TW202212362A - 抗ceacam5抗體及其結合物及用途 - Google Patents
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Abstract
本發明提供結合人類CEACAM5蛋白之抗體,及包含編碼該等抗體之序列之經分離核酸及宿主細胞。本發明亦提供包含該等抗體連接至生長抑制劑之免疫結合物,及包含本發明之抗體或免疫結合物之醫藥組合物。本發明亦提供本發明之抗體、免疫結合物及醫藥組合物於治療癌症或於診斷目的之用途。
Description
本發明係關於結合人類CEACAM5蛋白之抗體,及係關於包含編碼該等抗體之序列之經分離核酸及宿主細胞。本發明亦係關於包含連接至生長抑制劑之該等抗體之免疫結合物,及係關於包含本發明之抗體或免疫結合物之醫藥組合物。本發明亦係關於本發明之抗體、免疫結合物及醫藥組合物於治療癌症或於診斷目的之用途。
癌胚抗原(CEA)係參與細胞黏著之醣蛋白。1965年(Gold及Freedman, J Exp Med, 121, 439, 1965)將CEA首次鑑別為在妊娠前六個月期間由胎兒腸道正常表現及許多癌症(諸如結腸直腸癌或胰臟癌)中發現之蛋白質。CEA家族屬於免疫球蛋白超家族。由18個基因構成之CEA家族細分為兩個蛋白質子組:癌胚抗原相關細胞黏著分子(CEACAM)子組及妊娠特異性醣蛋白子組(Kammerer及Zimmermann, BMC Biology 2010, 8:12)。
在人類中,CEACAM子組由7個成員構成:CEACAM1、CEACAM3、CEACAM4、CEACAM5、CEACAM6、CEACAM7及CEACAM8。據報導,與初始鑑別之CEA相同之CEACAM5高度表現於癌細胞(諸如,舉例而言,結直腸、胃、肺及胰臟腫瘤細胞)表面上,且於正常組織中之表現僅限於少數正常上皮細胞(諸如結腸及食管上皮細胞)。因此,CEACAM5可構成適用於腫瘤特異性靶向方法之治療標靶,諸如免疫結合物。
CEACAM家族成員之細胞外域由重複之免疫球蛋白樣(Ig樣)域構成,根據序列同源性將該等域分為3種類型,A、B及N。CEACAM5含有七個此等域,即N、A1、B1、A2、B2、A3及B3。一方面CEACAM5 A1、A2及A3域,及另一方面B1、B2及B3域,顯示高序列同源性,人類CEACAM5之A域呈現84至87%成對序列相似性,及B域呈現69至80%成對序列相似性。此外,結構中呈現A及/或B域之其他人類CEACAM成員(即CEACAM1、CEACAM6、CEACAM7及CEACAM8)顯示與人類CEACAM5之同源性。特別地,人類CEACAM6蛋白之A及B域分別顯示與人類CEACAM5之A1及A3域及B1至B3域中之任一者之序列同源性,甚至高於彼等在人類CEACAM5之A域及B域中觀察到者。
已產生抗CEA抗體用於CEA靶向診斷或治療目的。對相關抗原之特異性始終作為此領域中之一關注點提及,例如Sharkey等人(1990, Cancer Research 50, 2823)。由於上文提及之同源性,先前描述之抗體中之一些可證實結合(例如)至不同免疫球蛋白域中存在之CEACAM5之重複性抗原決定基並顯示對其他CEACAM家族成員(諸如CEACAM1、CEACAM6、CEACAM7或CEACAM8)之交叉反應性,因此缺乏對CEACAM5之特異性。然而,CEA靶向療法需抗CEACAM5抗體之特異性,使得該抗體結合至表現人類CEACAM5之腫瘤細胞但不結合至表現其他CEACAM家族成員之某些正常組織。值得注意的是,已將CEACAM1、CEACAM6及CEACAM8描述為由人類及非人類靈長類動物之嗜中性球表現(EbrahImmnejad等人,2000, Exp Cell Res, 260, 365;Zhao等人,2004, J Immunol Methods 293, 207;Strickland等人,2009 J Pathol, 218, 380),其中其等已顯示調節顆粒球生成並在免疫反應中發揮作用。出於治療目的,抗CEACAM5抗體與CEACAM1、CEACAM6、CEACAM7或CEACAM8之交叉反應性可因此由於正常組織中毒性增加而降低該化合物之治療指數。因此,需要特異性針對CEACAM5之不與CEACAM家族之其他分子交叉反應的抗體,例如用作抗體藥物結合物(ADC)之部分或用於導致殺死靶細胞之任何其他方法中。
此外,由於將CEACAM5描述為表現於一些正常細胞組織中,因此需開發可結合至人類CEACAM5及食蟹獼猴(
Macaca fascicularis) CEACAM5之抗CEACAM5抗體,因為可在臨床前毒物學研究中在食蟹獼猴中容易測試此等抗體以評估其等安全性概況。
a)物種交叉反應性與b)對人類及食蟹獼猴CEACAM5之特異性(即與其他食蟹獼猴及人類CEACAM家族成員無交叉反應性)之需求之組合進一步增加開發新抗CEACAM5抗體之複雜性,尤其考慮到人類與食蟹獼猴CEACAM蛋白之間的整體序列同源性。
此外,文獻中將CEACAM5描述為差內化性表面蛋白(回顧Schmidt等人,2008, Cancer Immunol. Immunother. 57, 1879),其為針對此靶蛋白之抗體藥物結合物提出另一挑戰。
已知抗CEACAM5抗體包括Immunomedics之拉貝珠單抗(labetuzumab) (亦稱為hMN14;Sharkey等人,1995, Cancer Research 55, 5935)。已顯示此抗體不結合至相關抗原,且亦不與來自食蟹獼猴之CEACAM5交叉反應。拉貝珠單抗亦已用作抗體-藥物結合物(ADC)(即拉貝珠單抗哥維坦(labetuzumab govitecan))之部分。拉貝珠單抗哥維坦係由經由包含pH敏感性碳酸酯及短聚乙二醇(PEG)鏈之連接子(稱為CL2A)結合至抗CEACAM5抗體拉貝珠單抗之細胞毒性藥物SN38構成之ADC。拉貝珠單抗哥維坦之特徵在於所用連接子結構之顯著不穩定性,導致非經腸施用後細胞毒性有效載荷之早期系統性損失。此降解過程可限制抗腫瘤活性並增加副作用之風險。另一已知抗CEACAM5 ADC係賽諾菲之SAR408701 (妥沙米單抗拉夫坦辛(tusamitamab ravtansine)),其包含經由N-琥珀醯亞胺基4-(2-吡啶基二硫基丁酸酯(SPDB)連接子共價連接至細胞毒性劑DM4(一種有效微管去穩定化類美登素)之抗CEACAM5抗體SAR408377 (妥沙米單抗;亦稱為huMab2-3)。SAR408701與包括眼角膜之數個器官及組織之毒副作用(包括角膜炎及角膜病變)相關聯。此外,基於微管抑制劑之ADC於某些癌症適應症(諸如結腸直腸癌)中之有效性可受限制。迄今為止,尚無抗CEACAM5抗體或ADC已批准用於臨床中之任何治療用途;一般而言,很少ADC已批准用於治療實性瘤。仍需新穎且經改善之治療劑用於治療癌症,例如用於不同之實性瘤適應症,包括(例如) CRC、胰臟癌、胃癌、NSCLC、食道癌及前列腺癌。
本發明尤其藉由提供針對CEACAM5之單株抗體(可與人類及食蟹獼猴蛋白兩者反應)及藉由提供包含該等抗體之免疫結合物(本文中亦稱為抗體-藥物結合物(ADC))解決此需求及此項技術中之其他需求;此等免疫結合物具有細胞毒性效應、活體外殺死腫瘤細胞及活體內抑制腫瘤生長。本發明係關於隨附申請專利範圍中及本文下文進一步描述中描述之實施例。
為出於治療目的嘗試產生針對CEACAM5具有最佳特性之新抗體,特別以免疫結合物之形式,發明人已進行廣泛研究及開發,以選擇具有有利概況之抗體並以此為基礎開發免疫結合物。
發明人可選擇並產生意外包含數種所需特徵之最佳化IgG。此等抗體以高親和力結合至人類CEACAM5之A2-B2域且不識別人類CEACAM1、CEACAM6、CEACAM7及CEACAM8蛋白。在細胞情境下,此等抗體對表現CEACAM5之腫瘤細胞顯示高親和力且經內化。此外,此等抗體亦結合至食蟹獼猴CEACAM5蛋白,以分別對食蟹獼猴及人類蛋白於彼此10倍內之親和力。本發明之抗體結合至食蟹獼猴CEACAM5之A2-B2域,但其等不識別另一食蟹獼猴CEACAM蛋白(CEACAM6)。
發明人亦已顯示,其等已產生之抗體當與免疫結合物中之細胞毒性藥物組合時可活體外誘導對腫瘤細胞之細胞毒性效應。結合至細胞毒性藥物之抗體(即本發明之免疫結合物)亦可在攜載表現CEACAM5之腫瘤之小鼠中顯著抑制腫瘤生長。連接藥物及抗體之連接子係經設計以在非經腸施用後最大化全身穩定性。於靶細胞內自本發明之免疫結合物釋放依喜替康(exatecan)導致極高效力及顯著旁觀者效應。有效旁觀者效應可有利於治療具有異質靶向表現之病患。
定義
如本文使用,「CEACAM5」命名為「癌胚抗原相關細胞黏著分子5」,亦稱為「CD66e」 (分化簇66e)或CEA。CEACAM5係參與細胞黏著之醣蛋白。CEACAM5尤其高度表現於(例如)結腸直腸癌、胃癌、非小細胞肺癌、胰臟癌、食道癌、前列腺癌及其他實性瘤之表面上。全長人類CEACAM5之參考序列(包括訊息肽(位置1至34)及原肽(位置686至702))可以寄存編號AAA51967.1獲自基因庫資料庫;此胺基酸序列如下讀取:MESPSAPPHRWCIPWQRLLLTASLLTFWNPPTTAKLTIESTPFNVAEGKEVLLLVHNLPQHLFGYSWYKGERVDGNRQIIGYVIGTQQATPGPAYSGREIIYPNASLLIQNIIQNDTGFYTLHVIKSDLVNEEATGQFRVYPELPKPSISSNNSKPVEDKDAVAFTCEPETQDATYLWWVNNQSLPVSPRLQLSNGNRTLTLFNVTRNDTASYKCETQNPVSARRSDSVILNVLYGPDAPTISPLNTSYRSGENLNLSCHAASNPPAQYSWFVNGTFQQSTQELFIPNITVNNSGSYTCQAHNSDTGLNRTTVTTITVYAEPPKPFITSNNSNPVEDEDAVALTCEPEIQNTTYLWWVNNQSLPVSPRLQLSNDNRTLTLLSVTRNDVGPYECGIQNELSVDHSDPVILNVLYGPDDPTISPSYTYYRPGVNLSLSCHAASNPPAQYSWLIDGNIQQHTQELFISNITEKNSGLYTCQANNSASGHSRTTVKTITVSAELPKPSISSNNSKPVEDKDAVAFTCEPEAQNTTYLWWVNGQSLPVSPRLQLSNGNRTLTLFNVTRNDARAYVCGIQNSVSANRSDPVTLDVLYGPDTPIISPPDSSYLSGANLNLSCHSASNPSPQYSWRINGIPQQHTQVLFIAKITPNNNGTYACFVSNLATGRNNSIVKSITVSASGTSPGLSAGATVGIMIGVLVGVALI (SEQ ID NO: 1)。已在高加索人群體中以高於2%之頻率鑒別五個非同義SNP,其中之四者位於人類CEACAM5之N域中(於位置80、83、112、113處),最後一者位於人類CEACAM5之A2域中(於位置398處)。基因庫AAA51967.1含有主要單倍型(I80、V83、I112、I113及E398)。
「域」或「區域」可為蛋白質之任何區域,一般基於序列同源性定義且通常與特定結構或功能實體相關。已知CEACAM家族成員由Ig樣域構成。本檔案中使用之術語域用以指定個別Ig樣域(諸如「N域」)或用於連續域組(諸如「A2-B2域」)。
人類CEACAM5之域組織如下(基於基因庫AAA51967.1序列;SEQ ID NO: 1):
因此,人類CEACAM5之A2-B2域由SEQ ID NO: 1之胺基酸321至498構成。
人類 CEACAM5 域 | SEQ ID NO: 1 中之位置 |
N | 35-142 |
A1 | 143-237 |
B1 | 238-320 |
A2 | 321-415 |
B2 | 416-498 |
A3 | 499-593 |
B3 | 594-685 |
可獲得食蟹獼猴CEACAM5蛋白之參考序列(NCBI參考序列XP_005589491.1),且此胺基酸序列如下讀取:
mgspsaplhrwcipwqtllltaslltfwnppttaqltiesrpfnvaegkevlllahnvsqnlfgyiwykgervdasrrigscvirtqqitpgpahsgretidfnasllihnvtqsdtgsytiqvikedlvneeatgqfrvypelpkpyissnnsnpvedkdavaltcepetqdttylwwvnnqslpvsprlelssdnrtltvfniprndttsykcetqnpvsvrrsdpvtlnvlygpdaptisplntpyragenlnlschaasnptaqyfwfvngtfqqstqelfipnitvnnsgsymcqahnsatglnrttvtaitvya
elpkpyitsnnsnpiedkdavtltcepetqdttylwwvnnqslsvssrlelsndnrtltvfniprndttfyecetqnpvsvrrsdpvtlnvlygpdaptisplntpyragenlnlschaasnpaaqyswfvngtfqqstqelfipnitvnnsgsymcqahnsatglnrttvtaitvyvelpkpyissnnsnpiedkdavtltcepvaenttylwwvnnqslsvsprlqlsngnriltllsvtrndtgpyecgiqnsesakrsdpvtlnvtygpdtpiisppdlsyrsganlnlschsdsnpspqyswlingtlrqhtqvlfiskitsnnngayacfvsnlatgrnnsivknisvssgdsapgssglsa
ratvgiiigmlv gvalm(SEQ ID NO: 2) (訊息肽以斜體表示;A2-B2域加粗;GPI錨
加下劃線;在訊息肽與A2-B2域之間之N-A1-B1域以常規字體表示;在A2-B2域與GPI錨之間之A3-B3域以常規字體表示)。
「編碼序列」或「編碼」表現產物(諸如多肽、蛋白質或酶)之序列係核苷酸序列,其在表現時導致該多肽、蛋白質或酶之產生,即,該核苷酸序列編碼該多肽、蛋白質或酶之胺基酸序列。蛋白質之編碼序列可包括起始密碼子(通常ATG)及終止密碼子。
如本文使用,特異性蛋白質(例如抗體)之提及可包括具有天然胺基酸序列之多肽,以及無關來源或製備方式之變體及修飾形式。具有天然胺基酸序列之蛋白質係具有與自然獲得相同之胺基酸序列之蛋白質。此等天然序列蛋白質可自自然分離或可使用標準重組及/或合成方法製備。天然序列蛋白質特別包含天然生成之截短或可溶形式、天然生成之變體形式(例如選擇性剪接形式)、天然生成之對偶基因變體及形式(包括轉譯後修飾)。天然序列蛋白質包括攜載轉譯後修飾(諸如醣化或磷酸化),或一些胺基酸殘基之其他修飾之蛋白質。
術語「基因」意謂編碼或對應於包含一或多種蛋白質或酶中之所有或部分之胺基酸之特定序列之DNA序列,且可包括或可不包括調節DNA序列,諸如啟動子序列,其等決定(例如)表現該基因之條件。一些基因(其等非結構基因)可自DNA轉錄為RNA,但未轉譯為胺基酸序列。其他基因可用作結構基因之調節子或DNA轉錄之調節子。特別地,術語基因可預期用於編碼蛋白質之基因體序列,即包含調節子、啟動子、內含子及外顯子序列之序列。
本文中,與參考序列「具有至少85%一致性」之序列係在其整個長度上與該參考序列之整個長度具有85%或更大,例如90%、91%、92%、93%、94%、95%、96%、97%、98%或99%序列一致性之序列。因此,可藉由全域成對比對使用尼德曼(Needleman)及翁施(Wunsch)演算法(J. Mol. Biol. 48:443 (1970)),例如使用程序尼德爾(Needle) (EMBOSS)以BLOSUM62矩陣及下列參數於整個長度上比較兩個此等序列確定「序列一致性」之百分比:缺口開放=10,空位延伸=0.5,末端缺口罰分=假,末端缺口開放=10,末端空位延伸=0.5 (其等係標準設定)。
「保守胺基酸取代」係其中胺基酸殘基經具有相似化學性質(例如,電荷、大小或疏水性)之側鏈之另一胺基酸殘基取代者。一般而言,保守胺基酸取代將不大體上改變蛋白質之功能性質。具有相似化學性質之側鏈之胺基酸組之實例包括1)脂族側鏈:甘胺酸、丙胺酸、纈胺酸、白胺酸及異白胺酸;2)脂族羥基側鏈:絲胺酸及蘇胺酸;3) 含醯胺側鏈:天冬醯胺酸及麩醯胺酸;4)芳族側鏈:苯丙胺酸、酪胺酸及色胺酸;5)鹼性側鏈:離胺酸、精胺酸及組胺酸;6)酸性側鏈:天冬胺酸及麩胺酸;及7)含硫側鏈:半胱胺酸及甲硫胺酸。亦可基於胺基酸大小定義保守胺基酸取代基。
「抗體」 (亦稱為「免疫球蛋白」)可為(例如)其中兩個重鏈由二硫鍵彼此連接及各重鏈由二硫鍵連接至輕鏈之天然或習知類型之抗體。存在兩種類型之輕鏈,λ (I)及κ (k)。存在五種決定抗體分子之功能活性之態樣之主要重鏈類別(或同型):IgM、IgD、IgG、IgA及IgE。各抗體鏈含有不同序列域(或區域)。典型IgG抗體之輕鏈包括兩個區域,可變區(VL)及恆定區(CL)。典型IgG抗體之重鏈包括四個區域,即可變區(VH)及恆定區(CH),後者由三個恆定域(CH1、CH2及CH3)組成。輕鏈及重鏈兩者之可變區決定對抗原之結合及特異性。該輕鏈及重鏈之恆定區可賦予重要生物性質,諸如抗體鏈結合、分泌、跨胎盤遷移、補體結合及對Fc受體(FcR)之結合。Fv片段係抗體Fab片段之N端部分且由一個輕鏈及一個重鏈之可變部分構成。
抗體特異性在於抗體結合位點與抗原決定位之間的結構互補性。抗體結合位點由主要來自所謂之高變或互補決定區(CDR)之殘基組成。因此,互補決定區(CDR)係指共同定義抗體Fv區之結合親和力及特異性之胺基酸序列。抗體之輕(L)鏈及重(H)鏈各具有三個CDR,分別命名為CDR1-L、CDR2-L、CDR3-L及CDR1-H、CDR2-H、CDR3-H。因此,習知抗體之抗原結合位點包括六個CDR,其等包含來自重鏈及輕鏈可變區中之各者之CDR組。
「框架區」 (FR)係指插入CDR之間的胺基酸序列,即係指在單一物種之不同免疫球蛋白之間相對保守之免疫球蛋白輕鏈及重鏈可變區之彼等部分。免疫球蛋白之輕鏈及重鏈各具有四個FR,分別命名為FR1-L、FR2-L、FR3-L、FR4-L,及FR1-H、FR2-H、FR3-H、FR4-H。如本文使用,「人類框架區」係與天然生成之人類抗體之框架區大體上一致(約85%或以上,例如90%、91%、92%、93%、94%、95%、96%、97%、98%或99%)之框架區。
在本發明之內文中,免疫球蛋白輕鏈或重鏈中之CDR/FR定義係基於I MGT定義(Lefranc等人,Dev. Comp. Immunol., 2003, 27(1): 55-77;www.i mgt.org)確定。
如本文使用,術語「抗體」包括習知抗體及其片段,及單域抗體及其片段,諸如單域抗體之可變重鏈;如本文使用之術語「抗體」亦包括嵌合、人類化、雙特異性或多特異性抗體,及其他類型之工程化抗體。術語「抗體」包括單株抗體。
如本文使用之術語「單株抗體」或「mAb」係指單一胺基酸序列之抗體分子,其針對特異性抗原且不應視為需藉由任何特定方法產生。單株抗體可例如藉由B細胞或融合瘤之單一純系產生,但亦可為例如藉由涉及遺傳或蛋白質工程化之方法重組產生。
術語「嵌合抗體」係指在最廣泛之意義上含有來自一種抗體之一或多個區域及來自一或多種其他抗體之一或多個區域之工程化抗體。在一實施例中,嵌合抗體包含來源於非人類動物之抗體之VH及VL與另一抗體(在一些實施例中,其係人類抗體)之CH及CL之締合。作為該非人類動物,可使用任何動物(諸如小鼠、大鼠、倉鼠、兔或類似物。嵌合抗體亦可表示對至少兩種不同抗原具有特異性之多特異性抗體。
術語「人類化抗體」係指非人類來源之全部或部分且已經修飾以置換(例如)VH及VL之框架區中之某些胺基酸以避免或最小化人類中之免疫反應之抗體。人類化抗體之恆定區通常為人類CH及CL區。
抗體(例如習知抗體)之「片段」包含完整抗體(諸如IgG)之一部分,特別地該完整抗體之抗原結合區或可變區。抗體片段之實例包括Fv、Fab、F(ab')2、Fab'、dsFv、(dsFv)2、scFv、sc(Fv)2、雙功能抗體,及由抗體片段形成之雙特異性及多特異性抗體。習知抗體之片段亦可為單域抗體,諸如重鏈抗體或VHH。
術語「Fab」表示具有約50,000 Da分子量及抗原結合活性之抗體片段,其中重鏈N端側約一半及整個輕鏈通過二硫鍵結合在一起。其通常在藉由用蛋白酶(木瓜蛋白酶)處理IgG之片段中獲得。
術語「F(ab')2」係指具有約100,000 Da分子量及抗原結合活性之抗體片段,其略大於經由鉸鏈區之二硫鍵結合之2個相同Fab片段。其通常在藉由用蛋白酶(胃蛋白酶)處理IgG之片段中獲得。
術語「Fab'」係指具有約50,000 Da分子量及抗原結合活性之抗體片段,其係藉由切割該F(ab')2之鉸鏈區之二硫鍵獲得。
單鏈Fv (「scFv」)係共價連接之VH::VL異二聚體,其通常由包括由肽編碼連接子連接之VH及VL編碼基因之基因融合表現。本發明之人類scFv片段包括保持適當構型之CDR,例如藉由使用基因重組技術。二價及多價抗體片段可藉由單價scFv之締合自發形成,或可藉由以肽連接子偶合單價scFv產生,諸如二價sc(Fv)2。「dsFv」係由二硫鍵穩定之VH::VL異二聚體。「(dsFv)2」表示由肽連接子偶合之兩個dsFv。
術語「雙特異性抗體」或「BsAb」表示包含兩個不同抗原結合位點之抗體。因此,BsAb可(例如)同時結合兩種不同抗原。已愈加頻繁地使用基因工程化以設計、修飾及產生具有如(例如) EP 2 050 764 A1中描述之結合性質及效應功能之所需組之抗體或抗體衍生物。
術語「多特異性抗體」表示包含兩個或更多個不同抗原結合位點之抗體。
術語「雙功能抗體」係指具有兩個抗原結合位點之小抗體片段,其片段包含在相同多肽鏈(VH-VL)中連接至輕鏈可變域(VL)之重鏈可變域(VH)。藉由使用過短以致於不容許在相同鏈之兩個域之間配對之連接子,迫使該等域與另一鏈之互補域配對並產生兩個抗原結合位點。
術語「融合瘤」表示藉由令用抗原使非人類哺乳動物免疫製備之B細胞經受使用來源於小鼠或類似物之產生具有抗原特異性之所需單株抗體之骨髓瘤細胞進行細胞融合獲得之細胞。
「經純化」或「經分離」意謂當提及多肽(例如抗體)或核苷酸序列時,指示分子存在於大量缺乏相同類型之其他生物大分子之情況下。如本文使用之術語「經純化」意謂存在至少75重量%、85重量%、95重量%、96重量%、97重量%或98重量%相同類型之生物大分子。編碼特定多肽之「經分離」核酸分子係指大體上不含不編碼標的多肽之其他核酸分子之核酸分子;然而,該分子可包括不有害影響組合物之基本特性之一些另外鹼基或部分。
如本文使用,術語「個體」表示哺乳動物,諸如倉鼠、貓、犬、靈長類動物或人類。在本發明之實施例中,該個體(或病患)係人類。
本發明之抗體
發明人已成功產生、篩選及選擇特異性抗CEACAM5抗體,該等抗體意外顯示使得其等理想地適用於癌症療法中(特別地作為免疫結合物(抗體-藥物結合物)之部分)之數種特性之組合。例如,本發明之抗體對人類及食蟹獼猴CEACAM5蛋白兩者均顯示高親和力,且其等不與人類CEACAM1、CEACAM6、CEACAM7及CEACAM8蛋白,或不與食蟹獼猴CEACAM6蛋白顯著交叉反應。發明人已確定根據本發明之此等單株抗體之胺基酸序列。
本發明提供一種經分離抗體,其結合至人類CEACAM5蛋白且包含由胺基酸序列DGSVSRGGYY (SEQ ID NO: 3)構成之CDR1-H、由胺基酸序列IYYSGST (SEQ ID NO: 4)構成之CDR2-H、由胺基酸序列ARGIAVAPFDY (SEQ ID NO: 5)構成之CDR3-H、由胺基酸序列QSVRSN (SEQ ID NO: 6)構成之CDR1-L、由胺基酸序列AAS (SEQ ID NO: 7)構成之CDR2-L及由胺基酸序列QQYTNWPFT (SEQ ID NO: 8)構成之CDR3-L。此抗體亦可結合至食蟹獼猴CEACAM5蛋白。
在本發明之實施例中,具有上述六個CDR序列之抗體包括包含與胺基酸序列EVQLQESGPGLVKPSQTLSLTCTVS
DGSVSRGGYYLTWIRQHPGKGLEWIGY
IYYSGSTYFNPSLRSRVTMSVDTSKNQFSLKLSSVTAADTAVYYC
ARGIAVAPFDYWGQGTLVTVSS (SEQ ID NO: 9) (以粗體字顯示CDR)具有至少85%一致性之胺基酸序列之重鏈可變區(VH)及包含與胺基酸序列EIVLTQSPATLSVSPGERATLSCRTS
QSVRSNLAWYQQKPGQAPRLLIY
AASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYC
QQYTNWPFTFGPGTKVDIK (SEQ ID NO: 10) (以粗體字顯示CDR)具有至少85%一致性之胺基酸序列之輕鏈可變區(VL)。
在本發明之實施例中,具有上述六個CDR序列之抗體包括包含SEQ ID NO: 9之胺基酸序列之重鏈可變區(VH)及包含SEQ ID NO: 10之胺基酸序列之輕鏈可變區(VL)。
在本發明之實施例中,抗體進一步包括與胺基酸序列ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPSSIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 11)具有至少85%一致性之胺基酸序列之重鏈恆定區(CH)及包含與胺基酸序列RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 12)具有至少85%一致性之胺基酸序列之輕鏈恆定區(CL)。
在本發明之實施例中,抗體包括包含SEQ ID NO: 11之胺基酸序列之重鏈恆定區(CH)及包含SEQ ID NO: 12之胺基酸序列之輕鏈恆定區(CL)。
在更特定實施例中,本發明之抗體係一種經分離抗體,其結合至人類CEACAM5蛋白且包括包含與胺基酸序列EVQLQESGPGLVKPSQTLSLTCTVSDGSVSRGGYYLTWIRQHPGKGLEWIGYIYYSGSTYFNPSLRSRVTMSVDTSKNQFSLKLSSVTAADTAVYYCARGIAVAPFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPSSIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 13)具有至少85%一致性之胺基酸序列之重鏈(HC)及包含與胺基酸序列EIVLTQSPATLSVSPGERATLSCRTSQSVRSNLAWYQQKPGQAPRLLIYAASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYTNWPFTFGPGTKVDIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 14)具有至少85%一致性之胺基酸序列之輕鏈(LC)。在本發明之甚至更特定實施例中,該抗體包括包含SEQ ID NO: 13之胺基酸序列之重鏈(HC)及包含SEQ ID NO: 14之胺基酸序列之輕鏈(LC)。在本發明之又更特定實施例中,該抗體由包含SEQ ID NO: 13之胺基酸序列之兩個相同重鏈(HC)及包含SEQ ID NO: 14之胺基酸序列之兩個相同輕鏈(LC)構成。
在一些實施例中,本發明抗體之一或多個個別胺基酸可在上文提及序列(包括CDR序列)之一或多者中藉由取代(特別地藉由保守取代)加以改變。此改變可旨在(例如)移除醣化位點或脫醯胺位點,例如與該抗體之人類化有關。
在一些實施例中,本發明之抗體係一種經分離抗體,其結合至人類CEACAM5蛋白且由兩個相同重鏈(HC)及兩個相同輕鏈(LC)構成,重鏈(HC)由SEQ ID NO: 13之胺基酸序列構成,輕鏈(LC)由SEQ ID NO: 14之胺基酸序列構成;此特定抗體在本文中亦稱為「mAb1」。
在一些實施例中,本發明之抗體結合至人類及食蟹獼猴CEACAM5之A2-B2域。本發明亦提供與包含mAb1之重鏈及輕鏈可變區(即分別對應於SEQ ID NO: 9及10之VH及VL)之抗體競爭結合至人類及/或食蟹獼猴CEACAM5蛋白之A2-B2域之抗體。
候選抗體與包含mAb1之VH及VL之抗體(此後,在與候選抗體競爭之內文,稱為「參考」抗體)競爭結合至人類及/或食蟹獼猴CEACAM5蛋白之A2-B2域之能力可(例如)藉由競爭性ELISA容易分析,其中該抗原(即人類或食蟹獼猴CEACAM5之A2-B2域,或包含包括該A2-B2域之人類或食蟹獼猴CEACAM5之片段或由其構成之多肽,特別地人類或食蟹獼猴CEACAM5之細胞外域)分別結合至撐體並添加分別含有該候選抗體及該參考抗體之兩種溶液,且容許該等抗體競爭結合至該抗原。然後可量測結合至該抗原之參考抗體之量,並與當針對陰性對照(例如不含抗體之溶液)量測時結合至該抗原之參考抗體之量進行比較。在候選抗體之存在下經結合之參考抗體之量相較於在陰性對照之存在下經結合之參考抗體之量減少指示該候選抗體已與該參考抗體競爭。便利地,可標記(例如螢光)該參考抗體以促進偵測經結合之參考抗體。可用連續稀釋之候選及/或參考抗體進行重複量測。
在一些實施例中,本發明之抗體不與人類CEACAM1、人類CEACAM6、人類CEACAM7、人類CEACAM8及食蟹獼猴CEACAM6蛋白結合或顯著交叉反應。在一些實施例中,該抗體不與上述人類及食蟹獼猴CEACAM蛋白(除CEACAM5外)之細胞外域結合或顯著交叉反應。
「親和力」在理論上由全抗體與抗原之間的平衡締合定義。親和力可藉由多種已知方法進行實驗評估,諸如用表面電漿子共振量測結合率及解離率或在免疫化學分析(ELISA、FACS)中量測EC
50(或視K
D)。在此等分析中,該EC
50係在對指定濃度之抗原(藉由ELISA (酶聯免疫吸附分析))或表現該抗原之細胞(藉由FACS (螢光活化之細胞分選))曝露指定時間後誘導介於基線與最大值之間的一半之反應之抗體濃度。
當兩種抗原之EC
50在相似範圍內時,結合至抗原1 (Ag1)之單株抗體對抗原2 (Ag2)具有「交叉反應性」。在本申請案中,當結合至Ag1之單株抗體對Ag2之親和力係其對Ag1之親和力的10倍或以下(例如5倍內)時,結合至Ag1之單株抗體對Ag2具有交叉反應性,對兩種抗原的親和力係以相同方法量測。
當對兩種抗原之親和力非常不同時,結合至Ag1之單株抗體不與Ag2 「顯著交叉反應」。若結合反應過低,則對Ag2之親和力可無法量測。在本申請案中,當在相同實驗設定及相同抗體濃度下,該單株抗體對Ag2之結合反應小於相同單株抗體對Ag1之結合反應之5%時,結合至Ag1之單株抗體不與Ag2的顯著交叉反應。實際上,所用抗體濃度可為EC
50或達成用Ag1獲得之飽和平線區所需之濃度。當單株抗體不與Ag2顯著交叉反應時,該單株抗體「特異性結合」至Ag1 (或對Ag1「具有特異性」)。
