(例如一至十個,優選為二、三、四、五、六、七或八個)發生於親本抗體FR或CDR區的胺基酸取代。本申請將變體抗體序列的同一性或同源性定義為變體抗體序列中與親本抗體序列胺基酸殘基完全相同的殘基所占的百分比,該百分比是在將變體抗體序列與親本抗體序列對齊或在必要時切割對齊之後所實現的最大相同序列百分比。
抗體衍生物(衍生自親本抗體)保留其可與親本抗體結合至相同抗原(或者,優選地,結合至相同表位)的能力,或者,優選地,表現出至少一項優於親本抗體的特性或生物活性。例如,與親本抗體相比,所述抗體優選具有更佳的聚集穩定性,更強的親和力,更佳的藥代動力學性能,或者更高的抗原生物活性抑制能力。
本申請中所使用的“VHH衍生物”一詞是指在將親本VHH抗體序列中的一個或多個胺基酸殘基取代後產生的異於親本VHH抗體序列的胺基酸序列所對應的VHH抗體衍生物。在優選實施方式中,VHH抗體含有至少一個(例如一至十個,優選為二、三、四、五、六、七或八個)發生於親本抗體FR或CDR區的胺基酸取代。
抗體衍生物保留其可與親本抗體結合至相同抗原(或者,優選地,結合至相同表位)的能力,或者,優選地,表現出至少一項優於親本抗體的特性或生物活性。例如,與親本抗體相比,所述抗體優選具有更佳的聚集穩定性,更強的親和力,更佳的藥代動力學性能,或者更高的抗原生物活性抑制能力。
本申請中所使用的“親本VHH抗體”,或“初始VHH抗體”,或“野生VHH抗體”三詞是指分離自免疫或未免疫駱駝科動物且由用於生成VHH變體的胺基酸序列編碼的VHH抗體。雖然親本抗體可具有源於駱駝科動物的骨架序列(就VHH可變區而言),但是優選地,其輕鏈可變區的骨架序列完全或基本上為人源序列。
本申請中的“親本”,“初始”或“野生”抗體是指由用於生成變體的胺基酸序列編碼的抗體。
雖然親本抗體可具有源於駱駝科動物的骨架序列(就VHH可變區而言),但是優選地,其輕鏈可變區的骨架序列完全或基本上為人源序列。
本申請中所使用的“特異性結合”一詞是指如下情形:特異性結合過程所涉及的一方不與其(各)特異性結合物件之外的分子顯著結合。該詞還適用於例如本發明抗體的抗原結合位點對若干抗原所帶的特定表位元具有特異性的情況。在此情況下,所述具有抗原結合位點的特異性抗體可特異性結合至各種帶有表位的抗體。同理,本發明單克隆抗體雖特異性結合至人IL-17(IL-17A),但並不與人IL-17B,IL-17C,IL-17D或IL-17E特異性結合。此外,本發明單克隆抗體雖特異性結合至人IL-17以及食蟹猴IL-17,但卻既不與大鼠IL-17特異性結合,也不與鼠類IL-17特異性結合。
本申請中所使用的“優選結合”一詞是指如下情形:根據習知技術中已知方法的測定結果(例如,使用Octet裝置所獲得的競爭性ELISA測量結果或KD測量結果),抗體與特定抗原的結合量比其與任何其他抗原的結合量至少多20%,優選多約50%,或為其2倍,20倍,50倍,或100倍。抗體可優選結合抗原的一個表位,但不結合該同一抗原的另一表位。同理,本發明抗體優選結合人IL-17,但不結合兔IL-17。
本申請中所使用的“表位”一詞是指可被抗體識別並通過抗體的一個或幾個抗原結合位點與抗體結合的分子部分。表位通常包括分子的胺基酸或糖側鏈等化學活性表面基團,而且具有特定的三維結構特徵。當“抑定位停駐點”和/或“中和表位”用在描述完整抗原分子以及表位與特異性抗體結合的內容中時表示可導致上述分子或含有該分子的生物體的活性發生體內或體外損失或減少的表位。
本申請中所使用的“表位”一詞還指在動物(優選為在小鼠和人等哺乳動物)中具有抗原活性和/或免疫原活性的多肽片段。本申請中所使用的“抗原表位”一詞指可特異性結合抗體且可由習知技術所熟知的任何技術(例如,標準免疫測定法)檢測的多肽片段。抗原表位並非一定為免疫原性表位,但其可具有免疫原性。本申請中所使用的“免疫原性表位元”定義為根據習知技術任何方法的檢測結果,可激發動物的抗體應答的多肽片段。“非線性表位元”或“構象表位”含有可與表位特異性抗體結合的抗原蛋白質內的不相鄰的多肽(胺基酸)。
在本申請中,提及本發明抗體時所使用的“功能活性”或“功能特徵”兩種表達,或者“生物活性”或“活性”兩詞可互換,而且包括但不限於:表位/抗原親和力和特異性;在體內或體外中和IL-17或作為IL-17拮抗劑的能力;IC50;所述抗體的抗體穩定性和體內免疫原性。習知技術
中涉及的其他生物學特性或抗體特徵例如包括交叉反應性(即與靶肽的非人同源物或與其他蛋白質或靶體的反應),以及在哺乳動物細胞中保持高的蛋白質表達水準的能力。上述特性或特徵可通過習知技術中公認的方法進行觀察、測量或評價,所述方法包括但不限於:ELISA,競爭性ELISA,Octet分析,體外或體內(無限制)中和實驗,受體結合實驗,細胞因數或生長因數的產生和/或釋放,針對從包括人、靈長類動物或其他來源在內的各種來源獲得的組織切片的訊號轉導和免疫組化研究。
本申請中所使用的“單克隆抗體”群是指同源或基本同源的抗體群(即在ELISA實驗中競爭相同抗原/表位的抗體,或更優選地,在胺基酸序列方面相同的抗體在該群中所占的比例至少為96%或為96%,更優選為不小於約97%或98%,或更加優選為至少99%)。
原生的全長抗體是包含由二硫鍵連接的四條多肽鏈(兩條全長時約為50~70KDa的重(H)鏈,以及兩條全長時約為25KDa的輕(L)鏈)的免疫球蛋白分子。每條鏈的氨基端部分包括由約100~110或更多個用於結合抗原的胺基酸組成的可變區。每條鏈的接基端區域形成主要用於實現效應功能的恆定區。輕鏈分作κ和λ兩類,而且具有特定恆定區。每條輕鏈的特徵在於包括一個N端輕鏈可變區(下文稱為VL或VK)以及一個由單個區域構成的輕鏈恆定區(CL或CK)。重鏈分為γ、δ、α、μ和ε五類,而且分別定義了五類免疫球蛋白:IgG、IgM、IgA、IgD和IgE。某些免疫球蛋白類型還可進一步劃分成IgG1、IgG2、IgG3、IgG4、IgA1和IgA2等亞類(同種型)。每種重鏈類型的特徵在於其特定的恆定區Fc。每條重鏈包括一個N端可變區(下文稱為VH)以及恆定區CH。IgG、IgD和IgA的重鏈恆定區由三個區域構成(CH1、CH2和CH3),而IgM和IgE的重鏈恆定區由四個區域構成(CH1、CH2、CH3和CH4)。VH、
VHH和VL也可分為所謂的超變區(互補決定區,CDR),超變區分散於更為保守的骨架區(FR)之間。每個可變區包括三個CDR和各FR,其從N端至C端的位置順序如下:FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4。
在本申請中,三個重鏈CDR稱為“HCDR1、HCDR2和HCDR3”,而三個輕鏈CDR稱為“LCDR1、LCDR2和LCDR3”。CDR中包含了與抗原特異性相互作用的大部分胺基酸殘基。CDR殘基根據Kabat編號方案編號和定位。
