TW202330599A - 抗ccr8單株抗體及其用途 - Google Patents
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Abstract
本揭示提供了對人類趨化因子(C-C模體)受體8 (CCR8)蛋白具有結合特異性之抗體或其片段。此等抗體能夠以高親和力與CCR8結合並且可以介導抗體依賴性細胞毒性(ADCC)。
Description
趨化因子(C-C模體)受體8 (CCR8)係β趨化因子受體家族之成員,其係一種類似於G蛋白偶聯受體之七次跨膜蛋白。趨化因子及其受體對於各種細胞類型遷移到炎症部位很重要。此受體蛋白優先在胸腺中表現。CCR8之配體係CCL1。CCL8亦起到CCR8促效劑之作用。
CCR8主要在調節性T細胞(Treg)上表現,對CCR8
+Treg介導之免疫抑制很重要。最近的研究已經表明,CCR8在癌症患者之人類腫瘤駐留Treg中被獨特地上調。亦表明CCR8
+骨髓細胞在癌症患者中擴增。
在動物模型中,已顯示靶向CCR8之抗體可以顯著抑制腫瘤生長並提高長期存活。此抗腫瘤活性與腫瘤特異性T細胞之增加及CD4
+及CD8
+T細胞之浸潤增強相關。用抗體處理防止了Treg之誘導及抑制功能,而不影響CD8
+T細胞。因此,靶向CCR8係一種很有前景之癌症免疫治療方法。
本文發現之抗CCR8抗體對人類CCR8蛋白具有高結合親和力,並且在介導抗體依賴性細胞毒性(ADCC)方面有效。
在一個實施例中,提供了一種對人類趨化因子(C-C模體)受體8 (CCR8)蛋白具有結合特異性之抗體或其片段。該抗體或其片段包含重鏈可變區及輕鏈可變區,該重鏈可變區包含重鏈互補決定區CDRH1、CDRH2及CDRH3,該輕鏈可變區包含輕鏈互補決定區CDRL1、CDRL2及CDRL3。在一個實施例中,該CDRH1包含SEQ ID NO: 22之胺基酸序列,該CDRH2包含SEQ ID NO: 23之胺基酸序列,該CDRH3包含SEQ ID NO: 24之胺基酸序列,該CDRL1包含SEQ ID NO: 25或28之胺基酸序列,該CDRL2包含SEQ ID NO: 26之胺基酸序列,並且該CDRL3包含SEQ ID NO: 27之胺基酸序列。
在一個實施例中,該CDRH1包含SEQ ID NO: 35之胺基酸序列,該CDRH2包含SEQ ID NO: 36之胺基酸序列,該CDRH3包含SEQ ID NO: 37之胺基酸序列,該CDRL1包含SEQ ID NO: 25或28之胺基酸序列,該CDRL2包含SEQ ID NO: 26之胺基酸序列,並且該CDRL3包含SEQ ID NO: 27之胺基酸序列。
在一些實施例中,亦提供了包含該抗體或其片段及醫藥學上可接受之載劑之組合物。在一些實施例中,該組合物進一步包含對腫瘤抗原具有特異性之第二抗體。在一些實施例中,該第二抗體係腫瘤調理抗體。
亦提供了用於治療疾病及病症的方法及用途。在一個實施例中,提供了一種治療有需要患者之癌症的方法,其包含向該患者投與本揭示之抗體或其片段。
定義
應當注意,術語「一(a/an)」實體係指該實體之一個或多個(一種或多種);例如,「一種抗體」應理解為表示一種或多種抗體。這樣,術語「一個」、「一個(種)或多個(種)」及「至少一個(種)」在本文中可以互換使用。
如本文所用,術語「多肽」旨在涵蓋單數「多肽」及複數「多肽」,並且係指由藉由醯胺鍵(亦稱為肽鍵)線性連接之單體(胺基酸)構成之分子。術語「多肽」係指兩個或多個胺基酸之任何一條或多條鏈,並不指特定長度之產物。因此,「多肽」之定義中包括肽、二肽、三肽、寡肽、「蛋白質」、「胺基酸鏈」或用於指代兩個或更多個胺基酸之一條或多條鏈之任何其他術語,並且術語「多肽」可以代替此等術語中之任何術語使用,或與此等術語中之任何術語互換使用。術語「多肽」亦旨在指多肽之表現後修飾之產物,包括但不限於糖基化、乙醯化、磷酸化、醯胺化、藉由已知之保護/阻斷基團衍生化、蛋白水解切割或藉由非天然存在之胺基酸進行之修飾。多肽可以源自天然生物來源或藉由重組技術產生,但不一定自指定之核酸序列轉譯而來。其可以任何方式產生,包括藉由化學合成產生。
「同源性」或「同一性」或「相似性」係指兩條肽之間或兩個核酸分子之間的序列相似性。同源性可以藉由比較每個序列中之位置來確定,序列可以出於比較之目的而被比對。當比較序列中之一個位置被相同之鹼基或胺基酸佔據時,則分子在該位置係同源的。序列之間的同源性程度係序列共用之匹配位置或同源位置之數目之函數。「不相關的」或「非同源的」序列與本揭示之序列之一共用小於40%之同一性,但較佳小於25%之同一性。
多核苷酸或多核苷酸區(或多肽或多肽區)與另一個序列具有一定百分比(例如60%、65%、70%、75%、80%、85%、90%、95%、98%或99%)之「序列同一性」係指,當比對時,在比較兩個序列時鹼基(或胺基酸)相同之百分比。
術語「等效核酸或等效多核苷酸」係指具有與核酸或其互補物之核苷酸序列具有一定程度之同源性或序列同一性之核苷酸序列之核酸。雙鏈核酸之同源物旨在包括具有與其或其互補物具有一定程度同源性之核苷酸序列之核酸。在一個態樣中,核酸之同源物能夠與核酸或其互補物雜交。同樣地,「等效多肽」係指與參考多肽之胺基酸序列具有一定程度之同源性或序列同一性之多肽。在一些態樣中,序列同一性為至少約70%、75%、80%、85%、90%、95%、98%或99%。在一些態樣中,與參考多肽或多核苷酸相比,等效多肽或多核苷酸具有1、2、3、4或5個添加、缺失、取代及其組合。在一些態樣中,等效序列保留參考序列之活性(例如,抗原決定基結合)或結構(例如,鹽橋)。
如本文所用,「抗體」或「抗原結合多肽」係指特異性識別並結合抗原之多肽或多肽複合物。抗體可以係完整抗體及其任何抗原結合片段或單鏈。因此,術語「抗體」包括任何蛋白質或肽,其含有包括至少免疫球蛋白分子中具有與抗原結合之生物學活性之部分之分子。其實例包括但不限於重鏈或輕鏈之互補決定區(CDR)或其配體結合部分、重鏈或輕鏈可變區、重鏈或輕鏈恆定區、構架(FR)區或其任何部分,或結合蛋白之至少一個部分。
如本文所用,術語「抗體片段」或「抗原結合片段」係抗體之一部分,例如F(ab')
2、F(ab)
2、Fab'、Fab、Fv、scFv等。無論結構如何,抗體片段均與被完整抗體識別之同一抗原結合。術語「抗體片段」包括適配體(aptamer)、鏡像異構體(spiegelmer)及雙功能抗體(diabody)。術語「抗體片段」亦包括像抗體一樣藉由與特定抗原結合形成複合物而起作用之任何合成之或基因工程之蛋白。
「單鏈可變片段」或「scFv」係指免疫球蛋白之重鏈(V
H)及輕鏈(V
L)之可變區之融合蛋白。在一些態樣中,該區與10至約25個胺基酸之短接頭肽連接。接頭可以富含甘胺酸以提高柔性,並富含絲胺酸或蘇胺酸以提高溶解度,並且可以將V