在一些實施例中,根據本發明之抗體對食蟹獼猴CEACAM5之親和力係在其對人類CEACAM5之親和力之10倍或更小內(例如於5倍內)。因此,根據本發明之抗體可用於在食蟹獼猴中進行之毒物學研究中,因為食蟹獼猴中觀察到之毒性概況將與人類中之預期潛在副作用相關。
在一些實施例中,本發明之抗體對人類CEACAM5或食蟹獼猴CEACAM5,或兩者具有親和力,其係≤ 10 nM;例如,本發明之抗體可對人類CEACAM5具有親和力,其介於1至10 nM之間,諸如對人類CEACAM5之親和力係約6 nM。
在使用可溶性重組CEACAM5作為捕獲抗原之ELISA中,對人類CEACAM5或對食蟹獼猴CEACAM5之親和力可確定為(例如) EC50值。
或者,對於本發明之抗體,可藉由FACS分析(例如)對腫瘤細胞系MKN45 (DSMZ、ACC 409)測定視解離常數(視KD)。
另外,已顯示根據本發明之抗體可藉由免疫組織化學,例如以冷凍及福爾馬林固定及石蠟包埋之(FFPE)組織切片偵測CEACAM5表現。
本文中上文及下文描述之實施例之任何組合形成本發明之部分。
在一些實施例中,根據本發明之抗體係習知抗體,諸如習知單株抗體,或抗體片段、雙特異性或多特異性抗體。
在一些實施例中,根據本發明之抗體包含IgG或其片段或由其構成。
在一些實施例中,本發明之抗體可為(例如)鼠抗體、嵌合抗體、人類化抗體或人類抗體。用於抗體序列之人類化之許多方法為此項技術中已知;參見例如回顧Almagro及Fransson (2008) Front Biosci. 13: 1619-1633。一種常用方法係CDR移植,或抗體重塑,其涉及將供體抗體(一般小鼠抗體)之CDR序列植入具有不同特異性之人類抗體之框架支架內。由於CDR移植可減小CDR移植之非人類抗體之結合特異性及親和力,並因此減小其生物活性,因此可於CDR移植之抗體之所選位置引入回復突變以保留親代抗體之結合特異性及親和力。可使用文獻及抗體資料庫中可用之資訊進行可能回復突變之位置之鑑別。作為回復突變候選者之胺基酸殘基通常為彼等位於抗體分子表面處者,而通常將不改變經掩埋或低表面曝露程度之殘基。CDR移植及回復突變之替代人類化技術係表面重整,其中保留非人類來源之非表面曝露之殘基,而將表面殘基改變為人類殘基。另一替代技術稱為「引導選擇」 (Jespers等人,(1994) Biotechnology 12, 899)且可用以自鼠抗體衍生保留親代抗體之抗原決定基及結合特性之全人類抗體。
對於嵌合抗體,人類化通常涉及可變區序列之框架區之修飾。
作為CDR之部分之胺基酸殘基將通常不因為人類化而改變,儘管在某些情況下,可需改變個別CDR胺基酸殘基,例如以移除醣化位點、脫醯胺位點或非所需之半胱胺酸殘基。藉由在三肽序列Asn-X-Ser或Asn-X-Thr中將寡醣鏈結合至天冬醯胺酸殘基發生N連接之醣化,其中X可為除Pro外之任何胺基酸。藉由使Asn或Ser/Thr殘基突變為不同殘基,例如藉助於保守取代可達成N-醣化位點之移除。天冬醯胺酸及麩醯胺酸殘基之脫醯胺可取決於諸如pH及表面曝露之因素發生。天冬醯胺酸殘基特別易受脫醯胺影響,主要當存在於序列Asn-Gly中,且在較小程度上存在於其他二肽序列(諸如Asn-Ala)中時。當此脫醯胺位點(例如Asn-Gly)存在於CDR序列中時,因此可需移除位點,通常藉由保守取代以移除所涉及殘基中之一者。用以移除所涉及殘基中之一者之CDR序列中之取代亦旨在包含於本發明中。
在人類化抗體或其片段中,重鏈及輕鏈之可變域可包含人類受體框架區。若存在,則人類化抗體可進一步包含人類恆定重鏈及輕鏈域。
在一些實施例中,根據本發明之抗體可為選自由以下組成之群之抗體片段(例如人類化抗體片段):Fv、Fab、F(ab')2、Fab'、dsFv、(dsFv)2、scFv、sc(Fv)2及雙功能抗體。
在一些實施例中,根據本發明之抗體可為由抗體片段(至少一個抗體片段係根據本發明之抗體之片段)形成之雙特異性或多特異性抗體。多特異性抗體係如(例如) EP 2 050 764 A1或US 2005/0003403 A1中描述之多價蛋白質複合物。
根據本發明之雙特異性或多特異性抗體可對(a)人類及食蟹獼猴CEACAM5蛋白及(b)至少一種其他抗原具有特異性。在一些實施例中,該至少一種其他抗原不為人類或食蟹獼猴CEACAM家族成員。在其他實施例中,該至少一種其他抗原可為人類或食蟹獼猴CEACAM5上之除mAb1靶向之抗原決定基外之抗原決定基。
可藉由此項技術中已知的任何技術產生本發明之抗體。根據本發明之抗體可(例如)以分離(例如純化)形式使用或包含於載體(諸如膜或脂質囊泡(例如脂質體))中。
本發明之核酸及宿主細胞本發明之另一態樣係關於包含編碼如上文定義之本發明之抗體之核酸序列或由其構成之經分離核酸。
通常,該核酸係DNA或RNA分子,其可包括於任何合適之載體(諸如質體、黏接質體、游離基因體、人工染色體、噬菌體或病毒載體)中。
術語「載體」、「選殖載體」及「表現載體」意謂可將DNA或RNA序列(例如外源基因)引入宿主細胞內以轉形宿主並促進引入序列之表現(例如轉錄及轉譯)之媒介物。
因此,本發明之另一態樣係關於包含如上文定義之本發明核酸之載體。
此等載體可包含調節元件(諸如啟動子、強化子、終止子及類似物),以一經對個體投與即引起或引導該多肽之表現。用於動物細胞之表現載體中之啟動子及強化子之實例包括SV40之早期啟動子及強化子(Mizukami T等人,1987)、莫洛尼小鼠白血病病毒之LTR啟動子及強化子(Kuwana Y等人,1987)、免疫球蛋白H鏈之啟動子(Mason JO等人,1985)及強化子(Gillies SD等人,1983)及類似物。
可使用動物細胞之任何表現載體,只要可插入並表現編碼人類抗體C區之基因即可。合適載體之實例包括pAGE107 (Miyaji H等人,1990)、pAGE103 (Mizukami T等人,1987)、pHSG274 (Brady G等人,1984)、pKCR (O'Hare K等人,1981)、pSG1 β d2-4-(Miyaji H等人,1990)及類似物。
質體之其他實例包括包含複製起始序列之複製質體,或整合質體,諸如,舉例而言,pUC、pcDNA、pBR,及類似物。
病毒載體之其他實例包括腺病毒、逆轉錄病毒、皰疹病毒及AAV載體。此等重組病毒可藉由此項技術中已知的技術,諸如藉由轉染包裝細胞或藉由用輔助質體或病毒瞬時轉染產生。包裝病毒之細胞之典型實例包括PA317細胞、PsiCRIP細胞、GPenv+細胞、293細胞等。用於產生此等複製缺陷重組病毒之詳細方案可參見(例如)WO 95/14785、WO 96/22378、US 5,882,877、US 6,013,516、US 4,861,719、US 5,278,056及WO 94/19478。
本發明之另一目的係關於已藉由根據本發明之核酸及/或載體轉染、感染或轉形之宿主細胞。
術語「轉形」意謂將「外源」 (即外來)基因、DNA或RNA序列引入宿主細胞內,使得該宿主細胞將表現引入之基因或序列以產生所需物質,通常由該引入之基因或序列編碼之蛋白質或酶。接受並表現該引入之DNA或RNA之宿主細胞已經「轉形」。
本發明之核酸可用以在合適之表現系統中產生本發明之抗體。術語「表現系統」意謂在合適條件下(例如)用於表現由載體攜載並引入宿主細胞內之外源DNA編碼之蛋白質之宿主細胞及可相容載體。
常見表現系統包括大腸桿菌宿主細胞及質體載體、昆蟲宿主細胞及桿狀病毒載體,及哺乳動物宿主細胞及載體。宿主細胞之其他實例包括(但不限於)原核細胞(諸如細菌)及真核細胞(諸如酵母細胞、哺乳動物細胞、昆蟲細胞、植物細胞等)。特定實例包括大腸桿菌、克魯維酵母(
Kluyveromyces)或啤酒酵母(
Saccharomycesyeasts)、哺乳動物細胞系(例如,Vero細胞、CHO細胞、3T3細胞、COS細胞等)及原代或既定哺乳動物細胞培養物(例如,由淋巴母細胞、纖維母細胞、胚胎細胞、上皮細胞、神經細胞、脂肪細胞等產生)。實例亦包括小鼠SP2/0-Ag14細胞(ATCC CRL1581)、小鼠P3X63-Ag8.653細胞(ATCC CRL1580)、具有二氫葉酸還原酶基因(下文中稱為「DHFR基因」)缺陷之CHO細胞(Urlaub G等人;1980)、大鼠YB2/3HL.P2.G11.16Ag.20細胞(ATCC CRL1662,下文中稱為「YΒ2/0細胞」),及類似物。在一些實施例中,使用YB2/0細胞,因為當表現於此細胞中時,嵌合或人類化抗體之ADCC活性增強。
對於人類化抗體之表現,表現載體可為其中編碼抗體重鏈之基因及編碼抗體輕鏈之基因存在於不同載體上之類型或其中兩種基因均存在於相同載體上之類型(串聯型)。從構築人類化抗體表現載體之容易性、引入動物細胞內之容易性及動物細胞中抗體H與L鏈之表現程度間之平衡的方面考慮,人類化抗體表現載體為串聯型,Shitara K等人,J Immunol Methods. 1994 Jan. 3;167(1-2):271-8)。串聯型人類化抗體表現載體之實例包括pKANTEX93 (WO 97/10354)、pEE18及類似物。
本發明亦係關於一種產生表現根據本發明之抗體之重組宿主細胞之方法,該方法包括由以下構成之步驟:(i)將如上文描述之重組核酸或載體活體外或離體引入健全之宿主細胞內,(ii)活體外或離體培養獲得之重組宿主細胞,及(iii)視需要,選擇表現及/或分泌該抗體之細胞。
此等重組宿主細胞可用於產生本發明之抗體。
產生本發明之抗體之方法本發明之抗體可藉由此項技術中已知的任何技術諸如(但不限於)任何化學、生物、遺傳或酶技術單獨或組合產生。
已知所需抗體之胺基酸序列,熟習此項技術者可容易使用用於產生多肽之標準技術產生該等抗體或免疫球蛋白鏈。例如,該等抗體或免疫球蛋白鏈可使用眾所周知的固相方法使用市售肽合成裝置(諸如由Applied Biosystems, Foster City, California製造)並遵循製造商之說明書合成。或者,本發明之抗體及免疫球蛋白鏈可藉由如此項技術中熟知的重組DNA技術產生。例如,在將編碼所需多肽之DNA序列引入表現載體內並將此等載體引入將適用於表現所需多肽之真核或原核宿主內後作為DNA表現產物獲得此等多肽(例如抗體),隨後可使用熟知技術自真核或原核宿主分離該等多肽。
例如,本發明提供編碼抗體mAb1之下列DNA序列:
mAb1重鏈核苷酸序列
其中mVk訊息肽
加下劃線,
起始及終止密碼子呈斜體,
VH區序列
呈黑體字,及
CDR以
雙下劃線指示: ATG GAGACCGACACCCTGCTGCTGTGGGTGCTGCTGCTGTGGGTGCCCGGGTCGACCGGT GAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCACAGACCCTGTCCCTCACCTGCACTGTCTCT
GATGGCTCCGTCAGCAGGGGTGGTTACTACTTGACCTGGATCCGCCAGCACCCAGGGAAGGGCCTGGAGTGGATTGGGTAC
ATCTATTACAGTGGGAGCACCTACTTCAACCCGTCCCTCAGGAGTCGGGTTACCATGTCAGTAGACACGTCTAAGAACCAGTTCTCCCTGAAGCTGAGCTCTGTGACTGCCGCGGACACGGCCGTGTATTACTGT
GCGAGAGGGATAGCAGTGGCTCCCTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCTTCA
GCTAGCACCAAGGGCCCCAGCGTGTTCCCCCTGGCCCCCAGCAGCAAGTCCACAAGCGGAGGAACAGCCGCCCTGGGCTGCCTGGTGAAGGACTACTTCCCCGAGCCCGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCTCCGGCGTGCACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACAGTGCCAAGCAGCAGCCTGGGAACCCAGACCTACATCTGCAACGTGAACCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTGGAGCCCAAGAGCTGCGACAAGACCCATACCTGTCCACCCTGCCCAGCCCCCCCAGTGGCCGGACCCTCCGTGTTCCTGTTCCCCCCCAAGCCCAAGGACACCCTGATGATCAGCAGGACCCCCGAGGTGACCTGCGTGGTGGTGGACGTGAGCCACGAGGACCCAGAGGTGAAGTTCAATTGGTATGTGGACGGCGTGGAGGTGCACAACGCCAAGACCAAGCCCAGAGAGGAACAGTACAACAGCACCTACAGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCAAGGAATACAAGTGCAAGGTCTCCAACAAGGCCCTGCCCTCCAGCATCGAGAAAACCATCAGCAAGGCCAAGGGCCAGCCACGGGAGCCCCAGGTGTACACACTGCCCCCATCTCGGGAAGAAATGACCAAGAACCAGGTGTCCCTGACCTGTCTGGTGAAGGGCTTTTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCCTGTGCTGGACAGCGACGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGGACAAGTCCAGGTGGCAGCAGGGCAACGTGTTCAGCTGCAGCGTGATGCACGAGGCCCTGCACAACCACTACACACAGAAGAGCCTGAGCCTGTCCCCCGGC
TGA(SEQ ID NO: 15)
mAb1輕鏈核苷酸序列
其中uPA訊息肽
加下劃線,
起始及終止密碼子呈斜體,
VL區序列
呈黑體字,及
CDR以
雙下劃線指示: ATG AGGGCCCTGCTGGCTAGACTGCTGCTGTGCGTGCTGGTCGTGTCCGACAGCAAGGGC GAAATCGTACTCACGCAGTCTCCAGCCACCCTGTCTGTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGACCAGT
CAGAGTGTTCGCAGCAACTTAGCCTGGTACCAGCAGAAGCCTGGCCAGGCTCCCAGGCTCCTCATCTAT
GCTGCATCCACCAGGGCCACTGGTATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCACTCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGCAGTTTATTACTGT
CAGCAGTATACTAACTGGCCATTCACTTTCGGCCCTGGGACCAAAGTGGACATCAAA
CGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT
TGATAG(SEQ ID NO: 16)
本發明進一步係關於一種產生本發明之抗體之方法,該方法包括由以下構成之步驟:(i)培養根據本發明之經轉形宿主細胞;(ii)表現該抗體;及(iii)回收經表現之抗體。
可藉由習知免疫球蛋白純化程序(諸如,舉例而言,蛋白A-瓊脂糖、羥基磷灰石層析術、凝膠電泳、透析或親和力層析術)自培養基適當地分離本發明之抗體。
在一些實施例中,藉由獲得編碼如先前描述之人類化VL及VH區之核酸序列,藉由將其等插入具有編碼人類抗體CH及人類抗體CL之基因之動物細胞之表現載體內構築人類嵌合抗體表現載體,及藉由將該表現載體引入動物細胞內表現編碼序列,可產生本發明之人類化嵌合抗體。
至於人類嵌合抗體之CH域,可使用屬於人類免疫球蛋白重鏈之任何區域,例如IgG類之彼等係合適的,且可使用屬於IgG類之子類中之任一者,諸如lgG1、lgG2、lgG3及lgG4。此外,至於人類嵌合抗體之CL,可使用屬於人類免疫球蛋白輕鏈之任何區域,且可使用κ類或λ類之彼等。
用於產生人類化或嵌合抗體之方法可涉及習知重組DNA且基因轉染技術為此項技術中熟知(參見例如Morrison SL等人,(1984)及專利檔案US 5,202,238;及US 5,204,244)。
用於基於習知重組DNA及基因轉染技術產生人類化抗體之方法為此項技術中熟知(參見例如Riechmann L等人,1988;Neuberger MS等人,1985)。抗體可使用此項技術中已知的多種技術人類化,包括(例如)申請案WO 2009/032661中揭示之技術、CDR移植(EP 239,400;PCT公開案WO 91/09967;美國專利第5,225,539;5,530,101;及5,585,089號)、面飾法或表面重整(EP 592,106;EP 519,596;Padlan EA (1991);Studnicka GM等人,(1994);RogUS ka MA等人,(1994))及鏈混排(美國專利第5,565,332號)。亦已知用於製備此等抗體之一般重組DNA技術(參見歐洲專利申請案EP 125023及國際專利申請案WO 96/02576)。
本發明之Fab可藉由用蛋白酶(諸如木瓜蛋白酶)處理本發明之抗體(例如IgG)獲得。此外,Fab可藉由將編碼該抗體之Fab之兩個鏈的DNA序列插入用於原核表現或用於真核表現之載體內,及將該載體引入原核或真核細胞(視需要)內以表現該Fab產生。
本發明之F(ab')2可藉由用蛋白酶(胃蛋白酶)處理本發明之抗體(例如IgG)獲得。此外,該F(ab')2可藉由經由硫醚鍵或二硫鍵結合下文描述之Fab'產生。
本發明之Fab'可藉由用還原劑(諸如二硫蘇糖醇)處理本發明之F(ab')2獲得。此外,該Fab'可藉由將編碼抗體之Fab'鏈之DNA序列插入用於原核表現之載體內或用於真核表現之載體內,及將該載體引入原核或真核細胞(視需要)內以進行其表現產生。
本發明之scFv可藉由獲取如先前針對本發明之抗體描述之CDR或VH及VL域之序列,然後構築編碼scFv片段之DNA,將該DNA插入原核或真核表現載體內,及然後將該表現載體引入原核或真核細胞(視需要)內以表現該scFv產生。為產生人類化scFv片段,可使用稱為CDR移植之熟知技術,其涉及選擇根據本發明之互補決定區(CDR),並將其等移植至具有已知三維結構之人類scFv片段框架上(參見例如WO 98/45322;WO 87/02671;US 5,859,205;US 5,585,089;US 4,816,567;EP 0173494)。
本發明之抗體之修飾審慎考慮本文描述抗體之胺基酸序列修飾。例如,可需改善該抗體之結合親和力及/或其他生物性質。
可在本發明抗體之結構及編碼其等之DNA序列中作出修飾及改變,且仍導致具有所需特性之功能抗體或多肽。
當在多肽之胺基序列中作出改變時,可考慮胺基酸之親水指數。親水胺基酸指數對蛋白質之相互作用生物功能的重要性為此項技術中普遍知曉。公認該胺基酸之相對親水特性有助於所得蛋白質之二級結構,其進一步定義該蛋白質與其他分子(例如,酶、受質、受體、DNA、抗體、抗原,及類似物)之相互作用。各胺基酸已基於其等疏水性及電荷特性分配親水指數,此等為:異白胺酸(+4.5);纈胺酸(+4.2);白胺酸(+3.8) ;苯丙胺酸(+2.8);半胱胺酸(+2.5);甲硫胺酸(+1.9);丙胺酸(+1.8);甘胺酸(-0.4);蘇胺酸(-0.7);絲胺酸(-0.8);色胺酸(-0.9);酪胺酸(-1.3);脯胺酸(-1.6);組胺酸(-3.2);麩胺酸(-3.5);麩醯胺酸(-3.5);天冬胺酸(-3.5);天冬醯胺酸(-3.5);離胺酸(-3.9);及精胺酸(-4.5)。
本發明之另一態樣亦包含本發明多肽之功能保守變體。
例如,某些胺基酸可於蛋白質結構中經其他胺基酸取代而不明顯損失活性。由於蛋白質之相互作用能力及性質定義其生物功能活性,因此可在蛋白質序列及當然於其編碼DNA序列中作出某些胺基酸取代,同時仍獲得具有類似性質之蛋白質。因此審慎考慮,可在本發明之抗體序列,或編碼該等多肽之相應DNA序列中作出各種改變,而不明顯損失其等生物活性。
此項技術中已知,某些胺基酸可經具有相似親水指數或分數之其他胺基酸取代且仍導致具有相似生物活性之蛋白質,即仍獲得生物功能等效之蛋白質。亦可能使用完全建立之技術(諸如丙胺酸掃描方法),以在本發明之抗體或多肽中鑑別可經取代而不顯著損失結合至抗原之所有胺基酸。此等殘基可認定為中性,因為其等不參與抗原結合或維持該抗體之結構。此等中性位置中之一或多者可經丙胺酸或經另一胺基酸取代而不改變本發明之抗體或多肽之主要特性。
中性位置可視為其中可併入任何胺基酸取代之位置。實際上,在丙胺酸掃描之原理中,選擇丙胺酸,因為此殘基不攜載特定結構或化學特徵。通常公認,若丙胺酸可替代特定特定胺基酸而不改變蛋白質之性質,則許多其他(若非所有)胺基酸取代亦可為中性的。在丙胺酸係野生型胺基酸之相反情況下,若特定取代可顯示為中性,則其他取代很可能亦為中性。
如上文概述,胺基酸取代一般基於胺基酸側鏈取代基之相對相似性,例如,其等疏水性、親水性、電荷、大小,及類似物。考慮前述特性中之任一者之例示性取代為熟習此項技術者熟知且包括:精胺酸及離胺酸;麩胺酸及天冬胺酸;絲胺酸及蘇胺酸;麩醯胺酸及天冬醯胺酸;及纈胺酸、白胺酸及異白胺酸。
亦可需關於效應功能修飾本發明之抗體,(例如)以便於增強抗體之抗原依賴性細胞介導之細胞毒性(ADCC)及/或補體依賴性細胞毒性(CDC),或(例如)改變Fc受體之結合。此可藉由將一或多個胺基酸取代引入該抗體之Fc區中達成。或者或另外,可將半胱胺酸殘基引入Fc區中,藉此容許在此區域中形成鏈間二硫鍵。因此產生之同源二聚體抗體可具有經改善之內化能力及/或經增加之補體介導之細胞殺死及/或抗體依賴性細胞毒性(ADCC) (Caron PC等人,1992;及Shopes B. 1992)。在一些實施例中,本發明之抗體可為胺基酸序列經修飾以導致對大多數Fcγ受體之結合減少或消除之抗體,其可在表現此等受體(例如巨噬細胞、肝竇細胞等)之正常細胞及組織中減少攝取及毒性。此抗體之一實例係於位置234及235處包括兩個白胺酸(L)殘基取代為丙胺酸(A)者(即LALA);此雙重取代已證實減少Fc對FcγR之結合並因此減少ADCC及減少補體結合/活化。此抗體之另一實例係除LALA雙重取代外包括取代P329G者(即PG-LALA;參見例如Schlothauer等人,Novel human IgG1 and IgG4 Fc-engineered antibodies with completely abolished immune effector functions, Protein Engineering, Design and Selection,第29卷,第10期,2016年10月,第457至466頁)。在一些實施例中,本發明之抗體可因此為具有(i)含有(例如)取代之LALA或PG-LALA組,及(ii)與本文中上文參考各別SEQ ID NO描述之本發明抗體中之一者之胺基酸序列另外一致之胺基酸序列的抗體。
本發明抗體之另一類型之胺基酸修飾可適用於改變該抗體之原始醣化模式,即藉由刪除該抗體中發現之一或多個碳水化合物部分,及/或添加該抗體中不存在之一或多個醣化位點。三肽序列天冬醯胺酸-X-絲胺酸及天冬醯胺酸-X-蘇胺酸中之任一者(其中X係除脯胺酸外之任何胺基酸)之存在產生潛在醣化位點。對該抗體添加或刪除醣化位點可便利地藉由改變胺基酸序列使得其含有上文描述之三肽序列中之一或多者(對於N連接之醣化位點)進行。
另一類型之修飾涉及去除電腦模擬或實驗上鑑別之序列,因為可能在抗體製劑中導致降解產物或異質性。作為實例,天冬醯胺酸及麩醯胺酸殘基之脫醯胺可取決於諸如pH及表面曝露之因素發生。天冬醯胺酸殘基特別易受脫醯胺影響,主要當存在於序列Asn-Gly中,且在較小程度上存在於其他二肽序列(諸如Asn-Ala)中時。當此脫醯胺位點(特別地Asn-Gly)存在於抗體或多肽中時,因此可考慮移除該位點,通常藉由保守取代以移除所涉及殘基中之一者。序列中用以移除所涉及殘基中之一或多者之此等取代亦旨在包含於本發明中。
另一類型之共價修飾涉及將醣苷化學或酶促偶合至抗體。此等程序之優勢在於其等無需在針對N或O連接之醣化具有醣化能力之宿主細胞中產生該抗體。取決於所用偶合模式,糖可結合至(a)精胺酸及組胺酸,(b)游離羧基,(c)游離巰基,諸如半胱胺酸之游離巰基,(d)游離羥基,諸如絲胺酸、蘇胺酸或羥基脯胺酸之游離羥基,(e)芳族殘基,諸如苯丙胺酸、酪胺酸或色胺酸之芳族殘基,或(f)麩醯胺酸之醯胺基。例如,此等方法描述於WO 87/05330中。
移除抗體上存在之碳水化合物部分可化學或酶促進行。化學脫醣化需將該抗體曝露於化合物三氟甲磺酸或等效化合物。此處理導致除連接糖(N-乙醯葡萄胺糖或N-乙醯半乳胺糖)外之大多數或所有糖裂解,同時保持該抗體完整。化學脫醣化係由Sojahr H等人,(1987)及Edge, AS等人,(1981)描述。抗體上碳水化合物部分之酶促裂解可藉由使用如Thotakura, NR等人(1987)描述之多種內切及外切醣苷酶達成。
抗體之另一類型共價修飾包括(例如)以美國專利第4,640,835;4,496,689;4,301,144;4,670,417;4,791,192或4,179,337號中闡述之方式將該抗體連接至多種非蛋白質聚合物(例如聚乙二醇、聚丙二醇或聚環氧烷)中之一者。
此項技術中已知的其他胺基酸序列修飾亦可應用於本發明之抗體。
本發明之免疫結合物本發明提供免疫結合物,本文中亦稱為抗體-藥物結合物,或更簡稱為結合物。如本文使用,所有此等術語具有相同含義且可互換。適用於製備免疫結合物之方法為此項技術中已知。本發明之免疫結合物可藉由活體外方法(例如本文描述之方法)製備。
本發明提供一種免疫結合物,其包含本發明之抗體(諸如mAb1,或具有與mAb1相同之六個CDR之抗體)經由連接子共價連接至至少一種生長抑制劑。
術語「生長抑制劑」 (亦稱為「抗增生劑」)係指抑制細胞(諸如腫瘤細胞)活體外及/或活體內生長之分子或化合物或組合物。
在一些實施例中,生長抑制劑係細胞毒性藥物(亦稱為細胞毒性劑)。在一些實施例中,該生長抑制劑係放射性部分。
本文使用之術語「細胞毒性藥物」係指直接或間接抑制或防止細胞功能及/或引起細胞破壞之物質。術語「細胞毒性藥物」包括例如化學治療劑、酶、抗生素、毒素(諸如小分子毒素或酶活性毒素)、類毒素、長春花、紫杉烷、類美登素或類美登素類似物、托馬黴素(tomaymycin)或吡咯苯并二氮呯衍生物、念珠藻素衍生物、來普黴素衍生物、奧瑞他汀(auristatin)或尾海兔素(dolastatin)類似物、前藥、拓撲異構酶I抑制劑、拓撲異構酶II抑制劑、DNA烷化劑、抗微管蛋白劑、CC-1065及CC-1065類似物。
拓撲異構酶I抑制劑係抑制人類酶拓撲異構酶I之分子或化合物,其涉及藉由催化DNA單股之瞬時斷裂及重新連接而改變DNA拓撲結構。拓撲異構酶I抑制劑對分裂細胞(例如哺乳動物之分裂細胞)具有高度毒性。合適之拓撲異構酶I抑制劑之實例包括喜樹鹼(CPT)及其類似物,諸如拓撲替康(topotecan)、伊立替康(irinotecan)、斯拉替康(silatecan)、考司替康(cositecan)、依喜替康、勒托替康(lurtotecan)、吉馬替康(gimatecan)、貝洛替康(belotecan)及魯比替康(rubitecan)。
在一些實施例中,本發明之免疫結合物包含細胞毒性藥物依喜替康作為生長抑制劑。依喜替康具有化學名稱(1S,9S)-1-胺基-9-乙基-5-氟-1,2,3,9,12,15-六氫-9-羥基-4-甲基-10H,13H-苯并(de)哌喃并(3',4':6,7)吲并(1,2-b)喹啉-10,13-二酮。依喜替康由以下結構式(I)表示:
(I)
在本發明之其他實施例中,可使用其他CPT類似物及其他細胞毒性藥物(例如如上文列舉)。申請案WO 2008/010101中進一步給定一些細胞毒性藥物及結合方法之實例,該申請案以引用之方式併入本文中。
術語「放射性部分」係指包含適用於治療癌症之放射性同位素(諸如At
211、Bi
212、Er
169、I
131、I
125、Y
90、In
111、P
32、Re
186、Re
188、Sm
153、Sr
89,或Lu之放射性同位素)或由其構成之化學實體(諸如分子、化合物或組合物)。此等放射性同位素一般主要發射β-輻射。在一些實施例中,該放射性同位素係α-發射體同位素,例如發射α輻射之釷227。可例如如申請案WO 2004/091668中描述製備免疫結合物。
在本發明之免疫結合物中,本發明之抗體係經由連接子共價連接至至少一種生長抑制劑。如本文使用,「連接子」意謂包含將該生長抑制劑共價結合至該抗體之共價鍵及/或任何原子鏈之化學部分。連接子為此項技術中熟知且包括(例如)二硫基、硫醚基、酸不穩定基團、光不穩定基團、肽酶不穩定基團及酯酶不穩定基團。可(例如)使用多種雙功能蛋白質偶合劑進行本發明之抗體與細胞毒性藥物或其他生長抑制劑之結合,該等偶合劑包括(但不限於) N-琥珀醯亞胺吡啶基二硫代丁酸酯(SPDB)、丁酸4-[(5-硝基-2-吡啶基)二硫基]-2,5-二側氧基-1-吡咯啶基酯(硝基-SPDB)、4-(吡啶-2-基二氫硫基)-2-磺酸基-丁酸(磺酸基-SPDB)、(2-吡啶基二硫基)丙酸N-琥珀醯亞胺酯(SPDP)、(N-馬來醯亞胺基甲基)環己烷-1-羧酸琥珀醯亞胺酯(SMCC)、亞胺基硫雜環戊烷(IT)、亞胺酸酯之雙官能衍生物(諸如己二酸二甲酯鹽酸鹽)、活性酯(諸如辛二酸二琥珀醯亞胺酯)、醛(諸如戊二醛)、雙疊氮基化合物(諸如雙(對疊氮苯甲醯基)-己二胺)、雙重氮衍生物(諸如雙(對重氮苯甲醯基)-乙二胺)、二異氰酸酯(諸如甲苯2,6-二異氰酸酯),及雙活性氟化合物(諸如1,5-二氟-2,4-二硝基苯)。例如,蓖麻毒素免疫毒素可如Vitetta等人(1987)中描述製備。碳標記之1-異硫氰酸根合苯甲基甲基二伸乙基三胺五乙酸(MX-DTPA)係用於將放射性核苷酸結合至抗體之例示性螯合劑(WO 94/11026)。
在本發明之實施例中,連接子可為「可裂解連接子」,其可在細胞(例如腫瘤細胞)內部或附近促進細胞毒性藥物或其他生長抑制劑之釋放。在一些實施例中,該連接子係可在哺乳動物細胞之內體中可裂解之連接子。例如,可使用酸不穩定連接子、肽酶敏感性連接子、酯酶不穩定連接子、光不穩定連接子或含二硫鍵連接子(參見例如美國專利第5,208,020號)。
當提及表示免疫結合物之結構式時,本文亦使用下列命名法:生長抑制劑及連接子結合在一起亦稱為[(連接子)-(生長抑制劑)]部分;例如,依喜替康分子及連接子結合在一起亦稱為[(連接子)-(依喜替康)]部分。
在本發明之一些特定實施例中,連接子係可由人類酶葡萄醣醛酸酶裂解之連接子。例如,本發明之免疫結合物可因此具有下式(II),其包括可由葡萄醣醛酸酶裂解之連接子:
