TW202305005A - 抗siglec組合物及其用途 - Google Patents
抗siglec組合物及其用途 Download PDFInfo
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- TW202305005A TW202305005A TW111116333A TW111116333A TW202305005A TW 202305005 A TW202305005 A TW 202305005A TW 111116333 A TW111116333 A TW 111116333A TW 111116333 A TW111116333 A TW 111116333A TW 202305005 A TW202305005 A TW 202305005A
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Abstract
本發明係關於抗Siglec-10抗體及此類抗體在癌症療法中之用途。
Description
本發明係關於選擇性地結合人類Siglec-10之抗Siglec-10抗體,及此類抗體在癌症療法中之用途。
CD24為小型重度醣基化黏蛋白樣醣基磷脂醯-肌醇(GPI)連接之細胞表面蛋白。CD24在造血細胞,包括B細胞、T細胞、嗜中性球、嗜酸性球、樹突狀細胞及巨噬細胞,以及非造血細胞,包括神經細胞、神經節細胞、上皮細胞、角質細胞、肌肉細胞、胰臟細胞及上皮幹細胞上以較高水準表現。通常,CD24傾向於在先驅細胞及代謝活性細胞中以較高水準表現,且在終末分化細胞中以較低程度表現。尚未知曉CD24在大多數細胞類型中之功能,但已報導CD24之各種免疫功能。
CD24與先天免疫細胞上之Siglec-10相互作用以負向調節宿主對與炎症相關的細胞損傷之反應,且至少有兩種重疊的機制可解釋此活性。首先,CD24與若干種損傷相關分子模式(DAMP)結合,包括HSP70、90、HMGB1及核仁素,且抑制宿主對此等DAMP之反應。假定CD24可限制炎性刺激以防止其與TLR或RAGE發生相互作用。其次,藉由與其受體Siglec G (Siglec-10之小鼠同系物)之相互作用,CD24為宿主對組織損傷的反應提供強大的負向調節。為獲得此活性,CD24可結合Siglec G且由Siglec G刺激傳訊,其中Siglec G結合之SHP1觸發負向調節。兩種機制均可協同作用,因為任一基因發生靶向突變之小鼠產生強得多的發炎反應。
Siglec為I型跨膜蛋白,其中NH3
+端在細胞外空間中且COO
−端在細胞質內。Siglec-10之細胞外域含有N端V型免疫球蛋白域(Ig域),其充當唾液酸之結合受體,及五個C2型Ig域,其不具有結合活性,但使V型Ig結合域延伸遠離細胞表面。包括Siglec-10之大部分Siglec的細胞質域具有基於免疫受體酪胺酸之抑制性模體(ITIM),且藉由募集酪胺酸磷酸酶(諸如含有蛋白酪胺酸磷酸酶SHP1及SHP2之SH2域)來發出負信號。Siglec之主要功能為結合含有唾液酸之聚醣。此等受體-聚醣相互作用可用於細胞黏附、細胞傳訊及其他功能,此相互作用通常受限於其細胞分佈。人類Siglec-10為小鼠Siglec G之功能性異種同源物,且其與小鼠及人類CD24兩者結合。
許多癌症藉由過度表現稱作「不要吃我」信號之抗吞噬細胞表面蛋白來避免被免疫系統清除。此類蛋白質之實例包括PD-L1及CD47,其分別與免疫細胞上之PD-1及信號調節蛋白α (SIRPα)結合,從而抑制巨噬細胞之活性。因此,已開發阻斷或拮抗此等不要吃我途徑之抗體作為免疫腫瘤學藥物。已證明,CD24經由與Siglec-10之相互作用而代表另一種此類不要吃我信號,儘管CD24存在於許多正常組織及細胞類型中,但CD24在約70%的人類癌症中過度表現且為癌細胞中過度表現最多的蛋白質之一。CD24表現在腫瘤發生期間上調,表明其在腫瘤進程及轉移中之作用。癌症中之CD24的過度表現亦被鑑別為表明癌症患者之不良預後及疾病過程更具侵略性之標誌物。
因此,此項技術中需要用於治療癌症之靶向CD24:Siglec-10不要吃我軸之新穎免疫療法。
本發明提供抗Siglec-10抗體,其可包含:(a)重鏈可變區,其包含有包含SEQ ID NO: 3中所闡述之序列之互補決定區(CDR) 1、包含SEQ ID NO: 4中所闡述之序列之CDR2及包含SEQ ID NO: 5中所闡述之序列之CDR3中之一或多者;及(b)輕鏈可變區,其包含有包含SEQ ID NO: 6中所闡述之序列之CDR1、包含SEQ ID NO: 7所闡述之序列之CDR2及包含SEQ ID NO: 8所闡述之序列之CDR3中之一或多者。重鏈可變區可包含SEQ ID NO:1中所闡述之序列,且輕鏈可變區可包含SEQ ID NO:2中所闡述之序列。抗體可為嵌合抗體。
抗Siglec-10抗體之重鏈可變區可包含SEQ ID NO: 9-13中之一者中所闡述之序列,且輕鏈可變區可包含SEQ ID NO: 14-18中之一者中所闡述之序列。重鏈可變區可包含SEQ ID NO: 9、10或11中所闡述之序列;且輕鏈可變區可包含SEQ ID NO: 15中所闡述之序列。Siglec-10抗體之重鏈可變區可包含SEQ ID NO: 10或12中所闡述之序列;且輕鏈可變區可包含SEQ ID NO: 17中所闡述之序列。抗Siglec-10抗體之重鏈可變區可包含SEQ ID NO: 10或12中所闡述之序列;且輕鏈可變區可包含SEQ ID NO: 16中所闡述之序列。抗體可包含有包含SEQ ID NO: 9中所闡述之序列之重鏈可變區及包含SEQ ID NO: 15中所闡述之序列之輕鏈可變區。抗體可包含有包含SEQ ID NO: 25中所闡述之序列之重鏈,且可進一步包含有包含SEQ ID NO: 27中所闡述之序列之輕鏈。抗體可包含有包含SEQ ID NO: 10中所闡述之序列之重鏈可變區及包含SEQ ID NO: 15或16中所闡述之序列之輕鏈可變區。抗體可包含有包含SEQ ID NO: 32中所闡述之序列之重鏈及包含SEQ ID NO: 27中所闡述之序列之輕鏈。抗體可包含有包含SEQ ID NO: 32中所闡述之序列之重鏈及包含SEQ ID NO: 34中所闡述之序列之輕鏈。
本發明亦提供治療有需要之患者中之癌症的方法,其可包含向患者投與抗Siglec-10抗體。亦提供用於治療癌症之抗Siglec-10抗體及抗Siglec-10抗體在製造用於治療癌症之藥劑中之用途。亦提供用於治療癌症之包含抗Siglec-10抗體的組合物。組合物可為醫藥組合物。
抗Siglec-10抗體可與第二癌症療法組合投與,或可意欲與第二癌症療法組合使用。第二癌症療法可為靶向癌症之免疫療法或靶向免疫細胞之免疫療法。第二癌症療法可為抗CTLA-4抗體。
癌症可為晚期實體腫瘤、血液癌症,或包括與抗Siglec-10抗體結合之浸潤細胞的癌症。癌症可為晚期實體腫瘤,其可為肺腺癌(LUAD)、皮膚黑色素瘤-轉移(SKCM-TM)、肺鱗狀細胞癌(LUSC)、乳房侵襲性癌瘤-基底、乳房侵襲性癌瘤-Her2、胰臟腺癌、頭頸鱗狀細胞癌、腎臟透明細胞癌、胃腺癌、多形性膠質母細胞瘤、乳房侵襲性癌瘤-LumB或乳房侵襲性癌瘤-LumA、非小細胞肺癌、膠質母細胞瘤、黑色素瘤、低級別膠質瘤、腎癌、基底型乳癌、Her2+乳癌、胰臟癌或卵巢癌。肺腺癌可為非小細胞肺腺癌。血液癌症可為白血病、骨髓發育不良症候群、B細胞淋巴瘤或多發性骨髓瘤。
在實驗模型系統及患者中,免疫系統可識別及消除癌症。因此,癌症免疫療法正在成為癌症療法之最有前景之領域之一。活性癌症免疫療法涉及藉由阻斷免疫檢查點或不要吃我信號來增強自然免疫反應之藥劑(包括針對PD-1、PD-L1、CTLA-4及CD47之抗體)。
本發明提供相關抗Siglec-10抗體及其抗原結合片段。抗體分子可為單株抗體、人類抗體、嵌合抗體或人類化抗體。抗體可為單特異性、雙特異性、三特異性或多特異性。Siglec-10結合分子可包含與Siglec-10且尤其人類Siglec-10免疫特異性結合之抗體的抗原結合片段,該Siglec-10尤其可在活細胞表面以內源或經轉染之濃度表現。亦提供抗體分子,其抗原結合片段與Siglec-10結合。該抗體可以可偵測方式標記,或包含結合之毒素、藥物、受體、酶或受體配位體。
不同腫瘤類型及患者之反應各不相同,此意謂不同的抑制途徑可與不同的腫瘤類型或不同的群體有關。因此,識別額外的不要吃我信號可引起開發對某些腫瘤類型或患者更有效(無論單獨或可能呈組合形式)之新療法。本文所述之抗體分子可用於藉由投與本文所述之抗Siglec-10抗體而單獨或與其他療法組合用於治療癌症。
本發明人已發現對尤其細胞表面上之Siglec-10呈現出人意料地強力結合之抗Siglec-10抗體。該等抗體亦藉由抑制有效的不要吃我信號來增強強大的ADCC活性。
1. 定義
本文中所使用之術語僅出於描述特定實施例之目的且並不意欲為限制性的。除非上下文另外明確指示,否則如在說明書及所附申請專利範圍中所使用,單數形式「一(a/an)」及「該(the)」包括複數個指示物。與數值相關之字組「約」表示該數值的合理近似值。在某些情況下,「約」可被理解為在與其相關的特定數值之10%以內。舉例而言,片語「約100」將涵蓋在90與110之間的任何數值。
對於本文中之數字範圍之敍述,明確涵蓋具有相同精確程度之在其之間的各間插數字。舉例而言,對於6-9之範圍,除6及9以外亦涵蓋數字7及8,且對於範圍6.0-7.0,明確涵蓋數字6.0、6.1、6.2、6.3、6.4、6.5、6.6、6.7、6.8、6.9及7.0。
當提及保護動物免於患病時,「治療(Treatment/treating)」意謂預防、抑止、抑制或完全消除疾病。預防疾病涉及在疾病發作之前向動物投與本發明之組合物。抑制疾病涉及在疾病誘發之後,但在其臨床顯現之前,向動物投與本發明之組合物。抑制疾病涉及在疾病的臨床顯現之後,向動物投與本發明之組合物。
如本文所使用,術語「抗體」意欲指代具有「可變區」抗原識別位點之免疫球蛋白分子。術語「可變區」意欲將免疫球蛋白之此類域與由抗體廣泛地共用之域(諸如,抗體Fc域)區分開。可變區包含其中殘基負責抗原結合之「高變區」。高變區包含來自「互補決定區」或「CDR」之胺基酸殘基(亦即,通常大致在輕鏈可變域中之殘基24至34 (L1)、50至56 (L2)及89至97 (L3)處及大致在重鏈可變域中之殘基27至35 (H1)、50至65 (H2)及95至102 (H3)處)及/或來自「高變環」之殘基(亦即,輕鏈可變域中之殘基26至32 (L1)、50至52 (L2)及91至96 (L3)及重鏈可變域中之殘基26至32 (H1)、53至55 (H2)及96至101 (H3))。「構架區」或「FR」殘基為除如本文所定義之高變區殘基以外之可變域殘基。術語抗體包括單株抗體、多特異性抗體、人類抗體、人類化抗體、合成抗體、嵌合抗體、駱駝抗體、單鏈抗體、二硫鍵連接的Fv (sdFv)、胞內抗體及抗個體基因型(抗Id)抗體(包括例如針對本發明揭示之抗體的抗Id及抗抗Id抗體)。特定言之,此類抗體包括任何類型(例如,IgG、IgE、IgM、IgD、IgA及IgY)、類別(例如,IgG
1、IgG
2、IgG
3、IgG
4、IgA
1及IgA
2)或子類別之免疫球蛋白分子。
如本文所使用,術語抗體之「抗原結合片段」係指抗體的一或多個部分,其含有抗體之CDR及視情況選用之包含抗體之「可變區」抗原識別位點之構架殘基,且呈現免疫特異性結合抗原之能力。此類片段包括Fab'、F(ab')
2、Fv、單鏈(ScFv)及其突變體、天然存在之變異體,及包含抗體之「可變區」抗原識別位點及異源蛋白質(例如,毒素、不同抗原之抗原識別位點、酶、受體或受體配位體等)之融合蛋白。如本文所用,術語「片段」係指肽或多肽,其包含至少5個鄰接胺基酸殘基、至少10個鄰接胺基酸殘基、至少15個鄰接胺基酸殘基、至少20個鄰接胺基酸殘基、至少25個鄰接胺基酸殘基、至少40個鄰接胺基酸殘基、至少50個鄰接胺基酸殘基、至少60個鄰接胺基酸殘基、至少70個鄰接胺基酸殘基、至少80個鄰接胺基酸殘基、至少90個鄰接胺基酸殘基、至少100個鄰接胺基酸殘基、至少125個鄰接胺基酸殘基、至少150個鄰接胺基酸殘基、至少175個鄰接胺基酸殘基、至少200個鄰接胺基酸殘基或至少250個鄰接胺基酸殘基的胺基酸序列。
對於人類中之活體內使用,人類、嵌合或人類化抗體係尤其較佳的,然而鼠類抗體或其他物種之抗體可有利地用於許多用途(例如,活體外或原位偵測分析法、急性活體內用途等)。
「嵌合抗體」為一種分子,其中抗體之不同部分衍生自不同免疫球蛋白分子,諸如具有衍生自非人類抗體之可變區及人類免疫球蛋白恆定區的抗體。包含來自非人類物種之一或多個CDR及來自人類免疫球蛋白分子之構架區之嵌合抗體可藉由此項技術中已知的多種技術產生,包括例如CDR移植(EP 239,400;國際公開案第WO 91/09967號;及美國專利第5,225,539號、第5,530,101號及第5,585,089號,其內容各自以全文引用之方式併入本文中),面飾法或重鋪(EP 592,106;EP 519,596,其內容各自以引用之方式併入本文中),以及鏈改組(美國專利第5,565,332號,該案之內容以引用的方式併入本文中)。
本文亦涵蓋「人類化抗體」。如本文所用,術語「人類化抗體」係指包含人類構架區及一或多個來自非人類(通常為小鼠或大鼠)免疫球蛋白之CDR的免疫球蛋白。提供CDR之非人類免疫球蛋白稱為「供體」且提供構架之人類免疫球蛋白稱為「受體」。恆定區未必存在,但若其存在,則其必須與人類免疫球蛋白恆定區實質上一致,亦即,至少約85至90%,較佳約95%或更多一致。因此,除可能的CDR以外,人類化免疫球蛋白之所有部分與天然人類免疫球蛋白序列之對應部分實質上一致。人類化抗體為包含人類化輕鏈及人類化重鏈免疫球蛋白之抗體。舉例而言,人類化抗體不涵蓋典型的嵌合抗體,此係因為例如嵌合抗體之整個可變區為非人類的。供體抗體可稱為藉由「人類化」方法達成「人類化」,因為預期所得人類化抗體與提供CDR之供體抗體結合於相同抗原。在極大程度上,人類化抗體為人類免疫球蛋白(受體抗體),其中受體之高變區殘基經來自非人類物種(供體抗體) (諸如,具有所需特異性、親和性及能力之小鼠、大鼠、兔或非人類靈長類)之高變區殘基置換。在一些情況下,人類免疫球蛋白之構架區(FR)殘基經對應非人類殘基置換。此外,人類化抗體可包含未在受體抗體或供體抗體中發現之殘基。進行此等修飾以進一步改進抗體效能。一般而言,人類化抗體將包含實質上全部的至少一個且通常兩個可變域,其中所有或實質上所有高變區均對應於非人類免疫球蛋白之高變區,且所有或實質上所有FR均為人類免疫球蛋白序列之FR。人類化抗體視情況亦將包含免疫球蛋白恆定區(Fc)的至少一部分,通常為人類免疫球蛋白中之與FcγRIIB多肽免疫特異性結合之部分,其已藉由引入胺基酸殘基取代、缺失或添加(亦即,突變)而改變。
2. 抗 Siglec - 10 抗體組合物
本發明提供抗Siglec-10抗體或其抗原結合片段。應理解,本文所述之抗體的一或多個特徵亦可包括在抗原結合片段中。抗Siglec-10抗體可與腫瘤相關巨噬細胞結合,且可抑制對癌細胞上表現的CD24之結合或傳訊,由此抑制來自癌細胞之抗吞噬信號。抗Siglec-10抗體可為單株抗體、單鏈抗體、雙特異性抗體、三特異性抗體、多特異性抗體或嵌合抗體。
抗Siglec-10抗體可包含抗體31F11之一或多個序列,該抗體包含重鏈及輕鏈可變區,其分別包含SEQ ID NO: 1及2中所闡述之序列。抗體可包含有包含SEQ ID NO: 1中所闡述之序列之重鏈可變區,且可包含有包含SEQ ID NO: 2中所闡述之序列之輕鏈可變區。抗Siglec-10抗體之重鏈可變區可包含以下中之一或多者:包含SEQ ID NO: 3中所闡述之序列之CDR1,包含SEQ ID NO: 4中所闡述之序列之CDR2,及包含SEQ ID NO: 5中所闡述之序列之CDR3。抗Siglec-10抗體之輕鏈可變區可包含以下中之一或多者:包含SEQ ID NO: 6中所闡述之序列之CDR1,包含SEQ ID NO: 7中所闡述之序列之CDR2,及包含SEQ ID NO: 8中所闡述之序列之CDR3。在一個實例中,抗體為包含連接至人類Fc域的31F11之可變域之嵌合抗體。
在一個實施例中,重鏈可變區包含分別具有SEQ ID NO: 3-5之CDR1-3。在另一實施例中,輕鏈可變區包含分別具有SEQ ID NO: 6-8之CDR1-3。在另一實例中,抗Siglec-10抗體包含有包含SEQ ID NO: 3-5之重鏈可變區及包含SEQ ID NO: 6-8之輕鏈可變區。
抗Siglec-10抗體之一或多個重鏈及輕鏈亦可相對於31F11經人類化。抗Siglec-10抗體可包含一或多個重鏈可變區,其各自包含SEQ ID NO: 9、10、11、12及13中之一者中所闡述的序列(分別命名為Hu-VHv1、VHv2、VHv3、VHv4及VHv5)。抗Siglec-10抗體可包含一或多個輕鏈可變區,其各自包含在SEQ ID NO: 14-18中之一者中所闡述的序列(分別命名為Hu-VLv1、VLv2、VLv3、VLv4及VLv5)。
31F11之重鏈及輕鏈可變區的序列提供於下文中。
31F11重鏈可變區
31F11輕鏈可變區
人類化31F11重鏈可變區之序列提供於下文中(CDR加有下劃線)。
Hu-31F11-VHv1
Hu-31F11-VHv2
Hu-31F11-VHv3
Hu-31F11-VHv4
Hu-31F11-VHv5
人類化31F11輕鏈可變區之序列提供於下文中(CDR加有下劃線)。
Hu 31F11-VLv1
Hu 31F11-VLv2
Hu 31F11-VLv2-完全輕鏈
Hu 31F11-VLv2-完全輕鏈加信號肽
Hu 31F11-VLv3
Hu 31F11-VLv3-完全輕鏈
Hu 31F11-VLv3-完全輕鏈加信號肽
Hu 31F11-VLv4
Hu 31F11-VLv5
在一個實例中,抗Siglec-10抗體包含有包含SEQ ID NO: 9中所闡述之序列之重鏈可變區或包含SEQ ID NO: 25中所闡述之序列之重鏈,及包含SEQ ID NO: 15中所闡述之序列之輕鏈可變區或包含SEQ ID NO: 27中所闡述之序列之輕鏈。抗Siglec-10抗體可包含hu-VHv1VLv2。
在另一實例中,抗Siglec-10抗體包含有包含SEQ ID NO: 10中所闡述之序列之重鏈可變區或包含SEQ ID NO: 32中所闡述之序列之重鏈,及包含SEQ ID NO: 15中所闡述之序列之輕鏈可變區或包含SEQ ID NO: 27中所闡述之序列之輕鏈。抗Siglec-10抗體可包含hu-VHv2VLv2。