H之N-末端與V
L之C-末端相連,反之亦然。儘管去除了恆定區並引入了接頭,但該蛋白仍保留了原始免疫球蛋白之特異性。ScFv分子係此項技術中已知的,並且例如在美國專利5,892,019中被描述。
術語抗體涵蓋了各種廣泛類別之多肽,其可自生物化學上被區分。熟習此項技術者將理解,重鏈被分類為gamma、mu、alpha、delta或epsilon (γ、μ、α、δ、ε),其中有一些子類(例如γl-γ4)。該鏈之性質決定了抗體之「類別」分別為IgG、IgM、IgA、IgG或IgE。免疫球蛋白亞類(同型),例如IgG
1、IgG
2、IgG
3、IgG
4、IgG
5等,已被很好地表徵,並且已知賦予功能特異性。鑒於本揭示,此等類別及同型之每一個之修飾形式對於熟習此項技術者而言係容易辨別的,並且因此在本揭示之範疇內。所有之免疫球蛋白類別顯然均在本揭示之範疇內,下面之討論通常將針對免疫球蛋白分子之IgG類別。關於IgG,標準免疫球蛋白分子包含兩條相同之分子量約為23,000道爾頓之輕鏈多肽及兩條相同之分子量為53,000-70,000之重鏈多肽。四條鏈通常藉由二硫鍵以「Y」構型連接,其中輕鏈將重鏈括起來,自「Y」之口開始,一直延伸到可變區。
本揭示之抗體、抗原結合多肽、其變體或衍生物包括但不限於多株、單株、多特異性、人類、人源化、靈長類化(primatized)或嵌合之抗體,單鏈抗體,抗原決定基結合片段,例如Fab、Fab'及F(ab')
2、Fd、Fv、單鏈Fv(scFv)、單鏈抗體、二硫鍵連接之Fv(sdFv)、包含VK或VH域之片段、由Fab表現文庫產生之片段及抗獨特型(anti-idiotypic) (抗Id)抗體(包括例如本文揭示之針對LIGHT抗體之抗Id抗體)。本揭示之免疫球蛋白或抗體分子可為任何類型(例如,IgG、IgE、IgM、IgD、IgA及IgY)、類別(例如,IgG1、IgG2、IgG3、IgG4、IgA1及IgA2)或亞類之免疫球蛋白分子。
輕鏈分為kappa或lambda(κ、λ)。每個重鏈類別均可以與κ或λ輕鏈結合。通常,當免疫球蛋白由雜交瘤、B細胞或基因工程宿主細胞產生時,輕鏈及重鏈彼此共價鍵合,兩條重鏈之「尾」部藉由共價二硫鍵或非共價鍵彼此鍵合。在重鏈中,胺基酸序列自Y構型之分叉末端之N-末端延伸到每條鏈底部之C-末端。
輕鏈及重鏈均分為結構同源區及功能同源區。術語「恆定」及「可變」在功能上使用。就此而言,應當理解,輕鏈部分之可變域(VK)及重鏈部分之可變域(VH)決定了抗原之識別及特異性。相反地,輕鏈之恆定域(CK)及重鏈之恆定域(CH1、CH2或CH3)賦予重要之生物學特性,諸如分泌、跨胎盤遷移、Fc受體結合、互補物結合等。按照慣例,恆定區域之編號隨著其變得更遠離抗體之抗原結合位點或胺基末端而增加。N-末端部分係可變區,C-末端部分係恆定區;CH3及CK域實際上分別包含重鏈及輕鏈之羧基末端。
如上所述,可變區允許抗體選擇性識別並特異性結合抗原上之抗原決定基。亦即,抗體之VK域及VH域或互補決定區(CDR)之子集組合形成定義三維抗原結合位點之可變區。此四級抗體結構形成了存在於Y之各臂終端之抗原結合位點。更具體而言,抗原結合位點由VH及VK鏈各自上之三個CDR定義(亦即CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2及CDR-L3)。在某些情況下,例如某些源自駱駝科物種或基於駱駝科免疫球蛋白工程改造之免疫球蛋白分子,完整之免疫球蛋白分子可以僅由重鏈組成,而沒有輕鏈。參見,例如,Hamers-Casterman等,
Nature363:446-448 (1993)。
在天然存在之抗體中,在每個抗原結合域中存在之六個「互補決定區」或「CDR」係短的、非連續的胺基酸序列,該胺基酸序列經特異性定位為當在水性環境中該抗體呈現出其三維構型時形成抗原結合域。抗原結合域中之其餘胺基酸(稱為「構架」區)顯示出較小之分子間可變性。構架區主要採用β-摺疊結構,並且CDR形成環,該環連接β-摺疊結構,並在某些情況下形成β-摺疊結構之一部分。因此,構架區起形成支架之作用,該支架藉由鏈間非共價相互作用將CDR定位在正確之方向上。由定位之CDR形成之抗原結合域限定了與免疫反應性抗原上之抗原決定基互補之表面。此互補表面促進抗體與其同源抗原決定基之非共價結合。一般熟習此項技術者可以容易地針對任何給定之重鏈或輕鏈可變區分別鑑定包含CDR及構架區之胺基酸,因為其已經被精確地定義(參見「Sequences of Proteins of Immunological Interest」,Kabat, E.等,美國衛生與公共服務部(U.S. Department of Health and Human Services),(1983);及Chothia及Lesk,
J. MoI.Biol., 196:901-917(1987))。
在此項技術中使用及/或接受之術語有兩個或更多個定義之情況下,除非有明確之相反說明,否則如本文所用術語之定義旨在包括所有此等含義。一個具體實例係使用術語「互補決定區」(「CDR」)來描述在重鏈及輕鏈多肽之可變區內均發現之非連續抗原結合位點。此特定區已經由Kabat等,美國衛生與公共服務部(U.S. Dept. of Health and Human Services),「Sequences of Proteins of Immunological Interest」(1983)及Chothia等,
J. MoI.Biol.196:901-917(1987)描述,其以全文引用之方式併入本文中。當彼此比較時,根據Kabat及Chothia之CDR定義包括胺基酸殘基之重疊或子集。然而,任何一種用於指代抗體或其變體之CDR之定義之應用均旨在處於本文所定義及使用之術語之範疇內。作為比較,下表中列出了涵蓋如上述引用之參考文獻之各自所定義之CDR之合適胺基酸殘基。涵蓋特定CDR之確切殘基數將根據CDR之序列及大小而變化。給定了抗體之可變區胺基酸序列,熟習此項技術者可以常規地確定哪些殘基包含特定CDR。
Kabat | Chothia | |
CDR-H1 | 31-35 | 26-32 |
CDR-H2 | 50-65 | 52-58 |
CDR-H3 | 95-102 | 95-102 |
CDR-L1 | 24-34 | 26-32 |
CDR-L2 | 50-56 | 50-52 |
CDR-L3 | 89-97 | 91-96 |