(II),
其中該抗體係本發明之抗體,其中S係該抗體之硫原子,且其中n係共價連接至該抗體之[(連接子)-(生長抑制劑)]部分之數量。數字n可(例如)介於1至10之間;在更特定實施例中,n介於7至8之間;在甚至更特定之實施例中,n介於7.5至8.0之間(即約8)。在一些實施例中,S係該抗體之半胱胺酸之硫原子。在一些實施例中,該抗體係mAb1。
數字n亦稱為「藥物與抗體比」 (或「DAR」);此數字n應始終瞭解為任何給定免疫結合物(之製劑)之平均數。
在本發明之其他特定實施例中,連接子係可由人類酶豆莢蛋白(legumain)裂解之連接子。例如,本發明之免疫結合物可因此具有下式(III),其包括可由豆莢蛋白裂解之連接子:
(III),
其中該抗體係本發明之抗體,其中S係該抗體之硫原子,且其中n係共價連接至該抗體之[(連接子)-(生長抑制劑)]部分之數量。數字n (亦稱為DAR)可(例如)介於1至10之間;在更特定實施例中,n介於7至8之間;在甚至更特定之實施例中,n介於7.5至8.0之間(即約8)。在一些實施例中,S係該抗體之半胱胺酸之硫原子。在一些實施例中,該抗體係mAb1。
在上式(II)及(III)之各者中,抗體之硫原子與生長抑制劑之間的化學結構係連接子。此等連接子中之一者亦包含於下文進一步描述之式(IV)至(IX)之各者中。
在用可由葡萄醣醛酸酶或豆莢蛋白裂解之連接子之實施例之任一者中,如上文描述,例如,生長抑制劑可為依喜替康。
因此,在一些實施例中,本發明提供包含經由連接子共價連接至依喜替康之根據本發明之抗體之免疫結合物,其中該結合物具有下式(IV):
(IV),
其中S係該抗體之硫原子,且其中n係共價連接至該抗體之[(連接子)-(依喜替康)]部分之數量。數字n (亦稱為DAR)可(例如)介於1至10之間;在更特定實施例中,n介於7至8之間;在甚至更特定之實施例中,n介於7.5至8.0之間(即約8)。在一些實施例中,該抗體係mAb1。
在其他實施例中,本發明提供包含經由連接子共價連接至依喜替康之根據本發明之抗體之免疫結合物,其中該結合物具有下式(V):
(V),
其中S係該抗體之硫原子,且其中n係共價連接至該抗體之[(連接子)-(依喜替康)]部分之數量。數字n (亦稱為DAR)可(例如)介於1至10之間;在更特定實施例中,n介於7至8之間;在甚至更特定之實施例中,n介於7.5至8.0之間(即約8)。在一些實施例中,該抗體係mAb1。
在一些實施例中,在本發明之免疫結合物中,諸如如上文描述之與葡萄醣醛酸酶-或豆莢蛋白可裂解之連接子結合之依喜替康結合物,該連接子可於該抗體之半胱胺酸殘基之硫原子處共價結合至該抗體。例如,該抗體之此半胱胺酸殘基可為能夠形成鏈間二硫鍵(本文中亦稱為鏈間二硫橋)之半胱胺酸殘基。因為IgG1抗體中存在四個鏈間二硫鍵,涉及總計八個半胱胺酸殘基,所以該連接子與該抗體之此等半胱胺酸殘基之硫原子處之結合提供DAR可多達8,且在此等情況下,該DAR通常介於7至8之間,諸如介於7.5至8.0之間(即約8),前提條件為該抗體係IgG1或具有與IgG1相同數量之鏈間二硫鍵。
因此,在一些實施例中,本發明提供包含經由連接子共價連接至依喜替康之根據本發明之抗體之免疫結合物,其中該結合物具有下式(VI):
(VI),
其中S係該抗體之半胱胺酸之硫原子,且其中n係共價連接至該抗體之[(連接子)-(依喜替康)]部分之數量。數字n (亦稱為DAR)可(例如)介於1至10之間;在更特定實施例中,n介於7至8之間;在甚至更特定之實施例中,n介於7.5至8.0之間(即約8)。
在其他實施例中,本發明提供包含經由連接子共價連接至依喜替康之根據本發明之抗體之免疫結合物,其中該結合物具有下式(VII):
(VII),
其中S係該抗體之半胱胺酸之硫原子,且其中n係共價連接至該抗體之[(連接子)-(依喜替康)]部分之數量。數字n (亦稱為DAR)可(例如)介於1至10之間;在更特定實施例中,n介於7至8之間;在甚至更特定之實施例中,n介於7.5至8.0之間(即約8)。
在上文描述之免疫結合物之任一者中,可使用本發明之任何抗體(如本文中上下文描述)。在一些實施例中,本發明之免疫結合物包含作為抗體之mAb1。
因此,在一些實施例中,本發明提供包含經由連接子共價連接至依喜替康之mAb1之免疫結合物,其中該結合物具有下式(VIII):
(VIII),
其中S係該抗體mAb1之半胱胺酸之硫原子,且其中n係共價連接至mAb1之[(連接子)-(依喜替康)]部分之數量。數字n (亦稱為DAR)可(例如)介於1至10之間;在更特定實施例中,n介於7至8之間;在甚至更特定之實施例中,n介於7.5至8.0之間(即約8)。在一些實施例中,S係能夠形成鏈間二硫橋之mAb1之半胱胺酸之硫原子且該DAR係約8。實例中進一步描述此免疫結合物(即「ADC1」)之一實例。
在其他實施例中,本發明提供包含經由連接子共價連接至依喜替康之mAb1之免疫結合物,其中該結合物具有下式(IX):
(IX),
其中S係該抗體mAb1之半胱胺酸之硫原子,且其中n係共價連接至mAb1之[(連接子)-(依喜替康)]部分之數量。數字n (亦稱為DAR)可(例如)介於1至10之間;在更特定實施例中,n介於7至8之間;在甚至更特定之實施例中,n介於7.5至8.0之間(即約8)。在一些實施例中,S係能夠形成鏈間二硫橋之mAb1之半胱胺酸之硫原子且該DAR係約8。實例中進一步描述此免疫結合物(即「ADC2」)之一實例。
在本發明之其他實施例中,連接子可為「不可裂解之連接子」 (例如SMCC連接子)。該抗體一經溶體降解,即可發生自該抗體釋放生長抑制劑。
在本發明之其他實施例中,免疫結合物可為包含本發明之抗體及細胞毒性或生長抑制多肽(作為生長抑制劑)之融合蛋白;此等融合蛋白可藉由重組技術或藉由肽合成(即此項技術中熟知的方法)製得。編碼DNA之分子可包含編碼彼此相鄰或由編碼連接子肽之區域隔開之結合物之兩個部分(分別抗體及細胞毒性或生長抑制多肽)之各別區域。
本發明之抗體亦可用於定向酶前藥療法中,諸如抗體定向酶前藥療法,藉由將該抗體結合至將前藥(例如肽基化學治療劑,參見WO 81/01145)轉化為活性細胞毒性藥物之前藥活化酶(參見例如WO 88/07378及美國專利第4,975,278號)。適用於ADEPT之免疫結合物之酶組分可包括能夠以使得前藥轉化為其更活性細胞毒性形式之方式來作用於前藥的任何酶。適用於此情境中之酶包括(但不限於)適用於將含磷酸鹽前藥轉化為游離藥物之鹼性磷酸酶;適用於將含硫酸鹽前藥轉化為游離藥物之芳基硫酸酯酶;適用於將無毒氟胞嘧啶轉化為抗癌藥物5-氟尿嘧啶之胞嘧啶脫胺酶;蛋白酶,諸如鋸桿菌蛋白酶、嗜熱菌蛋白酶、枯草菌蛋白酶、羧肽酶及組織蛋白酶(諸如組織蛋白酶B及L),其等適用於將含肽前藥轉化為游離藥物;D-丙胺醯基羧肽酶,適用於轉化含有D-胺基酸取代基之前藥;碳水化合物裂解酶,諸如適用於將醣化前藥轉化為游離藥物之O-半乳糖苷酶及神經胺糖酸酶;適用於將經P-內醯胺衍生之藥物轉化為游離藥物之P-內醯胺酶;及青黴素醯胺酶,諸如青黴素V醯胺酶或青黴素G醯胺酶,適用於將於其等胺氮處經苯氧乙醯基或苯乙醯基衍生之藥物分別轉化為游離藥物。藉由此項技術中熟知的技術,諸如使用上文討論之連接子,可將該等酶共價結合至本發明之抗體。
適用於製備本發明之免疫結合物之方法為此項技術中熟知(參見例如Hermanson G. T., Bioconjugate Techniques,第三版,2013, Academic Press)。例如,熟知經由共價結合至該抗體之鏈間二硫橋之半胱胺酸殘基之連接子將細胞毒性藥物結合至抗體之方法。
一般而言,本發明之免疫結合物可(例如)藉由包括以下步驟之方法獲得:
(i)製備包含連接子及生長抑制劑(例如細胞毒性藥物)之化合物,本文中亦稱為「藥物-連接子化合物」;
(ii)使根據本發明之抗體之任選緩衝水溶液與藥物-連接子化合物之溶液接觸;
(iii)然後自未反應之抗體及/或藥物-連接子化合物任選分離(ii)中形成之結合物。
抗體之水溶液可用緩衝液(諸如,舉例而言,組胺酸、磷酸鉀、乙酸鹽、檸檬酸鹽或N-2-羥基乙基哌嗪-N'-2-乙磺酸(Hepes緩衝液))緩衝。該緩衝液可根據該抗體之性質選擇。可將該藥物-連接子化合物溶解於(例如)有機極性溶劑,諸如二甲亞碸(DMSO)或二甲基乙醯胺(DMA)中。
關於對抗體之半胱胺酸殘基之結合,該抗體在步驟(ii)前經受還原(例如使用TCEP )。適用於僅還原鏈間二硫鍵之還原條件為此項技術中已知。
用於結合之還原溫度通常介於20至40℃之間。反應時間可變化且通常為1至24小時。可藉由粒徑排阻層析術(SEC)以折射及/或UV偵測器監測抗體與藥物-連接子化合物之間的反應。若該結合物產率過低,則該反應時間可延長。
熟習此項技術者可使用許多不同之層析法以進行步驟(iii)之分離:該結合物可(例如)藉由SEC、吸附層析術(諸如離子交換層析術,IEC)、疏水性交互作用層析術(HIC)、親和力層析術、混合支持層析術(諸如羥基磷灰石層析術)、或高效液相層析術(HPLC) (諸如逆相HPLC純化結合物)純化。亦可使用藉由透析或過濾或滲濾之純化。
在步驟(ii)及/或(iii)後,含結合物溶液可經受另外之純化步驟(iv),例如藉由層析術、超濾及/或滲濾。此另外之純化步驟(例如藉由層析術、超濾及/或滲濾)亦可在還原反應後用含抗體溶液進行,在其中在結合前進行還原的情況下。
在此過程結束時於水溶液中回收結合物。藥物與抗體比(DAR)係可隨連同用於結合之實驗條件一起使用之抗體及藥物-連接子化合物之性質(諸如比率 (藥物-連接子化合物)/(抗體)、反應時間、溶劑及共溶劑(若存在)之性質)變化之數字。因此,該抗體與該藥物-連接子化合物之間的接觸可導致包含具有不同藥物與抗體比之彼此不同之數種結合物之混合物。因此測定之DAR為平均值。
使用具有四個鏈間二硫橋之抗體(例如mAb1或任何IgG1抗體)於鏈間二硫橋之半胱胺酸殘基處進行結合係此項技術中熟知的方法且提供以下優勢:約8之相對均質之DAR可藉由選擇容許結合繼續進行至完成(或至少接近完成)之反應條件達成。
可用以確定DAR之一例示性方法由以下構成:分光光度法量測純化結合物溶液於λ
D及280 nM處之吸光度比。280 nM係常用於量測蛋白質濃度(諸如抗體濃度)之波長。選擇該波長λ
D以便於容許區分藥物與該抗體,即如熟習此項技術者容易認知,λ
D係該藥物具有高吸光度且λ
D距離280 nM足夠遠之波長以避免該藥物及抗體之吸光度峰值大量重疊。例如,針對依喜替康(或針對喜樹鹼或其他喜樹鹼類似物),λ
D可選擇為370 nM,或針對類美登素分子,λ
D可選擇為252 nM。
可(例如)自Antony S. Dimitrov (編), LLC, 2009, Therapeutic Antibodies and Protocols,第525、445卷,Springer Science: The absorbances for the conjugate at λ
D(A
λD) and at 280 nM (A
280) are measured either on the monomeric peak of the size exclusion chromatography (SEC) analysis (容許計算「DAR(SEC)」參數)或使用經典分光光度計裝置(容許計算「DAR(UV)」參數)推導DAR計算方法。吸光度可如下表示:
A
λD= (C
DX ε
DλD) + (C
AX ε
AλD)
A
280= (C
DX ε
D280) + (C
AX ε
A280)
其中:
• C
D及C
A分別為該藥物及該抗體溶液中之濃度
• ε
DλD及ε
D280分別為該藥物於λ
D及280 nM處之莫耳消光係數
• ε
AλD及ε
A280分別為該抗體於λ
D及280 nM處之莫耳消光係數。
以兩個未知數對此等兩個方程進行求解導致下列等式:
C
D= [( ε
A280X A
λD) - (ε
AλDX A
280)] / [(ε
DλDX ε
A280) - ( ε
AλDX ε
D280)]
C
A =[A
280- (C
DX ε
D280)] / ε
A280然後根據該藥物濃度與該抗體濃度之比率計算平均DAR:DAR = C
D/ C
A。
實例中描述用於製備本發明之免疫結合物之例示性方法。
藥物 - 連接子化合物本發明亦提供包含連接子及生長抑制劑(例如細胞毒性藥物)之化合物,本文中亦稱為「藥物-連接子化合物」。例如,本發明提供下式(X)化合物:
(X)
或其生理上可接受之鹽;此化合物在本文中亦稱為「藥物-連接子化合物1」、「化合物DL1」或「DL1」。
此等藥物-連接子化合物可用以製備如本文中上下文描述之本發明之免疫結合物。
本發明之藥物-連接子化合物(例如彼等上文繪示之式(X)或(XI)者)可藉由化學合成製備,例如如下文實例中進一步描述。
醫藥組合物本發明之抗體或免疫結合物可與醫藥上可接受之載劑、稀釋劑及/或賦形劑組合,及任選與緩釋基質組合以形成醫藥組合物,該等緩釋基質包括(但不限於)可生物降解聚合物、不可生物降解聚合物、脂質或糖之類別。
因此,本發明之另一態樣係關於包含本發明之抗體或免疫結合物及醫藥上可接受之載劑、稀釋劑及/或賦形劑之醫藥組合物。
「醫藥」或「醫藥上可接受」係指分子實體及組合物在視需要對哺乳動物(尤其人類)投與時不產生不利、過敏或其他非所需反應。醫藥上可接受之載劑、稀釋劑或賦形劑係指任何類型之無毒固體、半固體或液體填充劑、稀釋劑、囊封材料或調配助劑。
如本文使用,「醫藥上可接受之載劑」包括任何及所有溶劑、分散介質、包衣、抗細菌劑及抗真菌劑,及生理上可相容之類似物。合適載劑、稀釋劑及/或賦形劑之實例包括(但不限於)以下中之一或多者:水、胺基酸、鹽水、磷酸鹽緩衝鹽水、緩衝磷酸鹽、乙酸鹽、檸檬酸鹽、琥珀酸鹽;胺基酸及衍生物,諸如組胺酸、精胺酸、甘胺酸、脯胺酸、甘胺醯甘胺酸;無機鹽,諸如NaCl或氯化鈣;糖或多元醇,諸如右旋糖、甘油、乙醇、蔗糖、海藻糖、甘露醇;表面活性劑,諸如聚山梨醇酯80、聚山梨醇酯20、泊洛沙姆188;及類似物,及其組合。在許多情況下,醫藥組合物中包括等滲劑,諸如糖、多元醇或氯化鈉將係有用的,及調配物亦可含有抗氧化劑(諸如色胺)及/或穩定劑(諸如吐溫20)。
醫藥組合物之形式、投與途徑、劑量及方案自然取決於待治療之病症、疾病之嚴重程度、病患之年齡、重量及性別等。
本發明之醫藥組合物可經調配用於局部、經口、非經腸、鼻內、靜脈內、肌內、皮下或眼內投與及類似物。
在一實施例中,醫藥組合物含有用於注射用調配物之醫藥上可接受之媒介物。此等可為等滲、無菌、鹽水溶液(磷酸一鈉或磷酸二鈉、氯化鈉、氯化鉀、氯化鈣或氯化鎂及類似物或此等鹽之混合物),或乾燥(尤其凍乾)組合物,其根據情況在添加無菌水或生理鹽水時,允許構成可注射溶液。
醫藥組合物可通過藥物組合裝置投與。
用於投與之劑量可隨各種參數變化,及例如隨所用投與模式、相關病理學,或者所需治療持續時間變化進行調整。
為製備醫藥組合物,可將有效量之本發明之抗體或免疫結合物溶解或分散於醫藥上可接受之載劑或水性介質中。
適用於可注射用途之醫藥形式包括無菌水溶液或分散液;包括芝麻油、花生油或丙二醇水溶液之調配物;及用於臨時製備無菌可注射溶液或分散液之無菌粉末;在所有此等情況下,該形式必須無菌且可用適用於遞送而不降解之裝置或系統注射,且其在製造及儲存條件下必須穩定及必須防止微生物(諸如細菌及真菌)之污染作用。
呈游離鹼或醫藥上可接受之鹽之活性化合物之溶液可製備於與表面活性劑適當混合之水中。分散液亦可製備於甘油、液體聚乙二醇,及其混合物及於油中。在儲存及使用之一般條件下,此等製劑可含有防腐劑以防止微生物生長。
本發明之抗體或免疫結合物可以中性或鹽形式調配成醫藥組合物。醫藥上可接受之鹽包括酸加成鹽(與蛋白質之游離胺基形成),其等與無機酸(諸如,舉例而言,鹽酸或磷酸)或有機酸(諸如乙酸、草酸、酒石酸或扁桃酸,及類似物)形成。與游離羧基形成之鹽亦可來源於無機鹼(諸如,舉例而言,氫氧化鈉、氫氧化鉀、氫氧化銨、氫氧化鈣或氫氧化鐵)及有機鹼(諸如異丙胺、三甲胺、甘胺酸、組胺酸、普魯卡因及類似物)。
載劑亦可為溶劑或分散介質,其含有(例如)水、乙醇、多元醇(例如,甘油、丙二醇及液體聚乙二醇,及類似物)、其合適混合物及植物油。可(例如)藉由使用包衣(諸如卵磷脂)、在分散液之情況下藉由維持所需粒度及藉由使用表面活性劑維持適當之流動性。可由各種抗細菌劑及抗真菌劑(例如,對羥基苯甲酸酯、氯丁醇、苯酚、山梨酸、乙汞硫柳酸鈉,及類似物)防止微生物作用。在某些情況下,其可需包括等滲劑(例如,糖或氯化鈉)。可藉由在組合物中使用延遲吸收之藥劑(例如,單硬脂酸鋁及明膠)引起可注射組合物之延遲吸收。
無菌可注射溶液可藉由將所需量的活性化合物視需要與上文枚舉之其他成分中之任一者一起併入適當溶劑內,接著過濾滅菌製備。一般而言,分散液可藉由將各種滅菌活性成分併入含有鹼性分散介質及來自彼等上文枚舉者之所需其他成分之無菌媒介物內製備。在用於製備無菌可注射溶液之無菌粉末之情況下,製備方法包括真空乾燥及凍乾技術,該等方法自其先前無菌過濾之溶液產生活性成分加任何另外所需成分之粉末。
亦審慎考慮製備用於直接注射之更濃縮或高度濃縮之溶液,其中設想使用DMSO作為溶劑以導致極快滲透,將高濃度活性劑遞送至小腫瘤區域。
一經調配,即可以與劑量調配物相容之方式及以治療有效之量投與溶液。可以多種劑量形式(諸如上文描述之可注射溶液之類型)容易地投與該等調配物,但亦可採用藥物釋放膠囊及類似物。
對於水溶液中之非經腸投與,例如,該溶液可視需要經適當緩衝,且液體稀釋劑首先與與足夠之鹽水或葡萄糖等滲。此等水溶液尤其適用於靜脈內、肌內、皮下及腹膜內投與。在此關聯中,鑒於本發明,熟習此項技術者已知可採用之無菌水性介質。例如,可將一個劑量溶解於1 ml等滲NaCl溶液中並添加至1000 ml皮下溶解液或於建議輸注位點處注射(參見例如,「Remington's Pharmaceutical Sciences」第15版,第1035至1038及1570至1580頁)。根據治療中之個體之狀況,劑量中將必然出現一些變化。在任何情況下,負責投與者均將決定適用於個別個體之劑量。
本發明之抗體或免疫結合物可調配於治療混合物內以包含(例如)每劑量約0.01至100毫克左右。
除經調配用於非經腸投與(諸如靜脈內或肌內注射)之抗體或免疫結合物外,其他醫藥上可接受之形式包括(例如)用於經口投與之錠劑或其他固體、釋放膠囊,及當前使用之任何其他形式。
在一些實施例中,審慎考慮使用脂質體及/或奈米顆粒以將多肽引入宿主細胞內。熟習此項技術者已知脂質體及/或奈米顆粒之形成及用途。
奈米膠囊可一般以穩定及可重複方式捕獲化合物。為避免由於細胞內聚合物過載引起之副作用,此等超細顆粒(尺寸約0.1 μm) 一般使用可活體內降解之聚合物設計。審慎考慮將滿足此等要求之可生物降解聚烷基-氰基丙烯酸酯奈米顆粒、或可生物降解聚乳酸或聚乳酸共乙交酯奈米顆粒用於本發明中,且此等顆粒可由熟習此項技術者容易製得。
脂質體可由磷脂分散於水性介質中並自發形成多層同心雙層囊泡(亦稱為多層囊泡(MLV))而形成。MLV一般具有25 nM至4 μm之直徑。MLV之音波處理導致形成直徑在200至500 A之範圍內,核心中含有水溶液之小單層囊泡(SUV)。脂質體之物理特性取決於pH、離子強度及二價陽離子之存在。
除上述實例外,亦審慎考慮其他醫藥形式,諸如奈米顆粒、微粒及膠囊、植入物(例如脂質植入物),或自固化或乳化系統。
治療方法及用途發明人已發現本發明之抗體(例如mAb1)可在結合後作為CEACAM5-抗體複合物之部分內化。此外,其等已顯示結合至細胞毒性藥物(依喜替康)之此抗體活體外介導對腫瘤細胞之細胞毒性效應。發明人亦已顯示例如在來源於病患之人類結腸直腸癌之鼠異種移植模型中,當以10 mg/kg之劑量以單次注射使用時,本發明之此等免疫結合物活體內誘導顯著之抗腫瘤活性。事實上,本發明之免疫結合物在大量活體外及活體內模型中顯示廣泛活性。細胞毒性效力與標靶(CEACAM5)表現密切相關且在靶標陰性細胞中低得多。在不同癌症類型之數種來源於細胞系之異種移植(CDX)及來源於病患之異種移植(PDX)模型中證實非常好的抗腫瘤活性。在非人類靈長類動物劑量範圍發現研究中,免疫結合物具有良好耐受性,及其副作用概況係拓撲異構酶-I抑制劑化學療法之典型特徵。臨床前資料為後期臨床測試指示良好之治療窗口。因此本發明之抗體、免疫結合物及醫藥組合物可適用於治療癌症。
因此,本發明提供本發明之抗體、免疫結合物或醫藥組合物,其用作藥劑。例如,本發明提供本發明之抗體、免疫結合物或醫藥組合物,其用以治療癌症。本發明進一步提供一種治療癌症之方法,其包括對有需要個體投與本發明之抗體、免疫結合物或醫藥組合物。
如相較於相同組織來源之正常(即非腫瘤)細胞,待用本發明之抗體、免疫結合物或醫藥組合物治療之癌症係較佳表現CEACAM5之癌症,更佳過表現CEACAM5之癌症。可(例如)藉由使用根據本發明之抗體(或市售抗CEACAM5抗體),例如如以下部分「診斷用途」中描述,及(例如)藉由免疫組織化學方法容易地分析由細胞表現CEACAM5。
在一些實施例中,待用本發明之抗體、免疫結合物或醫藥組合物治療之癌症係結腸直腸癌、非小細胞肺癌、胰臟癌、胃癌、宮頸癌、食道癌(例如食管腺癌)、膽管癌、乳癌、前列腺癌、卵巢癌、尿路上皮癌、膀胱癌,或胃、子宮、子宮內膜、甲狀腺或皮膚之癌症。在一些特定實施例中,待用本發明之抗體、免疫結合物或醫藥組合物治療之癌症係結腸直腸癌、胃癌、非小細胞肺癌、胰臟癌、食道癌或前列腺癌。
本發明之抗體或免疫結合物可單獨或與任何合適之生長抑制劑組合用於癌症療法中。
如上文描述,本發明之抗體可結合(連接)至生長抑制劑。因此本發明之抗體可適用於將該生長抑制劑靶向於表面上表現或過表現之CEACAM5癌細胞。
亦熟知治療性單株抗體可導致消耗攜載該抗體特異性識別之抗原之細胞。此消耗可通過至少三種機制介導:抗體介導之細胞毒性(ADCC)、補體依賴性裂解,及通過由該抗體靶向抗原介導之訊息直接抑制腫瘤生長。
「抗體依賴性細胞介導之細胞毒性」或「ADCC」係指一種細胞毒性形式,其中抗體結合至某些細胞毒性細胞(例如自然殺手(NK)細胞、嗜中性球及巨噬細胞)上存在之Fc受體(FcR)使得此等細胞毒性效應細胞特異性結合至攜載抗原之靶細胞及後續殺死靶細胞。為評估受關注分子之ADCC活性,可進行活體外ADCC分析,諸如美國專利第5,500,362或5,821,337號中描述之分析。
「補體依賴性細胞毒性」或「CDC」係指靶細胞在補體存在下之裂解。經典補體途徑之活化係藉由將補體系統之第一組分結合至與其等同源抗原結合之抗體啟動。為評估補體活化,可進行CDC分析,例如如Gazzano-Santoro等人,(Journal of Immunological Methods. 1997 Mar;202(2):163-171)中描述之分析。
在一些實施例中,本發明之抗體可為具有經修飾之胺基酸序列以導致減少或消除結合至大多數Fcγ受體之抗體,其可減少表現此等受體之正常細胞及組織(例如巨噬細胞、肝竇細胞等)中之攝取及毒性。
本發明之一態樣係關於一種治療癌症之方法,其包括對有需要個體投與治療有效量之本發明之抗體、免疫結合物或醫藥組合物。
在本發明之內文中,如本文使用,術語「治療(treating)」或「治療(treatment)」意謂逆轉、緩解此術語適用之疾患或病症或此疾患或病症之一或多種症狀、抑制此術語適用之疾患或病症或此疾患或病症之一或多種症狀之進展或預防抑制此術語適用之疾患或病症或此疾患或病症之一或多種症狀。如本文使用之術語「治療癌症」意謂抑制腫瘤惡性細胞之生長及/或自該腫瘤轉移之進展。此治療亦可導致腫瘤生長之消退,即,可量測腫瘤之尺寸減少。例如,此治療可導致該腫瘤或轉移之完全消退。
在本發明之治療應用之內文中,術語「個體」或「病患」或「有需要個體」或「有需要病患」係指受或可能受腫瘤影響之個體(例如人類或非人類哺乳動物)。例如,該病患可為已例如根據如本文中下文描述之方法確定對靶向CEACAM5之治療劑,特別地對根據本發明之抗體或免疫結合物敏感之病患。
「治療有效量」意謂以適用於任何醫學治療之合理收益/風險比治療該癌症疾病之足夠量。然而,將瞭解本發明之抗體、免疫結合物及醫藥組合物(統稱為「治療劑」)之總日用量將由主治醫師於合理醫學判斷之範圍內決定。用於任何特定病患之特定治療有效劑量將取決於多種因素,包括治療中之疾患及該疾患之嚴重程度;採用之特定治療劑之活性;該病患之年齡、體重、一般健康、性別及飲食;採用之特定治療劑之投與時間、投與途徑及排泄率;該治療之持續時間;與採用之特定治療劑組合或同時使用之藥物;及醫學領域中熟知的類似因素。例如,本技術領域中眾所周知,以低於彼等達成所需治療效應者之水準開始化合物之劑量並逐漸增加該劑量直至達成該所需效應。
本發明之抗體、免疫結合物或醫藥組合物亦可用於抑制癌症轉移之進展。
本發明之抗體、免疫結合物或醫藥組合物亦可與任何其他治療干預組合用於治療癌症(例如輔助療法)及/或用於減少轉移性癌症之生長。例如,用於此組合之其他治療干預可為用於待治療癌症之護理標準(SOC)治療劑。
使用根據本發明之抗體或免疫結合物或醫藥組合物之治療之效用可活體內(例如在癌症之小鼠模型中)及藉由量測(例如)治療組與對照組之間之腫瘤體積之變化、腫瘤消退%、部分消退或完全消退容易地分析。
診斷用途已報告CEACAM5高度表現於癌細胞(諸如,舉例而言,結直腸、胃、肺及胰臟腫瘤細胞)表面上,且正常組織中之表現僅限於少數正常上皮細胞(諸如結腸及食管上皮細胞)。
因此,CEACAM5構成癌症標誌物且有可能用以(例如)指示抗癌症療法之有效性或偵測疾病之復發。
在一實施例中,本發明之抗體在靶向表現CEACAM5之腫瘤之療法之內文中可用作分析之組分,以確定病患對治療劑之敏感性、監測抗癌症療法之有效性或偵測治療後該疾病之復發。在一些實施例中,本發明之相同抗體可用作該治療劑之組分及用作該診斷分析之組分。
因此,本發明之另一態樣係關於使用根據本發明之抗體在來自個體之生物樣本中離體偵測CEACAM5表現。本發明之另一態樣係關於使用本發明之抗體活體內偵測個體中之CEACAM5表現。當用於偵測CEACAM5時,該抗體可用可偵測分子(諸如,舉例而言,螢光團或酶)標記。
CEACAM5之偵測可預期用於(例如):
a)診斷個體中癌症之存在,或
b)確定患有癌症之病患對靶向CEACAM5之治療劑(特別地根據本發明之抗體或免疫結合物)之敏感性,或
c)監測抗CEACAM5癌症療法之有效性或偵測抗CEACAM5癌症療法後之癌症復發,特別地其中該療法係使用根據本發明之抗體或免疫結合物之療法;
藉由偵測腫瘤細胞上表面蛋白CEACAM5之表現。
在實施例中,抗體預期用於活體外或離體診斷用途。例如,可使用本發明之抗體在獲自個體之生物樣本中活體外或離體偵測CEACAM5。根據本發明之用途亦可為活體內用途。例如,可對個體投與根據本發明之抗體並可偵測及/或定量抗體-細胞複合物,藉此該等複合物之偵測指示癌症。
本發明進一步係關於一種在個體中偵測癌症存在之活體外或離體方法,其包括以下步驟:
(a)使來自個體之生物樣本與根據本發明之抗體接觸,特別地在適用於該抗體與該生物樣本形成複合物之條件下接觸;
(b)量測結合至該生物樣本之抗體之濃度;及
(c)藉由比較結合抗體與對照之量測濃度偵測癌症之存在,結合抗體之濃度相較於對照增加指示癌症。
本發明亦係關於一種測定患有癌症之病患對靶向CEACAM5之治療劑(特別地根據本發明之抗體或免疫結合物)之敏感性之活體外或離體方法,該方法包括以下步驟:
(a)使來自患有癌症之病患之生物樣本與根據本發明之抗體接觸,特別地在適用於該抗體與該生物樣本形成複合物之條件下接觸;
(b)量測結合至該生物樣本之抗體之濃度;及
(c)將結合至該生物樣本之抗體之量測濃度與結合至對照之抗體之濃度進行比較;
其中結合至該生物樣本之抗體之濃度相較於對照增加指示病患對靶向CEACAM5之治療劑之敏感性。
在上文方法中,該對照可為相同類型之正常、非癌性生物樣本,或確定為表示相同類型之正常生物樣本中之抗體結合濃度的參考值。
在一實施例中,本發明之抗體適用於診斷表現CEACAM5之癌症,諸如結腸直腸癌、胃癌、非小細胞肺癌、胰臟癌、食道癌、前列腺癌或表現CEACAM5之其他實性瘤。
本發明進一步係關於一種監測抗CEACAM5癌症療法之有效性之活體外或離體方法,其包括以下步驟:
(a)使來自經受抗CEACAM5癌症療法之個體的生物樣本與根據本發明之抗體接觸,特別地在適用於該抗體與該生物樣本形成複合物之條件下接觸;
(b)量測結合至該生物樣本之抗體之濃度;及
(c)將結合抗體之量測濃度與結合至對照之抗體之濃度進行比較;
其中結合至該生物樣本之抗體之濃度相較於對照下降指示該抗CEACAM5癌症療法之有效性。在該方法中,結合至該生物樣本之抗體之濃度相較於對照增加將指示該抗CEACAM5癌症療法無效。在監測有效性之此方法之一實施例中,該對照係與遞交分析之生物樣本相同類型之生物樣本,但其係在抗CEACAM5癌症療法過程中在較早時間點下自該個體獲得。
本發明進一步係關於一種偵測抗CEACAM5癌症療法後癌症復發之活體外或離體方法,其包括以下步驟:
(a)使來自個體(已完成抗CEACAM5癌症療法之個體)之生物樣本與根據本發明之抗體接觸,特別地在適用於該抗體與該生物樣本形成複合物之條件下接觸;
(b)量測結合至該生物樣本之抗體之濃度;及
(c)將結合抗體之量測濃度與結合至對照之抗體之濃度進行比較;
其中結合至該生物樣本之抗體之濃度相較於對照增加指示抗CEACAM5癌症療法後之癌症復發。特別地,該對照可為與遞交分析之生物樣本相同類型之生物樣本,但其係先前(即在該抗CEACAM5癌症療法一經完成或完成後)自該個體獲得。
該抗CEACAM5癌症療法係(例如)使用根據本發明之抗體或免疫結合物之療法。該抗CEACAM5癌症療法靶向表現CEACAM5之癌症,諸如結腸直腸癌、胃癌、非小細胞肺癌、胰臟癌、食道癌、前列腺癌或表現CEACAM5之其他實性瘤。
在一些實施例中,本發明之抗體可用可偵測分子或物質,諸如螢光分子或螢光團、放射性分子、酶或此項技術中已知提供(直接或間接)訊息之任何其他標記進行標記。
如本文使用,關於根據本發明之抗體,術語「標記」意欲包含藉由將可偵測物質諸如放射性劑或螢光團(例如螢光異硫氰酸鹽(FITC)或藻紅素(PE)或靛青(Cy5))偶合(即,物理連接)至多肽直接標記該抗體,及藉由與可偵測物質之反應性間接標記該多肽。
本發明之抗體可用放射性分子藉由此項技術中已知的任何方法標記。例如,放射性分子包括(但不限於)閃爍研究之放射性原子,諸如I
123、I
124、In
111、Re
186、Re
188、Tc
99。本發明之抗體亦可用核磁共振(NMR)成像(亦稱為磁振造影,MRI)之自旋標記,諸如碘-123、銦-111、氟-19、碳-13、氮-15、氧-17、釓、錳或鐵進行標記。
「生物樣本」包含獲自個體的可用於診斷或監測分析中之各種樣本類型。生物樣本包括(但不限於)血液及生物來源之其他液體樣本、固體組織樣本(諸如生檢樣本或組織培養物或來源於其之細胞,及其後代。因此,生物樣本包含臨床樣本、培養物中之細胞、細胞上清液、細胞溶胞產物、血清、血漿、生物體液及組織樣本(諸如腫瘤樣本)。
在一些實施例中,生物樣本可為福爾馬林固定及石蠟包埋(FFPE)之組織樣本。