“抗原”一詞是指抗體對其具有反應性的抗原靶,在本申請中,該詞的用法與專業人員在本技術領域對其使用時的用法相同,而且包括但不限於:多肽、肽、多糖、糖蛋白、多核苷酸(如DNA)或化學抗原,受體,或白介素。所述白介素可包括各族內的白介素,例如白介素1(α和β)、白介素2、白介素3、白介素4、白介素5、白介素6、白介素7、白介素8、白介素9、白介素10、白介素11、白介素17、白介素18、白介素33。
“抗原”一詞還可用於描述為了生產本發明抗體的目的而用於對動物(例如大羊駝)進行免疫的物質。在此方面,“抗原”可具有更為廣泛的含義,而且可涵蓋抗原的純化形式以及未純化或未完全分離形式,或純化的抗原產品,如細胞,細胞裂解物,或上清液,細胞碎片(例如,添加了與蛋白質載體偶聯的半抗原的細胞膜等)。免疫用抗原並不一定為與本發明抗體可最終結合的抗原靶在結構上完全相同的抗原。一般而言,免疫用抗原為抗原靶的縮減版本,例如,含有免疫原性表位的片段。關於免疫用抗原的更多細節詳見於文獻中,本技術領域的專業人員對此或許已非常熟悉。
每對輕鏈和重鏈的可變區形成抗體的抗原結合位點。因此,完整IgG抗體具有兩個結合位點。除雙功能或雙特異性抗體之外,上述兩結合位點完全相同。根據本申請,此處所述的“抗原結合區”,“抗原結合位點”,或“抗原結合區域”可互換,而且均指包含與抗原相互作用且賦予抗體針對抗原的特異性及親和力的胺基酸殘基的抗體區。該抗體片段包括保持抗原結合殘基的正確構象所需的骨架胺基酸殘基。
優選地,本發明抗體的VHH抗原結合區或整個抗原結合區的CDR完全源自駱駝科動物或基本源自駱駝科動物,而且包含為了提高抗體的特定性質(如KD、koff或IC50)而改變(例如由各種胺基酸殘基取代(例如,參考表6))的特定胺基酸殘基。優選地,本發明抗體的骨架區源自駱駝科動物或人,或者基本源自於人(例如至少80%、85%、90%、95%、96%、97%、98%或99%源自於人),而且符合Kabat編號方案。
“抗體片段”可以為抗體片段或具有全長抗體活性的抗體片段。所述抗體片段可以為F(ab')2、F(ab)2、Fab'、Fab Fv及scFv。
“白介素17”,也稱為“IL-17”或“IL-17A”,是一種20-30kD的同源二聚體糖蛋白。人IL-17基因所編碼的蛋白由155個胺基酸構成,包括一個19胺基酸的訊號序列以及一個136胺基酸的成熟節片。人IL-17的胺基酸序列與兔、小鼠及大鼠的胺基酸序列的相似度分別為80%,63%和58%。人IL-17的胺基酸序列與食蟹猴IL-17A的同一性為97%。
在本申請中,涉及本發明抗IL-17單克隆抗體(下文稱為“本發明抗體”)時使用的“抗體”一詞指單克隆抗體。
在本申請中,涉及本發明抗體活性時使用的“抑制”或“中和”兩詞是指可顯著阻斷、防止、限制、減慢、停止、降低或逆轉例如抑
制物件的發展或嚴重性的能力,包括但不限於,生物學活性(例如IL-I7活性)或特性,疾病或病症。本發明抗體與IL-17的結合所導致的IL-17活性的抑制或中和程度優選為至少20%、30%、40%、50%、60%、70%、80%、90%、95%或更高。
涉及核酸或蛋白質產物(如抗體)時的“分隔”或“分離”兩詞是指將該核酸分子或蛋白質分子與至少一種通常與天然來源結合的污染物質分隔並鑒定。優選地,“分離抗體”是指該抗體基本不含其他具有特定抗原特異性的抗體(例如,本發明藥物組合物所含的與IL-17A特異性結合的分離抗體基本不含與IL-17A之外的抗原特異性結合的抗體)。
本申請中所使用的“Kabat編號方案”或“根據Kabat的編號”是指用於對抗體重鏈及輕鏈可變區中比其他胺基酸殘基更為可變(即超變)的胺基酸殘基進行編號的系統(Kabat et al.Ann.NY Acad.Sci.,190:382-93(1971)(Kabat等.紐約科學院年報.190:382-93(1971);Kabat et al.Sequences of Proteins of Immunological Interest,Fifth Edition,U.S.Department of Health and Human Services,NIH Publication No.91-3242(1991)(Kabat等.免疫學方面重要蛋白質的序列,第五版,美國衛生及公共服務部.NIH發佈號91-3242(1991))。
多核苷酸與其他多核苷酸的功能性連接稱為“功能性結合”。例如,啟動子或增強子可功能性結合至其所參與轉錄的編碼序列上。如果兩條多肽的編碼多核苷酸(優選位於同一開放閱讀框架內)可功能性結合,則其中一條多肽可“功能性結合”至另一條多肽上。
本申請中所使用的“DNA構建體”一詞是指本發明抗體的編碼DNA或其片段。通常而言,先在開放閱讀框架內,將抗體(例如本發明抗體)的編碼DNA或其片段功能性(以可操作方式)結合至編碼另一
多肽(例如,IL-2受體等另一細胞因數受體的區域)的至少一個其他DNA片段上,然後再將其插入合適的表達載體中。一般情況下,DNA構建體通過如下方式形成:將編碼特定抗體位元點的複數個DNA片段在閱讀框架內功能性關聯,從而獲得編碼完整抗體或其功能性片段的固體構建體。例如,DNA構建體可從N端至C端編碼抗體。針對此類抗體,可進行表達、分離及活性評價。
“載體”是指通過合成及生物技術獲得且含有本領域已知某系列序列功能元素的核酸。某些載體在引入宿主細胞後,可在宿主細胞內自主複製,而其他載體可整合至宿主細胞基因組,並隨宿主基因組同時複製。此外,某些載體可介導其所功能性結合的基因的表達。在本申請中,此類載體稱為“重組表達載體”(或“表達載體”)。各示例性載體均為習知技術所熟知。
本申請中所使用的“細胞”、“宿主細胞”、“細胞系”和“細胞培養物”各詞可互換且指作為任何分離的本發明多核苷酸或任一(或多個)含有本發明抗體序列的重組載體的受體的單個細胞或細胞培養物。宿主細胞包含從單個宿主細胞獲得的各代細胞,由於天然、偶然或故意突變和/或變異,各代細胞可無需與原代宿主細胞完全相同(在形態或全DNA補體方面)。宿主細胞包括由重組載體或表達本發明多核苷酸或其重鏈或輕鏈的單克隆抗體所轉化、轉導或感染的細胞。含有本發明重組載體(無論是否整合入宿主染色體中)的宿主細胞也可稱為“重組宿主細胞”。優選地,本發明所使用的宿主細胞為CHO細胞(例如,ATCC CRL-9096),NS0細胞,SP2/0細胞,COS細胞(ATCC,例如,CRL-1650,CRL-1651)以及HeLa細胞(ATCC CCL-2)。本發明所使用的其他宿主細胞包括植物細胞,酵母細胞,其他哺乳動物細胞以及原核細胞。
抗體和抗原靶(抗原)之間的“特異性結合”一詞是指免疫特異性。如果抗體與某抗原表位
的結合強度高於與其他抗原表位的結合強度,則可稱抗體可特異性結合該抗原靶。特異性結合並不排除與帶有相似抗原表位的其他抗原間的交叉反應性。
本發明的抗體中的VL區既可為λ型VL,也可為κ型VL。“VL區”一詞涵蓋了含有一個或多個胺基酸取代、插入或缺失的VL的λ同種型和κ同種型。
“藥物組合物”一詞涵蓋了含有治療有效量的本發明抗體以及賦形劑(載體、稀釋劑、媒劑、溶劑和其它賦形劑)的製劑和/或組合物。