Kabat等亦定義了適用於任何抗體之可變域序列之編號系統。一般熟習此項技術者可以明確地將此「Kabat編號」系統分配給任何可變域序列,而不依賴序列本身以外之任何實驗數據。如本文所用,「Kabat編號」係指由Kabat等,美國衛生及公共服務部(U.S. Dept. of Health and Human Services),「Sequence of Proteins of Immunological Interest」(1983)中所示之編號系統。
除上表外,Kabat編號系統亦如下描述了CDR區:CDR-H1在大約第31位胺基酸處開始(亦即大約在第一個半胱胺酸殘基之後9個殘基),包括大約5-7個胺基酸,並在下一個色胺酸殘基處終止。CDR-H2在CDR-H1末端之後的第15個殘基處開始,包含約16-19個胺基酸,並在下一個精胺酸或離胺酸殘基處終止。CDR-H3在CDR-H2末端後大約第33個胺基酸殘基處開始;包含3-25個胺基酸;並在序列W-G-X-G處終止,其中X係任意胺基酸。CDR-L1在大約第24位殘基處開始(亦即在半胱胺酸殘基之後);包含大約10-17個殘基;並在下一個色胺酸殘基處終止。CDR-L2在CDR-L1末端之後大約第16個殘基處開始,包含大約7個殘基。CDR-L3在CDR-L2末端之後大約第33個殘基處(亦即在半胱胺酸殘基之後)開始;包含大約7-11個殘基,並在序列F或W-G-X-G處終止,其中X係任意胺基酸。
本文所揭示之抗體可以來自任何動物來源,包括鳥類及哺乳動物。較佳地,抗體係人類、鼠類、驢、兔、山羊、豚鼠、駱駝、美洲駝、馬或雞之抗體。在另一個實施例中,可變區可以係condricthoid來源(例如來自鯊魚)。
如本文所用,術語「重鏈恆定區」包含衍生自免疫球蛋白重鏈之胺基酸序列。包含重鏈恆定區之多肽包含以下至少一種:CH1域、鉸鏈(例如,上、中及/或下鉸鏈區)域、CH2域、CH3域,或其變體或片段。例如,用於本揭示之抗原結合多肽可以包含含CH1域之多肽鏈;含CH1域、鉸鏈域之至少一部分及CH2域之多肽鏈;含CH1域及CH3域之多肽鏈;含CH1域、鉸鏈域之至少一部分及CH3域之多肽鏈,或含CH1域、鉸鏈域之至少一部分、CH2域及CH3域之多肽鏈。在另一個實施例中,本揭示之多肽包含含CH3域之多肽鏈。進一步地,用於本揭示之抗體可以缺少CH2域之至少一部分(例如,CH2域之全部或部分)。如上所述,一般熟習此項技術者將理解,重鏈恆定區可經修飾,使得其在胺基酸序列上與天然存在之免疫球蛋白分子不同。
本文揭示之抗體之重鏈恆定區可以衍生自不同之免疫球蛋白分子。例如,多肽之重鏈恆定區可以包含衍生自IgG
1分子之CH1域及衍生自IgG
3分子之鉸鏈區。在另一個實例中,重鏈恆定區可以包含部分衍生自IgG
1分子且部分衍生自IgG
3分子之鉸鏈區。在另一個實例中,重鏈部分可以包含部分衍生自IgG
1分子且部分衍生自IgG
4分子之嵌合鉸鏈。
如本文所用,術語「輕鏈恆定區」包括衍生自抗體輕鏈之胺基酸序列。較佳地,輕鏈恆定區包含恆定κ域或恆定λ域中之至少一者。
「輕鏈-重鏈對」係指輕鏈及重鏈之集合,其可以藉由輕鏈之CL域及重鏈之CH1域之間的二硫鍵形成二聚體。
如前所述,各種免疫球蛋白類別之恆定區之亞基結構及三維構型係眾所周知的。如本文所用,術語「VH域」包括免疫球蛋白重鏈之胺基末端可變域,術語「CH1域」包括免疫球蛋白重鏈之第一(最胺基末端)恆定區域。CH1域與VH域相鄰,並且在免疫球蛋白重鏈分子之鉸鏈區之胺基末端。
如本文所用,術語「CH2域」包括重鏈分子的例如自抗體之約第244位殘基延伸至第360位殘基(使用習知編號方案) (第244至360位殘基,Kabat編號系統;及第231-340位殘基,EU編號系統;請參見Kabat等,美國衛生與公共服務部,「Sequences of Proteins of Immunological Interest」(1983))之部分。CH2域之獨特之處在於其不與另一個域緊密配對。而是,兩個N-連接之分枝碳水化合物鏈插入完整之天然IgG分子之兩個CH2域之間。亦充分證明,CH3域自CH2域延伸至IgG分子之C-末端,並包含約108個殘基。
如本文所用,術語「鉸鏈區」包括重鏈分子之連接CH1域及CH2域之部分。該鉸鏈區包含約25個殘基並且係柔性的,因此允許兩個N-末端抗原結合區獨立移動。鉸鏈區可細分為三個不同之域:上、中、下鉸鏈域(Roux等,
J.Immunol161:4083(1998))。
如本文所用,術語「二硫鍵」包括在兩個硫原子之間形成之共價鍵。胺基酸半胱胺酸包含硫醇基,其可以與第二硫醇基形成二硫鍵或橋連。在大多數天然存在之IgG分子中,CH1及CK區藉由二硫鍵連接,並且兩條重鏈藉由兩個在對應於第239及242位(使用Kabat編號系統) (第226或229位,EU編號系統)之二硫鍵連接。
如本文所用,術語「嵌合抗體」將被保持為意指其中免疫反應性區或免疫反應性位點獲自或衍生自第一物種並且恆定區(根據本揭示,其可以係完整的、部分的或修飾的)獲自第二物種之任何抗體。在某些實施例中,目標結合區或目標結合位點將來自非人類來源(例如小鼠或靈長類),而恆定區係人類的。
如本文所用,藉由確定人源化域及種系域之間的構架胺基酸差異(亦即非CDR差異)之數目,自胺基酸總數中減去該數目,然後除以胺基酸總數並乘以100來計算「人源化百分比」。
「特異性結合」或「對……具有特異性」通常係指抗體經由其抗原結合域與抗原決定基結合,並且該結合需要在抗原結合域及抗原決定基之間具有一定互補性。根據該定義,當抗體經由其抗原結合域與抗原決定基結合比抗體與隨機的、不相關的抗原決定基結合更容易時,抗體被稱為與該抗原決定基「特異性結合」。術語「特異性」在本文中用於限定某種抗體與某種抗原決定基結合之相對親和力。例如,可以認為抗體「A」對給定之抗原決定基具有比抗體「B」更高之特異性,或者可以說抗體「A」以比對相關抗原決定基「D」更高之特異性結合抗原決定基「C」。
如本文所用,術語「治療(treat/treatment)」係指治療性治療及預防性(prophylactic或preventative)措施,其中目的係預防或減緩(減輕)不期望之生理變化或病症,例如癌症之進展。有益之或期望之臨床結果包括但不限於無論係可偵測的抑或不可偵測的症狀緩解、疾病程度減輕、疾病狀態穩定(亦即不惡化)、疾病進展延遲或減慢、疾病狀態改善或減輕,及緩解(無論係部分抑或全部)。「治療」亦可能意謂與若未接受治療所預期之生存期相比,生存期延長。需要治療之彼等個體包括已經患有病狀或病症之彼等個體,易於患病狀或病症之彼等個體,或要預防病病狀或病症之彼等個體。
「個體」或「動物」或「患者」或「哺乳動物」係指需要診斷、預後或治療之任何個體,特別是哺乳動物個體。哺乳動物個體包括人類、家畜、農場動物及動物園動物、運動動物或寵物,例如狗、貓、豚鼠、兔子、大鼠、小鼠、馬、家牛、奶牛等。
如本文所用,短語諸如「需要治療之患者」或「需要治療之個體」包括將自投與本揭示所使用之抗體或組合物例如以用於偵測、用於診斷程序及/或用於治療而受益之個體,例如哺乳動物個體。