本發明亦係關於一種偵測個體中癌症之存在之活體內方法,其包括以下步驟:
a)對病患投與根據本發明之抗體,其中該抗體係經可偵測分子標記;
b)藉由成像,例如藉由偵測可偵測分子,偵測該抗體於該病患中之定位。
在該方法中,癌症可為表現CEACAM5之癌症,諸如結腸直腸癌、胃癌、非小細胞肺癌、胰臟癌、食道癌、前列腺癌或表現CEACAM5之其他實性瘤。
本發明之抗體亦可適用於癌症分期(例如,在放射成像中)。本發明之抗體可單獨或與其他癌症標誌物組合使用。
如本文使用之術語「偵測」或「經偵測」包括參考或不參考對照之定性及/或定量偵測(即量測濃度)。
在本發明之內文中,如本文使用,術語「診斷」意謂基於許多收集之資料,確定醫療狀況之性質,旨在識別影響該個體之病理學。
套組最後,本發明亦提供包含至少一種本發明之抗體或免疫結合物之套組。發現含有本發明之抗體之套組可用於偵測表面蛋白CEACAM5,或用於治療或診斷分析中。本發明之套組可含有偶合至撐體(例如,組織培養盤或珠(例如,瓊脂糖珠))之抗體。可提供含有用於活體外偵測及定量表面蛋白CEACAM5 (例如在ELISA或西方墨點法中)之抗體之套組。適用於偵測之此抗體可具有標記(諸如螢光或放射性標記)。
序列之簡述 胺基酸序列:SEQ ID NO: 1 根據基因庫寄存編號AAA51967.1之人類CEACAM5蛋白序列
SEQ ID NO: 2 食蟹獼猴CEACAM5蛋白序列(NCBI參考序列XP_005589491.1)
SEQ ID NO: 3 mAb1之CDR1-H
SEQ ID NO: 4 mAb1之CDR2-H
SEQ ID NO: 5 mAb1之CDR3-H
SEQ ID NO: 6 mAb1之CDR1-L
SEQ ID NO: 7 mAb1之CDR2-L
SEQ ID NO: 8 mAb1之CDR3-L
SEQ ID NO: 9 mAb1之VH
SEQ ID NO: 10 mAb1之VL
SEQ ID NO: 11 mAb1之CH
SEQ ID NO: 12 mAb1之CL
SEQ ID NO: 13 mAb1之HC
SEQ ID NO: 14 mAb1之LC
核酸序列:
SEQ ID NO: 15 編碼mAb1之HC 之DNA序列
SEQ ID NO: 16 編碼mAb1之LC之DNA序列
胺基酸序列:
SEQ ID NO: 17 抗體hu8G4之HC
SEQ ID NO: 18 抗體hu8G4之LC
SEQ ID NO: 19 最佳化抗體變體1之HC
SEQ ID NO: 20 最佳化抗體變體1之LC
SEQ ID NO: 21 最佳化抗體變體2之LC
SEQ ID NO: 22 最佳化抗體變體4之LC
SEQ ID NO: 23 最佳化抗體變體5之LC
SEQ ID NO: 24 最佳化抗體變體6之HC
SEQ ID NO: 25 huMab2-3之HC (異型)
SEQ ID NO: 26 huMab2-3之LC
SEQ ID NO: 27 hmn-14之HC
SEQ ID NO: 28 hmn-14之LC
SEQ ID NO: 29 rb8G4之HC
SEQ ID NO: 30 rb8G4之LC
實例 實例 1 :抗 CEACAM5 抗體1.1轉基因大鼠之免疫作用及融合瘤之分離
為產生對人類CEACAM5蛋白(癌胚抗原相關細胞黏著分子5;CD66e)之單株抗體,自CHARLES RIVER LABORATORIES INTERNATIONAL INC. (WIL MINGTON, MA)獲得人類免疫球蛋白基因轉基因大鼠(OmniRat
TM)。5隻動物用選殖至Aldevron專有免疫作用載體(pB8-CEA-hum-MC)內之CEACAM5 cDNA (編碼具有UniProt ID編號P06731之人類CEACAM5蛋白序列之胺基酸35至675;除SEQ ID NO: 1之E398經K398取代外,P06731之序列與SEQ ID NO: 1相同)免疫4次,並使用基因槍瞬時轉染至OMT大鼠細胞內。
藉由基於細胞之ELISA (CELISA)分析使用細胞膜上表現CEACAM5之細胞評估抗CEACAM5效價(下文呈現效價結果)。在免疫作用方案之第31天,在4輪遺傳物質免疫作用(IS31d-4)後採集經免疫之動物血清。藉由流式細胞分析技術對經選殖至Aldevron專有表現載體(pB1-CEA-hum-MC)內之CEACAM5 cDNA瞬時轉染之哺乳動物細胞測試稀釋於PBS + 3% FBS中之血清。使用10 μg/ml的山羊抗大鼠IgG R-藻紅素結合物(Southern Biotech, #3030-09)作為二級抗體。
處死所有動物並將來自淋巴結之淋巴球合併且冷凍保存以備將來使用。使細胞與Ag8小鼠骨髓瘤細胞系融合以產生活融合瘤。然後將來自此融合之融合瘤細胞轉移至十個96孔盤。
1.2 CEACAM5特異性
使用基於細胞之ELISA (CELISA)分析篩選融合瘤上清液用於偵測不結合CEACAM1 (BGP)、CEACAM3 (CGM1a)、CEACAM4 (CGM7)、CEACAM6 (NCA)及CEACAM8 (NCA-95)之抗CEACAM5抗體。使用10 μg/ml的山羊抗大鼠IgG R-藻紅素結合物(Southern Biotech, #3030-09)作為二級抗體。
將對人類CEACAM5顯示特異性及不對其相關蛋白質顯示特異性之純系轉移至一個96孔盤並在ELISA分析中評估融合瘤上清液的特異性及交叉反應性。在此分析中,8G4融合瘤純系及其子純系顯示對人類CEACAM5的特異性及對食蟹獼猴CEACAM5的交叉反應性。
1.3 偵測抗體序列及選殖
自各融合瘤純系根據RNeasy 96方案,Qiagen製備總RNA。隨後使用無規六聚體及SuperScript©III將總RNA轉錄成cDNA。
藉由qPCR品質控制所得cDNA並藉由PCR擴增VH及Vk。使用AMpure XP PCR淨化套組與KingFisher儀器之組合純化PCR產物。
使用同源重組程序(所謂之「Lucigen選殖」)將8G4子純系之VH及Vk基因分別選殖至目的載體hi00_pTT5_VH_ccdB及hh00_pTT5_Vk_ccdB內。在One Shot® Mach1™-T1R化學活性大腸桿菌中轉形反應混合物。藉由Sanger定序證實正確重組之純系。
1.4命中之人類化及生物化學表徵及候選物選擇
8G4及其他純系係經重新格式化並表現為人類IgG1分子。其等藉由SDS-PAGE、粒徑排阻層析術(SEC)、選擇性、親和力、細胞結合及效力評估。基於結果,選擇一種人類化候選抗體(命名為hu8G4)用於胺基酸序列最佳化以改善可製造性及親和力。
人類化候選抗體hu8G4之胺基酸序列如下:
重鏈:
EVQLVESGPGLVKPSQTLSLTCTVSDGSVSRGGYYLTWIRQHPGKGLEWIGYIYYSGSTYFNPSLRSRLTMSVDTSKNQFSLKLSSVTAADTAVYYCARGIAVAPFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 17)
輕鏈:
ETTLTQSPATLSVSPGERATLSCRTSQSVRSNLAWYQQKPGQAPRLLIYAASTRATGIPARFSGSGSGTEFTLTIGSLQSEDFAVYFCQQYTNWPFTFGPGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC (SEQ ID NO: 18)
1.5 hu8G4 (尤其導致mAb1)之生物物理改善策略
hu8G4之可變區序列之評估鑑別輕鏈框架中之六個非生殖系列胺基酸殘基及重鏈框架中之兩個非生殖系列胺基酸殘基。可能易於轉譯後修飾之胺基酸及序列基序(諸如脫醯胺基序、表面可及之甲硫胺酸及游離半胱胺酸)之評估未鑑別傾向增加之任何胺基酸殘基。產生數種經設計之抗體序列,其中某些胺基酸於該位置處經生殖系列相關胺基酸置換。然後使不同之VH及VL最佳化設計以Fab及完整IgG1分子的形式共表現於HEK 293 6E細胞中,進行純化並測試(參見例如下文最佳化變體1至10)。
以完整IgG1形式之10種最佳化抗體變體之胺基酸序列如下:
變體1 (VH1.00/VL1.00)
HC:
EVQLQESGPGLVKPSQTLSLTCTVSDGSVSRGGYYLTWIRQHPGKGLEWIGYIYYSGSTYFNPSLRSRLTMSVDTSKNQFSLKLSSVTAADTAVYYCARGIAVAPFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 19)
LC:
ETTLTQSPATLSVSPGERATLSCRTSQSVRSNLAWYQQKPGQAPRLLIYAASTRATGIPARFSGSGSGTEFTLTIGSLQSEDFAVYFCQQYTNWPFTFGPGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 20)
變體2 (VH1.00/VL1.01)
HC:SEQ ID NO: 19
LC:
EIVLTQSPATLSVSPGERATLSCRTSQSVRSNLAWYQQKPGQAPRLLIYAASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYFCQQYTNWPFTFGPGTKVDIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 21)
變體3 (VH1.00/VL1.02)
HC:SEQ ID NO: 19
LC:SEQ ID NO: 14
變體4 (VH1.00/VL1.03)
HC:SEQ ID NO: 19
LC:
EIVMTQSPATLSVSPGERATLSCRTSQSVRSNLAWYQQKPGQAPRLLIYAASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYFCQQYTNWPFTFGPGTKVDIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 22)
變體5 (VH1.00/VL1.04)
HC:SEQ ID NO: 19
LC:
EIVMTQSPATLSVSPGERATLSCRTSQSVRSNLAWYQQKPGQAPRLLIYAASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYTNWPFTFGPGTKVDIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 23)
變體6 (VH1.02/VL1.00)
HC:
EVQLQESGPG LVKPSQTLSL TCTVSDGSVS RGGYYLTWIR QHPGKGLEWI GYIYYSGSTY FNPSLRSRVT MSVDTSKNQF SLKLSSVTAA DTAVYYCARG IAVAPFDYWG QGTLVTVSSA STKGPSVFPL APSSKSTSGG TAALGCLVKD YFPEPVTVSW NSGALTSGVH TFPAVLQSSG LYSLSSVVTV PSSSLGTQTY ICNVNHKPSN TKVDKRVEPK SCDKTHTCPP CPAPELLGGP SVFLFPPKPK DTLMISRTPE VTCVVVDVSH EDPEVKFNWY VDGVEVHNAK TKPREEQYNS TYRVVSVLTV LHQDWLNGKE YKCKVSNKAL PAPIEKTISK AKGQPREPQV YTLPPSREEM TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVL DSDGSFFLYS KLTVDKSRWQ QGNVFSCSVM HEALHNHYTQ KSLSLSPGK (SEQ ID NO: 24)
LC:SEQ ID NO: 20
變體7 (VH1.02/VL1.01)
HC:SEQ ID NO: 24
LC:SEQ ID NO: 21
變體8 (VH1.02/VL1.02)
HC:SEQ ID NO: 24
LC:SEQ ID NO: 14
變體9 (VH1.02/VL1.03)
HC:SEQ ID NO: 24
LC:SEQ ID NO: 22
變體10 (VH1.02/VL1.04)
HC:SEQ ID NO: 24
LC:SEQ ID NO: 23
所有最佳化變體1至10在維持品質方面均表現相似,如藉由粒徑排阻層析術測定之聚集百分比,基於螢光監測熱解折疊(FMTU)維持穩定性,保持與MKN-45癌細胞系之結合並維持對標靶之選擇性。變體8 (即包括VH1.02及VL1.02之變體)經選為用於進一步開發作為最佳化變體,其序列與生殖系列特別相似。
對然後所選變體8進行進一步序列最佳化(尤其)以減少IgG Fc效應功能。相較於親代純系,所得最終序列最佳化(so)純系(命名為so8G4 (本文中亦稱為mAb1))顯示經改善之親和力及經改善之可製造性,且亦顯示減少或不結合至FcγRI、FcγRIIa、FcγRIIIa、FcγRIIIa/複合物、C1q、FcγRIIb及FcγRIIIb,同時維持對CEACAM5及FcRn之親和力。此最終序列最佳化抗體so8G4 (本文中亦稱為mAb1)之胺基酸序列如下:
重鏈(HC):SEQ ID NO: 13 (如本文中上文定義)
輕鏈(LC):SEQ ID NO: 14 (如本文中上文定義)
1.6 mAb1之活體外表徵
以活體外分析表徵抗體mAb1之數種性質,包括:結合親和力、選擇性及內化。
1.6.1 結合親和力
. 為測定可溶性抗體分析物對捕獲之靶蛋白CEACAM5 (人類或食蟹獼猴
Macaca fascicularis)之結合親和力。在Octet Red儀器上使用下列實驗條件:
. 塗覆鏈黴親和素之生物感測器。
. 生物素化靶蛋白濃度(其中ECD表示細胞外域):
¡ 在1000 rpm下以2.5 µg/ml將人類_CEACAM5_ECD-his-生物素R&D系統(使用例行性方法生物素化)捕獲900秒。
¡ 在1000 rpm下以5 µg/ml將獲自Syngene之重組食蟹獼猴CEACAM5_ECD-His-生物素(使用例行性方法生物素化)捕獲900秒。
. 分析物抗體濃度:200、100、50、25、12.5、6.25、0 nM。
. 用Octet評估軟體自量測之結合動力學結合(ka)及解離(kd)速率常數測定結合親和力KD (平衡解離常數)值,其中KD = kd/ka
. 以Fab形式使用抗體
由mAb1產生之Fab之結果:
人類CEACAM5之結合親和力KD係6.3 ± 1.98 nM。
食蟹獼猴-CEACAM5之結合親和力KD係14.1 ± 2.53 nM。
1.6.2. 選擇性
a)物種及域
在ELISA分析中,藉由將抗體自4 nM滴定至0.25 pM,並將其施用至1 µg/ml經結合之重組人類(rh) CEACAM5 ECD或其域N-A1-B1、A2-B2、A3-B3或經結合之重組食蟹獼猴(mf) CEACAM5 ECD(均獲自Syngene)進行mAb1之選擇性測定。結果顯示於圖1中並如下總結:
rhCEACAM5之結合EC50係153.4pM。
rhA2-B2域之結合EC50係166.9pM。
mfCEACAM5之結合EC50係324.3pM。
未偵測到對rhN-A1-B1或rhA3-B3或BSA (牛血清白蛋白,充當陰性對照)之結合。
b)不同CEACAM蛋白
在ELISA分析中進行mAb1之Fab對人類CEACAM5及其他人類CEACAM家族成員之選擇性測定。在96孔分析盤上塗覆蛋白質:huCEACAM5-His6 (R&D系統 # 4128-CM)、huCEACAM6-His6 (3934-CM R&D系統及獲自Syngene之重組蛋白)、huCEACAM1-His6 (2244-CM R&D系統)、huCEACAM3-His6 (C449 Novoprotein)、huCEACAM7-His6 (C926 Novoprotein)、huCEACAM8-His6 (C583 Novoprotein)、huPSG1-His6 (CC66 Novoprotein),各蛋白質以12 nM濃度塗覆該盤。
結果:
在ELISA分析中mAb1之Fab結合人類CEACAM5 (EC50為3.04 nM),但不結合其他人類CEACAM家族成員,甚至在使用1000 nM mAb1之Fab時,其係比結合至人類CEACAM5之EC50高超過300倍之濃度。
在ELISA分析中,在所有測試濃度下,mAb1之Fab亦不結合至無關蛋白(BSA)。
1.6.3 mAb1之細胞結合
藉由在表現標靶(例如人類CEACAM5)之細胞上滴定抗體並量測該等細胞之螢光MFI測定該抗體結合細胞上之其靶蛋白之能力。用於抗體結合比較之模型細胞係表現人類CEACAM5之MKN45細胞系及表現mfCEACAM5之CHO細胞系。用10點x4稀釋,曲線起始濃度2000 nM在分析緩衝液(含有1% BSA之PBSx1)中進行滴定。
例示性資料:
mAb1結合至表現人類CEACAM5之MKN-45細胞系且EC50 = 10.62 ± 1.6 nM。
mAb1結合至表現mfCEACAM5之CHO細胞系且EC50 = 4.8 ± 0.6 nM。
1.6.4對已知抗體之細胞結合比較
比較吾人主要抗體mAb1與ADC相關已知抗體huMab2-3 (如於已知ADC SAR408701中)及hMN14 (本文中亦稱為hmn-14) (如於已知ADC拉貝珠單抗哥維坦或IMMU-130中)對表現CEACAM5之MKN45細胞系之細胞結合。
在本文中下文描述之實驗中,下列胺基酸序列用於上述已知抗體:
huMab2-3:
HC (異型):
EVQLQESGPGLVKPGGSLSLSCAASGFVFSSYDMSWVRQTPERGLEWVAYISSGGGITYAPSTVKGRFTVSRDNAKNTLYLQMNSLTSEDTAVYYCAAHYFGSSGPFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 25)
LC:DIQMTQSPASLSASVGDRVTITCRASENIFSYLAWYQQKPGKSPKLLVYNTRTLAEGVPSRFSGSGSGTDFSLTISSLQPEDFATYYCQHHYGTPFTFGSGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 26)
hmn-14:
HC:EVQLVESGGGVVQPGRSLRLSCSASGFDFTTYWMSWVRQAPGKGLEWIGEIHPDSSTINYAPSLKDRFTISRDNAKNTLFLQMDSLRPEDTGVYFCASLYFGFPWFAYWGQGTPVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 27)
LC:DIQLTQSPSSLSASVGDRVTITCKASQDVGTSVAWYQQKPGKAPKLLIYWTSTRHTGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQYSLYRSFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 28)
利妥昔單抗(Rituximab)作為對照包括於比較中。結合至細胞之抗體之結果顯示於圖2中並如下總結:
mAb1 (so8G4) = 8.3 nM
huMab2-3 = 6 nM
hmn-14 = 11.8 nM
數個實驗之平均值 (EC50) :mAb1 (so8G4) = 10.4 nM ± 1.6 nM (n=12)
huMab2-3 = 4.9 nM ± 1.6 nM (n=3)
hmn-14 = 16 nM (n=2)
抗CEACAM5抗體對MKN45細胞系之細胞結合顯示mAb1及已知抗體之結合係相似。
1.6.5使用Cell Discoverer之內化分析
ADC之相關特性係其內化至表現標靶之細胞及溶體內,且因此內化係待用作ADC之部分之抗體之相關性質。藉由用pH敏感性染料(pHrodo)直接標記該等抗體可監測抗體內化至晚期內體及溶體(低pH囊泡)內之速率,pH敏感性染料一經激發即在低於6.0之pH下發射強螢光。此螢光可於Cell-Discoverer7 (Zeiss)中成像並可計算內化速率。
為分析數種抗體之內化速率,以25,000個細胞/孔將MKN45細胞接種於96孔、暗色、平坦透明底板(Cellvis)中。用100 µL/孔RMPI-1640 + 10% FBS (Thermo)將細胞培養整夜。移除細胞培養基,並在室溫(RT)下在黑暗中,用100 µL稀釋於PBS x 1中之10 µg/ml 赫斯特(Hoechst)染料將細胞染色15 min。然後用PBS x 1將細胞清洗兩次。
抗CEACAM5人類IgG抗體(so8G4 (即mAb1)、humab2-3、hmn-14),及抗MerTK抗體(Merck)用pHrodo直接標記,在無酚紅之溫RPMI1640 + 10% FBS中稀釋至100 nM之濃度,並添加至其等各別孔。如下文進一步描述,將盤在Cell Discoverer中在37℃,5% CO
2下培養20小時,且每20分鐘獲取影像。
藉由Cell-Discoverer7 (Zeiss)在567 nM之激發及592/25 nM之發射偵測器下使用螢光對經pHrodo標記之抗體內化至細胞之晚期內體及溶體內進行成像。用赫斯特標記細胞核並在385 nM之激發及425/30 nM之發射偵測器下成像。
每20 min記錄各孔之螢光,歷時20 h。藉由Zen軟體(ZEN3.1)及線性回歸之Excel分析計算每個細胞之總螢光強度(SFI)之分析。
結果顯示於圖3及圖4中且曲線之線性部分之斜率(參見圖4)亦總結於下表中:
結論:
1. so8G4 (mAb1)具有高於humab2-3 (18917±1416)及hmn-14 (22268±3060)之平均結合速率(28958±766)。
2. so8G4 (mAb1)亦具有高於humab2-3及hmn-14之內化強度。
樣本 | 曲線斜率 | R^2 |
so8G4 | 28519 | 99.41 |
so8G4 | 29844 | 99.66 |
so8G4 | 28513 | 99.92 |
humab2-3 | 19154 | 99.42 |
humab2-3 | 17398 | 99.19 |
humab2-3 | 20201 | 99.68 |
hmn-14 | 24350 | 98.61 |
hmn-14 | 18754 | 99.56 |
hmn-14 | 23701 | 99.58 |
1.7 產生例如用於結合藥物-連接子化合物一起使用之mAb1之例示性方法
在重組CHO-K1Sv細胞系中產生抗CEACAM5抗體mAb1。在200 l一次性生物反應器中以分批模式進行細胞培養。細胞在用葡萄糖補充之專有CHO分批補料生長培養基中在37℃下生長。在接種後第3、5、7及10天用專有進料組分之混合物進料培養物。
使用3x1.1 m
2Millistak+ Pod DOHC (Millipore MD0HC10FS1)及1.1 m
2Millistak+ Pod XOHC (Millipore #MX0HC01 FS1)過濾器淨化來自生物反應器運行之粗條件培養基,接著用Millipore Opticap XL3 0.5 / 0.2 µm過濾器(Millipore #KHGES03HH3)進行終端過濾。
淨化後,使用由蛋白A捕獲步驟及離子交換層析步驟構成之標準抗體純化過程純化抗體mAb1。抗CEACAM5抗體mAb1充當用於產生ADC分子之中間體。
1.8 mAb1之人類/兔嵌合變體之表現及純化及其於甲醛固定及石蠟包埋之細胞系及人類腫瘤組織上之免疫組織化學(IHC)中之用途
藉由例行性重組方法產生mAb1之人類/兔嵌合變體。mAb1之人類/兔嵌合變體(本文中亦稱為「rb8G4」)具有下列胺基酸序列:
重鏈
EVQLQESGPGLVKPSQTLSLTCTVSDGSVSRGGYYLTWIRQHPGKGLEWIGYIYYSGSTYFNPSLRSRVTMSVDTSKNQFSLKLSSVTAADTAVYYCARGIAVAPFDYWGQGTLVTVSSQPKAPSVFPLAPCCGDTPSSTVTLGCLVKGYLPEPVTVTWNSGTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTKVDKTVAPSTCSKPTCPPPELLGGPSVFIFPPKPKDTLMISRTPEVTCVVVDVSEDDPEVQFTWYINNEQVRTARPPLREQQFNSTIRVVSTLPIAHEDWLRGKEFKCKVHNKALPAPIEKTISKARGQPLEPKVYTMGPPREELSSRSVSLTCMINGFYPSDISVEWEKNGKAEDNYKTTPAVLDSDGSYFLYSKLSVPTSEWQRGDVFTCSVMHEALHNHYTQKSISRSPGK (SEQ ID NO: 29)
輕鏈
EIVLTQSPATLSVSPGERATLSCRTSQSVRSNLAWYQQKPGQAPRLLIYAASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYTNWPFTFGPGTKVDIKRDPVAPSVLLFPPSKEELTTGTATIVCVANKFYPSDITVTWKVDGTTQQSGIENSKTPQSPEDNTYSLSSTLSLTSAQYNSHSVYTCEVVQGSASPIVQSFNRGDC (SEQ ID NO: 30)
rb8G4藉由瞬時轉染表現於HEK細胞(Expi 293懸浮細胞)中並使用MabSelect SuRe及檸檬酸鹽緩衝液純化。然後將rb8G4用於甲醛固定及石蠟包埋之細胞系及人類腫瘤組織上之IHC:
材料及方法 細胞系及組織自Merck細胞庫培養人類癌細胞系,固定於4%緩衝甲醛中,並包埋於石蠟(FFPE)中。將石蠟包埋之細胞系排列成細胞系微陣列(CMA) (Zytomed)。具有人類器官之組織微陣列(TMA)之FFPE組織切片來自amsbio (FDA標準組織陣列,T8234701)。FFPE人類腫瘤樣本由BioIVT及Indivumed GmbH提供。
方法對於使用抗CEACAM-5抗體rb8G4之IHC染色,將經甲醛固定石蠟包埋(FFPE)之癌細胞系微陣列(CMA)及人類腫瘤組織之4 µm切片載於帶電載玻片(SuperFrost Ultra Plus , Thermo Fisher Scientific或TOMO, Matsunami)上。使用Discovery XT (Roche Diagnostics)染色平臺進行染色程序。去石蠟後,將該等切片在Tris-EDTA緩衝液pH 8 (CC1,Roche Diagnostics)中加熱以修復抗原決定基。該等切片與在磷酸鹽緩衝鹽水(PBS)或抗體稀釋劑緩衝液(DCS)中稀釋至0.5或0.7 µg/ml之初級單株抗體rb8G4培育。純系DA1E (兔單株IgG,NEB)用作同型對照抗體。該等初級抗體後為HQ抗兔IgG偵測套組(Roche Diagnostics)。載玻片用蘇木精複染,在自來水中清洗,脫水,並於Entellan Neu (VWR)永久封固劑中蓋上玻璃蓋玻片。
將CMAs及具有人類器官組織之TMA染色並使用NanoZoomer (Hamamatsu)以0.46 µm/像素之解析度掃描。將人類腫瘤切片染色並使用AxioScan.Z1 (Zeiss)儀器以0.44 µm/像素之解析度掃描。用影像分析軟體HALO (Indica Labs, USA)分析該等CMA之掃描。為測定存在之抗原量,將陽性棕色染色面積計算為活組織面積之面積百分比。將染色(任意單位)計算為:抗體染色(AU) =陽性組織面積%*棕色之平均光密度(OD範圍係0至1)。抗體染色之最大值係100 = 100%之組織區域為黑色(灰度OD值係1)。
癌細胞系之CEACAM-5 mRNA資料獲自癌細胞系百科全書(CCLE;Broad Institute of MIT & Harvard)。
結果對癌細胞系及人類正常組織之驗證
抗體rb8G4在FFPE癌細胞系上顯示在細胞質及質膜中之訊號(圖5)。
藉由將104個癌細胞系上之染色訊號與此等細胞系之mRNA表現(CCLE資料集)進行比較顯示抗體rb8G4對FFPE組織/細胞之特異性。所得r=0.88之皮爾森相關係數支持抗體rb8G4 (亦稱為SO8G4AB 323)偵測FFPE組織/細胞中之CEACAM-5抗原決定基之結論(圖6)。此癌細胞系微陣列及經個別選擇之陽性及陰性細胞系在人類正常及腫瘤組織之染色操作中用作對照基質。
在正常人類組織中用抗體rb8G4染色(圖7)與CEACAM-5 mRNA表現(圖8) (來源:http://www.proteinatlas.org/ENSG00000105388-CEACAM5/tissue)一致,進一步支持該抗體對CEACAM-5之特異性。
人類腫瘤組織
如結腸直腸癌(圖9)、胃癌(圖10)、食道癌(圖11)及非小細胞肺癌(圖12)中顯示,抗體rb8G4在數種人類腫瘤適應症中染色呈陽性。訊息位於細胞質中及於質膜處。
1.9使用mAb1及rb8G4之流式細胞分析技術及西方墨點法
比較mAb1、rb8G4及市售抗CEACAM5抗體對CEACAM5陽性及陰性細胞系之結合。
所用方法:在5 mL聚苯乙烯管中將5E5至1E6個細胞用於使用BD FACSCanto II (BD Biosciences)之流式細胞術分析。在50 μL 1% PBS/BSA中在4℃下用10 µg/mL初級抗體(mAb1、rb8G4、小鼠單株Agilent Dako #M7072純系#IL7)及各別螢光標記之二級抗體(驢抗人類IgG Jackson-Dianova #709-116-149;驢抗小鼠IgG Jackson ImmunoResearch #715-116-150、驢抗兔IgG Jackson-Dianova #711-116-152)進行染色20至30 min。在染色步驟之間及之後,使用1% PBS/BSA將細胞清洗三次並重新懸浮於500 μL 1% PBS/BSA (包括0.2 µg/mL DAPI用於活細胞門控)中用於流式細胞術分析。為評估資料,使用FlowJo軟體(BD Biosciences)。
結果:mAb1及rb8G4顯示結合僅對應於CEACAM5陽性細胞系之mRNA表現程度資料(下表1;MKN-45、NCI-H441)。相比之下,對於商業抗體,結合較弱且僅限於CEACAM5高細胞系(下表1;MKN-45)。總之,mAb1及rb8G4特異性偵測CEACAM5陽性癌細胞且可用作偵測劑。
表1:不同抗體對CEACAM5陽性及CEACAM5陰性細胞系之結合。對每個細胞系列舉各別抗體之中值螢光強度(MFI)除以二級抗體僅對照之MFI的商。