“使用”或“治療”一詞用於描述使用本發明抗體或含有本發明抗體的藥物組合物,治療及緩和本發明抗體可結合的受體所介導的疾病或失調的病程,加速其緩解,或降低其復發率的能力。
圖1:基於VHH的抗聚集抗體的制取及優化流程圖。
圖2A:人重組IL17A-His6-FLAG產物(15% PAGE+β-ME),其中:1)9E10 0.25μg+β-ME;2)9E10 0.5μg+β-ME;3)9E10 1μg+β-ME;4)---;5)未染色酶標記物;6)施加至IMACBioRad前的介質;7)施加至IMACBioRad後的介質;8)清洗1;9)清洗2;10)清洗3;11)5μL洗脫;12)5μL洗脫;13)10μL洗脫。
圖2B:在VHH區的45位上具有各種胺基酸取代的VHHIgG1產物
(12%PAGE+β-ME),其中:1)2.5μg IgG1對照;2)5μg IgG1對照;3)10μg IgG1對照;4)-;5)未染色酶PW標記物;6)5μL VHHIgG1 aIL17 A45/K8;7)5μL VHHIgG1 aIL17 D45/K8;8)5μL VHHIgG1 aIL17 F45/K8;9)-;10)5μL前VHHIgG1 aIL17 G45/K8培養液;11)5μL後VHHIgG1 aIL17 G45/K8培養液;12)5μL VHHIgG1 aIL17 G45/K8;13)-;14)5μL VHHIgG1 aIL17 H45/K8;15)5μL VHHIgG1 aIL17 I45/K8。
圖2C:在VHH區的45位上具有各種胺基酸取代的產物(8%PAGE,無β-ME),其中:1)2.5μg IgG1對照;2)5μg IgG1對照;3)10μg IgG1對照;4)-;5)未染色酶PW標記物;6)-;7)5μL VHHIgG1 aIL17 A45/K8;8)5μL VHHIgG1 aIL17 D45/K8;9)5μL VHHIgG1 aIL17 F45/K8;10)-;11)5μL前VHHIgG1 aIL17 G45/K8培養液;12)-;13)5μL後VHHIgG1 aIL17 H45/K8培養液;14)-;15)5μL VHHIgG1 aIL17 I45/K8。
圖3:大羊駝組合Fab文庫的合成流程圖。
圖4:用於克隆噬菌體展示Fab文庫的噬菌粒。
圖5:對VHH Fab克隆在與IL-17A結合方面的比較動力學參數進行測試時的傳感圖。
圖6A:三個VHH突變體的聚集穩定性。
圖6B:三個VHH突變體的親和力。
圖7:通過使用VHHIgG1VK4B11、mut1VHHIgG1、mut4VHHIgG1拮抗劑抑制IL-17A從而抑制IL-6生成的細胞試驗。
圖8:含人輕鏈mut4 VHHFab的嵌合變體的分離。
圖9:通過使用mut4VHHIgG1VK3c8、mut4VHHIgG1VK1A7、mut4VHHIgG1VK4E12拮抗劑抑制IL-17A從而抑制IL-6生成的細胞試驗。
圖10A:含在m4VHHc8的44和45位具有突變的抗體的產物在變性劑條件下的蛋白電泳(12%PAGE+β-ME),其中:1)2.5μg IgG1對照;2)Fermentos未染色標記物;3)10μL純化前44V45T VHHIgG1c8培養液;4)10μL純化後44V45T VHHIgG1c8培養液;5)5μL 44V45T VHHIgG1c8;6)5μL 44D45T VHHIgG1c8;7)5μL 44T45T VHHIgG1c8;8)5μL 44A45T VHHIgG1c8;9)5μL 44S45T VHHIgG1c8;10)5μL 44V45V VHHIgG1c8;11)5μL 44D45V VHHIgG1c8;12)5μL 44A45V VHHIgG1c8;13)5μL 44T45V VHHIgG1c8。
圖10B:含在m4VHHc8的44和45位具有突變的抗體的產物在變性劑條件下的蛋白電泳(12%PAGE+β-ME),其中:1)2.5μg IgG1對照;2)5μg IgG1對照;3)10μg IgG1對照;4)Fermentos未染色PW標記物;5)5μL 44V45T VHHIgG1c8;6)5μL 44D45T VHHIgG1c8;7)5μL 44T45T VHHIgG1c8;8)5μL 44A45T VHHIgG1c8;9)5μL 44S45T VHHIgG1c8;10)5μL 44V45V VHHIgG1c8;11)5μL 44D45V VHHIgG1c8;12)5μL 44A45V VHHIgG1c8;13)5μL 44T45V VHHIgG1c8。
圖11A和11B:基於由IL-17A誘導的IL6報告細胞的突變E44R45 m4VHHc8拮抗劑比較分析。
圖12:m4VHHc8的FR2中44和45位上決定輕鏈和重鏈可變區相互作用的不同突變的穩定性及功能特性,其中:與粗虛線對應的為聚集穩定性值和功能活性值之間實現最大程度均衡的組合;與細虛線對應的為具有合適聚集穩定性值且仍保持較高親和力的組合。
圖13:BCD109與各種來源IL-17A相互作用的動力學參數測定結果(測定試驗中使用Octet RED 96設備)。
圖14:BCD109抗體在熱應力施加前後的色譜圖。蛋白濃度在PBS中
調整均衡至10mg/mL,其中:a)為加熱前抗體譜圖;b)為加熱後抗體譜圖。
實施例1:制取基於VHH的抗體的流程
圖1為基於VHH的抗體的制取及優化流程圖。
實施例2:重組抗原及抗體在懸浮哺乳動物細胞培養物中的生成
根據已發表操作方法[26,27],在獲取自中國倉鼠卵巢細胞(CHO-K1)的已建立細胞系中生成抗體和抗原。所使用細胞是可對EBNA1蛋白質(Epstein-Barr病毒核抗原1)的基因進行組成性表達的細胞。上述懸浮培養實施於使用來自Life Technologies Corporation公司的無血清培養基的軌道式振盪器搖瓶內,而且實施過程符合生產商提供的指導內容。為了實現暫態表達,所使用細胞的濃度為2×106/mL,而且使用線性聚乙烯亞胺(Polysciences公司的PEIMAX)對所述細胞進行轉染。其中,DNA/PEI的比例為1:3~1:10。轉染後5~7天,先在2000g的離心力下對細胞培養物離心20分鐘,然後使用0.22μm的篩檢程式過濾。之後,使用親和高效液相色譜(HPLC)從培養液中分離目標蛋白。
使用Profinity IMAC鎳離子樹脂(Bio-Rad)對培養液中的蛋白進行分離和純化,所得蛋白質為C端區域含6個組氨酸的重組IL-17A蛋白質。純化步驟前,先在培養液中加入氯化鎳(NiCl2),並使其濃度達到1mmol/L。然後,再在培養液中加入5mL的Profinity IMAC鎳離子樹脂,並在室溫下通過振盪器混合1小時。將吸附劑移入5mL的Thermo Scientific聚丙烯柱內,並使用5倍於柱體積的磷酸鹽緩衝液(PBS)進行洗脫,以除去非特異性結合的物質。使用0.3mol/L咪唑(pH=8)以及150mmol/L氯化鈉(NaCl)將被結合抗原洗脫後,先通過SnakeSkin透析管