抗 CCR8 抗體
本揭示提供了抗CCR8抗體及片段,其對人類CCR8蛋白具有高親和力、在介導ADCC及ADCP方面有效,並且顯示出有效之活體內腫瘤抑制劑效果。有趣的係,當使用抗CCR8抗體(來自WO2020138489)作為基準時,本揭示之抗體表現出不與非CCR8表現細胞結合,而基準抗體亦與彼等對照細胞結合。因此,可以預期本發明之抗體在臨床應用中具有較少之不希望的副作用。因此,此等抗體係用於治療以過表現CCR8為特徵之各種疾病(諸如癌症)之合適藥劑。
因此,根據本揭示之一個實施例,提供了能夠與CCR8結合之抗體及其抗原結合片段。例示性抗體包括
表 1中列出之彼等鼠類抗體(例如137D1H10、88D2C6、89B6F8、132H8E10、10F11B2、40H10F3、53D6A9、352H11C11、362G7D3、362H10A3、367D10E7、370D2C10),及
表 2-3中之人源化抗體。亦包括包含與本文所示相同之CDR之彼等抗體。在一些實施例中,所揭示之抗體及片段包括與本文所示之彼等結合相同之抗原決定基之彼等,及與本揭示之抗體及片段競爭結合CCR8之彼等者。
根據本揭示之一個實施例,提供了一種包括具有本文揭示之CDR區之重鏈及輕鏈可變域之抗體或其片段,及其生物學等效物。
在一個實施例中,CDR係88D2C6或其人源化對應物之CDR,如
表 2B 及 2D中所例舉的。在一個實施例中,CDRH1包含SEQ ID NO: 22之胺基酸序列或其具有一個、兩個或三個缺失、添加、取代或其組合之變體,CDRH2包含SEQ ID NO: 23之胺基酸序列或其具有一個、兩個或三個缺失、添加、取代或其組合之變體,CDRH3包含SEQ ID NO: 24之胺基酸序列或其具有一個、兩個或三個缺失、添加、取代或其組合之變體,CDRL1包含SEQ ID NO: 25或28之胺基酸序列或其具有一個、兩個或三個缺失、添加、取代或其組合之變體,CDRL2包含SEQ ID NO: 26之胺基酸序列或其具有一個、兩個或三個缺失、添加、取代或其組合之變體,並且CDRL3包含SEQ ID NO: 27之胺基酸序列或其具有一個、兩個或三個缺失、添加、取代或其組合之變體。
在一個實施例中,CDRH1包含SEQ ID NO: 22之胺基酸序列或其具有一個、兩個或三個缺失、添加、取代或其組合之變體,CDRH2包含SEQ ID NO: 23之胺基酸序列或其具有一個、兩個或三個缺失、添加、取代或其組合之變體,CDRH3包含SEQ ID NO: 24之胺基酸序列或其具有一個、兩個或三個缺失、添加、取代或其組合之變體,CDRL1包含SEQ ID NO: 25之胺基酸序列或其具有一個、兩個或三個缺失、添加、取代或其組合之變體,CDRL2包含SEQ ID NO: 26之胺基酸序列或其具有一個、兩個或三個缺失、添加、取代或其組合之變體,並且CDRL3包含SEQ ID NO: 27之胺基酸序列或其具有一個、兩個或三個缺失、添加、取代或其組合之變體。
在一個實施例中,CDRH1包含SEQ ID NO: 22之胺基酸序列,CDRH2包含SEQ ID NO: 23之胺基酸序列,CDRH3包含SEQ ID NO: 24之胺基酸序列,CDRL1包含SEQ ID NO: 25或28之胺基酸序列,CDRL2包含SEQ ID NO: 26之胺基酸序列,CDRL3包含SEQ ID NO: 27之胺基酸序列。
在一些實施例中,亦提供了包含與88D2C6或其人源化對應物相同之CDR之彼等者。在一些實施例中,所揭示之抗體及片段包括與88D2C6或其人源化對應物結合相同抗原決定基之彼等者,及與其中任一者競爭結合CCR8之彼等者。
在一些實施例中,重鏈可變區包含選自由SEQ ID NO: 3 (小鼠或嵌合)及29-31 (人源化)組成之群的胺基酸序列,或與選自由SEQ ID NO: 3 (小鼠或嵌合)及29-31 (人源化)組成之群的胺基酸序列具有至少90%序列同一性之肽。
在一些實施例中,輕鏈可變區包含選自由SEQ ID NO: 2 (小鼠或嵌合)、32-34及41-43 (人源化)組成之群的胺基酸序列,或與選自由SEQ ID NO :2 (小鼠或嵌合)、32-34及41-43 (人源化)組成之群的胺基酸序列具有至少90%序列同一性之肽。
在一些實施例中,重鏈可變區包含SEQ ID NO: 29之胺基酸序列,且輕鏈可變區包含SEQ ID NO: 32-34及41-43中任一者之胺基酸序列。在一些實施例中,重鏈可變區包含SEQ ID NO: 30之胺基酸序列,且輕鏈可變區包含SEQ ID NO: 32-34及41-43中任一者之胺基酸序列。在一些實施例中,重鏈可變區包含SEQ ID NO: 31之胺基酸序列,且輕鏈可變區包含SEQ ID NO: 32-34及41-43中任一者之胺基酸序列。在一些實施例中,重鏈可變區包含SEQ ID NO: 29之胺基酸序列,且輕鏈可變區包含SEQ ID NO: 33之胺基酸序列。
在一個實施例中,CDR係137D1H10或其人源化對應物之CDR,如
表 3B 及 3D中所例舉的。在一個實施例中,CDRH1包含SEQ ID NO: 35之胺基酸序列或其具有一個、兩個或三個缺失、添加、取代或其組合之變體,CDRH2包含SEQ ID NO: 36之胺基酸序列或其具有一個、兩個或三個缺失、添加、取代或其組合之變體,CDRH3包含SEQ ID NO: 37之胺基酸序列或其具有一個、兩個或三個缺失、添加、取代或其組合之變體,CDRL1包含SEQ ID NO: 25或28之胺基酸序列或其具有一個、兩個或三個缺失、添加、取代或其組合之變體,CDRL2包含SEQ ID NO: 26之胺基酸序列或其具有一個、兩個或三個缺失、添加、取代或其組合之變體,並且CDRL3包含SEQ ID NO: 27之胺基酸序列或其具有一個、兩個或三個缺失、添加、取代或其組合之變體。
在一個實施例中,CDRH1包含SEQ ID NO: 35之胺基酸序列或其具有一個、兩個或三個缺失、添加、取代或其組合之變體,CDRH2包含SEQ ID NO: 36之胺基酸序列或其具有一個、兩個或三個缺失、添加、取代或其組合之變體,CDRH3包含SEQ ID NO: 37之胺基酸序列或其具有一個、兩個或三個缺失、添加、取代或其組合之變體,CDRL1包含SEQ ID NO: 25之胺基酸序列或其具有一個、兩個或三個缺失、添加、取代或其組合之變體,CDRL2包含SEQ ID NO: 26之胺基酸序列或其具有一個、兩個或三個缺失、添加、取代或其組合之變體,並且CDRL3包含SEQ ID NO: 27之胺基酸序列或其具有一個、兩個或三個缺失、添加、取代或其組合之變體。