細胞系 | mAb1 | rb8g4 | Agilent/Dako M7072純系il7 |
MKN-45 | 23.2 | 36.2 | 3.8 |
NCI-H441 | 2.2 | 3.2 | 1.1 |
A549 | 1.1 | 1.1 | 1.0 |
MDA-MB-468 | 1.1 | 1.0 | 1.0 |
亦藉由西方墨點法研究人類mAb1及rb8G4對CEACAM5陽性及陰性細胞系溶胞產物之結合。
所用方法:根據標準方案(Sambrook, J. & RUS sell, D.W., 2001. Molecular Cloning: A Laboratory Manual,第1卷,CSHL Press)進行西方墨點法。針對SDS-PAGE,接著膜濕印跡,每條泳道上樣藉由BCA套組(Thermo Scientific, #23227)定量之RIPA細胞溶胞產物之15 μg總蛋白。使用MOPS電泳緩衝液(Bio-Rad #1610788)之Criterion XT 4至12%凝膠(Bio-Rad, #3450125)用於Criterion電泳細胞(Bio-Rad, #1656001)中。藉由麗春紅染色證實蛋白質之轉移。在用0.5 µg/mL至1 µg/mL初級(mAb1或rb8G4)及二級抗體(抗人類IgG,Jackson ImmunoResearch #109-035-098或抗兔IgG,CellSignaling #7074)進行染色之前及之間進行膜清洗。由ECL偵測試劑使用FUSion FX成像系統(Vilber)將經染色之膜可視化。
結果顯示於圖13A及圖13B中:兩種抗體均以對應於高度醣化CEACAM5之預期遷移速度之可比較模式結合。mAb1 (圖13A)及rb8G4 (圖13B)之CEACAM5偵測對CEACAM5陽性細胞系特異,且強度與mRNA表現程度相關。以較低強度觀察到之第二條帶對應於先前描述之潛在第二同功型(Hatakeyama等人:Novel protein isoforms of carcinoembryonic antigen are secreted from pancreatic, gastric and colorectal cancer cells. BMC Research Notes 2013 6:381)。
向(2S,3S,4S,5R,6R)-3,4,5-三乙醯氧基-6-溴-四氫-哌喃-2-羧酸甲酯(8.30 g;20.90 mmol;1.00當量)及4-羥基-3-硝基-苯甲醛(5.24 g;31.35 mmol;1.50當量)於乙腈(83.00 ml;10.00 V)中之經攪拌溶液添加氧化銀(I) (9.69 g;41.80 mmol;2.00當量)。在室溫下將該反應混合物攪拌16 h。使該反應混合物濾過矽藻土。在真空下濃縮濾液以產生固體。將該固體溶解於EtOAc中並用10% NaHCO
3水溶液清洗以移除過量4-羥基-3-硝基-苯甲醛。在真空下濃縮有機層以產生呈沙色固體之化合物1。
產量:9.0 g
產量百分率:89.1%
分析資料:NMR:
1H-NMR (400 MHz, DMSO-d6): 9.98 (s,1H), 8.46 (s, 1H),8.25-8.21 (m, 1H),7.64 (d, J = 11.60Hz, 1H), 5.94 (d, J= 10.00 Hz,1H),5.51-5.44 (m, 1H),5.20-5.09 (m, 2H),4.80 (d, J = 13.20 Hz, 1H), 3.64 (s,3H), 2.09 (s, 9H)。
向化合物1 (9.00 g;18.62 mmol;1.00當量)於丙-2-醇(33.00 ml;3.67 V)及CHCl
3(167.00 ml;18.56 V)中之經攪拌溶液添加矽膠60-120 (3.60 g;112.09 mmol;6.02當量),接著添加硼氫化鈉(1.80 g;46.55 mmol;2.50當量)。在室溫下將該反應混合物攪拌1 h。完成後,用冷H
2O淬滅該反應混合物並濾過矽藻土。用二氯甲烷萃取濾液並經Na
2SO
4乾燥。濃縮溶劑以產生呈灰白色粉末之化合物2。
產量:8.70 g
產量百分率:92.4%
分析資料LCMS:管柱:ATLANTIS dC18 (50x4.6 mm) 5 μm;移動相A:0.1% HCOOH於H2O: ACN (95:5)中;B:ACN
RT ( min):2.05;M+H:503.2,純度:96.6%
向化合物2 (8.70 g;17.21 mmol;1.00當量)於乙酸乙酯(100.00 ml;11.49 V)及THF (100.00 ml;11.49 V)中之經攪拌溶液添加碳載鈀(10% w/w) (2.50 g;2.35 mmol;0.14當量)。在室溫下在氫氣氛下將該反應混合物攪拌3 h。完成後,通過矽藻土濾除該反應混合物。在真空下濃縮溶劑以產生呈灰白色固體之化合物3。
產量:8.5 g
產量百分率:100%
分析資料:LCMS:管柱:ATLANTIS dC18 (50x4.6 mm) 5 μm;移動相A:0.1% HCOOH於H2O:ACN (95:5)中;B:ACN
RT ( min):1.73;M+H:456.10,純度:95.1%
在0℃下向化合物3 (10.00 g;20.89 mmol;1.00當量)及(9H-茀-9-基甲氧基羰基胺基)-乙酸(7.60 g;25.06 mmol;1.20當量)於DCM (250.00 ml;25.00 V)中之經攪拌溶液添加2-乙氧基-2H-喹啉-1-羧酸乙酯(15.65 g;62.66 mmol;3.00當量)。在室溫下將該反應混合物攪拌16 h。完成後,在減壓下移除溶劑以產生粗產物。該粗產物藉由管柱層析術(56% EtOAc:石油醚)純化以產生純度80%之化合物。該化合物由具有30% EtOAc及石油醚之洗滌液進一步純化以產生呈白色固體之化合物4。
產量:8.5 g
產量百分率:50.7%
分析資料:LCMS:管柱:ATLANTIS dC18 (50x4.6 mm) 5 μm;移動相A:0.1% HCOOH於H
2O:ACN (95:5)中;B:ACN
RT ( min):3.03;M+H:735.2,純度:81.9%
在0℃下向化合物4 (2.00 g;2.49 mmol;1.00當量)於THF (40.00 ml;20.00 V)中之經攪拌溶液添加碳酸雙-(4-硝基-苯基)酯(3.06 g;9.97 mmol;4.00當量)及DIPEA (4.40 ml;24.92 mmol;10.00當量)。在室溫下將該反應混合物攪拌12 h。該反應完成後,在真空下濃縮反應混合物。粗產物藉由管柱層析術使用矽膠(230-400)及石油醚/乙酸乙酯作為溶析液純化以提供呈淡黃色固體之化合物5。
產量:2.0 g
產量百分率:84.6%
分析資料:LCMS:管柱:X-Bridge C8(50X4.6) mm,3.5 μm;移動相:A:0.1% TFA於MilliQ水中;B:ACN
RT ( min):3.24;M+H:900.20,純度:94.9%
將化合物5 (1.369 g;1.00當量)溶解於N,N-二甲基甲醯胺(15.00 ml)、甲磺酸依喜替康(679.7 mg;1.00當量)中,添加合成用4-甲基嗎啉(0.422 ml;3.00當量)及1-羥基苯并三唑(172.8 mg;1.00當量)。在室溫下將該反應混合物攪拌整夜。在攪拌時間後,該反應懸浮物變為棕色溶液。藉由LC-MS監測該反應,其顯示初始材料之完全轉化。該反應混合物經由RP急速層析術純化。將含有產物之溶離份組合,在真空中濃縮並凍乾整夜以提供呈黃色固體之化合物6。
產量:1.59 g
產量百分率:87.5%
分析資料:LCMS:管柱:Chromolith HR RP-18e (50-4.6 mm);移動相A:0.05% HCOOH於H
2O中;B:0.04% HCOOH及1% H
2O於ACN中;T:40℃;流動:3.3 ml/min;MS:100-2000,amu陽性;1% ->100% B:0 ->2.0 min;100% B:2.0 ->2.5 min
RT ( min):1.95;M+H:1196.40,純度:84.4%。
在0℃下將化合物6 (1.586 g;1.00當量)溶解於四氫呋喃(50.00 ml)中並滴加LiOH (含有氫氧化鋰水合物(281.77 mg;6.00當量)於水(67.100 ml))中之溶液(0.1 M)。在該添加期間檢查pH值。該pH應不超過10。LiOH溶液之添加在1.5小時後完成。藉由LC-MS監測該反應,LC-MS顯示初始材料之完全轉化。用檸檬酸溶液(pH調整至5)淬滅該反應物。在減壓下濃縮該反應混合物。藉由製備型HPLC純化該粗產物。將含有產物之溶離份組合並凍乾以提供呈深黃色固體之化合物7。
產量:728 mg
產量百分率:54.8%
分析資料:LCMS:管柱:Chromolith HR RP-18e (50-4.6 mm);移動相A:0.05% HCOOH於H
2O中;B:0.04% HCOOH及1% H
2O於ACN中;T:40℃;流動:3.3 ml/min;MS:100-2000,amu陽性;1% ->100% B:0 ->2.0 min;100% B:2.0 ->2.5 min
RT ( min):1.68;M+H:1056.30,純度:98.5%。
將化合物7 (728.000 mg;1.00當量)溶解於N,N-二甲基甲醯胺(20.00 ml)中。添加哌啶(136.513 μl;2.00當量)並在室溫下將該溶液攪拌總計4小時。藉由LC-MS監測該反應,LC-MS顯示初始材料之完全轉化。在減壓下濃縮該反應混合物並藉由RP急速層析術純化粗產物。將含有產物之溶離份組合,部分移除溶劑並將其凍乾整夜以提供呈黃色固體之化合物8。
產量:706 mg
產量百分率:100%
分析資料:LCMS:管柱:Chromolith HR RP-18e (50-4.6 mm);移動相A:0.05% HCOOH於H
2O中;B:0.04% HCOOH及1% H
2O於ACN中;T:40℃;流動:3.3 ml/min;MS:100-2000,amu陽性;1% ->100% B:0 ->2.0 min;100% B:2.0 ->2.5 min
RT ( min):1.22;M+H:834.30,純度:97.6%。
向化合物8 (854 mg;1.00當量)於二甲基甲醯胺(30.00 ml)中之溶液添加N-乙基二異丙胺(149.234 μl;1.00當量)及3-(2.5-二側氧基-2.5-二氫-吡咯-1-基)-丙酸2.5-二側氧基-吡咯啶-1-基酯(233.61 mg;1.00當量)。在室溫下將該反應混合物攪拌3小時。藉由LC-MS監測該反應,LC-MS顯示初始材料之完全轉化。在減壓下濃縮該反應混合物並藉由RP急速層析術純化粗產物。將含有產物之溶離份組合,濃縮並凍乾以產生91%純度之所需產物。藉由RP層析術再次純化此材料以產生呈黃色固體之化合物9。
產量:580 mg
產量百分率:60.1%
分析資料:LCMS:管柱:Chromolith HR RP-18e (50-4.6 mm);移動相A:0.05% HCOOH於H
2O中;B:0.04% HCOOH及1% H
2O於ACN中;T:40℃;流動:3.3 ml/min;MS:100-2000,amu陽性;1% ->100% B:0 ->2.0 min;100% B:2.0 ->2.5 min
RT ( min):1.38;M+H:985.30,純度:90% (其他10%異構體可藉由HPLC去除)
1HNMR (500 MHz, DMSO-d
6) δ 13.10 - 12.44 (m, 1H), 9.08 (s, 1H), 8.32 (t, J = 5.8 Hz, 1H), 8.16 (s, 1H), 8.02 (d, J = 8.8 Hz, 1H), 7.76 (d, J = 10.9 Hz, 1H), 7.31 (s, 1H), 7.15 - 7.09 (m, 2H), 6.98 (s, 2H), 5.48 - 5.38 (m, 2H), 5.32 - 5.22 (m, 3H), 5.11 - 5.01 (m, 2H), 4.87 (d, J = 7.6 Hz, 1H), 3.92 - 3.88 (m, 1H), 3.89 - 3.84 (m, 2H), 3.65 - 3.61 (m, 2H), 3.46 - 3.41 (m, 1H), 3.42 - 3.37 (m, 1H), 3.38 - 3.31 (m, 1H), 3.28 - 3.20 (m, 1H), 3.15 - 3.07 (m, 1H), 2.48 - 2.44 (m, 2H), 2.38 (s, 3H), 2.24 - 2.13 (m, 2H), 1.94 - 1.80 (m, 2H), 0.88 (t, J = 7.3 Hz, 3H)。
將4-硝基苯基碳酸4-[(2S)-3-胺甲醯基-2-[(2S)-2-[(2S)-2-({[(9H-茀-9-基)甲氧基]羰基}胺基)丙醯胺基]丙醯胺基]丙醯胺基]苯基}甲酯(400 mg;0.52 mmol;1.00當量) [市售自Levena Biopharma US]溶解於N,N-二甲基甲醯胺(5.00 ml)中。添加甲磺酸依喜替康(277.30 mg;0.52 mmol;1.00當量)、N-乙基二異丙胺(0.27 ml;1.57 mmol;3.00當量)及1-羥基苯并三唑(HOBT) (3.52 mg;0.03 mmol;0.05當量)。在室溫下將該反應混合物攪拌整夜。LC/MS指示完全轉化。
經由製備型HPLC純化粗反應混合物並凍乾產生365 mg (0.343 mmol) ((S)-1-(((S)-1-(((S)-4-胺基-1-((4-(((((1S,9S)-9-乙基-5-氟-9-羥基-4-甲基-10,13-二側氧基-2,3,9,10,13,15-六氫-1H,12H-苯并[de]哌喃并[3',4':6,7]吲并[1,2-b]喹啉-1-基)胺甲醯基)氧基)甲基)苯基)胺基)-1,4-二側氧基丁烷-2-基)胺基)-1-側氧基丙烷-2-基)胺基)-1-側氧基丙烷-2-基)胺基甲酸(9H-茀-9-基)甲酯
LC/MS:[M+H] = 1064.2
製備型HPLC:
管柱:sunfire製備型c18 obd - 75.0 g (250 bar)
溶劑A:Wasser 0.1%TFA 溶劑C:
溶劑B:乙腈0.1%TFA
步驟2
將((S)-1-(((S)-1-(((S)-4-胺基-1-((4-(((((1S,9S)-9-乙基-5-氟-9-羥基-4-甲基-10,13-二側氧基-2,3,9,10,13,15-六氫-1H,12H-苯并[de]哌喃并[3',4':6,7]吲并[1,2-b]喹啉-1-基)胺甲醯基)氧基)甲基)苯基)胺基)-1,4-二側氧基丁烷-2-基)胺基)-1-側氧基丙烷-2-基)胺基)-1-側氧基丙烷-2-基)胺基甲酸(9H-茀-9-基)甲酯(365 mg;0.34 mmol;1.00當量)溶解於N,N- (4.00 ml)中。添加合成用哌啶(0.07 ml;0.69 mmol;2.00當量)並在室溫下將該反應溶液攪拌1 h。
經由製備型HPLC純化反應混合物產生300 mg (0.314 mmol) ((1S,9S)-9-乙基-5-氟-9-羥基-4-甲基-10,13-二側氧基-2,3,9,10,13,15-六氫-1H,12H-苯并[de]哌喃并[3',4':6,7]吲并[1,2-b]喹啉-1-基)胺基甲酸4-((S)-4-胺基-2-((S)-2-((S)-2-胺基丙醯胺基)丙醯胺基)-4-側氧基丁醯胺基)苯甲酯。
LC/MS:[M+H]: 841.3
用於純化之製備型HPLC:
RediSEP Säule:C18 130 g
SN:E0410A0D24BE1 批號: 262118923W
流動速率:75 ml/min
條件-體積:390,0 ml
溶析液:A1水0.1%TFA
溶析液:B1乙腈0.1%TFA
步驟3
向((1S,9S)-9-乙基-5-氟-9-羥基-4-甲基-10,13-二側氧基-2,3,9,10,13,15-六氫-1H,12H-苯并[de]哌喃并[3',4':6,7]吲并[1,2-b]喹啉-1-基)胺基甲酸4-((S)-4-胺基-2-((S)-2-((S)-2-胺基丙醯胺基)丙醯胺基)-4-側氧基丁醯胺基)苯甲酯(571 mg;0.60 mmol;1.00 äq.)於N,N-二甲基甲醯胺(20ml)中之溶液添加N-乙基二異丙胺(203 µL;1.20 mmol;2.00當量)及3-馬來醯亞胺基丙酸N-琥珀醯亞胺(162 mg;0.60 mmol;1,00當量)。然後將該反應混合物攪拌10 min並經由LC/MS監測。
經由製備型HPLC純化反應混合物產生378 mg (0.35 mmol) DL2。
LC/MS:[M+H]: 992.4
用於純化之製備型HPLC:
RediSEP管柱:C18 86 g
SN:E0410A8B46130 批號: 281729189W
流動速率:60 ml/min
條件-體積:264,0 ml
溶析液1:A1水0.1%TFA
溶析液2:B1乙腈0.1%TFA
序列分析:
方法資訊:A:H
2O + 0.05% HCOOH | B:MeCN + 0.04% HCOOH + 1% H2O
T:40℃ |流動:3.3 ml/min | MS:100-2000 amu陽性
管柱:Chromolith HR RP-18e 50-4.6 mm
0% -> 100% B:0 -> 2.0 min | 100% B:2.0 -> 2.5 min
實例 4 :免疫結合物: mAb1 之基於葡萄糖醛酸之結合物 ( 稱為 ADC1) 之製備4.1結合過程
抗體製備
在2至8℃下將抗體mAb1 (如本文中上文定義)解凍長達3天,然後結合並儲存在2至8℃下直至使用。在室溫下在結合當天在使用前平衡mAb (> 10 g)。將該mAb (9.6 mg/mL)等分(10.0 g,1041.7 mL)並使用結合緩衝液(200 mM組胺酸,pH 6.5)稀釋至5.59 mg/mL。將該mAb溶液添加至3 L Chemglass夾套反應器內並設定至25 ± 2℃,同時在50 rpm下攪拌。
抗體之還原
將7.0 mol當量(9.7 mL) 50 mM TCEP溶液(50 mM TCEP於結合緩衝液中)添加至mAb溶液小瓶內並容許該反應在25 ± 2℃下進行3小時。
結合
將式(X)藥物-連接子化合物1 (DL1)稱重並溶解於DMSO中以製備20 mM溶液。將90% (148.6 mL)所需DMSO添加至反應器。在添加DMSO後,立即將10.0 mol當量(38.2 mL) 20 mM藥物-連接子溶液添加至該反應器。然後,使用10% (18.2 mL)剩餘之所需DMSO以沖洗藥物-連接子小瓶以確保完全轉移。最終添加後,容許該反應在25 ± 2℃下進行1小時。結合期間之總體積係1997.0 mL。
注意:反應之總DMSO濃度係10% (v/v) (DMSO +藥物連接子溶液)。
淬滅
將35 mol當量(48.5 mL) 50 mM NAC添加至反應器並容許該反應在25 ± 2℃下進行30分鐘。
過濾
自反應器轉移經過濾之粗結合物溶液及然後使用Millipak Gamma Gold 60 (MPGL06GH2)過濾以產生1993.6 mL (過濾器負載:324.7 g/m2 [蛋白質],66.5 L/m2 [溶液])經過濾之粗結合物。
滲濾
經過濾之粗結合物溶液用Pellicon 3 (30 kDa) Biomax膜(1 x 0.11 m2,300 LMH (550 mL/min),16 psi TMP,實際負載88.5 g/m2)進行緩衝液交換(DV= 1993.6 mL)。使用滲濾緩衝液(10 mm組胺酸,pH 5.5)以緩衝16倍體積之攪拌粗結合物。在緩衝液交換後,將該溶液濃縮至≥ 25 mg/mL,轉移至瓶子內,並用滲濾緩衝液沖洗該膜。自UF/DF回收之總體積係361.5 mL。
調配
用112.1 mL滲濾緩衝液(10 mm組胺酸,pH 5.5)將濃ADC (即ADC1)稀釋至20.0 mg/mL。用157.6 mL 4X調配緩衝液(10 mm組胺酸、12% (w/v)海藻糖二水合物、400 mm NaCl,pH 5.5)將所得溶液稀釋至15.0 mg/mL,以獲得濃度15.0 mg/mL之最終標靶原料藥(BDS)。
過濾
使用0.2 μm Millipak Gamma Gold 40 (MPGL04GH2)過濾器過濾經最終調配之ADC以產生619.6 mL (過濾器負載:464.6 g/m2 [蛋白質],31.0 L/m2 [溶液]) ADC1 BDS。將材料包裝於HDPE瓶內並儲存在≤ -65℃下。
4.2方法:原料藥表徵:ADC1
粒徑排阻層析術(SEC)方法
SEC方法參數
波長 280 nm
管柱 Tosoh TSKgel 7.8 mm x 300 mm,5 μm (P/N 0008541)
移動相 0.14 M磷酸二氫鉀
50 mm磷酸二氫鈉
0.06 M磷酸二氫鉀
0.25 M氯化鉀
5% IPA
注射體積 20 μL
溫度 25℃
流動速率 0.5 mL/min
運行時間 30 min
典型SEC層析圖顯示儲備mAb、UF後之結合物及最終BDS之純度:圖14。
針對上文顯示之BDS材料,已報告1.7% HMWS及96.9%之單體純度。
逆相HPLC (RP HPLC)方法
RP HPLC方法參數
波長 280 nM
管柱 PLRP-S 1000 Å (50 x 2.1 mm,8 μm)管柱,Agilent (P/N PL1912-1802)
移動相A 0.1%甲酸於具有0.01% TFA之水中
移動相B 0.1%甲酸於具有0.01% TFA之ACN中
梯度
注射體積 10 μL
管柱溫度 80℃
流動速率 1.0 mL/min
運行時間 30 min
樣本製備 將樣本稀釋至2 mg/mL並將40 μL添加至微量離心管。添加60 μL ~8 M鹽酸胍、~130 mm Tris、~1 mm EDTA,pH 7.6緩衝液。添加2 μL 500 mm DTT並渦旋混合。在37 ± 2℃下將樣本培養30 ± 2 min。
典型RP-HPLC層析圖顯示輕鏈及重鏈之分離:圖15。該層析圖顯示儲備mAb、粗ADC及最終BDS之重疊。
針對上文ADC1 BDS材料,報告7.9之DAR。
游離藥物法
游離藥物法參數
波長 254 nM
管柱 Phenomenex Gemini,C18,2 x 150 mm,3 μm (P/N 00F-4439-B0)
移動相A 0.1%甲酸於水中
移動相B 0.1%甲酸於乙腈中
梯度
注射體積 10.00 μL
管柱溫度 50℃
流動速率 0.75 mL/min
樣本製備 蛋白質滴:100 μL原料藥+ 250 μL冷MeOH + 50 μL 3 M MgCl
2。在20,000 rpm下旋轉10 min。
標準製劑 將20 μL 20 mm DL1 (藥物-連接子化合物1於DMSO中) + 20 μL DMSO + 40 μL MeOH + 20 μL 200 mM NAC混合於滲濾緩衝液中。培養整夜以提供4 mM DL-NAC。將4 mM DL-NAC稀釋於MeOH中以提供4 μM DL-NAC標準。
典型層析圖顯示NAC標準及最終BDS之游離藥物濃度:圖16。
針對上文顯示之ADC1 BDS材料,已報告低於2.4% (以莫耳比計)之殘餘游離藥物濃度。
實例 5 :免疫結合物: mAb1 之基於肽之結合物 ( 稱為 ADC2) 之製備5.1結合過程
抗體製備
在2至8℃下將抗體mAb1 (如本文中上文定義)解凍長達3天,然後結合並儲存在2至8℃下直至使用。在室溫下在結合當天在使用前平衡mAb (> 9.5 g)。將該mAb (9.6 mg/mL)等分(9.5 g,989.6 mL)並使用結合緩衝液(200 mM組胺酸,pH 6.5)稀釋至5.59 mg/mL。將該mAb溶液添加至3 L Chemglass夾套反應器內並設定至25 ± 2℃,同時在50 rpm下攪拌。
抗體之還原
將8.0 mol當量(10.5 mL) 50 mM TCEP溶液(50 mM TCEP於結合緩衝液中)添加至mAb溶液小瓶內並容許該反應在25 ± 2℃下進行3小時。
滲濾
經還原之mAb溶液針對6個DV (DV= 1706.9 mL)使用Pellicon 3 (30 kDa) Biomax膜(1 x 0.11 m2,300 LMH (550 mL/min),16 psi TMP,實際負載86.3 g/m2進行緩衝液交換。使用結合緩衝液(200 mM組胺酸,pH 6.5)對該經還原之抗體進行緩衝液交換。在緩衝液交換後,將該經還原之mAb溶液回收至反應器內並用結合緩衝液膜沖洗。
結合
將式(XI)藥物-連接子化合物2 (DL2)稱重並溶解於DMSO中以製備20 mM藥物-連接子溶液。將90% (142.6 mL)所需DMSO添加至反應器。在添加DMSO後,立即將9.5 mol當量(31.2 mL) 20 mM藥物-連接子溶液添加至該反應器。然後,使用10% (15.8 mL)剩餘之所需DMSO以沖洗藥物-連接子小瓶以確保完全轉移。最終添加後,容許該反應在25 ± 2℃下進行2小時。結合反應期間之總體積係1894.5 mL。
淬滅
將35 mol當量(46 mL) 50 mM NAC添加至反應器並容許該反應在25 ± 2℃下進行45分鐘。
過濾
自反應器轉移粗結合物溶液並使用Millipak Gamma Gold 60 (MPGL06GH2)過濾以產生1897.3 mL (過濾器負載:308.9 g/m2 [蛋白質],63.2 L/m2 [溶液])經過濾之粗結合物。
滲濾
經過濾之粗結合物溶液用Pellicon 3 (30 kDa) Biomax膜(1 x 0.11 m2,300 LMH (550 mL/min),16 psi TMP,實際負載84.2 g/m2)進行緩衝液交換(DV = 1897.3 mL)。使用結合緩衝液(200 mM組胺酸,pH 6.5)進行初始12個DV,及然後針對8個另外DV切換至標準滲濾緩衝液(10 mM組胺酸,pH 5.5)。在緩衝液完成該緩衝液交換後,然後將該溶液濃縮至≥ 25 mg/mL,轉移至瓶子內且該膜用滲濾緩衝液沖洗。自UF/DF回收之總合併體積係335.7 mL。
調配
用84.7 mL滲濾緩衝液(10 mM組胺酸,pH 5.5)將濃ADC (即ADC2)稀釋至20.0 mg/mL。用138.6 mL 4X調配緩衝液(10 mM組胺酸、12% (w/v)海藻糖二水合物、400 mm NaCl,pH 5.5)將所得溶液稀釋至15.0 mg/mL之最終標靶BDS濃度。
過濾
使用Millipak Gamma Gold 60 (MPGL06GH2)無菌過濾經最終調配之ADC以產生549.3 mL (過濾器負載:411.4 g/m2 [蛋白質],27.5 L/m2 [溶液]) ADC2 BDS。將材料包裝於HDPE瓶內並儲存在≤ -65℃下。
5.2方法:原料藥表徵:ADC2
粒徑排阻層析術(SEC)方法
SEC方法參數
波長 280 nm
管柱 Tosoh TSKgel 7.8 mm x 300 mm,5 μm (P/N 0008541)
移動相 50 mm磷酸二氫鈉
0.4 M過氯酸鈉
pH 6.3
注射體積 1 μL
管柱溫度 25℃
流動速率 0.5 mL/min
運行時間 30 min
典型SEC層析圖顯示儲備mAb及最終BDS之純度:圖17。
針對上文顯示之ADC2 BDS材料,已報告4.2% HMWS及95.8%之單體純度。
逆相HPLC (RP HPLC)方法
RP HPLC方法參數
波長 280 nm
管柱 PLRP-S 1000 Å (50 x 2.1 mm,8 μm)管柱,Agilent (P/N PL1912-1802)
移動相A 0.1%甲酸於具有0.01% TFA之水中
移動相B 0.1%甲酸於具有0.01% TFA之ACN中
梯度
注射體積 10 μL
管柱溫度 80℃
流動速率 1.0 mL/min
運行時間 30 min
樣本製備 將樣本稀釋至2 mg/mL並將40 μL添加至微量離心管。添加60 μL ~8 M鹽酸胍、~130 mM Tris、~1 mM EDTA,pH 7.6緩衝液。添加2 μL 500 mM DTT並渦旋混合。在37 ± 2℃下將樣本培養30 ± 2 min。
典型RP-HPLC層析圖顯示輕鏈及重鏈之分離:圖18。該層析圖顯示儲備mAb及最終BDS之重疊。
針對上文之ADC2 BDS材料,報告7.6之DAR。
游離藥物法
游離藥物法參數
波長 254 nm
管柱 Phenomenex Gemini,C18,2 x 150 mm,3 μm (P/N 00F-4439-B0)
移動相A 0.1%甲酸於水中
移動相B 0.1%甲酸於乙腈中
梯度
注射體積 10.00 μL
管柱溫度 50℃
流動速率 0.75 mL/min
樣本製備 蛋白質滴:100 μL原料藥+ 250 μL冷MeOH + 50 μL 3 M MgCl
2。在20,000 rpm下旋轉10 min。
標準製備 將20 μL 20 mM DL2 (藥物-連接子化合物2於DMSO中) + 20 μL DMSO + 40 μL MeOH + 20 μL 200 mM NAC混合於滲濾緩衝液中。培養整夜以提供4 mM DL-NAC。將4 mM DL-NAC稀釋於MeOH中以提供4 μM DL-NAC標準。
典型層析圖顯示NAC標準及最終BDS之游離藥物濃度:圖19。
針對上文顯示之ADC2 BDS材料,已報告低於1.9% (以莫耳比計)之殘餘游離藥物濃度。
實例6:ADC SAR408701之類似物
6.1抗體
出於其他比較實驗之目的,基於具有下列序列之單株抗體製備賽諾菲之抗CEACAM5 ADC SAR408701之類似物:
重鏈:SEQ ID NO: 25
輕鏈:SEQ ID NO: 26
6.2藥物-連接子化合物
使用SPDB-DM4 (獲自Levena Biopharma)作為待結合至上文提及之抗體之藥物-連接子分子:
產品名稱:SPDB-DM4
結構:
預期質量:994.35
觀察到之平均質量:995.5 (Ms+H
+)
質譜分析:一致,顯示正確之MW
HPLC分析:純度> 95%
外觀:白色粉末
6.3結合
在2至8℃下將抗體解凍長達3天,然後結合並儲存在2至8℃下直至使用。在室溫下在結合當天在使用前平衡抗體(175 mg)。使用結合緩衝液(PBS pH 7.4)及SPDB-DM4 (Levena Biopharma)之5 mM DMSO溶液(相對於該抗體為8 mol當量)將該抗體(7.9 mg/mL)稀釋至5 mg/mL。將該反應溶液混合並在25℃下培養4 h。
6.4製備型粒徑排阻層析術、脫鹽及過濾