技術將上述蛋白透析於PBS(pH=7.4)中,然後再將其過濾(0.22μm),轉移至管中並保存於-70℃。之後,使用SDS-PAGE法(圖2A-2C)測定所制得蛋白質的純度。
此外,使用1mL的HiTrap rProtein A FF柱(GE Healthcare)並按照上述用於IL-17A-Fc的步驟,對測試及對照IgG1抗體進行了純化,並使用SDS-PAGE法(圖2A-2C)對蛋白純度進行了測定。
實施例3:使用人IL-17對大羊駝的免疫以及噬菌體展示大羊駝抗體Fab文庫的生成
通過抗原物質的皮下給藥對大羊駝連續進行5次免疫,所述抗原物質混合有等體積的完全弗氏佐劑(第一次注射)或不完全弗氏佐劑(除第一次之外的所有其他注射)。上述抗原為重組蛋白混合物(每次注射中,每種蛋白的量為0.2mg),其中的一種重組蛋白為人IL-17A(R&D Systems試劑盒)。第二次注射(免疫階段)在第一次注射三周後實施,其他三次免疫的實施間隔為兩周。從第三次注射開始,每次注射後均採集血液樣品(50mL)。
使用含1mmol/L EDTA的PBS將採集血樣2倍稀釋。將35mL稀釋血樣置於15mL Histopaque®-1077介質(Sigma,密度為1.077g/mL)上,再在800g的離心力下離心20分鐘。從血漿/Histopaque介質兩相間的相間區域選取單核細胞(淋巴細胞和單核白血球),並使用含1mmol/L EDTA的PBS對其進行洗滌。
使用RNeasy MiniKit(QIAGEN)並按照其操作方法從大羊駝單核細胞中分離總RNA後,使用Nanovue(GE Healthcare)測定RNA濃度,其中還使用1.5%瓊脂糖凝膠電泳對已分離RNA的質量進行檢驗。
使用MMLV RT試劑盒(Evrogen)並按照所推薦操作方法實施反轉錄反應,
其中所述試劑盒使用MMuLV反轉錄酶以及隨機六聚體引物。
將上述反轉錄產物用作兩階段聚合酶鏈式反應(PCR)的基質材料,以獲得末端具有限制性位點的可變區基因。上述反應採用寡核苷酸試劑盒且按照文獻[27,28,29]所述操作方法實施。此外,還通過圖3所示的按順序實施酶切、連接和擴增反應,將輕鏈和重鏈可變區的編碼基因放入同一片段內。其中,各重鏈基因分別連接於κ和λ輕鏈基因。在上述情況下,所有反應中基質材料分子的估計數均不小於1011。所獲得的DNA產物(VL-CK-VH)經NheI/Eco91I限制性內切酶處理後連接至原始噬菌粒pH5。噬菌粒結構見圖4。此後,將連接產物轉化至按文獻[30]所述操作方法製備的SS320電感受態細胞內。所構建的κ及λ Fab文庫的所有組成成分數分別為5.1×108和3.7×108。原生噬菌體展示文庫的產物按照先前文獻[31]所述方法製備。
實施例4:選擇噬菌體展示抗體的Fab文庫
使用重組人IL-17A(R&D Systems試劑盒)從噬菌體Fab展示文庫中選出特異性抗IL17A噬菌體展示Fab抗體;一系列循環選擇均按上述操作執行[27,31,32]。在用淘選法實現上述選出過程時,先通過4℃過夜吸附使50mmol/L碳酸鹽緩衝液(pH=9.5)內的人IL-17A吸附于HighSorb管(Nunc)表面,然後使用PBS(pH=7.4)沖洗該管並使用含PBS(pH=7.4)溶液-無脂牛奶(0.5%重量/體積)封閉1小時。其後,將置於PBS(pH=7.4)-無脂牛奶(0.5%重量/體積)內的2~4mL噬菌體溶液(每毫升1012個噬菌體顆粒)與抗原一同移入上述管內,並將其整體在攪拌條件下溫育1小時。之後,通過多次PBS(pH=7.4)-吐溫20(0.1%體積比)沖洗去除未結合噬菌體。其中,沖洗次數從第一輪淘選至第三輪淘選逐步增加,分別為20,30,40次。將仍保持結合的噬菌體顆粒通過在100mmol/L甘氨酸-鹽酸溶液(pH=2.5)中攪拌15分鐘的方式洗脫後,再用1mol/L的Tris-鹽酸溶
液(pH=7.6)中和。使用所獲得的噬菌體感染大腸桿菌TG1,並進一步分離噬菌體,用於下一輪淘選。
上述第二和第三輪淘選後,多克隆噬菌體產物的ELISA檢測顯示已實現顯著富集。此後,將富含人Fab的克隆彙集物再次克隆至在重鏈CH1基因的C端含有myc標籤和His6標籤的表達質粒LL內。
實施例5:Fab與人IL-17A特異性結合分析
使用ELISA法對所調查的Fab片段與人IL-17A的結合特性進行測定。其中,將具有已發表AIN457序列(Novartis)的Fab用作陽性對照。首先,在ELISA板孔(Nunc Immuno Maxisorp)內塗敷50μL(在1倍塗敷碳酸鹽緩衝液內為0.5μg/mL)的IL-17A-Fc,然後將其在4℃下密閉溫育過夜。所有後續步驟均使用GenetixQ-pix2xt(Molecular Devices)和Tecan Freedom EVO 200(Tecan)等高性能系統並按照標準ELISA操作方法實施。其中,先加入用於阻斷非特異性結合的阻斷緩衝液BB(200μL含0.5%無脂牛奶的PBS),然後將孔板於振盪器上室溫溫育1小時。在經PBS-吐溫沖洗後,在每個板孔內塗敷50μL與等體積BB混合的含被測Fab的細胞上清液。其後,將孔板於振盪器上室溫溫育1小時,然後將使用PBS-吐溫緩衝液將每個板孔沖洗5次。沖洗後,在每個板孔內塗敷(50μL/孔)溶於PBS-吐溫(1:5000)內的與抗人Fab-HRP偶聯的第二抗體(Pierce-Thermo Scientific)。之後,將孔板移至旋轉振盪器上在室溫下振盪50分鐘,並以與上述同樣的方式使用PBS-吐溫緩衝液沖洗5次。其後,加入TMB(100μL/孔)直至飽和(平均3~5分鐘),以獲得比色訊號。為了防止進一步顯色,還加入終止溶液(100μL/孔,10%硫酸)。之後,採用合適的Tecan-Sunrise孔板讀取器(Tecan)在450nm處測定吸光度。其中,抗體結合性與生成訊號成正比。對於色度訊號比基線訊號高出5倍以上的克隆,還通過競爭性ELISA對其進行了測定,以揭示可
阻斷IL-17A配體和受體間相互作用的拮抗性Fab。
實施例6:阻斷IL-17A配體和IL17R受體間相互作用的競爭性ELISA
競爭性ELISA技術是用於測定通過上述方法選出的人IL-17A特異性Fab的拮抗能力。其中,將具有已發表AIN457序列(Novartis)的Fab用作陽性對照拮抗劑。首先,在ELISA板孔(Nunc Immuno Maxisorp)上以50μL/孔的量加入IL-17RA-Fc受體(R&D Systems,在1倍塗敷碳酸鹽緩衝液內為1μg/mL溶液),然後將其在4℃下溫育過夜。所有後續步驟均使用GenetixQ-pix2xt(Molecular Devices)和Tecan Freedom EVO 200(Tecan)等高性能系統並按照標準ELISA操作方法實施。其中,加入阻斷緩衝液BB(PBS內的200μL 0.5%無脂牛奶)阻斷非特異性結合,然後將孔板於振盪器上室溫溫育1小時。