在一個實施例中,CDRH1包含SEQ ID NO: 35之胺基酸序列,CDRH2包含SEQ ID NO: 36之胺基酸序列,CDRH3包含SEQ ID NO: 37之胺基酸序列,CDRL1包含SEQ ID NO: 25或28之胺基酸序列,CDRL2包含SEQ ID NO: 26之胺基酸序列,並且CDRL3包含SEQ ID NO: 27之胺基酸序列。
在一些實施例中,亦提供了包含與137D1H10或其人源化對應物相同之CDR之彼等者。在一些實施例中,所揭示之抗體及片段包括與137D1H10或其人源化對應物結合相同抗原決定基之彼等者,及與其中任一者競爭結合CCR8之彼等者。
在一些實施例中,重鏈可變區包含選自由SEQ ID NO: 1 (小鼠或嵌合)及38-40 (人源化)組成之群的胺基酸序列,或與選自由SEQ ID NO: 3 (小鼠或嵌合)及29-31 (人源化)組成之群的胺基酸序列具有至少90%序列同一性之肽。
在一些實施例中,輕鏈可變區包含選自由SEQ ID NO: 2 (小鼠或嵌合)、32-34及41-43 (人源化)組成之群的胺基酸序列,或與選自由SEQ ID NO: 2 (小鼠或嵌合)、32-34及41-43 (人源化)組成之群的胺基酸序列具有至少90%序列同一性之肽。
在一些實施例中,重鏈可變區包含SEQ ID NO: 38之胺基酸序列,且輕鏈可變區包含SEQ ID NO: 32-34及41-43中任一者之胺基酸序列。在一些實施例中,重鏈可變區包含SEQ ID NO: 39之胺基酸序列,且輕鏈可變區包含SEQ ID NO: 32-34及41-43中任一者之胺基酸序列。在一些實施例中,重鏈可變區包含SEQ ID NO: 40之胺基酸序列,且輕鏈可變區包含SEQ ID NO: 32-34及41-43中任一者之胺基酸序列。在一些實施例中,重鏈可變區包含SEQ ID NO: 40之胺基酸序列,且輕鏈可變區包含SEQ ID NO: 42中任一者之胺基酸序列。
包含此等CDR區之抗體,無論係小鼠的、人源化的抑或嵌合的,均具有有效的CCR8結合及抑制活性。如
實例 4所示,可以修飾CDR內之某些殘基以保留或改良特性或降低其產生轉譯後修飾(PTM)之可能性。此類修飾之CDR可以被稱為親和力成熟之或風險降低之CDR (例如,SEQ ID NO: 25)。
修飾之CDR可以包括具有一個、兩個或三個胺基酸添加、缺失及/或取代之彼等者。在一些實施例中,取代可為保守取代。
「保守胺基酸取代」係其中胺基酸殘基經具有相似側鏈之胺基酸殘基置換的取代。具有相似側鏈之胺基酸殘基家族已在此項技術中被定義,包括鹼性側鏈(例如離胺酸、精胺酸、組胺酸)、酸性側鏈(例如天冬胺酸、麩胺酸)、不帶電荷之極性側鏈(例如甘胺酸、天冬醯胺、麩醯胺酸、絲胺酸、蘇胺酸、酪胺酸、半胱胺酸)、非極性側鏈(例如丙胺酸、纈胺酸、白胺酸、異白胺酸、脯胺酸、苯丙胺酸、甲硫胺酸、色胺酸)、β分支鏈側鏈(例如蘇胺酸、纈胺酸、異白胺酸)及芳族側鏈(例如酪胺酸、苯丙胺酸、色胺酸、組胺酸)。因此,免疫球蛋白多肽中之非必需胺基酸殘基較佳經來自相同側鏈家族之另一個胺基酸殘基置換。在另一個實施例中,一串胺基酸可以經側鏈家族成員之順序及/或組成不同但結構上相似之串置換。
下表中提供了保守胺基酸取代之非限制性實例,其中相似性得分為0或更高的表明兩個胺基酸之間的保守取代。
表 A. 胺基酸相似性矩陣
表 B. 保守胺基酸取代
C | G | P | S | A | T | D | E | N | Q | H | K | R | V | M | I | L | F | Y | W | |
W | -8 | -7 | -6 | -2 | -6 | -5 | -7 | -7 | -4 | -5 | -3 | -3 | 2 | -6 | -4 | -5 | -2 | 0 | 0 | 17 |
Y | 0 | -5 | -5 | -3 | -3 | -3 | -4 | -4 | -2 | -4 | 0 | -4 | -5 | -2 | -2 | -1 | -1 | 7 | 10 | |
F | -4 | -5 | -5 | -3 | -4 | -3 | -6 | -5 | -4 | -5 | -2 | -5 | -4 | -1 | 0 | 1 | 2 | 9 | ||
L | -6 | -4 | -3 | -3 | -2 | -2 | -4 | -3 | -3 | -2 | -2 | -3 | -3 | 2 | 4 | 2 | 6 | |||
I | -2 | -3 | -2 | -1 | -1 | 0 | -2 | -2 | -2 | -2 | -2 | -2 | -2 | 4 | 2 | 5 | ||||
M | -5 | -3 | -2 | -2 | -1 | -1 | -3 | -2 | 0 | -1 | -2 | 0 | 0 | 2 | 6 | |||||
V | -2 | -1 | -1 | -1 | 0 | 0 | -2 | -2 | -2 | -2 | -2 | -2 | -2 | 4 | ||||||
R | -4 | -3 | 0 | 0 | -2 | -1 | -1 | -1 | 0 | 1 | 2 | 3 | 6 | |||||||
K | -5 | -2 | -1 | 0 | -1 | 0 | 0 | 0 | 1 | 1 | 0 | 5 | ||||||||
H | -3 | -2 | 0 | -1 | -1 | -1 | 1 | 1 | 2 | 3 | 6 | |||||||||
Q | -5 | -1 | 0 | -1 | 0 | -1 | 2 | 2 | 1 | 4 | ||||||||||
N | -4 | 0 | -1 | 1 | 0 | 0 | 2 | 1 | 2 | |||||||||||
E | -5 | 0 | -1 | 0 | 0 | 0 | 3 | 4 | ||||||||||||
D | -5 | 1 | -1 | 0 | 0 | 0 | 4 | |||||||||||||
T | -2 | 0 | 0 | 1 | 1 | 3 | ||||||||||||||
A | -2 | 1 | 1 | 1 | 2 | |||||||||||||||
S | 0 | 1 | 1 | 1 | ||||||||||||||||
P | -3 | -1 | 6 | |||||||||||||||||
G | -3 | 5 | ||||||||||||||||||
C | 12 |
胺基酸 | 取代為 |
丙胺酸 | D-Ala、Gly、Aib、β-Ala、L-Cys、D-Cys |
精胺酸 | D-Arg、Lys、D-Lys、Orn D-Orn |
天冬醯胺 | D-Asn、Asp、D-Asp、Glu、D-Glu Gln、D-Gln |