在另一實例中,抗Siglec-10抗體包含有包含SEQ ID NO: 10中所闡述之序列之重鏈可變區或包含SEQ ID NO: 32中所闡述之序列之重鏈,及包含SEQ ID NO: 16中所闡述之序列之輕鏈可變區或包含SEQ ID NO: 34中所闡述之序列之輕鏈。抗Siglec-10抗體可包含hu-VHv2VLv3。
抗Siglec-10抗體可包含有包含SEQ ID NO: 9、10或11中所闡述之序列之重鏈可變區;及包含SEQ ID NO: 15、27、16或34中所闡述之序列之輕鏈可變區。
在另一實例中,抗Siglec-10抗體包含有包含SEQ ID NO: 10中所闡述之序列之重鏈可變區及包含SEQ ID NO: 17中所闡述之序列之輕鏈可變區。抗Siglec-10抗體可包含hu-VHv2VLv4。在另一實例中,抗Siglec-10抗體包含有包含SEQ ID NO: 12中所闡述之序列之重鏈可變區及包含SEQ ID NO: 17中所闡述之序列之輕鏈可變區。抗Siglec-10抗體可包含hu-VHv4VLv4。抗Siglec-10抗體可包含有包含SEQ ID NO: 10或12中所闡述之序列之重鏈可變區;及包含SEQ ID NO: 17中所闡述之序列之輕鏈可變區。
在另一實例中,抗Siglec-10抗體包含有包含SEQ ID NO: 12中所闡述之序列之重鏈可變區及包含SEQ ID NO: 16或34中所闡述之序列之輕鏈可變區。抗Siglec-10抗體可包含hu-VHv4VLv3。
在另一實例中,抗Siglec-10抗體包含有包含SEQ ID NO: 10中所闡述之序列之重鏈可變區及包含SEQ ID NO: 15或17中所闡述之序列之輕鏈可變區。在另一實例中,抗Siglec-10抗體包含有包含SEQ ID NO: 12中所闡述之序列之重鏈可變區及包含SEQ ID NO: 16、34或17中所闡述之序列之輕鏈可變區。
抗Siglec-10抗體可包含人類Igκ多肽。在一個實例中,Igκ具有SEQ ID NO: 19中所闡述之序列。抗Siglec-10抗體可包含人類IgG多肽,其可為IgG1、IgG2、IgG3、IgG4、IgA1或IgA2。在一個實例中,IgG為IgG4,其可具有SEQ ID NO: 20中所闡述之序列。在另一實例中,IgG4可包括S228P突變,其可具有以下序列。
在另一實例中,抗Siglec-10抗體包含有包含SEQ ID NO: 9中所闡述之序列之重鏈可變區及包含SEQ ID NO: 24中所闡述之序列之S228P突變型IgG4。重鏈(VHv1)可包含以下闡述之序列。
具有SEQ ID NO: 25中所闡述之序列的重鏈(VHv1)可進一步包含信號肽,且可具有以下闡述之序列。
重鏈(VHv2)可包含以下序列:
重鏈(VHv2)亦可包含以下序列:
抗Siglec-10抗體可包含有包含SEQ ID NO: 9或25中所闡述之序列之重鏈,及包含SEQ ID NO: 15或27中所闡述之序列之輕鏈(VHv1VLv2)。在一個實例中,抗Siglec-10抗體可包含有包含SEQ ID NO: 25中所闡述之序列之重鏈,及包含SEQ ID NO: 27中所闡述之序列之輕鏈。抗Siglec-10抗體可包含有包含SEQ ID NO: 10或32中所闡述之序列之重鏈,及包含SEQ ID NO: 15或27中所闡述之序列之輕鏈(VHv2VLv2)。在一個實例中,抗體包含有包含SEQ ID NO: 32中所闡述之序列之重鏈及包含SEQ ID NO: 27中所闡述之序列之輕鏈。抗Siglec-10抗體可包含有包含SEQ ID NO: 10或32中所闡述之序列之重鏈,及包含SEQ ID NO: 16或34中所闡述之序列之輕鏈(VHv2VLv3)。在一個實例中,抗體包含有包含SEQ ID NO: 32中所闡述之序列之重鏈及包含SEQ ID NO: 34中所闡述之序列之輕鏈。
3. 雙特異性抗體組合物
本發明亦提供雙特異性抗體,其包含與Siglec-10結合之抗體,該抗體橋接至結合其他免疫刺激、靶向免疫細胞或靶向癌症之分子之抗體。在特定實施例中,雙特異性抗體包含抗Siglec-10抗體或其抗原結合片段,及靶向癌症之抗體或其抗原結合片段。此類分子將在腫瘤微環境中富集。所包括之靶向癌症之抗體可為特異性T-抗原、TN-抗原、以不同方式醣基化的黏蛋白、CD24、her-2或PMSA。
在另一實施例中,抗Siglec-10雙特異性抗體可包含靶向互補抗腫瘤途徑或機制之第二抗體或其抗原結合片段。在一個實施例中,本文所描述之抗Siglec-10抗體組合物可與增強自然免疫反應之癌症免疫療法抗體組合。此類癌症免疫療法抗體之實例包括抗PD-1、抗CTLA-4、抗PD-L1、抗B7-H3、抗B7-H4、抗LIGHT、抗LAG3、抗TIM3、抗TIM4、抗CD40、抗OX40、抗GITR、抗BTLA、抗CD27、抗CD47、抗ICOS或抗4-1BB。此類抗體可用於治療癌症。
此項技術中已知多種不同的雙特異性抗體技術。其中大部分需要雙組分抗體呈單鏈形式,使得兩個部分可在單一構築體中表現。較佳方法係以單鏈可變片段(scFv)形式表現抗體。雙特異性抗體技術之非限制性實例包括BiTE (雙特異性T細胞接合子),DART (雙親和力再靶向),Fabs串聯免疫球蛋白(Fabs-in-tandem immunoglobulin;FIT-Ig),以及杵臼結構(knobs-in-to-holes)。
治療方法
本發明提供本文所述之抗體組合物及其醫藥組合物的用途,其係用於治療癌症。如本文所使用,術語「癌症」係指由細胞之異常不受控生長產生之贅瘤或腫瘤。如本文所使用,癌症明確地包括白血病及淋巴瘤。該術語係指涉及具有轉移至遠端位點之潛力之細胞之疾病。
本文提供一種治療有需要之個體中之癌症或異常增生性疾病的方法,其可包含向個體投與抗體組合物。個體可為哺乳動物,諸如犬、貓、豬、馬、牛、猴、猿或人類。在一個實例中,個體為人類患者。亦提供包含抗體組合物之醫藥組合物,其係用於治療癌症或異常增生性疾病。亦提供抗體組合物的用途,其係用於製造用以治療癌症或異常增生性疾病之藥劑。在一個實例中,抗體組合物係作為單藥療法使用,其可促進巨噬細胞、ADCC及抗體依賴性細胞吞噬作用(ADCP)中之一或多者對癌細胞的吞噬作用。
癌症可為(但不限於)以下中之一或多者:癌瘤,包括膀胱、乳房、結腸、腎臟、肝臟、肺、卵巢、胰臟、胃、子宮頸、甲狀腺及皮膚之癌瘤;包括鱗狀細胞癌;淋巴系造血組織腫瘤,包括白血病、急性淋巴球性白血病、急性淋巴母細胞白血病、B細胞淋巴瘤、T細胞淋巴瘤、伯克特淋巴瘤(Berketts lymphoma);骨髓系造血組織腫瘤,包括急性及慢性骨髓性白血病及早幼粒細胞白血病;間質源性腫瘤,包括纖維肉瘤及橫紋肌肉瘤;其他腫瘤,包括黑色素瘤、精原細胞瘤、四聯細胞瘤、神經母細胞瘤及膠質瘤;中樞及周邊神經系統之腫瘤,包括星形細胞瘤、神經母細胞瘤、膠質瘤及分裂瘤;間質來源腫瘤,包括纖維肉瘤、橫紋肌肉瘤及骨肉瘤;及其他腫瘤,包括黑色素瘤、著色性乾皮病、角化棘皮瘤、精原細胞瘤、甲狀腺濾泡癌及畸胎癌。特定言之,癌症可為乳癌、三陰性乳癌、卵巢癌或本文揭示之白血病。癌症可包括與抗Siglec-10抗體結合之浸潤細胞。
癌症可為晚期實體腫瘤。晚期實體腫瘤可在接受標準治療型全身療法後發展。癌症可為肺腺癌(LUAD)、皮膚黑色素瘤-轉移(SKCM-TM)、肺鱗狀細胞癌(LUSC)、乳房侵襲性癌瘤-基底、乳房侵襲性癌瘤-Her2、胰臟腺癌、頭頸鱗狀細胞癌、腎臟透明細胞癌、胃腺癌、多形性膠質母細胞瘤、乳房侵襲性癌瘤-LumB或乳房侵襲性癌瘤-LumA、非小細胞肺癌、膠質母細胞瘤、黑色素瘤、低級別膠質瘤、腎癌、基底型乳癌、Her2+乳癌、胰臟癌或卵巢癌。在一個實施例中,癌症為LUAD、SKCM-TM或LUSC。特定言之,癌症可為非小細胞肺腺癌。癌症亦可為惡性血液病,其可為白血病、骨髓發育不良症候群、B細胞淋巴瘤或多發性骨髓瘤。
癌症可由細胞凋亡異常引起,且亦可藉由本文所述之方法及組合物來治療。癌症可為(但不限於)以下中一或多者:濾泡性淋巴瘤;具有p53突變之癌瘤;乳腺、前列腺或卵巢之激素依賴性腫瘤;以及癌前病變,諸如家族性腺瘤性息肉病或骨髓發育不良症候群。在特定實施例中,藉由本發明之方法及組合物來治療或預防卵巢、膀胱、乳房、結腸、肺、皮膚、胰臟或子宮中之惡性疾病或增殖異常改變(諸如化生及發育不良)或過度增殖病症。在其他特定實施例中,藉由本發明所述之方法及組合物來治療或預防肉瘤、黑色素瘤或白血病中之一或多者。
在另一實施例中,抗體組合物係與一或多種其他抗腫瘤療法組合使用,包括(但不限於)當前標準及實驗性化學療法、激素療法、生物療法、免疫療法、放射療法或手術。在一些實施例中,抗體組合物係與治療或預防有效量之一或多種藥劑、治療性抗體或熟習此項技術者已知之用於癌症、自體免疫疾病、傳染病或中毒之治療及/或預防之其他藥劑組合投與。此類藥劑包括例如以上論述之生物學反應調節劑、細胞毒素、抗代謝物、烷基化劑、抗生素或抗有絲分裂劑以及免疫治療劑中之任一者。
在本發明之較佳實施例中,抗體組合物係與一或多種抗腫瘤免疫療法一起使用。抗腫瘤免疫療法可為干擾或增強一或多種替代性免疫調節途徑(諸如TIM3、TIM4、OX40、CD40、GITR、4-1-BB、PD-L1、PD-1、B7-H3、B7-H4、CTLA-4、LIGHT、BTLA、ICOS、CD27、CD47、TIGIT或LAG3)或調節效應分子(諸如細胞介素(例如IL-4、IL-7、IL-10、IL-12、IL-15、IL-17、GF-β、IFNg、Flt3、BLys)及趨化介素(例如CCL21))之活性以便增強免疫調節作用的分子。在另一實施例中,抗體組合物係與一或多種活化免疫反應之不同階段或態樣的分子組合投與,以實現更廣泛的免疫反應。在更佳實施例中,抗體組合物與抗PD-1或抗4-1BB抗體相結合,而不加劇自體免疫副作用。
抗體組合物可與靶向腫瘤之抗體一起使用。靶向腫瘤之抗體可為任何引起ADCC或ADCP中之一或多者之抗體。靶向腫瘤之抗體可為西妥昔單抗(艾必妥(Erbitux))、利妥昔單抗(rituximab)(美羅華(Rituxan))、曲妥珠單抗(trastuzumab)(赫賽汀(Herceptin))或達雷妥尤單抗(daratumumab)(達拉蘭西(Darzalex))。抗體組合物亦可與靶向宿主細胞之免疫療法一起使用,該療法可為抗CTLA-4抗體。抗CTLA-4抗體為此項技術中已知的。抗CTLA-4抗體可揭示於美國專利第10,618,960號中,該案之內容以引用的方式併入本文中。在一個實例中,抗CTLA-4抗體具有包含SEQ ID NO: 21之重鏈可變區及包含SEQ ID NO: 22之輕鏈可變區。抗CTLA-4抗體輕鏈可進一步包含有包含SEQ ID NO: 29之恆定區,且重鏈可進一步包含有包含SEQ ID NO: 30或31之恆定區。在另一實例中,抗CTLA-4抗體具有重鏈,其包含有包含SEQ ID NO: 21之可變區及包含SEQ ID NO: 31之恆定區;及輕鏈,其包含有包含SEQ ID NO: 22之可變區及包含SEQ ID NO: 29之恆定區。
製備
本文所述之抗Siglec-10抗體可使用真核表現系統製備。表現系統可能需要自哺乳動物細胞(諸如中國倉鼠卵巢(Chinese Hamster Ovary;CHO)細胞)中之載體表現。系統亦可為病毒載體,諸如可用於感染真核細胞之複製缺乏型反轉錄病毒載體。抗體亦可由穩定細胞株產生,該穩定細胞株自載體或已整合於細胞基因體中之載體之一部分表現抗體。穩定細胞株可自經整合之複製缺乏型反轉錄病毒載體表現抗體。
可使用例如層析法(諸如親和層析法、離子交換層析法、疏水相互作用層析法、DEAE離子交換法、凝膠過濾法及羥磷灰石層析法)來純化本文所描述之抗Siglec-10抗體或其抗原結合片段。在一些實施例中,融合蛋白可經工程改造以含有額外的域,該額外的域含有允許將多肽捕獲於親和基質上之胺基酸序列。舉例而言,本文所述之包含免疫球蛋白域之Fc區的抗體可使用蛋白質A管柱自細胞培養物上清液或細胞質提取物分離。此外,可使用標籤(諸如c-myc、血球凝集素、聚組胺酸或Flag™ (Kodak))來輔助多肽純化。此類標籤可插入多肽內之任何位置,包括羧基端或胺基端。可適用之其他融合物包括有助於偵測多肽之酶,諸如鹼性磷酸酶。免疫親和層析亦可用於純化多肽。
醫藥組合物
本發明提供醫藥組合物,其包含治療有效量之一或多種本文所述之抗Siglec-10抗體及組合物,以及生理學上可接受之載劑或賦形劑。醫藥組合物可包含預防或治療有效量之抗Siglec-10抗體及醫藥學上可接受之載劑。
在特定實施例中,術語「醫藥學上可接受」意謂經聯邦政府或州政府之管制機構批准或在美國藥典(U.S. Pharmacopeia)或其他公認之藥典中列出適用於動物且更特定言之,適用於人類。術語「載劑」係指與治療劑一起投與之稀釋劑、佐劑(例如,弗氏佐劑(Freund's adjuvant) (完全及不完全)、賦形劑或媒劑。此類醫藥載劑可為無菌液體,諸如水及油,包括石油、動物、植物或合成來源之載劑,諸如花生油、大豆油、礦物油、芝麻油及其類似物。當靜脈內投與醫藥組合物時,水為較佳載劑。亦可使用生理鹽水溶液及右旋糖水溶液及甘油溶液作為液體載劑,尤其用於可注射溶液。適合的醫藥賦形劑包括澱粉、葡萄糖、乳糖、蔗糖、明膠、麥芽、稻穀、麵粉、白堊、矽膠、硬脂酸鈉、甘油單硬脂酸酯、滑石、氯化鈉、無水脫脂牛奶、甘油、丙烯、二醇、水、乙醇及其類似物。若需要,組合物亦可含有少量濕潤劑或乳化劑或pH緩衝劑。此等組合物可呈溶液、懸浮液、乳液、錠劑、丸劑、膠囊、散劑、持續釋放調配物及其類似物之形式。
一般而言,醫藥組合物之成分可分開供應或混合在一起以單位劑型供應,例如以乾燥的凍乾粉末或無水濃縮物形式於指示活性劑之量之氣密密封式容器(諸如安瓿或藥囊)中供應。在欲藉由輸注來投與組合物的情況下,其可用含有無菌醫藥級水或生理鹽水之輸注瓶來施配。當藉由注射來投與組合物時,可提供具有注射用無菌水或生理鹽水之安瓿,以使得可在投與前混合該等成分。
醫藥組合物可調配為中性或鹽形式。醫藥學上可接受之鹽包括(但不限於):用陰離子形成之鹽,諸如衍生自鹽酸、磷酸、乙酸、草酸、酒石酸等之鹽;及用陽離子形成之鹽,諸如衍生自鈉、鉀、銨、鈣、氫氧化鐵、異丙胺、三乙胺、2-乙胺基乙醇、組胺酸、普魯卡因(procaine)等之鹽。
醫藥組合物可包含組胺酸緩衝液、蔗糖及聚山梨醇酯80 (PS80)中之一或多者或全部。在一個實例中,醫藥組合物包含約15、16、17、18、19、20、21、22、23、24或25 mM組胺酸緩衝液。特定言之,組胺酸緩衝液之濃度可為20 mM。醫藥組合物可包含約6、7、8、9或10% w/v蔗糖。在一個實例中,醫藥組合物包含8%蔗糖。醫藥組合物可包含約0.01、0.02或0.03% PS80。在一個實例中,PS80濃度為0.02%。在一個實例中,醫藥組合物包含20 mM組胺酸緩衝液、8%蔗糖及0.02% w/v PS80。醫藥組合物可具有約5、5.5或6.0之pH。在一個實例中,pH為5.5。在投與個體前,醫藥組合物可在0.9%氯化鈉或5%葡萄糖溶液中稀釋。
抗Siglec-10抗體,其可為ONC-841,可以約10、15、20、25或30 mg/mL存在於醫藥組合物中。抗Siglec-10抗體可以約1、2、3、4、5、6、7、8或9 mg/kg之劑量投與。劑量可低於10 mg/kg。在一個實例中,劑量為3-9 mg/kg。在另一實例中,劑量為3 mg/kg。若個體出現與抗體組合物之投藥有關之不良反應,則可自先前劑量下調後續劑量。若抗體組合物對癌症沒有足夠強的效果,則可自先前劑量上調後續劑量。
投與方法
本文所述之抗Siglec-10抗體組合物及其醫藥組合物之投與方法包括(但不限於)腸胃外投與(例如皮內、肌內、腹膜內、靜脈內及皮下)、硬膜外投與及黏膜投與(例如鼻內及經口途徑)。在特定實施例中,肌內、靜脈內或皮下投與本發明之抗體。組合物可藉由任何便利途徑投與,例如藉由輸注或推注注射、藉由經上皮或黏膜皮膚內層(例如,口腔黏膜、直腸及腸黏膜等等)吸收,且可與其他生物學活性劑一起投與。投藥可為全身或局部的。
實例
本發明具有藉由以下非限制性實例說明之多個態樣。
實例 1 單株抗 Siglec - 10 抗體之產生
為產生拮抗劑,用Siglec-10轉染之小鼠細胞株使小鼠免疫,在三次免疫後,收集脾細胞以用於產生融合瘤。針對逆轉Siglec-10在ADCC中之抑制作用的活性來篩選融合瘤上清液,其係使用表現人類FcγRIIIa的效應細胞量測。在超過20,000種純系中,發現一種純系(31F11)在逆轉Siglec-10之抑制方面最有效(圖1)。與另一種抗Siglec-10抗體(10H3及5G6)相比,31F11對Siglec-10功能的拮抗作用更強。
為了確認31F11之特異性,吾人用由Siglec 1、2、3、5、6、7、9、10及11之細胞外域組成的融合蛋白塗佈盤,且測試3F11與此等Siglec之結合。如圖2中所示,僅Siglec-10顯示與31F11之明顯結合。作為替代方法,吾人用GFP標記之Siglec 2、3、5、9、10、12及15轉染293T細胞株。如圖3中所示,31F11與表現Siglec-10之細胞特異性結合,但不與所測試的表現任何其他Siglec之細胞結合。綜合而言,圖2及圖3中之資料表明,31F11與Siglec-10結合,但不與Siglec 1、2、3、5、6、7、9、11、12及15結合。
實例 2 抗 Siglec10 抗體阻斷 Siglec - 10 - Fc 與脾細胞之結合
為了確認31F11是否阻斷Siglec-10與其配位體之結合,吾人測試31F11對Siglec-10-Fc與小鼠脾細胞之結合的影響。如圖4中所示,在阻斷Siglec-10-Fc與脾細胞之結合方面,31F11比其他抗Siglec-10抗體(5G6及10H3)更有效。
實例 3 抗 siglec - 10 抗體吞噬作用分析法
為了測試抗Siglec-10是否促進巨噬細胞對癌細胞之吞噬作用,用補充有40 ng/ml M-CSF之RPMI-1640培養基刺激自末梢血液分離的人類單核球5-7天。隨後用50 ng/ml TGFβ1及IL10誘導M2巨噬細胞,持續24小時。用CellTracker™紫色BMQC染料標記MCF-7細胞,且與供體衍生之巨噬細胞在指定濃度的抗Siglec-10抗體存在下共同培養2小時。藉由流式細胞分析技術來確定經歷吞噬作用之巨噬細胞的百分比。如圖5中所示,31F11使吞噬作用增加超過一倍,而其他抗Siglec-10抗體效果並不顯著。因此,31F11之獨特性在於促進吞噬作用。
實例 4 與抗 hCD24 抗體組合之抗腫瘤活性
由於31F11在活體外促進ADCC,吾人假設該抗體在與靶向腫瘤細胞之抗體組合使用時可促進腫瘤排斥。為了測試此假設,將1×10
6個MC38-hCD24細胞接種至S10 BM嵌合小鼠(n-4-5)上。在第7、10、13及16天用100 μg hIgFc、α-hCD24、31F11 (αS10)或α-hCD24+ 31F11治療小鼠。如圖6中所示,抗CD24與31F11之組合(但並非單獨的任一者)在所有受體小鼠中誘導腫瘤排斥。此等資料支持在腫瘤排斥中使用抗Siglec-10抗體。