與此平行,在非結合96孔板中,將50μL含被測Fab的細胞上清液與50μL的IL-17A-His6-Flag(在由PBS-吐溫稀釋的1%牛奶中為0.4μg/mL)相混合,然後將該孔板在振盪器上以500rpm的速度在37℃溫育1小時。
在使用BB溶液對所述含有IL-17RA-Fc受體的孔板進行沖洗後,再以90μL每孔的量在其上塗敷Fab與IL-17A-His6-Flag的反應混合物。其後,將孔板在振盪條件下室溫溫育45分鐘,並使用PBS-吐溫緩衝液將每個板孔沖洗5次。此外,還以50μL/孔的量添加1μg/mL抗FLAG鼠M2抗體(Sigma),並將孔板在室溫下溫育45分鐘。溫育後,使用PBS-吐溫將每個板孔沖洗5次,然後在其上以50μL/孔的量塗敷以1:5000稀釋於PBS-吐溫內的與抗鼠IgG-HRP偶聯的第二抗體(Pierce-ThermoScientific)。之後,與上述相同,將孔板在旋轉振盪器上室溫溫育45分鐘後用PBS-吐溫沖洗5次。其後,加入TMB(100μL/孔)直至飽和(平均3~5分鐘),以獲得比色訊號。為了防止進一步顯色,還加入終止溶液(100μL/
孔,10%硫酸);採用合適的Tecan-Sunrise孔板讀取器(Tecan)在450nm處測定吸光度。其中,抗體結合性與生成訊號成正比。
將阻斷程度與作為對照的Fab抗體AIN457相當的克隆標為陽性,用於進一步試驗。此外,還使用Applied Biosystems 3130基因分析儀(Applied Biosystems),按照標準操作方法,對陽性克隆的可變區基因進行測序,並在其後對其進行適當的分析。其中,將含有3VHHFab可變區的克隆(見序列1)選出用於進一步分析,所述序列1如下所示:
1VHH
2VHH
3VHH
此外,已發現的是,3VHHFab克隆的表示式中結合有23個不同序列的輕鏈區,所述序列中的三個見序列2所示:
VK4B11
VLB5
VLF4
這說明了其具有相對結構抗力和對IL-17A結合貢獻尤其大的是VHH區而非輕鏈的事實。
實施例7:抗IL-17A VHHFab候選物的競爭性koff(kdiss)篩選
使用Pall ForteBio Octet Red 96系統對抗IL-17A Fab候選物實施競爭性koff篩選。將抗FABCH1的生物感測器在含10mmol/L PBS(pH=7.2~7.4),0.1%吐溫20以及0.1%牛血清白蛋白(BSA)的工作緩衝液中水化30分鐘後,將10倍工作緩衝液加入大腸桿菌上清液的測試樣品中,使得最終濃度變為1倍工作緩衝液。然後,將抗FABCH1生物感測器浸入含候選抗體Fab片段的大腸桿菌上清液中,並在4℃的溫度下溫育12小時。其後,將表面帶有Fab片段的感測器移入盛有工作緩衝液的板孔中,以設定基線值(60秒)。之後,將感測器移入盛有分析物溶液(30μg/mL的IL-17A)的板孔中,以實現抗原-抗體結合(300秒)。在此之後,將感測器再一次移入盛有工作緩衝液的板孔中,以進一步實現解離(300秒)。每次測試後,均通過將所使用感測器三次置於再生緩衝液(甘氨酸-鹽酸,
pH=1.7)中的方式使其再生,從而使其還可用於進一步實驗。所得曲線採用Octet資料分析軟體(7.0版)進行分析。其中,所述分析按照標準操作方法實施,並採用1:1相互作用模型。
圖5和表1所示為抗IL-17A Fab候選物的koff篩選結果,其表明所有各VHHFab均可與人IL-17A進行特異性高親和力結合,其中,3VHHFab具有極高的kon以及超出儀器檢測限的極低kdis(1/c)。
因此,根據上述分析結果,選出3VHHVK4B11候選物用於進一步分析。
實施例8:VHH可變區的FR1和FR2中含有突變的VHHIgG1抗體的生成
如實施例3中所述,將3VHHVK4B11候選物的輕鏈VHH和重鏈VHH的可變區基因克隆至pEE-Hc和pEE-Lc質粒中,以在CHO-EBNA細胞中共同暫態表達。進一步,還根據Q5®定點突變試劑盒(NEB)的操作方法以及文獻[33]中描述的步驟,通過由PfuUltraHS聚合酶(Stratagene)實現的寡核苷酸定點突變,在第44和45位(Kabat編號方案)引入胺基酸取代。此後,將質粒pEE-3VHH用作基質。PCR產物在低熔點瓊脂糖中相互分離後,再使用合適的純化柱純化。連接後,將DNA轉化至大腸桿菌。選出具有正確序列的突變克隆後,將3VHH具有突變的質粒與pEE-LcVK4B11共轉染(見序列3和表2)。所述序列3如下所示:
Wild 3VHHFab
mut1
mut2
mut3
mut4
實施例9:VHH可變區的FR1和FR2中含有突變的VHHFab抗體的動力學參數的比較分析
根據標準操作方法,使用Pall Forte Bio Octet Red 96系統對抗IL-17A VHHFab候選物實施競爭性koff篩選(參見實施例8)。結果顯示,與原生3VHHFab相比,mut1,mut2,mut4的koff顯著降低,而mut3的koff降低較為不顯著(見圖6A所示)。
實施例10:VHH可變區的FR1和FR2中含有突變的全長3VHHIgG1VK4B11抗體的熱-聚集特性的比較分析
按照下述步驟,對抗IL-17A VHHIgG1候選物的聚集特性進行比較分析。首先,將製備的VHHIgG1抗體(10mg/mL)在PBS緩衝液中於50℃加熱6小時。然後,使用尺寸排阻高效液相色譜對熱應力所引起的聚集進行評價。該試驗由配備7.8mm×30cm的Tosoh TSK-Gel G3000SWXL柱(產品編號:08541)以及6.0mm×4.0cm的Tosoh TSKgel Guard SWXL預柱(粒徑7μm,產品編號:08543)的1100高效液相色譜系統(Agilent)進行等度洗脫。流動相含有50mmol/L的磷酸鈉緩衝液以及0.3mol/L的NaCl(pH=7.0),流速為0.5mL/min,檢測波長為214nm和280nm。抗體樣品由PBS(pH=7.5)稀釋至濃度~1mg/mL,進樣體積為10μL。試驗前,使用凝膠過濾標準混合物(Bio-Rad,產品編號:151-1901)對色譜柱進行標定。
圖6B所示色譜圖及表3的總結內容表明:在熱應力的作用下,所有突變產物都發生了不同程度的聚集,其中,原生變體的穩定性最低,而含有經典VH結構常見的E44G(44位上甘氨酸對谷氨酸的取代)及R45L(45位上亮氨酸對精氨酸的取代)的mut1的穩定性最高。
此外,還使用Thermofluor法(也稱熱轉移分析)對所得製備物
的熱穩定性進行比較分析,該法用於測定蛋白熔點,用於衡量其在可與未折疊蛋白的疏水性表面特異性結合的染料寶石橙(SYPRO Orange)的螢光下所發生的改變[34]。針對變異產物,還使用StepOne即時PCR系統(Applied Biosystems)並根據所推薦的操作方法對其進行分析。分析結果示於表3。這些分析結果與上述熱應力試驗的結果關聯性非常高,從而證實mut1和mut4比野生3VHHIgG1VK4B11更加穩定。