天冬胺酸 | D-Asp、D-Asn、Asn、Glu、D-Glu、Gln、D-Gln |
半胱胺酸 | D-Cys、S-Me-Cys、Met、D-Met、Thr、D-Thr、L-Ser、D-Ser |
麩醯胺酸 | D-Gln、Asn、D-Asn、Glu、D-Glu、Asp、D-Asp |
麩胺酸 | D-Glu、D-Asp、Asp、Asn、D-Asn、Gln、D-Gln |
甘胺酸 | Ala、D-Ala、Pro、D-Pro、Aib、β-Ala |
異白胺酸 | D-Ile、Val、D-Val、Leu、D-Leu、Met、D-Met |
白胺酸 | Val、D-Val、Met、D-Met、D-Ile、D-Leu、Ile |
離胺酸 | D-Lys、Arg、D-Arg、Orn、D-Orn |
甲硫胺酸 | D-Met、S-Me-Cys、Ile、D-Ile、Leu、D-Leu、Val、D-Val |
苯丙胺酸 | D-Phe、Tyr、D-Tyr、His、D-His、Trp、D-Trp |
脯胺酸 | D-Pro |
絲胺酸 | D-Ser、Thr、D-Thr、allo-Thr、L-Cys、D-Cys |
蘇胺酸 | D-Thr、Ser、D-Ser、allo-Thr、Met、D-Met、Val、D-Val |
酪胺酸 | D-Tyr、Phe、D-Phe、His、D-His、Trp、D-Trp |
纈胺酸 | D-Val、Leu、D-Leu、Ile、D-Ile、Met、D-Met |
一般熟習此項技術者亦將理解,本文揭示之抗體可以被修飾,使得其在胺基酸序列上與衍生其之天然存在之結合多肽不同。例如,衍生自指定蛋白質之多肽或胺基酸序列可以與起始序列相似,例如與起始序列具有一定百分比之同一性,例如其可以為與起始序列具有60%、70%、75%、80%、85%、90%、95%、98%或99%之同一性。
在某些實施例中,抗體包含通常不與抗體相關之胺基酸序列或一個或多個部分。下面將更詳細地描述例示性修飾。例如,本揭示之抗體可以包含柔性接頭序列或可以經修飾以添加功能性部分(例如,PEG、藥物、毒素或標記物)。
本揭示之抗體、變體或其衍生物包括被修飾之衍生物,亦即藉由任何類型之分子與抗體之共價連接而被修飾,使得共價連接不會阻止抗體與抗原決定基結合。例如但不限於,抗體可以例如藉由糖基化、乙醯化、聚乙二醇化、磷酸化、磷酸化、醯胺化、藉由已知之保護/阻斷基團衍生化、蛋白水解切割、與細胞配體或其他蛋白質之連接等來修飾。可以藉由已知技術進行眾多化學修飾中之任何一種,該等已知技術包括但不限於特異性化學切割、乙醯化、甲醯化、衣黴素之代謝合成等。另外,抗體可以包含一種或多種非經典胺基酸。
在一些實施例中,抗體可以與治療劑、前藥、肽、蛋白質、酶、病毒、脂質、生物反應修飾劑、藥劑或PEG結合。
抗體可以與治療劑結合或融合,該治療劑可以包括可偵測之標記物(例如放射性標記物)、免疫調節劑、激素、酶、寡核苷酸、光活性治療劑或診斷劑、細胞毒素劑(其可為藥物或毒素)、超聲增強劑、非放射性標記物、其組合及此項技術中已知的其他此類試劑。
可以藉由將抗體與化學發光化合物偶聯,從而對抗體進行可偵測地標記。然後藉由偵測在化學反應過程中產生之發光之存在來確定帶化學發光標籤之抗原結合多肽之存在。特別有用之化學發光標記化合物之實例係魯米諾(luminol)、異魯米諾(isoluminol)、熱敏吖啶酯(theromatic acridinium ester)、咪唑、吖啶鹽及草酸酯。
亦可以使用螢光發射金屬(例如
152Eu或鑭系元素之其他金屬)可偵測地標記抗體。可以使用諸如二乙烯三胺五乙酸(DTPA)或乙二胺四乙酸(EDTA)之金屬螯合基團將此等金屬連接至抗體。將不同部分結合至抗體上之技術係所熟知的,參見,例如Arnon等人,「Monoclonal Antibodies For Immunotargeting Of Drugs In Cancer Therapy」,Monoclonal Antibodies And Cancer Therapy,Reisfeld等(編輯),第243-56頁(Alan R. Liss公司(1985));Hellstrom等人,「Antibodies For Drug Delivery」,Controlled Drug Delivery(第二版), Robinson等(編輯),Marcel Dekker公司,第623-53頁(1987);Thorpe,「Antibody Carriers Of Cytotoxic Agents In Cancer Therapy: A Review」,Monoclonal Antibodies '84: Biological And Clinical Applications,Pinchera等人(編輯),第475-506頁(1985);「Analysis, Results, And Future Prospective Of The Therapeutic Use Of Radiolabeled Antibody In Cancer Therapy」,Monoclonal Antibodies For Cancer Detection And Therapy,Baldwin等人(編輯),學術出版社,第303-16頁(1985),及Thorpe等人「The Preparation And Cytotoxic Properties Of Antibody-Toxin Conjugates」,
Immunol. Rev.(52:119-58 (1982))。
雙功能分子及聯合療法
CCR8係一種趨化因子及腫瘤抗原。作為腫瘤抗原靶向分子,對CCR8具有特異性之抗體或抗原結合片段可以與對免疫細胞具有特異性之第二抗原結合片段、或對免疫檢查點具有特異性之抗原結合片段聯合以產生聯合療法或雙特異性抗體。
在一些實施例中,免疫細胞選自由T細胞、B細胞、單核細胞、巨噬細胞、中性粒細胞、樹突細胞、吞噬細胞、自然殺手細胞、嗜酸性粒細胞、嗜鹼性粒細胞及肥大細胞組成之群。免疫細胞上可以被靶向之分子包括例如CCL1、CD3、CD16、CD19、CD28及CD64。其他實例包括PD-1、PD-L1、CTLA-4、LAG-3 (亦稱為CD223)、CD28、CD122、4-1BB(亦稱為CD137)、TIM3、OX-40或OX40L、CD40或CD40L、LIGHT、ICOS/ICOSL、GITR/GITRL、TIGIT、CD27、VISTA、B7H3、B7H4、HEVM或BTLA (亦稱為CD272)、殺傷細胞免疫球蛋白樣受體(KIR)及CD47。