實例 5 用於癌症療法之 31F11 的人類化
藉由檢索人類Ig資料庫,使用人類生殖系V區序列IGHV2-70*04及J區序列JH6作為31F11 VH之CDR區的人類構架受體。使用人類生殖系V區IGKV3-15*01及J區序列JK4作為31F11 VL之CDR區的人類構架受體。設計5個huVH版本(VHv1、VHv2、VHv3、VHv4及VHv5,具有SEQ ID NO: 9-13)及5個huVL版本(VLv1、VLv2、VLv3、VLv4及VLv5,具有SEQ ID NO: 14-18)。
為選擇用於Siglec-10結合之HuVH與HuVL之最佳工作組合,在表現構築體中合成編碼重鏈及輕鏈之DNA,且將不同的組合共同轉染至293細胞中,比較7種人類化抗體及嵌合親本抗體之與表現人類Siglec-10之Jurkat細胞的結合。表2概述純系之特性。
表2 31F11之特徵化人類化純系
產量 (mg/ml) | Rk | Tm1 | Tm2 | ADCC EC50 (ng/ml) | Rk | 結合 EC50 (ng/ml) | Rk | ka (1/Ms) | Rk | kd (1/s) | Rk | KD (M) | Rk | |||
嵌合 | 12.64 | 65.8 | N/A | 94.44 | 210.8 | 3.13E+05 | 5.02E-04 | 1.61E-09 | ||||||||
21# | 9.98 | 2 | 63.7 | 78.5 | 7 | 153.3 | 1 | 242.4 | 4 | 2.72E+05 | 2 | 5.89E-04 | 5 | 2.17E-09* | 4 | |
22# | 14.83 | 1 | 63.8 | 78.5 | 6 | 265.7 | 5 | 237.1 | 2 | 1.64E+05 | 3 | 2.02E-04 | 2 | 1.23E-09 | 2 | |
23# | 9.73 | 3 | 64.0 | 80.6 | 5 | 342.4 | 7 | 237.3 | 3 | 1.31E+05 | 4 | 1.97E-04 | 1 | 1.50E-09 | 3 | |
32# | 6.62 | 5 | 66.9 | N/A | 2 | 182.6 | 3 | 422.7 | 7 | |||||||
34# | 2.99 | 7 | 64.4 | 71.7 | 4 | 273 | 6 | 365.3 | 6 | |||||||
52# | 5.56 | 6 | 66.6 | N/A | 3 | 157.2 | 2 | 228 | 1 | 4.41E+05 | 1 | 3.70E-04 | 4 | 8.40E-10 | 1 | |
54# | 7.72 | 4 | 69.1 | N/A | 1 | 261.8 | 4 | 322.7 | 5 | 9.87E+04 | 5 | 2.15E-04 | 3 | 2.18E-09 | 5 | |
標有「Rk」之各行表示前一行中之各參數之相對排名。 * 因為此量測使用單獨實驗之資料,所以相對排名之可信度不高。 |
抗體組合如下:#21 (SEQ ID NO: 9及15)、#22 (SEQ ID NO: 10及15)、#23 (SEQ ID NO: 11及15)、#32 (SEQ ID NO: 10及17)、#34 (SEQ ID NO: 12及17)、#52 (SEQ ID NO: 10及16),及#54 (SEQ ID NO: 12及16)。其中,親本抗體之EC50為210 ng/ml,而人類化抗體之EC50在228 ng/ml與423 ng/ml之間(圖7)。此表明所有的抗體均顯示出與細胞表面Siglec-10之強力結合。熱穩定性分析表明,所有人類化抗體均呈現良好的熱穩定性(圖8)。使用Biacore分析,吾人量測5個等級靠前之抗體的親和力。如表2中所示,所有測試之5種抗體均顯示出與Siglec-10的高親和力結合。特定言之,五種抗體中之三種(#22、#23及#52)比嵌合親本純系的親和力更高。
為了測試生物學功能,吾人比較7種mAb與親本嵌合抗體之恢復ADCC活性之能力。如圖9中所示,在所有測試的純系中均偵測到強ADCC。
實例 6 抗 Siglec - 10 抗體之臨床前研究
臨床前研究表明,抗CTLA-4 mAb之治療功效係歸因於腫瘤內Treg的消耗,而其毒性係歸因於CTLA-4之下調。感興趣的是,將抗CTLA-4與可增加抗CTLA-4之ADCC的藥物組合。Siglec-10已成為有前景之標靶,因為吾人已證明Siglec-10為ADCC的負調節劑,包括藉由抗CTLA-4觸發之ADCC (圖10)。抗Siglec-10 mAb,31F11係基於其增強癌細胞之ADCC (圖11)及吞噬作用(圖12)的能力而開發。藉此開發用於治療人類癌症之抗體的人類化版本,命名為ONC-841。
綜合而言,Siglec-10之拮抗劑可藉由兩種獨特的機制來促進抗腫瘤免疫。首先,其可不活化DNEMS以促進腫瘤細胞之吞噬作用。其次,藉由ADCC之負調節劑之不活化,拮抗劑可增強基於ADCC之治療性抗體的治療活性。
作用機制
累積的資料表明,Siglec-10為吞噬作用、ADCC及ADCP之負調節劑。因此,ONC-841作為單藥療法或組合療法均可增強腫瘤排斥。
單藥療法
作為單藥療法,ONC-841藉由阻斷Siglec-10-CD24 DNEMS相互作用來促進腫瘤排斥,如圖13所示。此機制對於過度表現CD24或其他高親和力Siglec-10配位體之癌症應為活性最強的。現已知曉,約70%之所有人類癌症過度表現CD24且其表現與不良預後相對應。此外,Siglec-10亦在腫瘤相關巨噬細胞(TAM)中大量表現。預計ONC-841可在針對大多數癌症類型(包括非小細胞肺癌)之先天性免疫中具有廣泛影響。
組合療法
由於Siglec-10對ADCC及ADCP具有負調節作用,ONC-841與藉由ADCC及ADCP來實現抗腫瘤活性之藥物協同工作。此類藥物可靶向癌細胞(例如艾必妥、利妥昔單抗),或靶向宿主細胞(例如抗CTLA-4抗體)。Siglec-10負調節ADCC/ADCP,而CD24能夠負向傳訊Siglec-10以抑制ADCC/ADCP,資料顯示Siglec-10可識別非CD24配位體。因此,ONC-841可用於以與CD24表現無關之方式增強腫瘤類型的宿主或癌細胞的消耗。圖13說明ONC-841與抗CTLA-4 (諸如ONC-392)組合使用以增強TME中之Treg消耗之機制,亦即,藉由阻斷Siglec-10之負向傳訊。
實例 7 抗 Siglec - 10 抗體之藥理學及毒理學 活體外藥理學 ONC - 841 之特異性
為了確認ONC-841之結合特異性,吾人藉由ELISA來測試其與其他人類Siglec重組蛋白的結合。將具有His或Fc標籤之不同的Siglec細胞外域重組蛋白塗佈於ELISA盤上。添加經生物素標記的ONC-841以偵測與所塗佈的Siglec蛋白之結合。使用Avidin-HRP作為二級抗體以進行偵測。如圖14A及圖14B所示,ONC-841與Siglec 10強效結合,其中Kd為約0.02247 µg/mL,但不與所有其他測試的Siglec,包括Siglec 1-9、11、14及15結合。ONC-841在高濃度下顯示出與Siglec-5Fc、Siglec-6Fc、Siglec-11Fc及Siglec-14Fc之一些結合。為了闡明該結合是否對Siglec重組蛋白具有特異性或係與Fc為非特異性結合,吾人使用人類IgG1 Fc (hIgG1Fc)作為對照。結果顯示,ONC-841與Siglec-5Fc、Siglec-6Fc、Siglec-11Fc及Siglec-14Fc之結合係歸因於與Fc標籤的非特異性結合,因為其結合性與hIgGFc類似(圖14B)。
ONC - 841 阻斷 Siglec - 10 與其在人類惡性 Jurkat 細胞及 活體外 分化之調節性 T 細胞上之配位體的相互作用
Siglec蛋白識別細胞表面上的唾液酸化蛋白,對α2,6唾液酸化之偏好超過α2,3唾液酸化。為了測試ONC-841是否阻斷Siglec-10與其在惡性細胞上之天然配位體的相互作用,吾人測試ONC-841阻斷Siglec-10Fc與人類白血病Jurkat細胞株之結合之能力。由Siglec-10Fc-生物素與鏈黴抗生物素蛋白-PE (SA-PE)以4:1之莫耳比預先複合1小時,且隨後添加至不同濃度之ONC-841中保持5分鐘。基於Siglec-10Fc-生物素之濃度,將混合物以10 µg/mL之濃度添加至Jurkat-CTLA4細胞中,在室溫下培育一小時。將細胞充分洗滌以移除過量的未結合之試劑,且藉由流式細胞儀來收集。在排除死細胞後進行分析。如圖15所示,Siglec-10Fc與Jurkat細胞株強效結合,且此結合被ONC-841以劑量依賴性方式阻斷。估計IC50為2 µg/mL(13.3 nM)。
為了測試ONC-841對Siglec-10Fc-生物素與正常宿主細胞之結合之影響,吾人使用螢光Siglec-10Fc四聚體且使用上述相同的方法評估ONC-841之作用。吾人專注於Treg,以支持吾人提出之組合療法。Treg係由來自新鮮的PBMC分離之未經處理之CD4 T細胞分化。如圖16所示,Siglec-10Fc顯示與活體外分化之人類Treg之明顯結合。Siglec-10Fc與Tregs之相互作用被ONC-841以劑量依賴性方式阻斷。估計IC50為3.57 µg/mL (23.8 nM)。
ONC - 841 促進兩種靶向癌症之抗體之 ADCC 報導子活性
測試ONC-841促進靶向癌症之抗體之ADCC活性的能力,包括彼等靶向CD20、CTLA-4及表皮生長因子受體(EGFR)之抗體。利用Promega的ADCC報導子分析法,吾人藉由偵測在FcγRIIIA在靶向癌症之抗體存在下活化時,由效應細胞中之NFAT表現之發光來量測ADCC活性。簡而言之,將靶細胞與ADCC效應細胞、模擬轉移的ADCC效應細胞(ADCC-Mock)或表現人類Siglec-10之ADCC細胞(ADCC-hSiglec10)共同培育。以固定濃度添加靶向腫瘤之抗體及經滴定的ONC-841 mAb。量測相對發光單位(RLU)。如圖17A所示,ONC-841促進抗CD20對Raji淋巴瘤細胞株之ADCC活性,其中EC50為0.5 μg/ml。為了測試ONC-841對實體腫瘤之影響,吾人使用表現人類EGFR的B16黑色素瘤細胞株,且使用抗EGFR藥物西妥昔單抗來觸發ADCC。如圖17B所示,ONC-892幾乎使西妥昔單抗之ADCC活性倍增,其中EC50為0.3 μg/ml。為了支持吾人的組合療法試驗設計,吾人測試ONC-841促進ONC-392之ADCC之功效。如圖17C所示,ONC-841增強ONC-392之ADCC活性,其中IC50為0.08 μg/ml。與ONC-392之組合之EC50最低的事實支持吾人在早期臨床試驗中選擇ONC-392作為組合搭配物,且廣泛的活性證實在惡性血液病及實體腫瘤兩者中使用ONC-841與靶向癌症之抗體之組合療法之潛力。
ONC - 841 促進人類 NK 細胞對白血病細胞之 ADCC 及非抗體依賴性殺傷
為了測試ONC-841對NK細胞殺傷腫瘤細胞之影響,吾人使用經CTLA-4轉染之Jurkat細胞作為靶細胞,且使用新分離的人類NK細胞作為效應細胞。簡而言之,將經鈣黃綠素AM標記之Jurkat-CTLA-4靶細胞與來自新鮮全血的陰性選擇的人類NK細胞及經滴定的ONC-841 mAb在存在或不存在固定濃度之ONC-392之情況下共同培育6小時。在培育後,藉由流式細胞分析技術來分析細胞。基於與對照物相比之剩餘的鈣黃綠素AM+活細胞之數量計算細胞死亡百分比。如圖18A-圖18C中所示,ONC-841在不存在靶向腫瘤細胞之抗體的情況下增強NK介導之Jurkat細胞之細胞殺傷,其中估計EC50為0.3744 μg/ml。在存在飽和量的ONC-392 (20 μg/ml)之情況下,ONC-841進一步增強NK細胞活性,其中估計EC50為2.274 μg/ml。因此,ONC-841促進NK細胞對惡性白血病細胞之ADCC及非抗體依賴性細胞溶解。
ONC - 841 促進 人類 PBMC 之人類腫瘤細胞殺傷
Siglec-10主要表現於骨髓細胞上。因此,ONC-392之影響將很可能會延伸超出NK細胞。為更全面地理解抗腫瘤效果,吾人測試ONC-841對自3名個別供體之新鮮全血分離的PBMC之白血病細胞溶解的影響。將經鈣黃綠素AM標記的Jurkat-CTLA-4靶細胞與自新鮮全血分離之PBMC及經滴定的ONC-841 mAb共同培育。在培育後,藉由流式細胞分析技術來分析細胞。基於與對照物相比之剩餘的鈣黃綠素AM+活細胞之數量計算細胞死亡百分比。如圖19所示,在低劑量之ONC-841下實現明顯的溶解,其中供體1、供體2及供體3之估計的EC50分別為0.3645、0.01761及0.009572 μg/ml。此等資料表明,ONC-841可在不存在靶向白血病之抗體之情況下促進白血病殺傷。
活體內藥理學研究
為了測試ONC-841在動物模型中之治療活性,吾人製備轉殖基因小鼠模型,在該模型中吾人分別藉由Siglecg基因之靶向突變及插入含有人類Siglec-10的桿狀病毒質體純系(Bacmid clone)來移除小鼠Siglec-G及插入其人類Siglec-10異種同源物(參見下文)。由於Siglec-10在轉殖基因小鼠中之組織分佈與其在人類白血球中的分佈一致,吾人使用此模型來測試在兩種不同的模型中ONC-841對腫瘤排斥之影響。
單藥療法及與 靶向癌症之抗體之 組合療法
為了評估對實體腫瘤之治療效果,吾人使用表現人類EGFR的B16F10細胞株。在腫瘤細胞攻擊之後6天,用對照IgG、ONC-841或ONC-841+西妥昔單抗治療帶有腫瘤之小鼠,且盲式量測腫瘤生長。在腫瘤接種之後第6天開始,每三天一次以腹腔內方式用200 μg對照hIgGFc或ONC-841及以瘤內方式用10 μg對照hIgGFc或西妥昔單抗治療帶有B16-EGFR腫瘤(s.c.)之
Siglec10TG +/+ ;
Siglecg -/- 小鼠(n=4-5)持續四次注射。如圖20所示,瘤內注射西妥昔單抗之效果最小,而使用ONC-841之單藥療法則實現腫瘤生長的部分阻滯。以組合方式,實現更明顯的腫瘤生長阻滯。此等資料表明,ONC-841對小鼠模型中之實體腫瘤具有治療活性。
為了測試腫瘤體積減少50%所需之ONC-841的量,吾人在組合療法模型中滴定ONC-841之劑量。西妥昔單抗之瘤內治療劑量固定為每次注射10 μg,而全身性ONC-841之劑量為5、10及20 mg/kg。簡而言之,將5×10
5個B16-EGFR腫瘤細胞(s.c.)注射至
Siglec10TG +/+ ;
Siglecg -/- 小鼠(n=4-5)中且當腫瘤直徑達到4-7 mm時開始治療。每三天一次以腹腔內方式用2.5、10或20 mg/kg ONC-841治療帶腫瘤之小鼠且瘤內注射10 μg hIgFc或西妥昔單抗持續四次注射。如圖21所示,實現腫瘤體積之ONC-841劑量依賴性減少。使用線性回歸分析,確定ONC-841之EC50為16.49 mg/kg。
與抗 CTLA - 4 抗體之組合療法
作為顯示ONC-841與靶向宿主之免疫治療抗體之組合效果的模型,吾人使用未經修飾之B16F10模型及抗小鼠CTLA-4 mAb,即9D9。如圖22所示,9D9與ONC-841均未引起腫瘤生長阻滯。然而,以組合方式,觀測到腫瘤生長之顯著減少。
藥理學 相關物種 ONC - 841 不 與小鼠及非人類靈長類動物 Siglec G / 10 反應。
已知Siglec蛋白可快速演化且在來自不同物種之異種同源物之間具有有限的同源性。人類Siglec-10與其一些NHP異種同源物具有高類似性:與食蟹獼猴及恆河猴Siglec-10之類似性為90%,而與小鼠Siglec-G之類似性僅為60% (來自:Ensembl.org)。
為了確定哪些動物物種為ONC-841之合適的毒理學物種,吾人在3種分析法中評估ONC-841抗體與NHP Siglec-10或小鼠異種同源物Siglec-G之結合:
A. 與重組Siglec-10/Siglec-G之結合
B. 與短暫表現NHP Siglec-10/Siglec-G之expi293細胞之結合
C. 與食蟹獼猴PBMC之結合
所有分析法均未顯示ONC-841與NHP Siglec-10或小鼠Siglec-G之特異性結合,表明此等物種並未共有ONC-841所結合的特異性抗原決定基。
與來自其他物種之重組 Siglec - 10 / Siglec - G 之 結合
經His標記之重組人類及食蟹獼猴Siglec-10及小鼠Siglec-G係購自ACROBiosystems。將Siglec蛋白塗佈在ELISA盤上作為捕獲抗原。使用山羊抗人類抗體偵測所捕獲的ONC-841。如以下圖23所示,ONC-841顯示出與人類Siglec-10之特異性結合,但不與食蟹獼猴或小鼠蛋白特異性結合。
與經 NHP Siglec - 10 基因轉染之 293T 細胞之結合
分別用人類、食蟹獼猴、恆河猴及狨猴Siglec-10表現質體轉染expi293細胞,以在細胞表面產生此等蛋白。使用流式細胞分析技術在活expi293細胞上評估ONC-841之結合,且使用針對Siglec-10之多株抗體驗證不同Siglec-10蛋白的表現(圖24,淺灰色線)。ONC-841僅顯示與表現人類Siglec-10的細胞結合,而不與任何NHP Siglec-10結合(圖24,深灰色線)。
與食蟹獼猴 PBMC 之 結合
為了測試ONC-841與天然表現之Siglec-10的結合,對人類及食蟹獼猴PBMC進行染色且藉由流式細胞分析技術來評估。Siglec-10由單核球(CD14+細胞)及B細胞(CD20+細胞)表現且因此,在此等群體中測試ONC-841之結合。為了驗證特異性染色且消除ONC-841經由Fc受體之可能的結合,在染色前用過量的人類IgG阻斷各物種之額外細胞樣品。ONC-841明確顯示出與人類單核球及B細胞兩者之高特異性結合,且該結合不受存在過量的人類IgG影響(圖25)。相比之下,ONC-841顯示對食蟹獼猴之兩個細胞亞群的弱結合。此外,過量的人類IgG顯著減少此結合,表明ONC-841與此等NHP Siglec-10之低特異性至非特異性結合特性(圖27)。
產生不具有內源性 Siglecg 基因之 人類 SIGLEC - 10 轉殖基因 小鼠: Siglec10TG +/+ ; Siglecg -/-
由於ONC-841不與來自可用的NHP及小鼠物種之白血球結合,因此NHP及小鼠均不被視為毒性及藥理研究之相關物種。與所測試的NHP相比,其他常用的毒性物種在遺傳學上與人類之差異更大且因此不大可能與毒性研究有關。因此,吾人提出開發用於毒性研究之轉殖基因小鼠模型,其中人類