使用製備型粒徑排阻層析術純化反應混合物。將Superdex 200 pg (50/60)管柱連接至Äkta Avant 25系統(GE Healthcare)並用PBS pH 7.4根據製造商之說明書平衡。接著,注射該反應混合物並通過管柱以10 ml/min之流動速率及PBS pH 7.4作為電泳緩衝液運行。經由280 nM下之紫外光吸收測定含有ADC之溶離份,合併並濃縮。使用15 ml Amicon Ultra 50 kDa截止離心裝置(Merck Millipore)根據製造商之說明書濃縮ADC材料。使用HiPrep 26/10脫鹽管柱(GE Healthcare)以10 ml/min之流動速率在Äkta Avant 25系統(GE Healthcare)上根據製造商之說明書將經濃縮之ADC材料轉移至調配緩衝液(10 mM組胺酸、130 mM甘胺酸、5%蔗糖,pH 5.5)內。使用0.2 µm過濾器(Merck Millipore)過濾所得ADC材料,等分並隨後在液氮中急速冷凍。該ADC材料之最終濃度係5.82 mg/ml並將該材料保持在-80℃下直至進一步使用。由此工作產生之ADC在本文中亦稱為「ADC SAR DM4」,或簡稱為「ADC SAR」;此ADC係SAR408701之類似物。
實例7:基於mAb1及SPDB-DM4之ADC
基於抗體mAb1 (如本文中上文描述)及藥物-連接子化合物SPDB-DM4,即與上文描述之ADC SAR DM4中相同之藥物-連接子化合物製備另一ADC。由此工作產生之ADC在本文中稱為「ADC mAb1 DM4」並如下製備:
7.1所用材料:
•抗體:mAb1,1 mg/mL於10 mM HEPES (pH 5.8)中
•結合緩衝液:10 mM HEPES,pH 5.8
•藥物-連接子化合物:SPDB-DM4,2 mg/mL於DMF中
7.2方法:
•結合:使用約30倍莫耳過量之藥物-連接子分子進行結合(75 mL抗體+ 7.1 mL SPDB-DM4藥物-連接子),在室溫下培養5 h並緩慢搖動
•純化:將ADC的緩衝液交換成20 mM組胺酸、150 mM NaCl,pH 6.0以移除游離藥物
•調配緩衝液:20 mM組胺酸、150 mM NaCl,pH 6.0
7.3經純化之ADC分析細節:
•最終產量:40 mg
•濃度:2.2 mg/mL
• DAR:4.4
實例8:由ADC1及ADC2釋放之藥物之表徵
8.1材料及方法
8.1.1測試製品
ADC編號 | ADC之簡述 |
ADC1 | mAb1-葡萄糖醛酸-依喜替康(亦參見上文實例4) |
ADC2 | mAb1-AAN-依喜替康(亦參見上文實例5) |
ADC3 | 抗CEACAM5-CL2A-SN-38 ADC (Creative Biolabs, CAT#:ADC-091LCT,人類化IgG1單株抗CEACAM5抗體,諸如經由CL2A連接子結合至SN38之拉貝珠單抗) |
8.1.2材料
根據製造商之說明書儲存所有試劑及緩衝液並在批次有效期前使用。
縮寫名稱 | 來源及內容物 |
人類肝溶體 | Sekisui Xenotech, H0610.L |
豆莢蛋白分析緩衝液 | 50 mM MES、250 mM NaCl |
10 x分解代謝緩衝液 | Sekisui Xenotech |
人類血清 | Biowest, S4200-100, 批號# S15594 S4200 |
小鼠血清 | Biowest, S2160-100, 批號# S18169 S2160 |
食蟹獼猴血清 | Abcam, cat: ab155109, 批號: GR316568-1 |
HEP ES | Sigma, cat: H3784-100g 批號: SLBR6536V |
PIC III | Calbiochem,蛋白酶抑制劑混合物III組,不含EDTA,#539134 |
甲醇 | Merck, cat: 1060092500 |
8.1.3儀器
儀器 | 供應商 |
CO2培養器 | Heraeus |
緊湊型熱混合器 | Eppendorf |
HTC PAL自動進樣器 | CTC Analytics |
1200 HPLC | Agilent Technologies |
API4000三重四極桿 | Sciex |
8.1.4程序
8.1.4.1血清樣本製備
2 M HEPES溶液:將52.1 g HEPES溶解於75 mL MiliQ水及15 mL HCl 25%中,調整至pH 7.55並添加高達100 mL。此溶液以15%v/v與血清混合以獲得pH 7.3至7.4之穩定血清。將來自Biowest (批號S15594S4200)之人類血清解凍。100 mL血清與15 mL 2 M HEPES緩衝液混合。將來自Biowest (批號S18169S2160)之小鼠血清解凍。100 mL血清與15 mL 2 M HEPES緩衝液混合。將食蟹獼猴血清解凍且8.5 mL血清與1.5 mL 2 M HEPES緩衝液混合。量測pH (7.37)並將血清無菌過濾。在-20℃下冷凍2 mL等分試樣。
在室溫下解凍製得之血清。所需ADC蛋白濃度以180 µg/mL一式三份製備,用於後續經由LC-MS進行游離有效載荷分析。在將該等ADC添加至該血清後,混合個別批次並分成20 µL等分試樣。另外,對於各ADC,吸移一個20 µL 96 h樣本,並用於總後處理分析以量測回收率。在-80℃下直接冷凍0 h樣本,在37℃及5% CO2下培養殘餘樣本並使反應於經由在-80℃下儲存培養2/ 4/ 6/ 24/ 48/ 72,96小時停止。
8.1.4.2人類肝溶體樣本製備
使用分析緩衝液將pH調整至pH 5.0或pH 4.0。溶體穩定性製劑:製備80 µL人類肝溶體用於一式三份量測,如針對ADC1 (n=3)例示性顯示:2.76 µL ADC1 + 6 µL人類肝溶體+ 71.2 µL豆莢蛋白分析緩衝液。MeOH + PIC (1:200)之製備:10 µL PIC III + 1990 µL MeOH。將Eppendorf管一經轉移至預熱至37℃之熱混合器即開始反應。接著,在0、1、2、4、24及48小時後抽取10 µL等分試樣並與40 µL PIC III (1:200)混合。
8.2結果
人類、小鼠及食蟹獼猴血清之ADC穩定性(圖20)。使用游離依喜替康(標準化資料)計算經結合之依喜替康濃度(初始劑量~10 µM)。針對人類、食蟹獼猴及小鼠血清獲得相似概況。僅觀察到少量彈頭釋放,小鼠血清中的ADC2 (於96 h,初始結合之有效載荷之5.9%游離)及ADC1 (1.4%)最為明顯。
小鼠血清及緩衝液之ADC3對照穩定性(圖21)。使用游離之SN38 (未標準化)計算經結合之SN38濃度(初始劑量50 µg/mL ADC蛋白濃度)。針對兩種基質,觀察到明顯之SN-38釋放。
ADC1及ADC2於人類肝溶體(pH 5.0)中之有效載荷釋放曲線(圖22)。使用(例如)游離依喜替康(初始濃度~10 µM依喜替康)標準化資料計算經結合之藥物濃度。針對ADC1及ADC2裂解介導之有效載荷釋放觀察到中間體濃度之有效載荷釋放(均為初始總結合之有效載荷之~40%)。
ADC分解代謝產物圖譜分析證實游離依喜替康為溶體釋放產物(圖23)。為證實依喜替康為主要釋放產物,在人類溶體提取物中進行ADC1分解代謝產物圖譜分析研究。此時,不同時間點之TIC-MS及提取離子層析圖之比較顯示,預期之依喜替康分解代謝產物後續在培養期間(0 h、4 h、24 h)自ADC1釋放。滯留時間9.33 min,偵測質量m/z 436.1671 ([M+H]
+,C
24H
23O
4N
4F)及偵測之分解代謝產物之MS/MS譜與依喜替康之彼等一致。
實例9:ADC1及ADC2以高效力活體外特異性殺死癌細胞
使用人類癌細胞系以評估ADC1及ADC2殺死癌細胞之潛力。ADC1及ADC2顯示針對不同CEACAM5陽性細胞系之亞奈莫耳活體外效力及對CEACAM5陰性細胞系之較小影響(下表2)。如例示性劑量反應曲線(圖24A/B)中顯示,ADC1及ADC2針對CEACAM5陽性細胞系SK-CO-1及SNU-16非常有效。相比之下,ADC1及ADC2對抗原陰性MDA-MB-231之影響僅限於測試之最高濃度(圖24C)。
利用相同連接子有效載荷作為ADC1及ADC2之同型對照ADC對SK-CO-1細胞系顯示低得多的影響(圖25)。
總之,ADC1及ADC2以高效力活體外特異性殺死表現CEACAM5之人類癌細胞系。
表2:ADC1、ADC2及游離有效載荷針對多種人類細胞系之效力。在最高測試化合物濃度下相較於未處理之對照之最大效應指示於括號中。針對各細胞系,指示CEACAM5表現。
MKN-45 IC50 [M]; n≥3 | SNU-16 IC50 [M]; n≥3 | SK-CO-1 IC50 [M]; n≥4 | LS174T IC50 [M]; n≥3 | MDA-MB-468 IC50 [M]; n≥2 | MDA-MB-231 IC50 [M]; n≥3 | |
ADC1 | 6.2E-10 (-78%) | 3.2E-10 (-91%) | 8.5E-11 (-97%) | 3.8E-10 (-72%) | >1E-08 (-85%) | >1E-08 (-67%) |
ADC2 | 4.7E-10 (-90%) | 2.8E-10 (-96%) | 6.9E-11 (-98%) | 2.8E-10 (-81%) | 6.7E-09 (-97%) | 1.5E-08 (-84%) |
有效載荷 | 8.9E-10 (-96%) | 4.4E-10 (-99%) | 2.5E-10 (-99%) | 5.3E-10 (-88%) | 2.1E-10 (-99%) | 9.3E-10 (-92%) |
CEACAM5 | 陽性 | 陽性 | 陽性 | 陽性 | 陰性 | 陰性 |
方法-存活率分析:
藉由細胞存活率分析量測ADC對癌細胞系之細胞毒性效應。在處理前一天以90 µL體積將細胞接種於96孔盤中。測試化合物(ADC或游離有效載荷)以10倍起始濃度調配於細胞培養基中。將測試化合物連續稀釋(1:4)並將10 µL各稀釋液一式三份添加至該等細胞。在37℃下於CO2培養器中將盤培養六天。對於細胞存活率量測,將細胞Titer-Glo®試劑(Promega™ Corp, Madison, WI)添加至各孔,並根據製造商之說明書處理盤。使用Varioskan讀盤器(Thermo Fisher)量測發光訊息。將發光讀數轉化為相對於未處理之細胞之存活率%。用非線性回歸分析、使用對數(抑制劑)相比於反應、可變斜率、使用GraphPad Prism之4參數擬合方程擬合資料。資料顯示為相對細胞存活率%相比於莫耳化合物濃度,誤差槓指示一式三份之標準偏差(SD)。計算來源於多個實驗之IC50之幾何平均值。
使用與上文相同之方法,亦將ADC1及ADC2與ADC SAR DM4在其等對抗原陽性SK-CO-1及抗原陰性MDA-MB-231細胞系之細胞毒性效應方面進行比較。ADC1及ADC2顯示比ADC SAR DM4針對SK-CO-1癌細胞分別高2.9及2.7倍之效力(圖26A)。相較於ADC1及ADC2,ADC SAR DM4針對抗原陰性MDA-MB-231之非特異性效應略高(圖26B)。ADC SAR DM4及ADC mAb1 DM4針對SK-CO-1顯示可比較之效力,及ADC mAb1 DM4略微傾向於較高效力(圖26A)。
實例10:ADC1及ADC2在與抗原陽性細胞共培養時介導針對抗原陰性細胞之有效旁觀者效應
在旁觀者分析中評估ADC1及ADC2在抗原陽性細胞附近介導針對抗原陰性細胞之旁觀者效應之潛力。ADC1及ADC2在CEACAM5陽性SK-CO-1之存在下顯示針對CEACAM5陰性MDA-MB-231細胞之有效旁觀者效應(圖27A)。在單培養存活率分析中在1E-9 M之測試濃度下,觀察到ADC1及ADC2處理導致對SK-CO-1細胞之最大影響(圖26A),對MDA-MB-231無影響(圖26B)。與此等發現一致,在僅用MDA-MB-231對照之旁觀者分析設定中未觀察到ADC1或ADC2之非特異性效應(圖27B)。
總之,ADC1及ADC2在與抗原陽性細胞共培養時介導針對抗原陰性癌細胞之有效旁觀者效應。此等發現指示有效靶向具有異質標靶表現之腫瘤之潛力。
相較於ADC SAR,ADC1及ADC2在與抗原陽性細胞共培養時介導有效得多的對抗原陰性細胞的旁觀者效應(圖28A、圖28B)。利用與ADC1及ADC2中相同之抗體(即mAb1)及ADC SAR DM4中利用之藥物-連接子分子(即SPDB-DM4)之ADC mAb1 DM4亦顯示比ADC SAR DM4更明顯之旁觀者效應(圖28A、圖28B)。此指示相較於利用不同抗體之ADC SAR,mAb1有助於針對ADC1及ADC2觀察到更高旁觀者效應。
針對所有測試之ADC,旁觀者效應之程度隨添加至恆定數量之抗原陰性細胞之抗原陽性細胞之數量增加而增加(比較圖28A及圖28B)。此指示該等抗原陽性細胞處理更多ADC以釋放負責對抗原陰性細胞之旁觀者效應之游離有效載荷。
未觀察到測試ADC對單獨MDA-MB-231細胞之非特異性效應(圖28C)。
方法-旁觀者分析
藉由旁觀者分析量測ADC與抗原陽性癌細胞系共培養時對抗原陰性癌細胞系之細胞毒性效應。將一千個CEACAM5陰性MDA-MB-231細胞接種於每孔具有750或3000個CEACAM5陽性SK-CO-1細胞之共培養實驗中。作為對照,僅平行接種1000個MDA-MB-231細胞。在處理前一天以90 µL總體積將細胞接種於96孔盤中。以1E-9 M之最終濃度的10倍將測試化合物調配於細胞培養基中並一式兩份將10 µL添加至該等細胞。在37℃下於CO2培養器中將盤培養六天。
在免疫螢光染色之前,移除培養基並用100%甲醇(-20℃)將細胞處理30分鐘。在移除甲醇及一個PBS清洗步驟後,在室溫下用2.5%多聚甲醛(PFA)及於PBS中之0.2% Triton X-100將細胞處理15分鐘。在移除溶液及一個PBS清洗步驟後,在室溫下用於PBS中之1% BSA / 0.1%吐溫/ 0.1%疊氮化鈉將細胞處理至少一個小時。藉由用10 µg/mL人類抗CEACAM5 (mAb1)初級抗體及1:2000稀釋之驢抗人類IgG螢光(藻紅素)標記之二級抗體(Jackson ImmunoResearch #709-116-149)進行免疫螢光染色以區分抗原陽性及抗原陰性細胞。藉由細胞核染色使用1 µg/mL赫斯特33342 (Life technologies,目錄號H3570)染料鑑別細胞。在室溫下於1% BSA / 0.1%疊氮化鈉PBS溶液中進行染色30分鐘。二級抗體染色與赫斯特染料染色組合。在染色步驟之間及之後,用PBS將細胞清洗三次。
用共聚焦定量影像細胞儀CQ1 (Yokogawa® Electric Corporation, Tokyo, Japan)將盤成像。自CQ1軟體(Yokogawa)模板「細胞核及偽細胞體」調整分析並使用FlowJo (BD)分析FCS導出檔。基於細胞核周圍經螢光標記之抗體之染色或不染色,區分並定量抗原陽性及抗原陰性細胞。條形圖顯示每種處理條件下鑑別之抗原陽性及抗原陰性細胞之數量。
實例11:ADC1及ADC2在來源於結腸直腸癌(CRC)病患之異種移植(PDX)小鼠模型中之效用
已在來源於人類病患之CRC異種移植模型COPF217 (Shanghai LideBiotech CO., LTD)中評估活體內抗腫瘤效用。將COPF217腫瘤片段皮下植入六至八週齡免疫缺陷雌性小鼠(NU-Foxn1nu, Charles River)之右側腹內。當腫瘤達成165 mm³之平均體積時,6隻小鼠/組用媒介物(鹽水溶液)或用ADC1或ADC2靜脈內處理一次(各以10 mg/kg之劑量;第0天)。用卡尺量測腫瘤長度(L)及寬度(W)並使用式L×(W^2)/2計算腫瘤體積。
使用10 mg/kg之劑量之ADC1或ADC2之單次處理導致顯著之抗腫瘤效應。兩種物質均顯示導致腫瘤停滯之可比較效應(圖29)。用ADC1或ADC2處理對體重無顯著影響(資料未顯示)。
使用其他CRC PDX模型之其他實驗:
在對應於上文針對COPF217描述者之另外實驗中,使用ADC1之單一處理亦在12個具有高CEACAM5表現之其他CRC PDX模型中導致腫瘤停滯或腫瘤消退。
實例12:ADC1在非小細胞肺癌(NSCLC) PDX小鼠模型中之效用
已在來源於人類病患之NSCLC異種移植模型LUPF160151 (Shanghai LideBiotech CO., LTD)中評估活體內抗腫瘤效用。將LUPF160151腫瘤片段皮下植入六至八週齡免疫缺陷雌性小鼠(NU-Foxn1nu, Charles River)之右側腹內。當腫瘤達成180 mm³之平均體積時,5隻小鼠/組用媒介物(鹽水溶液)或用ADC1 (6 mg/kg;第0天)靜脈內處理一次。用卡尺量測腫瘤長度(L)及寬度(W)並使用式L×(W^2)/2計算腫瘤體積。
使用6 mg/kg之劑量之ADC1之單次處理導致對體重無影響(資料未顯示)之顯著抗腫瘤效應(圖30)。模型LUPF160151顯示異質CEACAM5表現,及CEACAM5陰性腫瘤細胞與CEACAM5陽性腫瘤細胞相鄰。因此,ADC1於此模型中之良好效用指示ADC之有效旁觀者效應。
實例13:ADC1於胃癌PDX小鼠模型中之效用
在來源於人類病患之胃癌異種移植模型GAX066 (Shanghai ChemPartner Co., Ltd)中評估活體內抗腫瘤效用。將腫瘤片段皮下植入免疫缺陷雌性小鼠(Nu/Nu小鼠,Beijing Vital River Lab Animal Technology Co. Ltd, 18至22 g)之右側腹內。當腫瘤達成220 mm³之平均體積時,6隻小鼠/組用媒介物(鹽水溶液)或用ADC1 (3或10 mg/kg;第0天)靜脈內處理一次。用卡尺量測腫瘤長度(L)及寬度(W)並使用式L×(W^2)/2計算腫瘤體積。
使用3或10 mg/kg ADC1之單次處理引起對體重無影響(資料未顯示)之顯著抗腫瘤效應(圖31)。在六個腫瘤之五者中,用10 mg/kg處理導致腫瘤完全消退。
實例14:ADC1相較於ADC3在來源於胰細胞系之腫瘤模型中之效用
已在來源於人類胰細胞系之異種移植模型HPAF-II (ATCC,CRL-1997)中評估ADC1相較於ADC3之效用。將5x10
6個HPAF-II細胞皮下注入六至八週齡免疫缺陷雌性小鼠(Hsd:無胸腺裸Foxn1nu, Envigo)之右側腹內。當腫瘤達成150 mm³之平均體積時,10隻小鼠/組用媒介物(鹽水溶液)或ADC1 (1 mg/kg或6 mg/kg;第0天)或用ADC3 (1 mg/kg或6 mg/kg;第0天)靜脈內處理一次。用卡尺量測腫瘤長度(L)及寬度(W)並使用L×(W^2)/2計算腫瘤體積。
使用6 mg/kg之劑量之ADC1之單次處理導致顯著之抗腫瘤效應。該效應係劑量依賴性的,因為僅使用1 mg/kg之單次處理導致輕微但顯著、短暫之抗腫瘤效應。相比之下,使用相同劑量之ADC3之單次處理在任一劑量下均未顯示顯著之抗腫瘤效應(圖32)。所有處理對體重均無顯著影響(資料未顯示)。
實例15:ADC1相較於ADC SAR DM4於兩個CRC PDX小鼠模型中之效用
在來源於人類病患之CRC異種移植模型COPF230及REPF210 (Shanghai LideBiotech CO., LTD)中評估活體內抗腫瘤效用。將腫瘤片段皮下植入六至八週齡免疫缺陷雌性小鼠(NU-Foxn1nu, Charles River)之右側腹內。當腫瘤達成約170 mm³之平均體積時,6隻小鼠/組用媒介物(鹽水溶液)、ADC1 (6 mg/kg)或ADC SAR DM4 (6 mg/kg) (第0天)靜脈內處理一次。用卡尺量測腫瘤長度(L)及寬度(W)並使用式L×(W^2)/2計算腫瘤體積。
使用ADC1之單次處理在兩個PDX模型COPF230 (圖33)及REP F210 (圖34)中均導致顯著之抗腫瘤效應。相比之下,使用相同劑量ADC SAR DM4之單一處理在CRC PDX模型之任一者中均不顯示抗腫瘤效應(圖33、圖34)。在處理組之任一者中未觀察到對體重有顯著影響(資料未顯示)。
實例16:ADC1相較於ADC SAR DM4在胃PDX小鼠模型(GAPF313)中之效用
在來源於人類病患之胃異種移植模型GAPF313 (Shanghai LideBiotech CO., LTD)中評估活體內抗腫瘤效用。將腫瘤片段皮下植入六至八週齡免疫缺陷雌性小鼠(NU-Foxn1nu, Charles River)之右側腹內。當腫瘤達成約180 mm³之平均體積時,6隻小鼠/組自第0天起每兩週用媒介物(鹽水溶液)、ADC1 (4 mg/kg或7 mg/kg Q2Wx3)或ADC SAR DM4 (4.7 mg/kg Q2Wx3)靜脈內處理3次。用卡尺量測腫瘤長度(L)及寬度(W)並使用式L×(W^2)/2計算腫瘤體積。
進行中之實驗之臨時資料分析證實ADC1在此模型中之明顯抗腫瘤效用且ADC SAR DM4無影響(圖35)。所有處理均耐受良好(資料未顯示)。
實例17:ADC1之安全性概況-食蟹獼猴中之前導性毒性研究
為研究安全性概況,藉由以0、3、10及30 mg/kg之劑量對食蟹獼猴靜脈內輸注30 min投與ADC1,以3週時間間隔輸注三次(在第1、22及43天),並在第50天處死動物用於大體及組織病理學檢查。因此,發現ADC1具有相對有利之安全性概況,因為ADC1在受已知ADC之毒副作用影響之某些器官中缺乏毒性。
圖1:ELISA分析中mAb1對重組人類(rh) CEACAM5 ECD或其域N-A1-B1、A2-B2、A3-B3或對重組食蟹獼猴(mf) CEACAM5 ECD之結合。
圖2:結合至MKN-45細胞之抗CEACAM5抗體之EC50:mAb1相較於抗體huMab2-3及hmn-14對表現CEACAM5之MKN45細胞系之細胞結合。
圖3:經pHrodo標記之抗體內化至細胞之晚期內體及溶體內(每個細胞之總螢光強度,三次重複之平均值)。
圖4:每個細胞自700分鐘至1200分鐘之螢光強度,其係曲線之線性部分。在樣本之間量測並比較線性斜率(參見實例1.6.5)。
圖5:抗體rb8G4於FFPE癌細胞系之IHC染色。
圖6:104種癌細胞系之CEACAM5 mRNA表現及IHC染色之相關性。
圖7:抗體rb8G4於正常人類組織之IHC染色。
圖8:正常人類組織中之CEACAM5 mRNA表現。
圖9:抗體rb8G4於人類結腸直腸癌組織之IHC染色。
圖10:抗體rb8G4於人類胃癌組織之IHC染色。
圖11:抗體rb8G4於人類食道癌組織之IHC染色。
圖12:抗體rb8G4於人類非小細胞肺癌組織之IHC染色。
圖13:藉由西方墨點法研究mAb1 (圖13A)及rb8G4 (圖13B)對癌細胞系溶胞產物中之CEACAM5之結合。
圖14:顯示儲備mAb、UF後結合物及最終BDS之純度之典型SEC層析圖。
圖15:顯示輕鏈及重鏈之分離之典型RP-HPLC層析圖。該層析圖顯示儲備mAb、粗ADC及最終BDS之重疊。
圖16:顯示NAC標準及最終BDS之游離藥物濃度之典型層析圖。
圖17:顯示儲備mAb及最終BDS之純度之典型SEC層析圖。
圖18:顯示輕鏈及重鏈之分離之典型RP-HPLC層析圖。該層析圖顯示儲備mAb及最終BDS之重疊。
圖19:顯示NAC標準及最終BDS之游離藥物濃度之典型層析圖。
圖20:人類、小鼠及食蟹獼猴血清之ADC穩定性。使用游離依喜替康(標準化資料)計算經結合之依喜替康濃度(初始劑量~10 µM)。
圖21:小鼠血清及緩衝液之ADC3對照穩定性。使用游離SN38 (未標準化)計算經結合之SN38濃度(初始劑量50 µg/mL ADC蛋白濃度)。
圖22:人類肝溶體中ADC1及ADC2之有效載荷釋放曲線(pH 5.0)。使用(例如)游離依喜替康(初始濃度~10 µM依喜替康)標準化資料計算經結合之藥物濃度。
圖23:ADC分解代謝產物圖譜分析證實游離依喜替康係溶體釋放產物。
圖24:ADC1、ADC2及游離有效載荷針對抗原陽性SK-CO-1 (圖24A)及SNU-16 (圖24B)細胞系相較於抗原陰性MDA-MB-231 (圖24C)細胞系之活體外效力。顯示一項代表性實驗,三次重複之平均值±SD。如圖24C中顯示,將三個不同系列之資料點分別分配至ADC1、ADC2及有效載荷之圖例亦適用於圖24A及圖24B。
圖25:ADC1及ADC2與各別同型對照對SK-CO-1細胞系之比較。顯示一項代表性實驗,三次重複之平均值±SD。
圖26:ADC1、ADC2、ADC SAR DM4、ADC mAb1 DM4及游離有效載荷針對抗原陽性SK-CO-1 (圖26A)相較於抗原陰性MDA-MB-231 (圖26B)細胞系之活體外效力。顯示一項代表性實驗,三次重複之平均值±SD;圖26B中顯示之圖例亦適用於圖26A。
圖27:ADC1及ADC2對與抗原陽性SK-CO-1細胞共培養之抗原陰性MDA-MB-231細胞之有效旁觀者效應(圖27A)。ADC1或ADC2對單獨MDA-MB-231細胞無非特異性效應(圖27B)。顯示一項代表性實驗,重複之平均值±SD。
圖28:ADC1及ADC2對與抗原陽性SK-CO-1細胞共培養之抗原陰性MDA-MB-231細胞之旁觀者效應比對ADC SAR DM4更有效(圖28A及圖28B)。測試ADC對單獨MDA-MB-231細胞無非特異性效應(圖28C)。顯示一項代表性實驗,重複之平均值±SD。
圖29:單次治療後ADC1及ADC2在CRC PDX模型(COPF217)中之效用。
圖30:單次治療後ADC1在NSCLC PDX模型(LUPF160151)中之效用。
圖31:單次治療後ADC1在胃癌PDX模型(GAX066)中之效用。
圖32:胰臟異種移植模型(HPAF-II)中ADC1相較於ADC3之效用。
圖33:CRC PDX模型(COPF230)中ADC1相較於ADC SAR DM4之效用。
圖34:CRC PDX模型(REP F210)中ADC1相較於ADC SAR DM4之效用。
圖35:胃PDX模型GAPF313 (進行中之實驗之期中分析)中ADC1相較於ADC SAR DM4之效用。
<![CDATA[<110> 德商馬克專利公司(Merck Patent GmbH)]]> <![CDATA[<120> 抗CEACAM5抗體及其結合物及用途]]> <![CDATA[<130> P20-166 WO-PCT]]> <![CDATA[<150> EP20195559.8]]> <![CDATA[<151> 2020-09-10]]> <![CDATA[<150> EP20194711.6]]> <![CDATA[<151> 2020-09-04]]> <![CDATA[<160> 30]]> <![CDATA[<170> BiSSAP 1.3.6]]> <![CDATA[<210> 1]]> <![CDATA[<211> 702]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<220> ]]> <![CDATA[<223> 根據基因庫寄存編號AAA51967.1之人類CEACAM5蛋白序列]]> <![CDATA[<400> 1]]> Met Glu Ser Pro Ser Ala Pro Pro His Arg Trp Cys Ile Pro Trp Gln 1 5 10 15 Arg Leu Leu Leu Thr Ala Ser Leu Leu Thr Phe Trp Asn Pro Pro Thr 20 25 30 Thr Ala Lys Leu Thr Ile Glu Ser Thr Pro Phe Asn Val Ala Glu Gly 35 40 45 Lys Glu Val Leu Leu Leu Val His Asn Leu Pro Gln His Leu Phe Gly 50 55 60 Tyr Ser Trp Tyr Lys Gly Glu Arg Val Asp Gly Asn Arg Gln Ile Ile 65 70 75 80 Gly Tyr Val Ile Gly Thr Gln Gln Ala Thr Pro Gly Pro Ala Tyr Ser 85 90 95 Gly Arg Glu Ile Ile Tyr Pro Asn Ala Ser Leu Leu Ile Gln Asn Ile 100 105 110 Ile Gln Asn Asp Thr Gly Phe Tyr Thr Leu His Val Ile Lys Ser Asp 115 120 125 Leu Val Asn Glu Glu Ala Thr Gly Gln Phe Arg Val Tyr Pro Glu Leu 130 135 140 Pro Lys Pro Ser Ile Ser Ser Asn Asn Ser Lys Pro Val Glu Asp Lys 145 150 155 160 Asp Ala Val Ala Phe Thr Cys Glu Pro Glu Thr Gln Asp Ala Thr Tyr 165 170 175 Leu Trp Trp Val Asn Asn Gln Ser Leu Pro Val Ser Pro Arg Leu Gln 180 185 190 Leu Ser Asn Gly Asn Arg Thr Leu Thr Leu Phe Asn Val Thr Arg Asn 195 200 205 Asp Thr Ala Ser Tyr Lys Cys Glu Thr Gln Asn Pro Val Ser Ala Arg 210 215 220 Arg Ser Asp Ser Val Ile Leu Asn Val Leu Tyr Gly Pro Asp Ala Pro 225 230 235 240 Thr Ile Ser Pro Leu Asn Thr Ser Tyr Arg Ser Gly Glu Asn Leu Asn 245 250 255 Leu Ser Cys His Ala Ala Ser Asn Pro Pro Ala Gln Tyr Ser Trp Phe 260 265 270 Val Asn Gly Thr Phe Gln Gln Ser Thr Gln Glu Leu Phe Ile Pro Asn 275 280 285 Ile Thr Val Asn Asn Ser Gly Ser Tyr Thr Cys Gln Ala His Asn Ser 290 295 300 Asp Thr Gly Leu Asn Arg Thr Thr Val Thr Thr Ile Thr Val Tyr Ala 305 310 315 320 Glu Pro Pro Lys Pro Phe Ile Thr Ser Asn Asn Ser Asn Pro Val Glu 325 330 335 Asp Glu Asp Ala Val Ala Leu Thr Cys Glu Pro Glu