實施例11:抗IL17A 3VHHIgG1VK4B11突變產物阻斷IL-17A誘導IL-6生成的能力的細胞試驗
利用IL-17誘導人HT1080細胞(ATCC:CCL-121)生成IL-6的能力,對VHHIgG1候選物mut1和mut4對人重組IL-17A的中和活性進行分析。首先,在添加有10%滅活胎牛血清、慶大黴素和穀氨醯胺的DMEM培養基中培養細胞,然後將細胞以5×104個/孔的量等量接種于96孔培養板中,並使其附著5小時。其後,將40ng/mL重組IL-17與20ng/mL TNF-α的混合物與VHHIgG1稀釋液在37℃下共同
溫育1小時。之後,在板孔中添加細胞因數/抗體混合物並放置過夜。其中,HT1080細胞所生成IL-6的量與IL-17的添加量成正比。此外,通過ELISA技術,並使用DuoSet ELISA開發系統的人IL6(RD System,產品編號:DY206),對釋放於細胞上清液樣品中的IL-6的量進行測定。圖7所示為VHHIgG1候選物與AIN457(來自Novartis的抗IL-17A抗體)的拮抗特性測定結果比較。mut1的IC50值幾乎為原生變體的30倍,而mut4變體幾乎完全保持其抑制能力。此外,mut4候選物的IC50值為was 30±10pmol/L。基於本分析中所得結果以及整體的物化及生物特性,將上述候選物選為進一步開發和優化的物件。
實施例12:含人輕鏈mut4VHHFab抗體的基因改造
根據合適的操作方法(QIAGEN),使用RNeasy Mini試劑盒對55名人類供體的B淋巴細胞總RNA進行分離。此外,還使用Nanovue試劑盒(GE Healthcare)測定RNA濃度,並使用1.5%瓊脂糖凝膠電泳對已分離RNA的質量進行檢驗。
使用MMLV RT試劑盒(Evrogen)並按照所推薦操作方法實施反轉錄反應,其中所述試劑盒使用MMuLV反轉錄酶以及隨機六聚體引物。
將上述反轉錄產物用作兩階段聚合酶鏈式反應(PCR)的基質,以獲得末端具有限制性位點的可變區基因。該反應採用寡核苷酸試劑盒且按照文獻[27]所述操作方法實施。與上述相同,還根據WO93/06213所述方法,使用噬菌粒pH5生成與IL-17A具有特異性的嵌合Fab。此外,還通過圖8所示按順序實施的酶切、連接和擴增反應,將人輕鏈可變區的編碼基因與mut4 VHH可變區的編碼基因放入同一片段內。在此情況下,所有反應中基質分子的估計數為不小於1012。所獲得的DNA產物(VL-CK-VH)經NheI/Eco91I限制性內切酶處理後連接至原始噬菌粒pH5。此後,將連接產物轉化至按文獻[30]所述操作方法製備的SS320電感受態細胞內。基於混合κ及λ人鏈的嵌合mut4 VHH Fab文庫的總轉化體
數為2.8×109。嵌合噬菌體展示Fab文庫按照以上所述方法[27]製備。
噬菌體展示嵌合Fab文庫的淘選條件與上述相同(參見實施例5),但不包括將已結合IL17A的噬菌體抗體在20μg/mL溶解IL-17A中於37℃進一步溫育12小時。
在利用IL-17A的第二輪淘選後,所述文庫呈現顯著富集。此後,將所得的富集後嵌合mut4 VHH Fab文庫的克隆彙集物用於按照標準操作方法(參見實施例6)實施針對IL-17A的篩選,並將最終所得陽性克隆測序。
序列4所示是來源於高親和性mut4 VHHFab的VK1A7,VK3cl8,VK3cl18,VK4clE12四個人輕鏈可變區序列;其中:
VK1A7
VK3cl8
VK3cl18
VK4clE12
上述序列屬於含最少體突變的不同人κ生殖細胞系VK1,VK3,VK4。應當注意到的是,雖然人序列VK4clE12顯示出與上述選出的大羊駝輕鏈VK4B1的高度同源性,但兩者之間仍然具有性狀差異。
實施例13:含有各種輕鏈變體的全長mut4VHHIgG1抗體的熱-聚集特性的比較分析
如實施例3中所述,將mut4 VHH候選物的重VHH鏈可變區基因克隆至pEE-Hc質粒中,並將人輕鏈可變區基因VK1A7,VK3cl8,VK3cl18,VK3A4,VK4E12克隆至pEE-Lc質粒中,以在CHO-EBNA細胞中共同暫態表達。此外,還將獲得的抗體暴露於熱應力下,並按照實施例9所述方式分析其聚集特性。所得結果示於匯總表內(表4)。
此外,還使用與實施例11所述類似的Thermofluor法,對所得產物實施熱穩定性比較分析。根據所得資料,可得出的結論是,選出的含人輕鏈的mut4VHH對的穩定性高於含VVK4B11大羊駝輕鏈的原生變體。因此,上述比較分析表明mut4 VHHIgG1VK1A7及mut4 VHHIgG1VK3c18組合具有最佳的聚集穩定性參數。
實施例14:使用mut4 VHHIgG1VK3c8和mut4 VHHIgG1VK1A7阻斷IL-17A誘導IL-6生成的能力的細胞試驗
利用IL-17誘導人HT1080細胞(ATCC:CCL-121)生成IL-6的能力,對VHHIgG1候選
物mut4 VHHIgG1VK3c8和mut4 VHHIgG1VK1A7對人重組IL-17A的中和活性進行分析(參見實施例12)。該阻斷試驗結果如圖9所示。應當注意到的是,mut4 VHHIgG1VK1A7變體(其特徵為具有最大穩定性)呈現出顯著的IC50值降低,而mut4 VHHIgG1VK3c8變體(中等穩定性)的抑制能力比穩定性更高的mut4 VHHIgG1VK1A7變體高出數倍。
實施例15:在VHH可變區FR2的44和45位上含各種突變的mut4 VHHIgG1全長抗體的基因改造及其聚集和功能特性的比較分析
為了進一步提高聚集穩定性,使用寡核苷酸定點突變方法在mut4 VHHIgG1VK3c8候選物(下稱m4VHHc8)的VHH的FR2區內44和45位上引入胺基酸取代。由於存在潛在免疫原性及結構上不允許,此分析中不包含在44位上為芳香族胺基酸,脂肪族胺基酸或正電荷胺基酸的變體。各變體按照實施例2所述方式暫態表達。其中,雖然不同實驗內各突變體產物具有不同的量,但是應該注意的是,同一實驗內所有取代具有類似產率(圖10A:還原性SDS-PAGE;圖10B:非還原性SDS-PAGE)。將所得突變產物暴露於熱應力下,不同突變體所獲得的
試驗結果見表5所示。可以看出,較為不穩定的突變產物為44G45G和44G45D,其穩定性小於m4VHHc8的初始44G45R組合。在較大程度上保持穩定性的突變產物為44G45N,44V45T,44D45T,44T45T,44D45V。所有其他組合均實現了提高m4VHHc8聚集穩定性的疊加效應,其中最為穩定的是45位上含芳香族或脂肪族基團的突變產物。然而,44G45V,44G45T,44V45V,44A45V,44T45V,44A45T,44S45T等在上述兩位上均含有小的親水及疏水性胺基酸的突變產物同樣顯示出了顯著的穩定性。