Siglec10基因取代其小鼠異種同源物
Siglecg。
Siglec10轉殖基因系(在此稱為
Siglec10TG +/+ )係由Cyagen, Inc. (Santa Clara, CA)使用含有人類
Siglec10、
Siglec8及
Siglec12基因之基因體序列的桿狀病毒質體純系自C57/BL6小鼠產生。使用具有人類調節及編碼序列之基因體純系可使小鼠以與人類白血球中之表現方式基本類似的方式表現Siglec10。吾人在此提供之資料支持此假設。此外,為了捕獲活體內阻斷Siglec-10之作用,吾人藉由將轉殖基因雜交至
Siglecg -/- 小鼠中來移除內源性小鼠
Siglecg基因,其中
Siglecg之外顯子2-11由GFP/Neo卡匣取代。
C57BL/6
Siglec10TG +/+ J Siglecg -/- 系為藉由將
Siglec10TG +/+ 與
Siglecg -/- 小鼠雜交而產生的。藉由血球之流式細胞分析技術,針對hSiglec-10及Siglec-G的表現來篩選雜交小鼠之F1及F2代(圖26頂部及中部),以選擇所需的
Siglec10TG + ; Siglecg -/- 之基因型。此染色證實人類Siglec-10之表現及不存在小鼠Siglec-G。資料顯示Siglec-10在>30%之小鼠B細胞、NK細胞、單核球、樹突狀細胞(DC)及嗜中性球中及在小鼠PBMC中之<10%之T細胞中表現。
為了比較在
Siglec10TG +/+ ; Siglecg -/- 中觀測到的ONC-841與血液中之細胞亞群之結合與ONC-841與表現內源性Siglec-10之人類細胞的結合,針對譜系標記及經螢光標記的ONC-841或市售抗Siglec-10抗體對人類PBMC進行染色。如文獻中所報導,圖26底部小圖顯示單核球及B細胞上之ONC-841對Siglec-10之明顯染色,而T細胞未發生明顯的染色。出人意料地,儘管資料顯示ONC-841增強自PBMC分離之NK細胞的ADCC活性(圖26),但血液中之NK細胞(無論CD16陽性或16陰性NK細胞)未發生明顯的染色。一種可能的解釋為人類NK細胞表現較少量之Siglec-10,且當前分析法不敏感。另一個選項為所購買的來自人類PBMC之NK細胞為冷凍的,且經解凍以用於Siglec-10染色。將進一步探究在
Siglec10TG +/+ ; Siglecg -/- 之間觀測到的差異。
對來自
Siglec10TG +/+ ; Siglecg -/- 小鼠之冷凍切片進行免疫組織化學以偵測小鼠組織中的ONC-841結合。簡而言之,將快速冷凍的小鼠組織切片且安裝在載玻片上。對切片進行阻斷,且隨後用1 µg/mL之ONC-841進行探測,接著用經HRP標記之抗人類二級抗體進行偵測。使用產生棕色之DAB作為HRP之色原體受質以目視方式觀測ONC-841的結合,且用蘇木精進行對比染色以目視方式觀測呈藍色之細胞核。載玻片之檢查顯示造血器官及大部分其他組織中的免疫細胞之染色。此為將重複進行之初步實驗,且將由受過訓練的病理學家來檢查切片。染色之實例可見於圖27中。
在來自
Siglec10TG +/+ ; Siglecg -/- 小鼠之大部分組織/器官中之組織駐留白血球上發現Siglec-10的廣泛表現,表明該小鼠模型對於毒性及藥理學研究係有價值的。
活體外細胞介素釋放分析法
已證實某些單株抗體治療劑可誘發一系列可引起患者之不良事件的急性輸注反應,包括細胞介素釋放症候群(CRS)。在分子層面上,CRS之特徵在於投藥後1-2小時TNF-α及IFN-γ水準提高,隨後IL-6、IL-10且有時IL-2及IL-8增加。為了測試單獨或與ONC-392組合的ONC-841誘導CRS之可能性,進行初步細胞介素釋放分析法(CRA)。將不同濃度(至多為2 mg/mL)之ONC-841在存在或不存在ONC-392之情況下塗佈於96孔盤中隔夜。使用市售人類IgG抗體(hIgG)作為陰性對照,且使用CD3_CD28珠粒作為陽性對照。次日,洗滌盤且將來自4個不同健康供體之PBMC添加至孔中。在添加PBMC之後48小時,使用BioLegend之LegendPlex人類炎症集合1 (LegendPlex Human Inflammation Panel 1)(目錄號740809)測試釋放至上清液中的細胞介素且包括IL-1β、IFN-α2、IFN-γ、TNF-α、MCP-1 (CCL2)、IL-6、IL-8 (CXCL8)、IL-10、IL-12p70、IL-17A、IL-18、IL-23及IL-33。用來自4個不同供體之PBMC進行分析法,且結果為來自一個供體之代表性資料(圖29)。在存在或不存在ONC-392之情況下,與在未經塗佈之孔中偵測到的水準相比,ONC-841未誘導細胞介素。僅CD3/CD28珠粒之陽性對照的孔中之細胞介素被誘導。含有市售來源之IgG4的孔中之一些細胞介素亦被誘導。總體而言,資料表明,ONC-841未誘導wPBMC釋放細胞介素,且不會在患者中誘發CRS。
進行額外的活體外分析法以評估在存在或不存在類似濃度之ONC-392之情況下,ONC-841是否能夠誘導正常、休眠人類PBMC釋放細胞介素。根據將預測TGN1412之高CRS風險之方案進行細胞介素釋放分析法。將測試至少10個供體。用單獨的ONC-392進行的實驗證實其不會直接活化T細胞。
實例 8 抗 Siglec - 10 抗體之臨床試驗 適應症
對於第1階段,將招募以組織學或細胞學方式確診患有實體腫瘤之患者,該等患者在公認的標準醫學抗癌療法失效或不耐受後(如根據標準護理規範,諸如NCCN規範)出現進行性局部晚期或轉移性疾病。
對於第2階段,將選擇免疫療法失效之非小細胞肺癌患者進行開放標記研究,以使用西蒙氏兩階段設計(Simon's two stage design)測試臨床功效。
基本原理之概述
如抗PD(L)1及抗CTLA-4抗體在臨床中之成功所例示,緩解腫瘤微環境中之T細胞的抑制之抗體對癌症患者的護理產生變革性影響。該成功突出靶向適應性T細胞免疫性之免疫檢查點的能力。近期研究表明,以抑制NK細胞及巨噬細胞之功能的固有免疫檢查點為目標,可提供改良癌症免疫療法之新方法。此等假定之固有檢查點包括對巨噬細胞及NK細胞之腫瘤細胞吞噬或殺傷進行負調節的途徑。抑制巨噬細胞吞噬作用之分子被統稱為「不要吃我」信號(DNEMS)。在已知的DNEMS中,CD47-SIRPα途徑為癌症免疫治療之主要固有免疫檢查點,且正在臨床研究中積極地測試抗CD47 mAb。
臨床前研究發現,CD24-Siglec-10相互作用為可與CD47-SIRPα途徑競爭之強力DNEMS。CD24-Siglec-10途徑首先由OncoC4之共同發現者揭示為將組織損傷的炎症反應降至最低之固有免疫檢查點[4]。CD24Fc為Siglec-10促效劑,已證實其對病毒性肺炎及病毒性大腸炎發揮保護作用。近期第3階段臨床試驗表明,CD24Fc對住院的COVID-19患者具有顯著保護作用。相比之下,儘管有效臨床前資料表明,靶向此途徑可促進腫瘤細胞吞噬作用,但未在臨床上測試CD24-Siglec-10途徑之拮抗劑。藉由測試抗Siglec-10 mAb,即ONC-841在標準護理療治療劑失效或不耐受之癌症患者中之安全性及有效性,所提出之臨床試驗可填補此重大缺口。
除增強巨噬細胞吞噬腫瘤細胞方面的作用之外,吾人之臨床前研究揭示ONC-841亦促進抗體依賴性細胞介導的細胞毒性(ADCC)。此新發現結果促使吾人測試ONC-841與經由抗體依賴性細胞介導的細胞毒性(ADCC)及/或ADCP來發揮主要功能之藥物(包括靶向癌細胞之抗體及靶向免疫細胞之抗體)之組合。細胞毒性T淋巴球相關蛋白4 (CTLA-4),亦稱為CD152 (分化叢集152),為細胞表面蛋白受體,其與B7-1 (CD80)及B7-2 (CD86)相互作用以確保調節T細胞之正常功能,且保護宿主免患自體發炎性疾病。抗CTLA-4單株抗體(mAb) (諸如已獲批准之抗體伊匹單抗(由Bristol Myers Squibb以YERVOY®出售)已在各種臨床前模型中顯示出強大且廣泛的癌症免疫治療劑效果(CITE),且在臨床上作為單藥療法及與納武單抗(Nivolumab) (抗PD-1,由Bristol Myers Squibb以OPDIVO®出售)之組合療法的一部分使用。然而,CTLA-4單藥療法比抗PD-1/PD-L1療法具有更多的免疫療法相關不良反應(irAEs)。此外,在接受伊匹單抗與納武單抗之組合之黑色素瘤患者中,嚴重irAE (3級及4級)發生率達到55%。嚴重irAE進一步限制癌症患者之耐受劑量。儘管如此,伊匹單抗與抗PD-1納武單抗之組合使多種類型之癌症的反應率及總存活率顯著改良。此外,抗CTLA-4抗體在癌症患者中誘導持久的免疫性。因此,CTLA-4仍然為重要的免疫療法標靶,但在改良抗CTLA-4 mAb之安全性及功效方面仍然存在重大挑戰。
ONC-392為針對CTLA-4之高選擇性、人類化單株IgG1-κ同型抗體。吾人已證實,ONC-392在低pH值下與CTLA-4解離,使其逃避溶酶體降解且再循環至細胞表面。吾人已提供若干條證據證明以下觀點:在Treg消耗及腫瘤排斥方面,pH值敏感性抗體,如ONC-392比非pH值敏感性的伊匹單抗更安全且更有效。
由於抗CTLA-4 mAb之治療功效係歸因於ADCC及/或ADCP對腫瘤內Treg的消耗,而其毒性係歸因於CTLA-4之下調,因此感興趣的是,將ONC-392與ONC-841組合,以觀察是否可由此經由增強ADCC消耗Treg來引起更強的抗腫瘤活性,同時將ONC-392保持在更安全之劑量水準以避免irAE。
Siglec-10已成為免疫療法之有前景的標靶。來自活體外及活體內研究之臨床前研究表明,Siglec-10為ADCC的負調節劑,包括由ONC-392引發之ADCC。吾人基於ONC-841增強ONC-392之ADCC的能力開發ONC-841。吾人已在動物模型中證實,ONC-841增強抗CTLA-4 mAb誘導之腫瘤排斥反應。
綜合而言,作為Siglec-10之拮抗劑,ONC-841可藉由兩種獨特的機制來促進抗腫瘤免疫性。首先,其可不活化DNEMS以促進腫瘤細胞之吞噬作用。其次,藉由阻斷ADCC中經由Siglec-10之負傳訊,ONC-841可增強基於ADCC之治療性抗體的治療活性。為了充分利用此等生物活性及治療潛力,設計當前研究以評估作為單藥療法之ONC-841及ONC-841與ONC-392之組合在晚期或轉移性實體腫瘤患者中之安全性、藥代動力學及功效。
研究設計之概述
在患有晚期/轉移性實體腫瘤之參與者中,進行作為單一藥劑之ONC-841及其與ONC-392之組合之靜脈內(IV)投藥的1/2階段開放標記劑量遞增研究。
1A 階段 , 劑量發現研究
1A階段研究由分別定義單藥療法(A部分)及組合療法(B部分)之RP2D的兩個部分組成:
(1) A部分:單藥療法劑量遞增,以定義單藥療法之所建議的第2階段劑量(RP2D-M)。ONC-841之劑量遞增將招募未用ONC-392治療的各種組織學類型之晚期癌症患者。將測試六種水準之ONC-841,其中將根據GLP毒性資料確定起始劑量。每21天一次(q3w)藉由IV輸注來投與ONC-841。該研究將使用患者內劑量遞增直至次最高劑量,屆時將過渡至3+3設計。六名患者將被納入最終劑量水準,其中若在2名或更多的患者中觀測到DLT,則可選擇降低劑量。當6名患者中少於2名出現DLT時,將RP2D-M確定為最高劑量水準。
(2) B部分:組合療法劑量研究,以確定ONC-841與3.0、6.0或10.0 mg/kg之ONC-392之組合的所建議的第2階段劑量(RP2D-C)。第一劑量將比RP2D-M低一個劑量級別,與ONC-392組合,q3w。遵循3+3設計,第一群組將納入三名患者。若未觀測到DLT,則將劑量增加至RP2D-M。若存在一個DLT,將納入另外3名患者。若六名患者中不超過一名出現DLT,則下一群組中之ONC-841將為介於比RP2D-M低一個級別與RP2D-M之間的中間水準或為RP2D-M,如由安全性資料確定。將六名患者納入最終劑量水準。當6名患者中少於2名出現DLT時,將RP2D-C確定為最高劑量水準。
1B 階段,擴展群組
1B階段由用於測試以下之安全性及臨床活性的兩個劑量擴展組組成:在RP2D-M下之ONC-841單藥療法(組A)或在RP2D-C下之ONC-841與3.0、6.0或10.0 mg/kg的ONC-392之組合(組B)。
吾人計劃每組招募30名晚期實體腫瘤或在標準護理(SOC)下發生疾病進展或對SOC不耐受之患者。適用性準則將與1A階段之準則相同。
階段 2
階段2試驗將遵循西蒙氏兩階段設計。在階段1中,將招募總共29名非小細胞肺癌患者以確定客觀反應率。若超過4名或更多的患者實現客觀反應,試驗將進入階段2以招募足以實現可拒絕反應率低於20%的虛無假設之80%功效之患者(80至130名)。
吾人對22種主要癌症類型對使用ONC-392+ONC-841之組合療法的潛在反應性進行評級。此亦係基於其由RNAseq及TCGA資料庫中之基因體資料重構築之免疫學景觀。如圖28所示,吾人由來自癌症基因體圖譜(The Cancer Genomics Atlas;TCGA)資料庫之屬於22種癌症類型之7279個獨立癌症樣品的RNAseq及基因體資料產生免疫腫瘤微環境之景觀。主要由隨後被鑑別為抗CTLA-4抗體伊匹單抗之反應者及無反應者的黑色素瘤患者之治療前臨床樣品之基因體及RNAseq資料,吾人鑑別抗CTLA-4反應性之5個排名組分,包括CTLA-4基因表現、ADCC潛力、突變負擔,以及促進CTLA-4反應性之基因富集及細胞組成。總的排名數為由5個獨立分區值之和計算,各分區值包含1-3個組分。對ONC-841之反應之排名係基於SIGLEC10表現的豐度及巨噬細胞之豐度,由RNAseq資料確定。對組合療法之反應之排名係基於其對各抗體的反應(表3)。吾人之分析表明,非小細胞肺腺癌為反應最強烈之癌症類型。ONC-392之單一藥劑活性得到吾人正在進行的臨床試驗支持。
表3 22種癌症類型對ONC-392、ONC-841及其組合之反應的相對排名
癌症類型 | ONC-392 索引 | ONC-841 索引 | 組合排名索引 |
LUAD | 2 | 1 | 1 |
SKCM-TM | 1 | 4 | 2 |
LUSC | 5 | 3 | 3 |
BRCA-基底 | 4 | 6 | 4 |
BRCA-Her2 | 7 | 7 | 5 |
PAAD | 8 | 8 | 6 |
HNSC | 3 | 16 | 7 |
KIRC | 9 | 10 | 8 |
STAD | 6 | 14 | 9 |
GBM | 21 | 2 | 10 |
BRCA_LumB | 13 | 11 | 11 |
BRCA_LumA | 14 | 13 | 12 |
COAD | 10 | 17 | 13 |
LGG | 22 | 5 | 14 |
SKCM-TP | 12 | 15 | 15 |
KIRP | 20 | 9 | 16 |
OV | 18 | 12 | 17 |
READ | 11 | 21 | 18 |
LIHC | 15 | 19 | 19 |
ESCA | 17 | 18 | 20 |
BLCA | 16 | 20 | 21 |
PRAD | 19 | 22 | 22 |
基於吾人之臨床資料及電腦模擬分析,吾人選擇非小細胞肺腺癌作為階段2研究中之第一臨床適應症,以測試ONC-841與ONC-392之組合療法之臨床功效。
劑量 / 劑型、途徑及給藥方案
對於單藥療法中之劑量遞增,ONC-841將以最小60分鐘靜脈內輸注方式給藥。將對ONC-841之六個劑量水準進行評估。給藥間隔為21天。ONC-841將按照Q3W之方案給藥。在ONC-392與ONC-841的組合中,ONC-841將首先以至少60分鐘靜脈內輸注方式投與。然後ONC-392將以3.0、6.0或10.0 mg/kg之劑量以至少60分鐘靜脈內輸注方式投與。ONC-392及ONC-841不應混合投藥,且兩種藥物之投藥之間應具有至少30分鐘的間隔。單獨的ONC-841或ONC-392與ONC-841之組合將按照Q3W方案投與。
圖 1顯示抗Siglec-10抗體在抗體依賴性細胞介導的細胞毒性(ADCC)之報導分析法中的拮抗劑活性。比較4種不同的抗Siglec-10抗體之分級劑量補救由Jurkat ADCC效應細胞中異位表現之Siglec-10抑制的ADCC的能力。標靶:CHO-CTLA4-OFP純系9 (2×10e4)。效應物:Jurkat-PWPI-Siglec10 (2×10
4)。ADCC-觸發抗體:抗CTLA4 mAb (0.1 μg/ml)。
圖 2顯示如藉由ELISA測定之抗Siglec-10 mAb 31F11之結合特異性。將Siglec融合蛋白塗佈於盤上,且加入生物素標記之31F11。藉由辣根過氧化酶結合之鏈黴抗生物素蛋白來偵測結合的抗體。
圖 3顯示如藉由流式細胞分析技術測定之抗Siglec-10 mAb 31F11之結合特異性。用GFP結合的Siglec cDNA轉染293T細胞用31F11將細胞染色且用Canto II細胞計數器進行分析。
圖 4A - 圖 4B顯示抗Siglec-10 mAb 31F11對Siglec-10Fc與小鼠脾細胞之結合呈現強力的抑制作用。圖4A.實驗方案之流程圖。圖4B.Siglec-10Fc(S10)與脾細胞之結合之抑制百分比。
圖 5顯示抗Siglec-10 mAb 31F11促進巨噬細胞對癌細胞之吞噬作用。用補充有40 ng/ml M-CSF之RPMI-1640培養基刺激自末梢血液分離的人類單核球5-7天。隨後用50 ng/ml TGFβ1及IL10誘導M2巨噬細胞,持續24小時。用CELLTRACE™紫色BMQC染料標記MCF-7細胞,且在抗siglec-10 mAbs、5G6、10H3及31F11 (mFc=鼠Fc;hFc=人類Fc)存在下,與供體衍生之M2巨噬細胞共同培養2小時。用APC結合的抗CD11b Ab對細胞進行染色,且藉由流式細胞分析技術根據總CD11b+細胞中之紫色染料陽性CD11b+細胞之百分比來確定吞噬作用(%)。資料顯示為藉由流式細胞分析技術確定的吞噬癌細胞之巨噬細胞%的平均值及標準差。
圖 6A - 圖 6B顯示抗CD24及抗Siglec-10抗體之協同抗腫瘤活性。將1×10
6個MC38-hCD24細胞皮下接種至包含來自表現人類Siglec-10 (n-4-5)之轉殖基因小鼠之骨髓細胞的BM嵌合小鼠中。在腫瘤移植後之第7、10、13及16天,用100 μg hIgFc、α-hCD24、31F11 (α-S10)或α-hCD24+ 31F11 Ab治療小鼠。圖6A.腫瘤生長之動力學。圖6B.隨時間變化的負載腫瘤之小鼠之百分比。
圖 7顯示人類化31F11純系之針對其與Jurkat細胞上異位表現的細胞表面Siglec-10之結合之表徵。資料顯示為抗體分級劑量之最大結合百分比。