Ile Gln Asn Thr 340 345 350 Thr Tyr Leu Trp Trp Val Asn Asn Gln Ser Leu Pro Val Ser Pro Arg 355 360 365 Leu Gln Leu Ser Asn Asp Asn Arg Thr Leu Thr Leu Leu Ser Val Thr 370 375 380 Arg Asn Asp Val Gly Pro Tyr Glu Cys Gly Ile Gln Asn Glu Leu Ser 385 390 395 400 Val Asp His Ser Asp Pro Val Ile Leu Asn Val Leu Tyr Gly Pro Asp 405 410 415 Asp Pro Thr Ile Ser Pro Ser Tyr Thr Tyr Tyr Arg Pro Gly Val Asn 420 425 430 Leu Ser Leu Ser Cys His Ala Ala Ser Asn Pro Pro Ala Gln Tyr Ser 435 440 445 Trp Leu Ile Asp Gly Asn Ile Gln Gln His Thr Gln Glu Leu Phe Ile 450 455 460 Ser Asn Ile Thr Glu Lys Asn Ser Gly Leu Tyr Thr Cys Gln Ala Asn 465 470 475 480 Asn Ser Ala Ser Gly His Ser Arg Thr Thr Val Lys Thr Ile Thr Val 485 490 495 Ser Ala Glu Leu Pro Lys Pro Ser Ile Ser Ser Asn Asn Ser Lys Pro 500 505 510 Val Glu Asp Lys Asp Ala Val Ala Phe Thr Cys Glu Pro Glu Ala Gln 515 520 525 Asn Thr Thr Tyr Leu Trp Trp Val Asn Gly Gln Ser Leu Pro Val Ser 530 535 540 Pro Arg Leu Gln Leu Ser Asn Gly Asn Arg Thr Leu Thr Leu Phe Asn 545 550 555 560 Val Thr Arg Asn Asp Ala Arg Ala Tyr Val Cys Gly Ile Gln Asn Ser 565 570 575 Val Ser Ala Asn Arg Ser Asp Pro Val Thr Leu Asp Val Leu Tyr Gly 580 585 590 Pro Asp Thr Pro Ile Ile Ser Pro Pro Asp Ser Ser Tyr Leu Ser Gly 595 600 605 Ala Asn Leu Asn Leu Ser Cys His Ser Ala Ser Asn Pro Ser Pro Gln 610 615 620 Tyr Ser Trp Arg Ile Asn Gly Ile Pro Gln Gln His Thr Gln Val Leu 625 630 635 640 Phe Ile Ala Lys Ile Thr Pro Asn Asn Asn Gly Thr Tyr Ala Cys Phe 645 650 655 Val Ser Asn Leu Ala Thr Gly Arg Asn Asn Ser Ile Val Lys Ser Ile 660 665 670 Thr Val Ser Ala Ser Gly Thr Ser Pro Gly Leu Ser Ala Gly Ala Thr 675 680 685 Val Gly Ile Met Ile Gly Val Leu Val Gly Val Ala Leu Ile 690 695 700 <![CDATA[<210> 2]]> <![CDATA[<211> 705]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 食蟹獼猴]]> <![CDATA[<220> ]]> <![CDATA[<223> 食蟹獼猴CEACAM5蛋白序列(NCBI參考序列XP_005589491.1)]]> <![CDATA[<400> 2]]> Met Gly Ser Pro Ser Ala Pro Leu His Arg Trp Cys Ile Pro Trp Gln 1 5 10 15 Thr Leu Leu Leu Thr Ala Ser Leu Leu Thr Phe Trp Asn Pro Pro Thr 20 25 30 Thr Ala Gln Leu Thr Ile Glu Ser Arg Pro Phe Asn Val Ala Glu Gly 35 40 45 Lys Glu Val Leu Leu Leu Ala His Asn Val Ser Gln Asn Leu Phe Gly 50 55 60 Tyr Ile Trp Tyr Lys Gly Glu Arg Val Asp Ala Ser Arg Arg Ile Gly 65 70 75 80 Ser Cys Val Ile Arg Thr Gln Gln Ile Thr Pro Gly Pro Ala His Ser 85 90 95 Gly Arg Glu Thr Ile Asp Phe Asn Ala Ser Leu Leu Ile His Asn Val 100 105 110 Thr Gln Ser Asp Thr Gly Ser Tyr Thr Ile Gln Val Ile Lys Glu Asp 115 120 125 Leu Val Asn Glu Glu Ala Thr Gly Gln Phe Arg Val Tyr Pro Glu Leu 130 135 140 Pro Lys Pro Tyr Ile Ser Ser Asn Asn Ser Asn Pro Val Glu Asp Lys 145 150 155 160 Asp Ala Val Ala Leu Thr Cys Glu Pro Glu Thr Gln Asp Thr Thr Tyr 165 170 175 Leu Trp Trp Val Asn Asn Gln Ser Leu Pro Val Ser Pro Arg Leu Glu 180 185 190 Leu Ser Ser Asp Asn Arg Thr Leu Thr Val Phe Asn Ile Pro Arg Asn 195 200 205 Asp Thr Thr Ser Tyr Lys Cys Glu Thr Gln Asn Pro Val Ser Val Arg 210 215 220 Arg Ser Asp Pro Val Thr Leu Asn Val Leu Tyr Gly Pro Asp Ala Pro 225 230 235 240 Thr Ile Ser Pro Leu Asn Thr Pro Tyr Arg Ala Gly Glu Asn Leu Asn 245 250 255 Leu Ser Cys His Ala Ala Ser Asn Pro Thr Ala Gln Tyr Phe Trp Phe 260 265 270 Val Asn Gly Thr Phe Gln Gln Ser Thr Gln Glu Leu Phe Ile Pro Asn 275 280 285 Ile Thr Val Asn Asn Ser Gly Ser Tyr Met Cys Gln Ala His Asn Ser 290 295 300 Ala Thr Gly Leu Asn Arg Thr Thr Val Thr Ala Ile Thr Val Tyr Ala 305 310 315 320 Glu Leu Pro Lys Pro Tyr Ile Thr Ser Asn Asn Ser Asn Pro Ile Glu 325 330 335 Asp Lys Asp Ala Val Thr Leu Thr Cys Glu Pro Glu Thr Gln Asp Thr 340 345 350 Thr Tyr Leu Trp Trp Val Asn Asn Gln Ser Leu Ser Val Ser Ser Arg 355 360 365 Leu Glu Leu Ser Asn Asp Asn Arg Thr Leu Thr Val Phe Asn Ile Pro 370 375 380 Arg Asn Asp Thr Thr Phe Tyr Glu Cys Glu Thr Gln Asn Pro Val Ser 385 390 395 400 Val Arg Arg Ser Asp Pro Val Thr Leu Asn Val Leu Tyr Gly Pro Asp 405 410 415 Ala Pro Thr Ile Ser Pro Leu Asn Thr Pro Tyr Arg Ala Gly Glu Asn 420 425 430 Leu Asn Leu Ser Cys His Ala Ala Ser Asn Pro Ala Ala Gln Tyr Ser 435 440 445 Trp Phe Val Asn Gly Thr Phe Gln Gln Ser Thr Gln Glu Leu Phe Ile 450 455 460 Pro Asn Ile Thr Val Asn Asn Ser Gly Ser Tyr Met Cys Gln Ala His 465 470 475 480 Asn Ser Ala Thr Gly Leu Asn Arg Thr Thr Val Thr Ala Ile Thr Val 485 490 495 Tyr Val Glu Leu Pro Lys Pro Tyr Ile Ser Ser Asn Asn Ser Asn Pro 500 505 510 Ile Glu Asp Lys Asp Ala Val Thr Leu Thr Cys Glu Pro Val Ala Glu 515 520 525 Asn Thr Thr Tyr Leu Trp Trp Val Asn Asn Gln Ser Leu Ser Val Ser 530 535 540 Pro Arg Leu Gln Leu Ser Asn Gly Asn Arg Ile Leu Thr Leu Leu Ser 545 550 555 560 Val Thr Arg Asn Asp Thr Gly Pro Tyr Glu Cys Gly Ile Gln Asn Ser 565 570 575 Glu Ser Ala Lys Arg Ser Asp Pro Val Thr Leu Asn Val Thr Tyr Gly 580 585 590 Pro Asp Thr Pro Ile Ile Ser Pro Pro Asp Leu Ser Tyr Arg Ser Gly 595 600 605 Ala Asn Leu Asn Leu Ser Cys His Ser Asp Ser Asn Pro Ser Pro Gln 610 615 620 Tyr Ser Trp Leu Ile Asn Gly Thr Leu Arg Gln His Thr Gln Val Leu 625 630 635 640 Phe Ile Ser Lys Ile Thr Ser Asn Asn Asn Gly Ala Tyr Ala Cys Phe 645 650 655 Val Ser Asn Leu Ala Thr Gly Arg Asn Asn Ser Ile Val Lys Asn Ile 660 665 670 Ser Val Ser Ser Gly Asp Ser Ala Pro Gly Ser Ser Gly Leu Ser Ala 675 680 685 Arg Ala Thr Val Gly Ile Ile Ile Gly Met Leu Val Gly Val Ala Leu 690 695 700 Met 705 <![CDATA[<210> 3]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> mAb1之CDR1-H]]> <![CDATA[<400> 3]]> Asp Gly Ser Val Ser Arg Gly Gly Tyr Tyr 1 5 10 <![CDATA[<210> 4]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> mAb1之CDR2-H]]> <![CDATA[<400> 4]]> Ile Tyr Tyr Ser Gly Ser Thr 1 5 <![CDATA[<210> 5]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> mAb1之CDR3-H]]> <![CDATA[<400> 5]]> Ala Arg Gly Ile Ala Val Ala Pro Phe Asp Tyr 1 5 10 <![CDATA[<210> 6]]> <![CDATA[<211> 6]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> mAb1之CDR1-L]]> <![CDATA[<400> 6]]> Gln Ser Val Arg Ser Asn 1 5 <![CDATA[<210> 7]]> <![CDATA[<211> 3]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> mAb1之CDR2-L]]> <![CDATA[<400> 7]]> Ala Ala Ser 1 <![CDATA[<210> 8]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> mAb1之CDR3-L]]> <![CDATA[<400> 8]]> Gln Gln Tyr Thr Asn Trp Pro Phe Thr 1 5 <![CDATA[<210> 9]]> <![CDATA[<211> 119]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> mAb1之VH]]> <![CDATA[<400> 9]]> Glu Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Asp Gly Ser Val Ser Arg Gly 20 25 30 Gly Tyr Tyr Leu Thr Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Phe Asn Pro Ser 50 55 60 Leu Arg Ser Arg Val Thr Met Ser Val Asp Thr Ser Lys Asn Gln Phe 65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Gly Ile Ala Val Ala Pro Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <![CDATA[<210> 10]]> <![CDATA[<211> 107]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> mAb1之VL]]> <![CDATA[<400> 10]]> Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Thr Ser Gln Ser Val Arg Ser Asn 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Thr Asn Trp Pro Phe 85 90 95 Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys 100 105 <![CDATA[<210> 11]]> <![CDATA[<211> 328]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> mAb1之CH]]> <![CDATA[<400> 11]]> Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60 Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95 Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 100 105 110 Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys 115 120 125 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 130 135 140 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 145 150 155 160 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 165 170 175 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 180 185 190 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 195 200 205 Ala Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 210 215 220 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met 225 230 235 240 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 245 250 255 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 260 265 270 Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 275 280 285 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 290 295 300 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 305 310 315 320 Lys Ser Leu Ser Leu Ser Pro Gly 325 <![CDATA[<210> 12]]> <![CDATA[<211> 107]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> mAb1之CL]]> <![CDATA[<400> 12]]> Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 1 5 10 15 Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 20 25 30 Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln 35 40 45 Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 50 55 60 Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 65 70 75 80 Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 85 90 95 Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 100 105 <![CDATA[<210> 13]]> <![CDATA[<211> 447]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> mAb1之HC]]> <![CDATA[<400> 13]]> Glu Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Asp Gly Ser Val Ser Arg Gly 20 25 30 Gly Tyr Tyr Leu Thr Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Phe Asn Pro Ser 50 55 60 Leu Arg Ser Arg Val Thr Met Ser Val Asp Thr Ser Lys Asn Gln Phe 65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Gly Ile Ala Val Ala Pro Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser 225 230 235 240 Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 245 250 255 Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 260 265 270 Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 275 280 285 Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 290 295 300 Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 305 310 315 320 Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ser Ser Ile Glu Lys Thr 325 330 335 Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 340 345 350 Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys 355 360 365 Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 370 375 380 Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 385 390 395 400 Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 405 410 415 Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 420 425 430 Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445 <![CDATA[<210> 14]]> <![CDATA[<211> 214]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> mAb1之LC]]> <![CDATA[<400> 14]]> Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Thr Ser Gln Ser Val Arg Ser Asn 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Thr Asn Trp Pro Phe 85 90 95 Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <![CDATA[<210> 15]]> <![CDATA[<211> 1404]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 編碼mAb1之HC之DNA序列]]> <![CDATA[<400> 15]]> atggagaccg acaccctgct gctgtgggtg ctgctgctgt gggtgcccgg gtcgaccggt 60 gaggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcacagac cctgtccctc 120 acctgcactg tctctgatgg ctccgtcagc aggggtggtt actacttgac ctggatccgc 180 cagcacccag ggaagggcct ggagtggatt gggtacatct attacagtgg gagcacctac 240 ttcaacccgt ccctcaggag tcgggttacc atgtcagtag acacgtctaa gaaccagttc 300 tccctgaagc tgagctctgt gactgccgcg gacacggccg tgtattactg tgcgagaggg 360 atagcagtgg ctccctttga ctactggggc cagggaaccc tggtcaccgt ctcttcagct 420 agcaccaagg gccccagcgt gttccccctg gcccccagca gcaagtccac aagcggagga 480 acagccgccc tgggctgcct ggtgaaggac tacttccccg agcccgtgac cgtgtcctgg 540 aacagcggag ccctgacctc cggcgtgcac accttccccg ccgtgctgca gagcagcggc 600 ctgtacagcc tgagcagcgt ggtgacagtg ccaagcagca gcctgggaac ccagacctac 660 atctgcaacg tgaaccacaa gcccagcaac accaaggtgg acaagagagt ggagcccaag 720 agctgcgaca agacccatac ctgtccaccc tgcccagccc ccccagtggc cggaccctcc 780 gtgttcctgt tcccccccaa gcccaaggac accctgatga tcagcaggac ccccgaggtg 840 acctgcgtgg tggtggacgt gagccacgag gacccagagg tgaagttcaa ttggtatgtg 900 gacggcgtgg aggtgcacaa cgccaagacc aagcccagag aggaacagta caacagcacc 960 tacagggtgg tgtccgtgct gaccgtgctg caccaggact ggctgaacgg caaggaatac 1020 aagtgcaagg tctccaacaa ggccctgccc tccagcatcg agaaaaccat cagcaaggcc 1080 aagggccagc cacgggagcc ccaggtgtac acactgcccc catctcggga agaaatgacc 1140 aagaaccagg tgtccctgac ctgtctggtg aagggctttt accccagcga catcgccgtg 1200 gagtgggaga gcaacggcca gcccgagaac aactacaaga ccaccccccc tgtgctggac 1260 agcgacggca gcttcttcct gtacagcaag ctgaccgtgg acaagtccag gtggcagcag 1320 ggcaacgtgt tcagctgcag cgtgatgcac gaggccctgc acaaccacta cacacagaag 1380 agcctgagcc tgtcccccgg ctga 1404 <![CDATA[<210> 16]]> <![CDATA[<211> 708]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 編碼mAb1之LC之DNA序列]]> <![CDATA[<400> 16]]> atgagggccc tgctggctag actgctgctg tgcgtgctgg tcgtgtccga cagcaagggc 60 gaaatcgtac tcacgcagtc tccagccacc ctgtctgtgt ctccagggga aagagccacc 120 ctctcctgca ggaccagtca gagtgttcgc agcaacttag cctggtacca gcagaagcct 180 ggccaggctc ccaggctcct catctatgct gcatccacca gggccactgg tatcccagcc 240 aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagcag cctgcagtct 300 gaagattttg cagtttatta ctgtcagcag tatactaact ggccattcac tttcggccct 360 gggaccaaag tggacatcaa acgtacggtg gctgcaccat ctgtcttcat cttcccgcca 420 tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 480 cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 540 gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 600 ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 660 ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gttgatag 