作為免疫檢查點抑制劑,可以將對CCR8具有特異性之抗體或抗原結合片段與對腫瘤抗原具有特異性之第二抗原結合片段組合,以產生雙特異性抗體。「腫瘤抗原」係在腫瘤細胞中產生之抗原性物質,亦即,其觸發宿主中之免疫反應。腫瘤抗原可以用於鑑定腫瘤細胞,並且係用於癌症治療之潛在候選物。活體內之正常蛋白質不係抗原性的。但是,某些蛋白質係在腫瘤發生過程中產生的或過表現的,因此對人類體來說係「外來的」。其可以包括與免疫系統完全隔離之正常蛋白質、正常情況下以極少量產生之蛋白質、正常情況下僅在某些發育階段產生之蛋白質或結構因突變而被修飾之蛋白質。
大量之腫瘤抗原在此項技術中係已知的,並且可以藉由篩選容易地鑑定出新之腫瘤抗原。腫瘤抗原之非限制性實例包括EGFR、Her2、EpCAM、CD20、CD30、CD33、CD47、CD52、CD133、CD73、CEA、gpA33、黏蛋白、TAG-72、CIX、PSMA、葉酸結合蛋白、GD2、GD3、GM2、VEGF、VEGFR、整合素、αVβ3、α5β1、ERBB2、ERBB3、MET、IGF1R、EPHA3、TRAILR1、TRAILR2、RANKL、FAP及腱生蛋白(Tenascin)。
在一些態樣中,與相應之非腫瘤細胞相比,單價單元對在腫瘤細胞上過表現之蛋白質具有特異性。本文所用之「相應之非腫瘤細胞」係指與腫瘤細胞之來源為相同細胞類型之非腫瘤細胞。需要注意的係,此類蛋白質不一定與腫瘤抗原不同。非限制性實例包括癌胚抗原(CEA),其在大多數結腸癌、直腸癌、乳癌、肺癌、胰臟癌及胃腸道癌中過表現;調蛋白受體(HER-2、
neu或c-
erbB-2),其在乳癌、卵巢癌、結腸癌、肺癌、前列腺癌及宮頸癌中經常過表現;表皮生長因子受體(EGFR),其在包括乳癌、頭頸癌、非小細胞肺癌及前列腺癌在內之一系列實體瘤中高表現;去唾液酸糖蛋白受體;轉鐵蛋白受體;絲胺酸蛋白酶抑制劑酶複合物受體,其在肝細胞上表現;纖維母細胞生長因子受體(FGFR),其在胰臟導管腺癌細胞上過表現;血管內皮生長因子受體(VEGFR),其用於抗血管生成基因治療;葉酸受體,其在90%之非黏液性卵巢癌中選擇性過表現;細胞表面糖萼;碳水化合物受體;及多聚免疫球蛋白受體,其可用於將基因遞送至呼吸道上皮細胞,並且對諸如囊性纖維化之肺疾病之治療具有吸引力。
亦提供了不同形式之雙特異性抗體。在一些實施例中,抗PD-L1片段及第二片段中之每一者各自獨立地選自Fab片段、單鏈可變片段(scFv)或單域抗體。在一些實施例中,雙特異性抗體進一步包括Fc片段。
亦提供了不是僅包括抗體或抗原結合片段之雙功能分子。作為腫瘤抗原靶向分子,例如本文此處所描述的對CCR8具有特異性之抗體或抗原結合片段可以視情況地藉由肽接頭與免疫細胞介素或配體聯合。連接之免疫細胞介素或配體包括但不限於IL-2、IL-3、IL-4、IL-5、IL-6、IL-7、IL-10、IL-12、IL-13、IL-15、GM-CSF、TNF-α、CD40L、OX40L、CD27L、CD30L、4-1BBL、LIGHT及GITRL。此類雙功能分子可以將免疫檢查點阻斷作用與腫瘤部位局部免疫調節相聯合。
抗體藥物結合物
在一些實施例中,抗體或片段可以與治療劑、前藥、肽、蛋白質、酶、病毒、脂質、生物反應修飾劑、藥劑或PEG結合。
在一個實施例中,本揭示之抗體或片段與藥物部分共價連接。藥物部分可為與抗體上之結合點反應之基團或被修飾以包括與抗體上之結合點反應之基團。例如,藥物部分可以藉由烷基化(例如,在ε-胺基離胺酸或抗體之N-末端)、氧化碳水化合物之還原胺化、羥基及羧基之間的酯交換、胺基或羧基之醯胺化及與硫醇基結合來連接。
在一些實施例中,每個抗體分子所結合之藥物部分之數目p之範圍平均為1至8;1至7、1至6、1至5、1至4、1至3或1至2。在一些實施例中,p之範圍平均為2至8、2至7、2至6、2至5、2至4或2至3。在其他實施例中,p平均為1、2、3、4、5、6、7或8。在一些實施例中,p之範圍平均為約1至約20、約1至約10、約2至約10、約2至約9、約1至約8、約1至約7、約1至約6、約1至約5、約1至約4、約1至約3、或約1至約2。在一些實施例中,p之範圍為約2至約8、約2至約7、約2至約6、約2至約5、約2至約4或約2至約3。
例如,當蛋白質之化學活化導致形成游離硫醇基時,蛋白質可以與巰基反應劑結合。在一個態樣中,該試劑係一種實質上對游離硫醇基特異之試劑。此類試劑包括例如馬來醯亞胺、鹵代乙醯胺(例如碘代、溴代或氯代)、鹵酯(例如碘代、溴代或氯代)、鹵代甲基酮(例如碘代、溴代或氯代)、苄基鹵化物(例如碘化物、溴化物或氯化物)、乙烯基碸及吡啶巰基。
藥物可以藉由接頭與抗體或片段連接。合適之接頭包括例如可切割的及不可切割的接頭。可切割接頭通常在細胞內條件下易於切割。合適之可切割接頭包括例如可被細胞內蛋白酶切割之肽接頭,例如溶酶體蛋白酶或內體蛋白酶。在例示性實施例中,接頭可為二肽接頭,例如纈胺酸-瓜胺酸(val-cit)、苯丙胺酸-離胺酸(phe-lys)接頭或馬來醯亞胺己酸-纈胺酸-瓜胺酸-對胺基苄氧羰基(mc-Val-Cit-PABA)接頭。另一種接頭係磺基琥珀醯亞胺基-4-[N-馬來醯亞胺甲基]環己烷-1-羧酸酯(smcc)。Sulfo-smcc結合經由與巰基(sulfhydryl) (硫醇基,-SH)反應之馬來醯亞胺基團發生,而其Sulfo-NHS酯對一級胺(如在離胺酸及蛋白質或肽N-末端發現之一級胺)具有反應性。另一種接頭係馬來醯亞胺己醯基(mc)。其他合適之接頭包括在特定pH或pH範圍可水解之接頭,諸如腙接頭。其他合適之可切割接頭包括二硫鍵接頭。接頭可以與抗體共價結合,以達到抗體必須在細胞內降解以釋放藥物之程度,例如mc接頭等。
接頭可以包括用於與抗體連接之基團。例如,接頭可以包括胺基、羥基、羧基或巰基反應基團(例如,馬來醯亞胺、鹵代乙醯胺(例如,碘代、溴代或氯代)、鹵酯(例如,碘代、溴代或氯代)、鹵甲基酮(例如,碘代、溴代或氯代)、苄基鹵化物(例如碘化物、溴化物或氯化物)、乙烯基碸及吡啶硫基)。
在一些實施例中,藥物部分係細胞毒素劑或細胞生長抑制劑、免疫抑制劑、放射性同位素、毒素等。結合物可用於抑制腫瘤細胞或癌細胞之增殖,引起腫瘤或癌細胞之凋亡,或用於治療患者之癌症。結合物可以相應地用於各種環境以治療動物癌症。結合物可以用於將藥物遞送至腫瘤細胞或癌細胞。不受理論束縛,在一些實施例中,結合物與表現密蛋白18.2之癌細胞結合或相關,並且結合物及/或藥物可以藉由受體介導之內吞作用被吸收至腫瘤細胞或癌細胞內。
一旦進入細胞,結合物內(例如,在接頭中)之一個或多個特定肽序列被一種或多種腫瘤細胞或癌細胞相關之蛋白酶水解切割,導致藥物釋放。然後釋放之藥物在細胞內自由遷移並誘導細胞毒性或細胞抑制或其他活性。在一些實施例中,藥物在腫瘤細胞或癌細胞外自抗體切割下來,藥物隨後穿透細胞,或在細胞表面起作用。