針對各突變產物(圖11A至11B),還實施實驗,以對實施例12所述細胞試驗內的中和活性進行評價。試驗結果見表5所示。其表明,VHH FR2的44及45位上小的胺基酸表現出高的拮抗活性,而45位上大的胺基酸(脂肪族及芳香族)導致IC50降低10倍。圖12所示為含有各種決定輕重鏈可變區相互作用的胺基酸取代的突變產物的穩定性及功能特性。
實施例16:抗IL17A 3VHH區CDR的掃描誘變
通過使用Q5®定點突變試劑盒(NEB)的NNK隨機化技術[26],並按照該試劑盒的操作方法,在候選物CDR的各個位置插入突變。其後,將質粒pLL-Fab用作基質。PCR產物在低熔點瓊脂糖中相互分離後,再使用合適的純化柱純化。連接後,將DNA轉化至大腸桿菌表達菌株BL21 gold(Stratagene)。其後,以與上述相同的方式,通過96孔板在所獲得的各克隆上增添Fab表達物。然後,通過與上述相同條件的ELISA,並使用高性能Genetix Q-pix2xt及Tecan Freedom EVO200系統,對含有突變Fab臂的上清液進行分析。其中,被固定IL-17A的濃度為0.2μg/mL。在使用1:5000稀釋的山羊抗人IgG F(ab')2(HRP)偶聯物(Pierce)以及TMB+雙氧水/硫酸染色劑對結合的Fab臂染色後,在450nm波長處測定吸光度。
上述掃描誘變的結果如表6所示。如該表所示,與野生型序列相比,CDR內取代所導致的突變Fab與人IL-17的結合訊號下降率小於或等於30%。由此可見,所述各突變產物及其任何組合均屬於本發明範圍內。
其表明,此類胺基酸取代並不會顯著改變抗體對人IL-17的親和力。因此,此類胺基酸取代可用於改善該候選物的各種特性。
實施例17:BCD109候選物的基因改造及其與不同來源IL-17A親和力的評價通過在含44G45T取代(見實施例16中描述)的m4VHHc8變體的VHH內引入不導致穩定性和IC50(資料未給出)發生改變的人源化突變Q5V(5位上纈氨酸對穀氨醯胺的取代)和R89V(89位上纈氨酸對精氨酸的取代),以及在其CH2區的FcIgG1內引入232Y(232位酪氨酸)、234T(234位蘇氨酸)和236E(236位谷氨酸)三個插入突變,獲得BCD109抗體,以提高該抗體的藥代動力學特性。其中,所述抗體為已暫態表達抗體。
其後,採用OctetRed 96系統(ForteBio)對BCD109與人、猴及大鼠IL-17A的結合親和力進行試驗。其中,根據製造商手冊中所述的標準操作方法,將BCD109非特異性地固定於胺反應性二代感測器(AR2G)表面上。上述試驗在30℃的溫度下進行,並使用含0.1%吐溫20和0.1% BSA的PBS作為工作緩衝液。使用上述工作緩衝液以2為漸增量,將人、猴及大鼠IL-17A從126nmol/L滴定至2nmol/L。
採用Octet資料分析軟體(7.0版)對結合曲線(已減去參考訊號)進行分析。其中,所述分析按照標準操作方法實施並使用1:1相互作用模型,分析結果見圖13所示。
可以看出,BCD109以pmol/L級的親和力與人和猴IL-17A結合(表7和表8)。此外,所述候選物並不與大鼠IL-17A相互作用(曲線未示出)。
實施例18:BCD109在熱應力作用下聚集穩定性的測定
按照實施例9所述操作方法,將製備的BCD109在PBS中以10mg/mL的濃度於50℃下加熱6小時。
圖14所示結果表明:BCD109抗體在熱應力作用下仍保持穩定,聚集物含量小於5%。
實施例19:含有本發明抗體的藥物組合物的制取
將BCD109抗體以50mg/mL的濃度溶於適量的注射用水中,並使用檸檬酸將其pH值調至5.5。所述溶液經過濾(過濾除菌)後密封於安瓿中。所得產品在6個月內保持穩定,未出現沉澱。
或者,將BCD109溶於含有甘露醇的水中,並在過濾(過濾滅菌)後冷凍乾燥,其中,甘露醇作為凍幹保護劑。所得粉末分裝至無菌小瓶後,用橡膠塞塞緊後鋁蓋密封。所述抗體產物可通過注射用水從上述凍幹物中得以恢復。
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Claims (28)
- 一種特異性結合人IL-17A的人源化單克隆IgG抗體,其中可變區包含:a)一種含有HCDR1、HCDR2和HCDR3三個超變區的駱駝科動物的重鏈可變區VHH衍生物,其中:HCDR1包含SEQ ID NO.1所示的如下胺基酸序列:G-T-F-A-T-X32-X33-X34-X35(根據Kabat指數編號),其中:X32是選自S、N、K、R、E、W、Q、D、A、V和F的胺基酸;X33是選自P或S的胺基酸;X34是選自M和I的胺基酸;X35是選自G、N、S、A、L、I、R、V和Q的胺基酸;HCDR2包含SEQ ID NO.2所示的如下胺基酸序列:X50-I-X52-X52a-S-G-X55-D-R-I-Y-A-D-S-V-K-G,其中:X50是選自A、G和L的胺基酸;X52是選自S的胺基酸;X52a是選自P和A的胺基酸;X55是選自G、S、T、L、R、D、E、K和A的胺基酸;HCDR3包含SEQ ID NO.3所示的如下胺基酸序列:C-A-X94-X95-X96-X97-F-X99-X100-X100a-X100b-X100c-X100d-X100e-X100f-D-Y-D-S,其中:X94是選自K、S、T、V、D和G的胺基酸;X95是選自R和K的胺基酸;X96是選自G、R、Y、H、D、W和K的胺基酸; X97是選自R、A、V、S、L和H的胺基酸;X99是選自D、E、G、A、R、V、K和Q的胺基酸;X100是選自G、S和N的胺基酸;X100a是選自G、T、P、V、R、N和K的胺基酸;X100b是選自V、S、T、L、A、H、G和I的胺基酸;X100c是選自Y、W和S的胺基酸;X100d是選自R、V、L、Y、A、W、K、G、Q和I的胺基酸;X100e是選自T、L、A和S的胺基酸;X100f是選自T、L、G、P、N、A、Q、F、I和D的胺基酸;以及b)一種人抗體的輕鏈VL可變區或人源化抗體的輕鏈可變區。
- 如請求項1所述的抗體,其中VHH衍生物包含在44和45位上的如下胺基酸取代:a)44X2,其中,X2=G、A、V、S、T;b)45X3,其中,X3=A、V、T、H;或其組合。
- 如請求項1或2所述的抗體,其中VHH衍生物與分離自免疫動物的初始VHH抗體相比具有增加的聚集穩定性,所述免疫動物源自駱駝科。
- 如請求項1所述的抗體,其中所述輕鏈VL可變區是人抗體衍生物。
- 如請求項1所述的抗體,其中所述輕鏈VL可變區是哺乳類動物抗體的人源化片段。
- 如請求項1所述的抗體,其中所述的抗體是以下任一同型:IgG1、 IgG2、IgG3或IgG4。
- 如請求項1所述的抗體,其中所述抗體具有如下聚集穩定性:當使用濃度高於10mg/mL且在50℃下儲存6小時以上後,溶液中聚集物含量的增加量不超過初始含量的5%。
- 如請求項1所述的抗體,其中所述抗體的解離常數KD10-9M。
- 如請求項1所述的抗體,其中所述抗體的抗體-抗原相互作用的動力學結合常數kon105 1/ms。