708 <![CDATA[<210> 17]]> <![CDATA[<211> 449]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 抗體hu8G4之HC]]> <![CDATA[<400> 17]]> Glu Val Gln Leu Val Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Asp Gly Ser Val Ser Arg Gly 20 25 30 Gly Tyr Tyr Leu Thr Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Phe Asn Pro Ser 50 55 60 Leu Arg Ser Arg Leu Thr Met Ser Val Asp Thr Ser Lys Asn Gln Phe 65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Gly Ile Ala Val Ala Pro Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 355 360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445 Lys <![CDATA[<210> 18]]> <![CDATA[<211> 214]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 抗體hu8G4之LC]]> <![CDATA[<400> 18]]> Glu Thr Thr Leu Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Thr Ser Gln Ser Val Arg Ser Asn 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Gly Ser Leu Gln Ser 65 70 75 80 Glu Asp Phe Ala Val Tyr Phe Cys Gln Gln Tyr Thr Asn Trp Pro Phe 85 90 95 Thr Phe Gly Pro Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <![CDATA[<210> 19]]> <![CDATA[<211> 449]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 最佳化抗體變體1之HC]]> <![CDATA[<400> 19]]> Glu Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Asp Gly Ser Val Ser Arg Gly 20 25 30 Gly Tyr Tyr Leu Thr Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Phe Asn Pro Ser 50 55 60 Leu Arg Ser Arg Leu Thr Met Ser Val Asp Thr Ser Lys Asn Gln Phe 65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Gly Ile Ala Val Ala Pro Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 355 360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445 Lys <![CDATA[<210> 20]]> <![CDATA[<211> 214]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 最佳化抗體變體1之LC]]> <![CDATA[<400> 20]]> Glu Thr Thr Leu Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Thr Ser Gln Ser Val Arg Ser Asn 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Gly Ser Leu Gln Ser 65 70 75 80 Glu Asp Phe Ala Val Tyr Phe Cys Gln Gln Tyr Thr Asn Trp Pro Phe 85 90 95 Thr Phe Gly Pro Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <![CDATA[<210> 21]]> <![CDATA[<211> 214]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 最佳化抗體變體2之LC]]> <![CDATA[<400> 21]]> Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Thr Ser Gln Ser Val Arg Ser Asn 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser 65 70 75 80 Glu Asp Phe Ala Val Tyr Phe Cys Gln Gln Tyr Thr Asn Trp Pro Phe 85 90 95 Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <![CDATA[<210> 22]]> <![CDATA[<211> 214]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 最佳化抗體變體4之LC]]> <![CDATA[<400> 22]]> Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Thr Ser Gln Ser Val Arg Ser Asn 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser 65 70 75 80 Glu Asp Phe Ala Val Tyr Phe Cys Gln Gln Tyr Thr Asn Trp Pro Phe 85 90 95 Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <![CDATA[<210> 23]]> <![CDATA[<211> 214]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 最佳化抗體變體5之LC]]> <![CDATA[<400> 23]]> Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Thr Ser Gln Ser Val Arg Ser Asn 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Thr Asn Trp Pro Phe 85 90 95 Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <![CDATA[<210> 24]]> <![CDATA[<211> 449]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 最佳化抗體變體6之HC]]> <![CDATA[<400> 24]]> Glu Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Asp Gly Ser Val Ser Arg Gly 20 25 30 Gly Tyr Tyr Leu Thr Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Phe Asn Pro Ser 50 55 60 Leu Arg Ser Arg Val Thr Met Ser Val Asp Thr Ser Lys Asn Gln Phe 65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Gly Ile Ala Val Ala Pro Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 355 360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445 Lys <![CDATA[<210> 25]]> <![CDATA[<211> 450]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> huMab2-3之HC (異型)]]> <![CDATA[<400> 25]]> Glu Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Ser Leu Ser Cys Ala Ala Ser Gly Phe Val Phe Ser Ser Tyr 20 25 30 Asp Met Ser Trp Val Arg Gln Thr Pro Glu Arg Gly Leu Glu Trp Val 35 40 45 Ala Tyr Ile Ser Ser Gly Gly Gly Ile Thr Tyr Ala Pro Ser Thr Val 50 55 60 Lys Gly Arg Phe Thr Val Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ala His Tyr Phe Gly Ser Ser Gly Pro Phe Ala Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp 210 215 220 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 225 230 235 240 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 245 250 255 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 260 265 270 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 275 280 285 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 290 295 300 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 305 310 315 320 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 325 330 335 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 340 345 350 Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu 355 360 365 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 370 375 380 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 385 390 395 400 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 405 410 415 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 420 425 430 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 435 440 445 Gly Lys 450 <![CDATA[<210> 26]]> <![CDATA[<211> 214]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> huMab2-3之LC]]> <![CDATA[<400> 26]]> Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Asn Ile Phe Ser Tyr 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ser Pro Lys Leu Leu Val 35 40 45 Tyr Asn Thr Arg Thr Leu Ala Glu Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Ser Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln His His Tyr Gly Thr Pro Phe 85 90 95 Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <![CDATA[<210> 27]]> <![CDATA[<211> 449]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hmn-14之HC]]> <![CDATA[<400> 27]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ser Ala Ser Gly Phe Asp Phe Thr Thr Tyr 20 25 30 Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Glu Ile His Pro Asp Ser Ser Thr Ile Asn Tyr Ala Pro Ser Leu 50 55 60 Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Phe 65 70 75 80 Leu Gln Met Asp Ser Leu Arg Pro Glu Asp Thr Gly Val Tyr Phe Cys 85 90 95 Ala Ser Leu Tyr Phe Gly Phe Pro Trp Phe Ala Tyr Trp Gly Gln Gly 100 105 110 Thr Pro Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 355 360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445 Lys <![CDATA[<210> 28]]> <![CDATA[<211> 213]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hmn-14之LC]]> <![CDATA[<400> 28]]> Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Gly Thr Ser 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Trp Thr Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Leu Tyr Arg Ser 85 90 95 Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro 100 105 110 Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr 115 120 125 Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 130 135 140 Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu 145 150 155 160 Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser 165 170 175 Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala 180 185 190 Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 195 200 205 Asn Arg Gly Glu Cys 210 <![CDATA[<210> 29]]> <![CDATA[<211> 441]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> rb8G4之HC]]> <![CDATA[<400> 29]]> Glu Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Asp Gly Ser Val Ser Arg Gly 20 25 30 Gly Tyr Tyr Leu Thr Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Phe Asn Pro Ser 50 55 60 Leu Arg Ser Arg Val Thr Met Ser Val Asp Thr Ser Lys Asn Gln Phe 65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Gly Ile Ala Val Ala Pro Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Gln Pro Lys Ala Pro Ser Val Phe Pro 115 120 125 Leu Ala Pro Cys Cys Gly Asp Thr Pro Ser Ser Thr Val Thr Leu Gly 130 135 140 Cys Leu Val Lys Gly Tyr Leu Pro Glu Pro Val Thr Val Thr Trp Asn 145 150 155 160 Ser Gly Thr Leu Thr Asn Gly Val Arg Thr Phe Pro Ser Val Arg Gln 165 170 175 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Ser Val Thr Ser Ser 180 185 190 Ser Gln Pro Val Thr Cys Asn Val Ala His Pro Ala Thr Asn Thr Lys 195 200 205 Val Asp Lys Thr Val Ala Pro Ser Thr Cys Ser Lys Pro Thr Cys Pro 210 215 220 Pro Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys 225 230 235 240 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 245 250 255 Val Val Asp Val Ser Glu Asp Asp Pro Glu Val Gln Phe Thr Trp Tyr 260 265 270 Ile Asn Asn Glu Gln Val Arg Thr Ala Arg Pro Pro Leu Arg Glu Gln 275 280 285 Gln Phe Asn Ser Thr Ile Arg Val Val Ser Thr Leu Pro Ile Ala His 290 295 300 Glu Asp Trp Leu Arg Gly Lys Glu Phe Lys Cys Lys Val His Asn Lys 305 310 315 320 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Arg Gly Gln 325 330 335 Pro Leu Glu Pro Lys Val Tyr Thr Met Gly Pro Pro Arg Glu Glu Leu 340 345 350 Ser Ser Arg Ser Val Ser Leu Thr Cys Met Ile Asn Gly Phe Tyr Pro 355 360 365 Ser Asp Ile Ser Val Glu Trp Glu Lys Asn Gly Lys Ala Glu Asp Asn 370 375 380 Tyr Lys Thr Thr Pro Ala Val Leu Asp Ser Asp Gly Ser Tyr Phe Leu 385 390 395 400 Tyr Ser Lys Leu Ser Val Pro Thr Ser Glu Trp Gln Arg Gly Asp Val 405 410 415 Phe Thr Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 420 425 430 Lys Ser Ile Ser Arg Ser Pro Gly Lys 435 440 <![CDATA[<210> 30]]> <![CDATA[<211> 213]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> rb8G4之LC]]> <![CDATA[<400> 30]]> Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Thr Ser Gln Ser Val Arg Ser Asn 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Thr Asn Trp Pro Phe 85 90 95 Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Arg Asp Pro Val Ala 100 105 110 Pro Ser Val Leu Leu Phe Pro Pro Ser Lys Glu Glu Leu Thr Thr Gly 115 120 125 Thr Ala Thr Ile Val Cys Val Ala Asn Lys Phe Tyr Pro Ser Asp Ile 130 135 140 Thr Val Thr Trp Lys Val Asp Gly Thr Thr Gln Gln Ser Gly Ile Glu 145 150 155 160 Asn Ser Lys Thr Pro Gln Ser Pro Glu Asp Asn Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Ser Leu Thr Ser Ala Gln Tyr Asn Ser His Ser Val Tyr 180 185 190 Thr Cys Glu Val Val Gln Gly Ser Ala Ser Pro Ile Val Gln Ser Phe 195 200 205 Asn Arg Gly Asp Cys 210
Claims (42)
- 一種經分離之抗體,其結合至人類CEACAM5蛋白,且其包含由SEQ ID NO: 3之胺基酸序列構成之CDR1-H、由SEQ ID NO: 4之胺基酸序列構成之CDR2-H、由SEQ ID NO: 5之胺基酸序列構成之CDR3-H、由SEQ ID NO: 6之胺基酸序列構成之CDR1-L、由SEQ ID NO: 7之胺基酸序列構成之CDR2-L及由SEQ ID NO: 8之胺基酸序列構成之CDR3-L。
- 如請求項1之抗體,其包括包含與SEQ ID NO: 9之胺基酸序列具有至少85%一致性之胺基酸序列之重鏈可變區(VH)及包含與SEQ ID NO: 10之胺基酸序列具有至少85%一致性之胺基酸序列之輕鏈可變區(VL)。
- 如請求項1或2之抗體,其包括包含SEQ ID NO: 9之胺基酸序列之重鏈可變區(VH)及包含SEQ ID NO: 10之胺基酸序列之輕鏈可變區(VL)。
- 如請求項1至3中任一項之抗體,其包括包含與SEQ ID NO: 11之胺基酸序列具有至少85%一致性之胺基酸序列之重鏈恆定區(CH)及包含與SEQ ID NO: 12之胺基酸序列具有至少85%一致性之胺基酸序列之輕鏈恆定區(CL)。
- 如請求項1至4中任一項之抗體,其包括包含SEQ ID NO: 11之胺基酸序列之重鏈恆定區(CH)及包含SEQ ID NO: 12之胺基酸序列之輕鏈恆定區(CL)。
- 如請求項1至5中任一項之抗體,其包括包含SEQ ID NO: 13之胺基酸序列之重鏈(HC)及包含SEQ ID NO: 14之胺基酸序列之輕鏈(LC)。
- 一種經分離之抗體,其與包含SEQ ID NO: 9之胺基酸序列之重鏈可變區(VH)及SEQ ID NO: 10之胺基酸序列之輕鏈可變區(VL)之抗體競爭結合至人類CEACAM5蛋白之A2-B2域。
- 如請求項7之抗體,其中該抗體亦與包含SEQ ID NO: 9之胺基酸序列之重鏈可變區(VH)及SEQ ID NO: 10之胺基酸序列之輕鏈可變區(VL)之抗體競爭結合至食蟹獼猴( Macaca fascicularis) CEACAM5蛋白之A2-B2域。
- 如請求項7或8之抗體,其中該抗體不與人類CEACAM1、人類CEACAM6、人類CEACAM7、人類CEACAM8及食蟹獼猴CEACAM6顯著交叉反應。
- 如請求項1至9中任一項之抗體,其中該抗體係抗體片段。
- 如請求項10之抗體,其中該抗體係選自由以下組成之群之抗體片段:Fv、Fab、F(ab')2、Fab'、dsFv、(dsFv)2、scFv、sc(Fv)2,及雙功能抗體(diabodies)。
- 如請求項1至11中任一項之抗體,其係雙特異性或多特異性抗體。
- 一種經分離之抗體,其結合至人類CEACAM5蛋白,且其由包含SEQ ID NO: 13之胺基酸序列之兩個相同重鏈(HC)及包含SEQ ID NO: 14之胺基酸序列之兩個相同輕鏈(LC)構成。
- 一種經分離之核酸,其包含編碼如請求項1至13中任一項之抗體之核酸序列。
- 一種宿主細胞,其已經如請求項14之核酸轉形。
- 一種免疫結合物,其包含如請求項1至13中任一項之抗體經由連接子共價連接至至少一種生長抑制劑。
- 如請求項16之免疫結合物,其中該生長抑制劑係細胞毒性藥物或放射性部分。
- 如請求項16或17之免疫結合物,其中該生長抑制劑係選自由以下組成之群:化學治療劑、酶、抗生素、毒素(諸如小分子毒素或酶活性毒素)、類毒素、長春花、紫杉烷、類美登素(maytansinoids)或類美登素類似物、托馬黴素(tomaymycin)或吡咯苯并二氮呯衍生物、念珠藻素(cryptophycin)衍生物、來普黴素(leptomycin)衍生物、奧瑞他汀(auristatin)或尾海兔素(dolastatin)類似物、前藥、拓撲異構酶I抑制劑、拓撲異構酶II抑制劑、DNA烷化劑、抗微管蛋白劑、CC-1065及CC-1065類似物。
- 如請求項16至18中任一項之免疫結合物,其中該生長抑制劑係依喜替康(exatecan)。
- 如請求項16至19中任一項之免疫結合物,其中連接子係可裂解連接子。
- 如請求項16至20中任一項之免疫結合物,其中該連接子係可於哺乳動物細胞之內體中裂解之連接子。
- 如請求項16至21中任一項之免疫結合物,其中該連接子係可由選自葡萄醣醛酸酶及豆莢蛋白(legumain)之人類酶裂解之連接子。
- 如請求項16至26中任一項之免疫結合物,其中該S係該抗體之半胱胺酸之硫原子。
- 如請求項27之免疫結合物,其中該抗體之半胱胺酸係能夠形成鏈間二硫鍵之半胱胺酸中之一者。
- 如請求項23至28中任一項之免疫結合物,其中n係介於7與8之間。
- 如請求項23至29中任一項之免疫結合物,其中n係介於7.5與8.0之間。
- 一種醫藥組合物,其包含如請求項1至13中任一項之抗體或如請求項16至30中任一項之免疫結合物,其進一步包含醫藥上可接受之載劑、稀釋劑及/或賦形劑。
- 如請求項1至13中任一項之抗體或如請求項16至30中任一項之免疫結合物或如請求項31之醫藥組合物,其用作藥劑。
- 如請求項1至13中任一項之抗體或如請求項16至30中任一項之免疫結合物或如請求項31之醫藥組合物,其用以治療癌症。
- 如請求項33使用之抗體、免疫結合物或醫藥組合物,其中該癌症係表現CEACAM5之癌症。
- 如請求項33或34使用之抗體、免疫結合物或醫藥組合物,其中該癌症係結腸直腸癌、胃癌、肺癌、胰臟癌、食道癌或前列腺癌。
- 一種治療癌症之方法,其包括對個體(subject)投與如請求項1至13中任一項之抗體或如請求項16至30中任一項之免疫結合物或如請求項31之醫藥組合物。
- 如請求項36之方法,其中該癌症係表現CEACAM5之癌症。
- 如請求項36或37之方法,其中該癌症係結腸直腸癌、胃癌、肺癌、胰臟癌、食道癌或前列腺癌。
- 一種使用如請求項1至13中任一項之抗體離體偵測來自個體之生物樣本中CEACAM5表現之方法。
- 如請求項39之方法,其中該抗體係經可偵測分子標記。
- 一種如請求項1至13中任一項之抗體之用途,其用於離體偵測來自個體之生物樣本中CEACAM5表現。
- 如請求項41之用途,其中該抗體係經可偵測分子標記。
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WO2024091437A1 (en) * | 2022-10-25 | 2024-05-02 | Merck Sharp & Dohme Llc | Exatecan-derived adc linker-payloads, pharmaceutical compositions, and uses thereof |
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