圖 8顯示人類化31F11純系之熱穩定性。各純系之資料顯示於表1中。
表1 人類化31F11純系之Tm
Tm1 | Tm2 | |||||
嵌合 | 65.8 | 65.8 | 65.8 | |||
#21 | 63.6 | 63.7 | 63.7 | 78.6 | 78.5 | 78.5 |
#22 | 63.7 | 63.8 | 63.8 | 78.5 | 78.5 | 78.5 |
#23 | 64 | 64 | 63.9 | 80.6 | 80.7 | 80.6 |
#32 | 67 | 66.6 | 67 | |||
#34 | 64.5 | 64.4 | 64.4 | 71.6 | 71.7 | 71.7 |
#52 | 66.7 | 66.6 | 66.6 | |||
#54 | 69.2 | 68.9 | 69.2 |
圖 9基於人類化31F11純系在補救抗體依賴性細胞介導的細胞毒性(ADCC)報導分析法中之活性來顯示其拮抗劑活性。將5×10
4個Jurkat-PWPI-S10細胞及5×10
4個CHO-hCTLA4細胞與指定濃度之0.1 µg/ml的抗hCTLA4及抗siglec 10抗體共同培養。培育16-24小時後,將BIO-GLO™螢光素酶分析試劑添加至所有測試孔中,且使用具有輝光型發光讀取能力之盤讀取器量測發光。資料顯示為抗體分級劑量之最大ADCC活性%。
圖 10A - 圖 10B顯示SIGLEC-10傳訊抑制ADCC報導活性。圖10A.報導分析法之圖式。在表現CTLA-4之靶細胞及不同濃度之抗CTLA-4 mAb,即伊匹單抗(Ipilimumab)的存在下,Jurkat報導細胞在FcγRIIIA的活化後活化NFAT之表現。圖10B.表現載體對照物(ADCC3-p)、WT Siglec-10蛋白質(ADCC3-10)或在ITIM域667位置具有Y>A突變之突變體Siglec-10的Jurkat報導細胞之報導活性,該等細胞部分阻止Siglec-10 (ADCC3-10-667)之負傳訊。
圖 11顯示31F11在增強ADCC活性方面之優良活性。使用表現Siglec-10之Jurkat報導細胞ADCC3-10作為報導細胞。使用表現CTLA-4之CHO細胞作為靶細胞。在0.1 µg/mL之抗CTLA-4 mAb ONC-392及連續稀釋之抗Siglec-10 mAb 10H3、5G6及31F11的存在下共同培養細胞。分析設計圖示於圖10A中。比較3種抗Siglec-10 mAb之給定劑量。
圖 12顯示認為ONC-841如何阻斷CD24-Siglec-10之不要吃我信號(DNEMS)以促進腫瘤細胞之吞噬作用的示意圖。
圖 13顯示ONC-841與ONC-392組合療法之機制。ONC-392藉由選擇性地消耗腫瘤微環境中之Treg,藉此增強瘤內的T細胞反應來引起腫瘤排斥反應;而ONC-841藉由拮抗Siglec-10介導之抑制來增強ADCC/ACDP介導之Treg消耗。
圖 14A - 圖 14B顯示ONC-841與重組Siglec家族蛋白之結合。圖14A.ONC-841對經His標記或Fc標記之Siglec的特異性。圖14B.ONC-841在高濃度下顯示出與Siglec-5Fc、Siglec-6Fc、Siglec-11Fc及Siglec-14Fc之模式類似的與人類IgG1Fc之結合,表明ONC-841與Siglec-5Fc、Siglec-6Fc、Siglec-11Fc及Siglec-14Fc之結合係歸因於與Fc標記的非特異性結合且不與重組Siglec蛋白特異性結合。
圖 15顯示NC-841阻斷Siglec-10Fc與Jurkat-CTLA4細胞之結合。Siglec-10 Fc-生物素與鏈黴抗生物素蛋白-PE預複合,且與逐漸增加之濃度的ONC-841一起培育5分鐘,隨後在與Jurkat-CTLA4細胞一起培育1小時。
圖 16A - 圖 16B顯示ONC-841對Siglec-10Fc與Treg之結合影響。圖16A.顯示在存在(淺灰色)或不存在(深灰色) 100 µg/mL之ONC-841情況下,Siglec-10-生物素+鏈黴抗生物素蛋白-PE與Treg之結合之代表性資料。鏈黴抗生物素蛋白-PE作為陰性對照顯示為灰色。圖16B.ONC-841阻斷Siglec-10Fc-生物素+鏈黴抗生物素蛋白-PE與Treg之結合之非線性回歸分析。
圖 17A - 圖 17C顯示ONC-841在抗體依賴性ADCC報導分析法中之效果。圖17A.ONC-841促進針對Raji細胞之抗CD20依賴性ADCC。圖17B.ONC-841促進針對表現EGFR之B16細胞的西妥昔單抗(cetuximab)依賴性ADCC。圖17C.ONC-841促進針對表現CTLA-4之CHO細胞的ONC-392依賴性ADCC。所顯示之資料係經標準化以顯示ADCC活性相對於基線的倍數增加。
圖 18A - 圖 18C顯示ONC-841在人類NK細胞對白血病細胞的ADCC及非抗體依賴性殺傷中之作用。圖18A.不存在ONC-392。圖18B.存在ONC-392。圖18C.ONC-841對ONC-392介導之ADCC的增強%。
圖 19顯示ONC-841在人類PBMC對白血病細胞的非抗體依賴性殺傷中之作用。ONC-841在不存在靶向癌細胞之抗體的情況下促進PBMC殺傷Jurkat-CTLA-4細胞。
圖 20說明ONC-841在實體瘤中之治療活性。使用表現人類EGFR之B16F10細胞株。在腫瘤細胞攻擊之後6天,用對照IgG、ONC-841或ONC-841+西妥昔單抗治療帶有腫瘤之小鼠,且盲式量測腫瘤生長。在腫瘤接種之後第6天開始,每三天一次以腹腔內(i.p.)方式用200 μg對照hIgGFc或ONC-841及以瘤內(i.t.)方式用10 μg對照hIgGFc或西妥昔單抗治療帶有B16-EGFR腫瘤(s.c.)之
Siglec10TG +/+ ;
Siglecg -/- 小鼠(n=4-5)持續四次注射。
圖 21A - 圖 21B顯示組合療法中之ONC-841之劑量反應。圖21A.腫瘤生長動力學。圖21B.使用圖21A中最後一個時間點之資料的用於確定EC50之線性回歸分析。
圖 22顯示ONC-841與抗CTLA-4抗體9D9之組合引起B16F10黑色素瘤細胞之排斥。在第8、11、14及17天用200 μg 9D9或/及400 μg ONC-841腹腔內治療帶有B16-F10腫瘤之C57BL/6
SIGLEC10TG +/+ ;
Siglecg -/- 小鼠(n=5-6)。每3天一次量測腫瘤體積。資料顯示為平均值及SEM。
圖 23顯示用於偵測ONC-841與來自不同物種之經His標記的Siglec-10/Siglec-G結合之比色ELISA分析法。
圖 24顯示ONC-841與expi293上表現之Siglec-10異種同源物之結合的流式細胞分析技術評估。使用Zombie染料對活細胞進行圈選,且評估ONC-841(深灰色線)之結合且與多株抗Siglec-10抗體(淺灰色線)進行比較。使用螢光減一(Fluorescent-minus-one;FMO,灰色)作為陰性對照。各直方圖之圖例中的數字顯示各樣品之中值螢光強度。
圖 25顯示ONC-841與人類及食蟹獼猴單核球及B細胞之結合之流式細胞分析技術評估。使用Zombie染料對活細胞進行圈選,且評估ONC-841 (深灰色線)之結合且與作為陰性對照之螢光減一(FMO,灰色)進行比較。為了測試結合是否為特異性的,在染色前,在一些試管中加入過量之人類IgG (淺灰色線)。各直方圖之圖例中的數字顯示各樣品之中值螢光強度。
圖 26A - 圖 26C顯示ONC-841與Siglec10轉殖基因小鼠及人類PBMC之結合。圖26A.左側,由人類Siglec10轉殖基因小鼠與SiglecG基因剔除小鼠之雜交產生的F1小鼠的血液分析。小鼠表現人類Siglec-10及Siglec G兩者。右側,雜交F1小鼠之血液分析及被選擇用於產生轉殖基因群落的小鼠之表現型。選擇僅具有人類Siglec-10染色之F2小鼠進行進一步培育。小鼠血液用市售抗體進行染色。圖26B.對小鼠血液子集進行額外染色:NK細胞、B細胞、樹突狀細胞(DC)、嗜中性球、單核球及T細胞。在X軸上顯示Siglec-10染色,且非轉殖基因小鼠之各細胞亞型染色顯示在左圖且人類Siglec-10轉殖基因小鼠之染色顯示在右圖。圖26C.人類PBMC之代表性染色。Y軸(淺灰色)為ONC-841,X軸(深灰色)為市售5G6抗Siglec-10 mAb抗體,各小圖具有顯示單獨的各抗體之染色的相鄰的直方圖。顯示對Siglec-10呈陽性之B細胞及單核球的陽性細胞之百分比。
圖 27顯示來自
Siglec10TG +/+ ;
Siglecg -/- 小鼠之不同器官的冷凍切片之免疫組織化學染色。最上面一列顯示表現Siglec-10 (左側)及Siglec-10陰性(右側)的細胞集結粒之陽性及陰性染色。棕色顯示ONC-841之結合,藍色為核染色(蘇木精(Hematoxylin))。所有切片均以20倍放大倍數顯示。
圖 28顯示將人類癌症對抗CTLA-4抗體治療之反應性進行排序的策略圖。吾人首先基於CTLA-4反應資料庫確定影響抗CTLA-4抗體之治療反應之組分,考慮新發現的抗CTLA-4抗體之作用機制以及另一組對FCGR3A多形性及伊匹單抗反應性進行的分析。基於各組分之中值將人類癌症類型分級。以相同方式將此等組分加權且分為5個類別,且在各類別上分級。隨後對五個類別之等級進行加權,得出最終分級。
圖 29顯示ONC-841不會誘發細胞介素釋放症候群(CRS)。顯示來自4個供體中之一者的代表性資料。一式兩份地進行分析法。
<![CDATA[<110> 美商昂科C4公司(OncoC4, Inc.)]]> 美國馬里蘭大學巴爾的摩分校(University of Maryland, Baltimore) <![CDATA[<120> 抗SIGLEC抗體及其用途]]> <![CDATA[<130> 111005.0900.01PC00]]> <![CDATA[<150> 63182271]]> <![CDATA[<151> 2021-04-30]]> <![CDATA[<160> 35 ]]> <![CDATA[<170> PatentIn version 3.5]]> <![CDATA[<210> 1]]> <![CDATA[<211> 120]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 小家鼠]]> <![CDATA[<400> 1]]> Gln Val Thr Leu Lys Glu Ser Gly Pro Gly Ile Leu Gln Ser Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Ser Phe Ser Gly Phe Ser Leu Ser Thr Ser 20 25 30 Gly Met Gly Leu Ser Trp Ile Arg Gln Pro Ser Gly Lys Gly Leu Glu 35 40 45 Trp Leu Ala His Ile Tyr Trp Asp Asp Asp Lys Arg Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Arg Asn Gln Val 65 70 75 80 Phe Leu Lys Ile Thr Ser Val Asp Thr Ala Asp Thr Ala Thr Tyr Tyr 85 90 95 Cys Val Arg Gly Leu Tyr Gly Asn Trp Phe Phe Asp Val Trp Gly Ala 100 105 110 Gly Thr Thr Val Thr Val Ser Ser 115 120 <![CDATA[<210> 2]]> <![CDATA[<211> 107]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 小家鼠]]> <![CDATA[<400> 2]]> Asp Ile Val Met Thr Gln Ser Gln Lys Phe Met Ser Thr Ser Val Gly 1 5 10 15 Asp Arg Val Ser Ile Thr Tyr Lys Ala Ser Gln Asn Val Gly Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile 35 40 45 Tyr Ser Ala Ser Asn Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Asn Met Gln Ser 65 70 75 80 Glu Asn Leu Ala Asn Tyr Phe Cys Gln Gln Tyr Ser Ser Tyr Pro Leu 85 90 95 Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys 100 105 <![CDATA[<210> 3]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 小家鼠]]> <![CDATA[<400> 3]]> Thr Ser Gly Met Gly Leu Ser 1 5 <![CDATA[<210> 4]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 小家鼠]]> <![CDATA[<400> 4]]> His Ile Tyr Trp Asp Asp Asp Lys Arg Tyr Asn Pro Ser Leu Lys Ser 1 5 10 15 <![CDATA[<210> 5]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 小家鼠]]> <![CDATA[<400> 5]]> Gly Leu Tyr Gly Asn Trp Phe Phe Asp Val 1 5 10 <![CDATA[<210> 6]]> <![CDATA[<211> 11]]> <![CDATA[<212> P]]>RT <![CDATA[<213> 小家鼠]]> <![CDATA[<400> 6]]> Lys Ala Ser Gln Asn Val Gly Thr Ala Val Ala 1 5 10 <![CDATA[<210> 7]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 小家鼠]]> <![CDATA[<400> 7]]> Ser Ala Ser Asn Arg Tyr Thr 1 5 <![CDATA[<210> 8]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 小家鼠]]> <![CDATA[<400> 8]]> Gln Gln Tyr Ser Ser Tyr Pro Leu Thr Phe 1 5 10 <![CDATA[<210> 9]]> <![CDATA[<211> 120]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工]]> <![CDATA[<220>]]> <![CDATA[<223> 人類化抗體]]> <![CDATA[<400> 9]]> Gln Val Thr Leu Lys Glu Ser Gly Pro Ala Leu Val Lys Pro Thr Gln 1 5 10 15 Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser Thr Ser 20 25 30 Gly Met Gly Leu Ser Trp Ile Arg Gln Pro Pro Gly Lys Ala Leu Glu 35 40 45 Trp Leu Ala His Ile Tyr Trp Asp Asp Asp Lys Arg Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val 65 70 75 80 Val Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr 85 90 95 Cys Val Arg Gly Leu Tyr Gly Asn Trp Phe Phe Asp Val Trp Gly Gln 100 105 110 Gly Thr Thr Val Thr Val Ser Ser 115 120 <![CDATA[<210> 10]]> <![CDATA[<211> 120]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工]]> <![CDATA[<220>]]> <![CDATA[<223> 人類化抗體]]> <![CDATA[<400> 10]]> Gln Val Thr Leu Lys Glu Ser Gly Pro Ala Leu Val Lys Pro Thr Gln 1 5 10 15 Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser Thr Ser 20 25 30 Gly Met Gly Leu Ser Trp Ile Arg Gln Pro Pro Gly Lys Ala Leu Glu 35 40 45 Trp Leu Ala His Ile Tyr Trp Asp Asp Asp Lys Arg Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val 65 70 75 80 Val Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr 85 90 95 Cys Val Arg Gly Leu Tyr Gly Asn Trp Phe Phe Asp Val Trp Gly Ala 100 105 110 Gly Thr Thr Val Thr Val Ser Ser 115 120 <![CDATA[<210> 11]]> <![CDATA[<211> 120]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工]]> <![CDATA[<220>]]> <![CDATA[<223> 人類化抗體]]> <![CDATA[<400> 11]]> Gln Val Thr Leu Lys Glu Ser Gly Pro Ala Leu