- 如請求項1所述的抗體,其中所述抗體的抗體-抗原相互作用的動力學解離常數dis10-4 1/s。
- 如請求項1所述的抗體,其中:所述HCDR1包含SEQ ID NO.4所示的胺基酸序列:G-T-F-A-T-S-P-M-G;所述HCDR2包含SEQ ID NO.5所示的胺基酸序列:A-I-S-P-S-G-G-D-R-I-Y-A-D-S-V-K-G;以及所述HCDR3包含SEQ ID NO.6所示的胺基酸序列:C-A-V-R-R-R-F-D-G-T-S-Y-Y-T-G-D-Y-D-S。
- 如請求項1所述的抗體,其中所述重鏈可變區VHH衍生物含有SEQ ID NO.7所示的如下胺基酸序列:
- 如請求項1所述的抗體,其中所述重鏈可變區VHH衍生物包含 SEQ ID NO.7所示胺基酸序列,以及所述人抗體的輕鏈VL可變區含有SEQ ID NO.8所示如下胺基酸序列:
- 如請求項1所述的抗體,其中所述重鏈可變區VHH衍生物包含:SEQ ID NO.9所示如下胺基酸序列: ;以及所述人抗體輕鏈VL可變區含有SEQ ID NO.10所示如下胺基酸序列:
- 如請求項1所述的抗體,其中所述抗體與人IL-17A的結合親和力的特徵參數KD10-10M。
- 如請求項1所述的抗體,其中所述抗體與人IL-17A的動力學結合常數kon105 1/ms。
- 如請求項1所述的抗體,其中所述抗體與人IL-17A的動力學解離常數dis10-5 1/s。
- 如請求項1所述的抗體,其中所述的抗體產自哺乳動物、酵母或細菌細胞。
- 一種包含如請求項1至18任一項所述的抗體的片段,其中該片段係為Fab(fragment of antigen binding)片段。
- 一種DNA構建體,包含編碼的請求項1至18任一項所述的抗體或請求項19所述的抗體片段。
- 一種表達載體,包含一個或多個請求項20所述的DNA構建體。
- 一種細胞系,包含請求項20所述的DNA構建體或如請求項21所述的表達載體。
- 一種生產請求項1至18任一項所述的抗體或請求項19所述的抗體片段的方法,包含將請求項22所述的細胞系在足以獲得所述抗體或其片段的條件下培養於培養基中,然後對所獲得的抗體或其活性片段進行分離純化。
- 一種宿主細胞,包含請求項21所述的表達載體。
- 一種生產請求項1至18任一項所述的抗體或請求項19所述的抗體片段的方法,包含將請求項24所述的宿主細胞在足以獲得所述抗體或其片段的條件下培養於培養基中,然後對所獲得的抗體或其活性片段進行分離純化。
- 一種藥物組合物,包含請求項1至18任一項所述的抗體或請求項19所述的抗體片段與一種或多種藥學上適用的賦形劑、稀釋劑或載體的組合。
- 如請求項26所述的藥物組合物,更包含選自TNF-α抑制劑的活性藥物成分。
- 一種請求項26所述的藥物組合物用於製備治療IL-17A介導的疾病或失調的藥物的應用。
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RU2680011C2 (ru) | 2016-04-29 | 2019-02-14 | Закрытое Акционерное Общество "Биокад" | Триспецифические антитела против il-17a, il-17f и другой провоспалительной молекулы |
JP2021506310A (ja) | 2017-12-22 | 2021-02-22 | アルゲン−エックス ビーブイビーエー | 二重特異性抗原結合コンストラクト |
GB201802487D0 (en) | 2018-02-15 | 2018-04-04 | Argenx Bvba | Cytokine combination therapy |
JP7122672B2 (ja) * | 2018-06-08 | 2022-08-22 | パナソニックIpマネジメント株式会社 | Vhh抗体 |
JPWO2020054829A1 (ja) * | 2018-09-14 | 2021-09-02 | ルカ・サイエンス株式会社 | ミトコンドリアのリンパ器官への移植およびそのための組成物 |
EP3689907A1 (en) | 2019-01-31 | 2020-08-05 | Numab Therapeutics AG | Antibodies targeting il-17a and methods of use thereof |
JP7525499B2 (ja) | 2019-01-31 | 2024-07-30 | ヌマブ セラピューティクス アクチェンゲゼルシャフト | TNFα及びIL-17Aに対する特異性を有する多重特異性抗体、IL-17Aを標的とする抗体、及びそれらの使用方法 |
RU2754760C2 (ru) * | 2019-04-02 | 2021-09-07 | Закрытое Акционерное Общество "Биокад" | Водная фармацевтическая композиция анти-il17a антитела и ее применение |
CN112239501B (zh) * | 2020-10-29 | 2022-01-07 | 东莞市朋志生物科技有限公司 | 抗新型冠状病毒的抗体、检测新型冠状病毒试剂和试剂盒 |
CN114380917B (zh) * | 2022-03-25 | 2022-06-14 | 南京融捷康生物科技有限公司 | 针对IL-17A和TNFα的双特异性单域抗体及其用途 |
CN114380906B (zh) * | 2022-03-25 | 2022-06-14 | 南京融捷康生物科技有限公司 | 一种抗il-17a的单域抗体及其用途 |
CN117843777B (zh) * | 2023-12-21 | 2024-08-27 | 北京贝来药业有限公司 | 用于炎性疾病治疗的新型纳米抗体及其产品和方法 |
CN117843802B (zh) * | 2023-12-29 | 2024-09-06 | 北京贝来药业有限公司 | 串联抗体及其下游产品和应用 |
CN117820479A (zh) * | 2023-12-29 | 2024-04-05 | 北京贝来药业有限公司 | 抗il-17a的新型纳米抗体 |
CN117843801B (zh) * | 2023-12-29 | 2024-08-02 | 北京贝来药业有限公司 | 以白介素家族成员为靶点的新型抗体以及下游产品 |
CN118206654B (zh) * | 2024-03-05 | 2024-09-20 | 北京贝来药业有限公司 | 用于疾病治疗的新型抗体及其产品和应用 |
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