Val Lys Pro Thr Gln 1 5 10 15 Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser Thr Ser 20 25 30 Gly Met Gly Leu Ser Trp Ile Arg Gln Pro Pro Gly Lys Ala Leu Glu 35 40 45 Trp Leu Ala His Ile Tyr Trp Asp Asp Asp Lys Arg Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val 65 70 75 80 Val Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr 85 90 95 Cys Ala Arg Gly Leu Tyr Gly Asn Trp Phe Phe Asp Val Trp Gly Gln 100 105 110 Gly Thr Thr Val Thr Val Ser Ser 115 120 <![CDATA[<210> 12]]> <![CDATA[<211> 120]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工]]> <![CDATA[<220>]]> <![CDATA[<223> 人類化抗體]]> <![CDATA[<400> 12]]> Gln Val Thr Leu Lys Glu Ser Gly Pro Ala Leu Val Lys Pro Thr Gln 1 5 10 15 Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser Thr Ser 20 25 30 Gly Met Gly Leu Ser Trp Ile Arg Gln Pro Pro Gly Lys Ala Leu Glu 35 40 45 Trp Leu Ala His Ile Tyr Trp Asp Asp Asp Lys Arg Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val 65 70 75 80 Val Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr 85 90 95 Cys Ala Arg Gly Leu Tyr Gly Asn Trp Phe Phe Asp Val Trp Gly Ala 100 105 110 Gly Thr Thr Val Thr Val Ser Ser 115 120 <![CDATA[<210> 13]]> <![CDATA[<211> 120]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工]]> <![CDATA[<220>]]> <![CDATA[<223> 人類化抗體]]> <![CDATA[<400> 13]]> Gln Val Thr Leu Lys Glu Ser Gly Pro Ala Leu Val Lys Pro Thr Gln 1 5 10 15 Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser Thr Ser 20 25 30 Gly Met Gly Leu Ser Trp Ile Arg Gln Pro Pro Gly Lys Ala Leu Glu 35 40 45 Trp Leu Ala His Ile Tyr Trp Asp Asp Asp Lys Arg Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val 65 70 75 80 Val Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr 85 90 95 Cys Ala Arg Gly Leu Tyr Gly Asn Trp Phe Phe Asp Val Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 <![CDATA[<210> 14]]> <![CDATA[<211> 107]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工]]> <![CDATA[<220>]]> <![CDATA[<223> 人類化抗體]]> <![CDATA[<400> 14]]> 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 Lys Ala Ser Gln Asn Val Gly Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Ser Ala Ser Asn Arg Tyr Thr Gly Val 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 Ser Ser Tyr Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <![CDATA[<210> 15]]> <![CDATA[<211> 107]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工]]> <![CDATA[<220>]]> <![CDATA[<223> 人類化抗體]]> <![CDATA[<400> 15]]> Asp 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 Lys Ala Ser Gln Asn Val Gly Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Ser Ala Ser Asn Arg Tyr Thr Gly Val 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 Ser Ser Tyr Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <![CDATA[<210> 16]]> <![CDATA[<211> 107]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工]]> <![CDATA[<220>]]> <![CDATA[<223> 人類化抗體]]> <![CDATA[<400> 16]]> 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 Tyr Lys Ala Ser Gln Asn Val Gly Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Ser Ala Ser Asn Arg Tyr Thr Gly Val 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 Ser Ser Tyr Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <![CDATA[<210> 17]]> <![CDATA[<211> 107]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工]]> <![CDATA[<220>]]> <![CDATA[<223> 人類化抗體]]> <![CDATA[<400> 17]]> Asp 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 Tyr Lys Ala Ser Gln Asn Val Gly Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Ser Ala Ser Asn Arg Tyr Thr Gly Val 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 Ser Ser Tyr Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <![CDATA[<210> 18]]> <![CDATA[<211> 107]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工]]> <![CDATA[<220>]]> <![CDATA[<223> 人類化抗體]]> <![CDATA[<400> 18]]> Asp Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Thr Tyr Lys Ala Ser Gln Asn Val Gly Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Ser Ala Ser Asn Arg Tyr Thr Gly Val 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 Ser Ser Tyr Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <![CDATA[<210> 19]]> <![CDATA[<211> 106]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 19]]> Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Asp Glu Gln 1 5 10 15 Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr 20 25 30 Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser 35 40 45 Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr 50 55 60 Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys 65 70 75 80 His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro 85 90 95 Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 100 105 <![CDATA[<210> 20]]> <![CDATA[<211> 326]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 20]]> Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg 1 5 10 15 Ser Thr Ser Glu Ser 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 Lys Thr 65 70 75 80 Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95 Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro 100 105 110 Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 115 120 125 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 130 135 140 Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp 145 150 155 160 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe 165 170 175 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 180 185 190 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu 195 200 205 Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 210 215 220 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys 225 230 235 240 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 245 250 255 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 260 265 270 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 275 280 285 Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser 290 295 300 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 305 310 315 320 Leu Ser Leu Ser Leu Gly 325 <![CDATA[<210> 21]]> <![CDATA[<211> 125]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工]]> <![CDATA[<220>]]> <![CDATA[<223> 人類化抗體]]> <![CDATA[<400> 21]]> Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr 20 25 30 Gly Leu Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Tyr Ile Trp Tyr Asp Gly Asn Thr Asn Phe His Ser Pro Leu Lys 50 55 60 Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu 65 70 75 80 Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Lys Thr Glu Gly His Tyr Tyr Gly Ser Asn Tyr Gly Tyr Tyr Ala Leu 100 105 110 Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 125 <![CDATA[<210> 22]]> <![CDATA[<211> 107]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工]]> <![CDATA[<220>]]> <![CDATA[<223> 人類化抗體]]> <![CDATA[<400> 22]]> Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Asn Ile Tyr Ser Asn 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Gln Gly Lys Ala Pro Lys Leu Leu Leu 35 40 45 Tyr Ala Ala Thr Asn Leu Gln Asp Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Phe Cys Gln His Leu Trp Gly Thr Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 <![CDATA[<210> 23]]> <![CDATA[<211> 120]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工]]> <![CDATA[<220>]]> <![CDATA[<223> 人類化]]> <![CDATA[<400> 23]]> Gln Val Thr Leu Lys Glu Ser Gly Pro Ala Leu Val Lys Pro Thr Gln 1 5 10 15 Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser Thr Ser 20 25 30 Gly Met Gly Leu Ser Trp Ile Arg Gln Pro Pro Gly Lys Ala Leu Glu 35 40 45 Trp Leu Ala His Ile Tyr Trp Asp Asp Asp Lys Arg Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val 65 70 75 80 Val Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr 85 90 95 Cys Val Arg Gly Leu Tyr Gly Asn Trp Phe Phe Asp Val Trp Gly Gln 100 105 110 Gly Thr Thr Val Thr Val Ser Ser 115 120 <![CDATA[<210> 24]]> <![CDATA[<211> 327]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工]]> <![CDATA[<220>]]> <![CDATA[<223> 突變型人類IgG4 Fc]]> <![CDATA[<400> 24]]> Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg 1 5 10 15 Ser Thr Ser Glu Ser 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 Lys Thr 65 70 75 80 Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95 Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro 100 105 110 Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 115 120 125 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 130 135 140 Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp 145 150 155 160 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe 165 170 175 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 180 185 190 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu 195 200 205 Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 210 215 220 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys 225 230 235 240 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 245 250 255 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 260 265 270 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 275 280 285 Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser 290 295 300 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 305 310 315 320 Leu Ser Leu Ser Leu Gly Lys 325 <![CDATA[<210> ]]>25 <![CDATA[<211> 447]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工]]> <![CDATA[<220>]]> <![CDATA[<223> 人類化抗體]]> <![CDATA[<400> 25]]> Gln Val Thr Leu Lys Glu Ser Gly Pro Ala Leu Val Lys Pro Thr Gln 1 5 10 15 Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser Thr Ser 20 25 30 Gly Met Gly Leu Ser Trp Ile Arg Gln Pro Pro Gly Lys Ala Leu Glu 35 40 45 Trp Leu Ala His Ile Tyr Trp Asp Asp Asp Lys Arg Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val 65 70 75 80 Val Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr 85 90 95 Cys Val Arg Gly Leu Tyr Gly Asn Trp Phe Phe Asp Val Trp Gly Gln 100 105 110 Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser 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 Lys Thr Tyr Thr Cys Asn Val Asp His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro 210 215 220 Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser 290 295 300 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys 435 440 445 <![CDATA[<210> 26]]> <![CDATA[<211> 466]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工]]> <![CDATA[<220>]]> <![CDATA[<223> 人類化抗體]]> <![CDATA[<400> 26]]> Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly 1 5 10 15 Val His Ser Gln Val Thr Leu Lys Glu Ser Gly Pro Ala Leu Val Lys 20 25 30 Pro Thr Gln Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu 35 40 45 Ser Thr Ser Gly Met Gly Leu Ser Trp Ile Arg Gln Pro Pro Gly Lys 50 55 60 Ala Leu Glu Trp Leu Ala His Ile Tyr Trp Asp Asp Asp Lys Arg Tyr 65 70 75 80 Asn Pro Ser Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys 85 90 95 Asn Gln Val Val Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala 100 105 110 Thr Tyr Tyr Cys Val Arg Gly Leu Tyr Gly Asn Trp Phe Phe Asp Val 115 120 125 Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly 130 135 140 Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser 145 150 155 160 Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 165 170 175 Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 180 185 190 Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 195 200 205 Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val 210 215 220 Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys 225 230 235 240 Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly 245 250 255 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 260 265 270 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu 275 280 285 Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 290 295 300 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg 305 310 315 320 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 325 330 335 Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu 340 345 350 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 355 360 365 Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu 370 375 380 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 385 390 395 400 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 405 410 415 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp 420 425 430 Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His 435 440 445 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu 450 455 460 Gly Lys 465 <![CDATA[<210> 27]]> <![CDATA[<211> 214]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工]]> <![CDATA[<220>]]> <![CDATA[<223> 人類化抗體]]> <![CDATA[<400> 27]]> Asp 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 Lys Ala Ser Gln Asn Val Gly Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Ser Ala Ser Asn Arg Tyr Thr Gly Val 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 Ser Ser Tyr Pro Leu 85 90 95 Thr Phe Gly Gly 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> 28]]> <![CDATA[<211> 234]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工]]> <![CDATA[<220>]]> <![CDATA[<223> 人類化抗體]]> <![CDATA[<400> 28]]> Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Asp Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser 20 25 30 Val Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Lys Ala Ser Gln Asn 35 40 45 Val Gly Thr Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro 50 55 60 Arg Leu Leu Ile Tyr Ser Ala Ser Asn Arg Tyr Thr Gly Val Pro Ala 65 70 75 80 Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser 85 90 95 Ser Leu Gln Ser Glu Asp Phe Ala Val Tyr Phe Cys Gln Gln Tyr Ser 100 105 110 Ser Tyr Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg 115 120 125 Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln 130 135 140 Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr 145 150 155 160 Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser 165 170 175 Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr 180 185 190 Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys 195 200 205 His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro 210 215 220 Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 225 230 <![CDATA[<210> 29]]> <![CDATA[<211> 107]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 29]]> 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> 30]]> <![CDATA[<211> 329]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 30]]> 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 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 115 120 125 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 130 135 140 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 195 200 205 Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu 225 230 235 240 Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 305 310 315 320 Gln Lys Ser Leu Ser Leu Ser Pro Gly 325 <![CDATA[<210> 31]]> <![CDATA[<211> 329]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工]]> <![CDATA[<220>]]> <![CDATA[<223> 突變型變異體]]> <![CDATA[<400> 31]]> 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 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 115 120 125 Lys Pro Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys 130 135 140 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 165 170 175 Glu Gln Tyr Asn Ala Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 195 200 205 Lys Ala Leu Pro Ala Pro Ile Ala Ala Thr Ile Ser Lys Ala Lys Gly 210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu 225 230 235 240 Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 305 310 315 320 Gln Lys Ser Leu Ser Leu Ser Pro Gly 325 <![CDATA[<210> 32]]> <![CDATA[<211> 447]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工]]> <![CDATA[<220>]]> <![CDATA[<223> 人類化抗體]]> <![CDATA[<400> 32]]> Gln Val Thr Leu Lys Glu Ser Gly Pro Ala Leu Val Lys Pro Thr Gln 1 5 10 15 Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser Thr Ser 20 25 30 Gly Met Gly Leu Ser Trp Ile Arg Gln Pro Pro Gly Lys Ala Leu Glu 35 40 45 Trp Leu Ala His Ile Tyr Trp Asp Asp Asp Lys Arg Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val 65 70 75 80 Val Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr 85 90 95 Cys Val Arg Gly Leu Tyr Gly Asn Trp Phe Phe Asp Val Trp Gly Ala 100 105 110 Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser 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 Lys Thr Tyr Thr Cys Asn Val Asp His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro 210 215 220 Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser 290 295 300 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys 435 440 445 <![CDATA[<210> 33]]> <![CDATA[<211> 466]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工]]> <![CDATA[<220>]]> <![CDATA[<223> 人類化抗體]]> <![CDATA[<400> 33]]> Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly 1 5 10 15 Val His Ser Gln Val Thr Leu Lys Glu Ser Gly Pro Ala Leu Val Lys 20 25 30 Pro Thr Gln Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu 35 40 45 Ser Thr Ser Gly Met Gly Leu Ser Trp Ile Arg Gln Pro Pro Gly Lys 50 55 60 Ala Leu Glu Trp Leu Ala His Ile Tyr Trp Asp Asp Asp Lys Arg Tyr 65 70 75 80 Asn Pro Ser Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys 85 90 95 Asn Gln Val Val Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala 100 105 110 Thr Tyr Tyr Cys Val Arg Gly Leu Tyr Gly Asn Trp Phe Phe Asp Val 115 120 125 Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly 130 135 140 Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser 145 150 155 160 Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 165 170 175 Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 180 185 190 Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 195 200 205 Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val 210 215 220 Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys 225 230 235 240 Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly 245 250 255 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 260 265 270 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu 275 280 285 Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 290 295 300 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg 305 310 315 320 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 325 330 335 Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu 340 345 350 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 355 360 365 Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu 370 375 380 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 385 390 395 400 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 405 410 415 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp 420 425 430 Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His 435 440 445 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu 450 455 460 Gly Lys 465 <![CDATA[<210> 34]]> <![CDATA[<211> 214]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工]]> <![CDATA[<220>]]> <![CDATA[<223> 人類化抗體]]> <![CDATA[<400> 34]]> 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 Tyr Lys Ala Ser Gln Asn Val Gly Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Ser Ala Ser Asn Arg Tyr Thr Gly Val 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 Ser Ser Tyr Pro Leu 85 90 95 Thr Phe Gly Gly 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> 35]]> <![CDATA[<211> 234]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工]]> <![CDATA[<220>]]> <![CDATA[<223> 人類化抗體]]> <![CDATA[<400> 35]]> Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser 20 25 30 Val Ser Pro Gly Glu Arg Ala Thr Leu Ser Tyr Lys Ala Ser Gln Asn 35 40 45 Val Gly Thr Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro 50 55 60 Arg Leu Leu Ile Tyr Ser Ala Ser Asn Arg Tyr Thr Gly Val Pro Ala 65 70 75 80 Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser 85 90 95 Ser Leu Gln Ser Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Ser 100 105 110 Ser Tyr Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg 115 120 125 Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln 130 135 140 Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr 145 150 155 160 Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser 165 170 175 Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr 180 185 190 Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys 195 200 205 His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro 210 215 220 Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 225 230
Claims (53)
- 一種抗Siglec-10抗體,其中該抗體包含(a)重鏈可變區,其包含有包含SEQ ID NO: 3中所闡述之序列之互補決定區(CDR) 1、包含SEQ ID NO: 4中所闡述之序列之CDR2及包含SEQ ID NO: 5中所闡述之序列之CDR3中之一或多者;及(b)輕鏈可變區,其包含有包含SEQ ID NO: 6中所闡述之序列之CDR1、包含SEQ ID NO: 7中所闡述之序列之CDR2及包含SEQ ID NO: 8中所闡述之序列之CDR3中之一或多者。
- 如請求項1之抗Siglec-10抗體,其中該重鏈可變區包含SEQ ID NO: 1中所闡述之序列且該輕鏈可變區包含SEQ ID NO: 2中所闡述之序列。
- 如請求項1或2之抗Siglec-10抗體,其中該抗體為嵌合抗體。
- 如請求項1之抗Siglec-10抗體,其中該重鏈可變區包含SEQ ID NO: 9-13中的一者中所闡述之序列,且該輕鏈可變區包含SEQ ID NO: 14-18中的一者中所闡述之序列。
- 如請求項4之抗Siglec-10抗體,其中該重鏈可變區包含SEQ ID NO: 9、10或11中所闡述之序列,且該輕鏈可變區包含SEQ ID NO: 15中所闡述之序列。
- 如請求項5之抗Siglec-10抗體,其中該重鏈可變區包含SEQ ID NO: 9中所闡述之序列。
- 如請求項6之抗Siglec-10抗體,其中該重鏈包含SEQ ID NO: 25中所闡述之序列。
- 如請求項7之抗Siglec-10抗體,其中該輕鏈包含SEQ ID NO: 27中所闡述之序列。
- 如請求項5之抗Siglec-10抗體,其中該重鏈可變區包含SEQ ID NO: 10中所闡述之序列。
- 如請求項9之抗Siglec-10抗體,其中該重鏈包含SEQ ID NO: 32中所闡述之序列。
- 如請求項10之抗Siglec-10抗體,其中該輕鏈包含SEQ ID NO: 27中所闡述之序列。
- 如請求項5之抗Siglec-10抗體,其中該重鏈可變區包含SEQ ID NO: 11中所闡述之序列。
- 如請求項4之抗Siglec-10抗體,其中該重鏈可變區包含SEQ ID NO: 10或12中所闡述之序列,且該輕鏈可變區包含SEQ ID NO: 17中所闡述之序列。
- 如請求項13之抗Siglec-10抗體,其中該重鏈可變區包含SEQ ID NO: 10中所闡述之序列。
- 如請求項13之抗Siglec-10抗體,其中該重鏈可變區包含SEQ NO: 12中所闡述之序列。
- 如請求項4之抗Siglec-10抗體,其中該重鏈可變區包含SEQ ID NO: 10或12中所闡述之序列,且該輕鏈可變區包含SEQ ID NO: 16中所闡述之序列。
- 如請求項16之抗Siglec-10抗體,其中該重鏈可變區包含SEQ ID NO: 10中所闡述之序列。
- 如請求項17之抗Siglec-10抗體,其中該重鏈包含SEQ ID NO: 32中所闡述之序列。
- 如請求項18之抗Siglec-10抗體,其中該輕鏈包含SEQ ID NO: 34中所闡述之序列。
- 如請求項16之抗Siglec-10抗體,其中該重鏈可變區包含SEQ ID NO: 12中所闡述之序列。
- 一種治療有需要之患者中之癌症的方法,其包含向該患者投與如請求項1至20中任一項之抗Siglec-10抗體。
- 如請求項21之方法,其中該抗Siglec-10抗體係與第二癌症療法組合投與。
- 如請求項22之方法,其中該第二癌症療法係靶向癌症之免疫療法或靶向免疫細胞之免疫療法。
- 如請求項23之方法,其中該第二癌症療法為抗CTLA-4抗體。
- 如請求項21至24中任一項之方法,其中該癌症為晚期實體腫瘤、血液癌症、或包括與該抗Siglec-10抗體結合之浸潤細胞的癌症。
- 如請求項25之方法,其中該癌症為選自由以下組成之群之晚期實體腫瘤:肺腺癌(LUAD)、皮膚黑色素瘤-轉移(SKCM-TM)、肺鱗狀細胞癌(LUSC)、乳房侵襲性癌瘤-基底、乳房侵襲性癌瘤-Her2、胰臟腺癌、頭頸鱗狀細胞癌、腎臟透明細胞癌、胃腺癌、多形性膠質母細胞瘤、乳房侵襲性癌瘤-LumB或乳房侵襲性癌瘤-LumA、非小細胞肺癌、膠質母細胞瘤、黑色素瘤、低級別膠質瘤、腎癌、基底型乳癌、Her2+乳癌、胰臟癌、及卵巢癌。
- 如請求項26之方法,其中該肺腺癌為非小細胞肺腺癌。
- 如請求項25之方法,其中該癌症為選自由以下組成之群之血液癌症:白血病、骨髓發育不良症候群、B細胞淋巴瘤、及多發性骨髓瘤。
- 一種抗Siglec-10抗體,其中重鏈包含SEQ ID NO: 32中所闡述之序列且輕鏈包含SEQ ID NO: 27中所闡述之序列;該重鏈包含SEQ ID NO: 25中所闡述之序列且該輕鏈包含SEQ ID NO: 27中所闡述之序列;或該重鏈包含SEQ ID NO: 32中所闡述之序列且該輕鏈包含SEQ ID NO: 34中所闡述之序列。
- 一種治療有需要之患者中之癌症的方法,其包含向該患者投與如請求項29之抗Siglec-10抗體。
- 如請求項30之方法,其中該抗Siglec-10抗體係與第二癌症療法組合投與。
- 如請求項31之方法,其中該第二癌症療法係靶向癌症之免疫療法或靶向免疫細胞之免疫療法。
- 如請求項32之方法,其中該第二癌症療法為抗CTLA-4抗體。
- 如請求項30至33中任一項之方法,其中該癌症為晚期實體腫瘤、血液癌症、或包括與該抗Siglec-10抗體結合之浸潤細胞的癌症。
- 如請求項34之方法,其中該癌症為選自由以下組成之群之晚期實體腫瘤:肺腺癌(LUAD)、皮膚黑色素瘤-轉移(SKCM-TM)、肺鱗狀細胞癌(LUSC)、乳房侵襲性癌瘤-基底、乳房侵襲性癌瘤-Her2、胰臟腺癌、頭頸鱗狀細胞癌、腎臟透明細胞癌、胃腺癌、多形性膠質母細胞瘤、乳房侵襲性癌瘤-LumB或乳房侵襲性癌瘤-LumA、非小細胞肺癌、膠質母細胞瘤、黑色素瘤、低級別膠質瘤、腎癌、基底型乳癌、Her2+乳癌、胰臟癌、及卵巢癌。
- 如請求項35之方法,其中該肺腺癌為非小細胞肺腺癌。
- 如請求項34之方法,其中該癌症為選自由以下組成之群之血液癌症:白血病、骨髓發育不良症候群、B細胞淋巴瘤、及多發性骨髓瘤。
- 一種如請求項1至20中任一項之抗Siglec-10抗體的用途,其係用於製造用以治療癌症之藥劑。
- 如請求項38之用途,其中該藥劑意欲與第二癌症療法組合使用。
- 如請求項39之用途,其中該第二癌症療法係靶向癌症之免疫療法或靶向免疫細胞之免疫療法。
- 如請求項40之用途,其中該第二癌症療法為抗CTLA-4抗體。
- 如請求項38至41中任一項之用途,其中該癌症為晚期實體腫瘤、血液癌症、或包括與該抗Siglec-10抗體結合之浸潤細胞的癌症。
- 如請求項42之用途,其中該癌症為選自由以下組成之群之晚期實體腫瘤:肺腺癌(LUAD)、皮膚黑色素瘤-轉移(SKCM-TM)、肺鱗狀細胞癌(LUSC)、乳房侵襲性癌瘤-基底、乳房侵襲性癌瘤-Her2、胰臟腺癌、頭頸鱗狀細胞癌、腎臟透明細胞癌、胃腺癌、多形性膠質母細胞瘤、乳房侵襲性癌瘤-LumB或乳房侵襲性癌瘤-LumA、非小細胞肺癌、膠質母細胞瘤、黑色素瘤、低級別膠質瘤、腎癌、基底型乳癌、Her2+乳癌、胰臟癌、及卵巢癌。
- 如請求項43之用途,其中該肺腺癌為非小細胞肺腺癌。
- 如請求項42之用途,其中該癌症為選自由以下組成之群之血液癌症:白血病、骨髓發育不良症候群、B細胞淋巴瘤、及多發性骨髓瘤。
- 一種如請求項29之抗Siglec-10抗體的用途,其係用於製造用以治療癌症之藥劑。
- 如請求項46之用途,其中該藥劑意欲與第二癌症療法組合使用。
- 如請求項47之用途,其中該第二癌症療法係靶向癌症之免疫療法或靶向免疫細胞之免疫療法。
- 如請求項48之用途,其中該第二癌症療法為抗CTLA-4抗體。
- 如請求項46至49中任一項之用途,其中該癌症為晚期實體腫瘤、血液癌症、或包括與該抗Siglec-10抗體結合之浸潤細胞的癌症。
- 如請求項50之用途,其中該癌症為選自由以下組成之群之晚期實體腫瘤:肺腺癌(LUAD)、皮膚黑色素瘤-轉移(SKCM-TM)、肺鱗狀細胞癌(LUSC)、乳房侵襲性癌瘤-基底、乳房侵襲性癌瘤-Her2、胰臟腺癌、頭頸鱗狀細胞癌、腎臟透明細胞癌、胃腺癌、多形性膠質母細胞瘤、乳房侵襲性癌瘤-LumB或乳房侵襲性癌瘤-LumA、非小細胞肺癌、膠質母細胞瘤、黑色素瘤、低級別膠質瘤、腎癌、基底型乳癌、Her2+乳癌、胰臟癌、及卵巢癌。
- 如請求項51之用途,其中該肺腺癌為非小細胞肺腺癌。
- 如請求項50之用途,其中該癌症為選自由以下組成之群之血液癌症:白血病、骨髓發育不良症候群、B細胞淋巴瘤、及多發性骨髓瘤。
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TW201612518A (en) * | 2014-01-17 | 2016-04-01 | Sanofi Sa | Methods of identifying patients suffering from liver cancer who will most likely benefit from a treatment with an antagonist anti-FGFR4 antibody |
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