藥物部分或有效載荷之實例選自由以下組成之群:DM1 (美登素(maytansine)、N2'-脫乙醯基-N2'-(3-巰基-1-側氧基丙基)-或N2'-脫乙醯基-N2'-(3-巰基-1-側氧基丙基)-美登素)、mc-MMAD(6-馬來醯亞胺己醯基-單甲基澳瑞他汀-D或N-甲基-L-纈胺醯基-N-[(1S,2R)-2-甲氧基-4-[(2S)-2-[(1R,2R)-1-甲氧基-2-甲基-3-側氧基-3-[[(1S)-2-苯基-1-(2-噻唑基)乙基]胺基]丙基]-1-吡咯啶基]-1-[(1S)-1-甲基丙基]-4-側氧基丁基]-N-甲基-(9Cl)-L-纈胺醯胺)、mc-MMAF(馬來醯亞胺己醯基-單甲基澳瑞他汀F或N-[6-(2,5-二氫-2,5-二側氧基-1H-吡咯-1-基)-1-側氧基己基]-N-甲基-L-纈胺醯基-L-纈胺醯基-(3R,4S,5S)-3-甲氧基-5-甲基-4-(甲胺基)庚醯基-(αR,βR,2S)-β-甲氧基-α-甲基-2-吡咯啶丙醯基-L-苯丙胺酸)及mc-Val-Cit-PABA-MMAE(6-馬來醯亞胺己醯基-ValcCit-(對胺基苄氧羰基)-單甲基澳瑞他汀E或N-[[[4-[[N-[6-(2,5-二氫-2,5-二側氧基-1H-吡咯-1-基)-1-側氧基己基]-L-纈胺醯基-N5-(胺基羰基)-L-鳥胺醯基]胺基]苯基]甲氧基]羰基]-N-甲基-L-纈胺醯基-N-[(1S,2R)-4-[(2S)-2-[(1R,2R)-3-[[(1R,2S)-2-羥基-1-甲基-2-苯乙基]胺基]-1-甲氧基-2-甲基-3-側氧基丙基]-1-吡咯啶基]-2-甲氧基-1-[(1S)-1-甲基丙基]-4-側氧基丁基]-N-甲基-L-纈胺醯胺)。DM1係微管蛋白抑制劑美登素之衍生物,而MMAD、MMAE及MMAF係奧瑞他汀衍生物。在一些實施例中,藥物部分選自由mc-MMAF及mc-Val-Cit-PABA-MMAE組成之群。在一些實施例中,藥物部分係美登醇(maytansinoid)或奧瑞他汀。
抗體或片段可以與治療劑結合或融合,治療劑可以包括可偵測之標記物(諸如放射性標記物)、免疫調節劑、激素、酶、寡核苷酸、光活性治療劑或診斷劑、細胞毒素劑(其可為藥物或毒素)、超聲增強劑、非放射性標記、其組合,及此項技術中已知的其他此類試劑。
可以藉由將抗體與化學發光化合物偶聯,從而對抗體進行可偵測地標記。然後藉由偵測在化學反應過程中產生之發光之存在來確定帶化學發光標籤之抗原結合多肽之存在。特別有用之化學發光標記化合物之實例係魯米諾(luminol)、異魯米諾(isoluminol)、熱敏吖啶酯(theromatic acridinium ester)、咪唑、吖啶鹽及草酸酯。
亦可以使用螢光發射金屬(例如
152Eu或鑭系元素之其他金屬)可偵測地標記抗體。可以使用諸如二乙烯三胺五乙酸(DTPA)或乙二胺四乙酸(EDTA)之金屬螯合基團將此等金屬連接至抗體。將不同部分結合到抗體上之技術係所熟知的,參見,例如Arnon等人,「Monoclonal Antibodies For Immunotargeting Of Drugs In Cancer Therapy」,Monoclonal Antibodies And Cancer Therapy,Reisfeld等(編輯),第243-56頁(Alan R. Liss公司(1985));Hellstrom等人,「Antibodies For Drug Delivery」,Controlled Drug Delivery(第二版), Robinson等(編輯),Marcel Dekker公司,第623-53頁(1987);Thorpe,「Antibody Carriers Of Cytotoxic Agents In Cancer Therapy: A Review」,Monoclonal Antibodies '84: Biological And Clinical Applications,Pinchera等人(編輯),第475-506頁(1985);「Analysis, Results, And Future Prospective Of The Therapeutic Use Of Radiolabeled Antibody In Cancer Therapy」,Monoclonal Antibodies For Cancer Detection And Therapy,Baldwin等人(編輯),學術出版社,第303-16頁(1985),及Thorpe等人「The Preparation And Cytotoxic Properties Of Antibody-Toxin Conjugates」,
Immunol. Rev.(52:119-58 (1982))。
編碼抗體之多核苷酸及製備抗體的方法
本揭示亦提供了編碼本揭示之抗體、其變體或衍生物之分離之多核苷酸或核酸分子。本揭示之多核苷酸可以在相同多核苷酸分子上或在分別之多核苷酸分子上編碼抗原結合多肽、其變體或衍生物之整個重鏈及輕鏈可變區。另外,本揭示之多核苷酸可以在相同多核苷酸分子上或在分別之多核苷酸分子上編碼抗原結合多肽、其變體或衍生物之重鏈及輕鏈可變區之部分。
製備抗體的方法係此項技術中所熟知的並且在本文中描述。在某些實施例中,本揭示之抗原結合多肽之可變區及恆定區均係全人類的。可以使用此項技術中描述的及如本文描述的技術製備全人類抗體。例如,針對特定抗原之全人類抗體可以藉由向轉基因動物投與該抗原來製備,該轉基因動物已經修飾以產生此抗體以對抗原攻擊作出反應,但其內源性基因座已被禁用。可以用於製備此抗體之例示性技術在美國專利:6,150,584、6,458,592、6,420,140中進行了描述,其以全文引用之方式併入。
治療方法
如本文該,本揭示之抗體、變體或衍生物可用於某些治療及診斷方法。
本揭示進一步係關於基於抗體之療法,其涉及將本揭示之抗體投與至患者諸如動物、哺乳動物及人類以治療本文之一種或多種病症或病狀。本揭示之治療性化合物包括但不限於本揭示之抗體(包括如本文之其變體及衍生物)及編碼本揭示之抗體(包括如本文之其變體及衍生物)之核酸或多核苷酸。
本揭示之抗體亦可用於治療或抑制癌症。在一些實施例中,患者中之癌細胞表現或過表現CCR8。如上所述,CCR8可以在腫瘤細胞中過表現,特別是在胃、胰臟、食管、卵巢及肺之腫瘤中。抑制CCR8被證明可用於治療腫瘤。
因此,在一些實施例中,提供了用於治療有需要患者之癌症的方法。在一個實施例中,該方法需要向患者投與有效量之本揭示之抗體。在一些實施例中,患者中之至少一種癌細胞(例如,基質細胞)過表現CCR8。
在本揭示中亦提供了細胞療法,例如嵌合抗原受體(CAR)T細胞療法。可以使用合適之細胞,其與本揭示之抗CCR8抗體接觸(或替代地經工程改造以表現本揭示之抗CCR8抗體)。在一些實施例中,抗體以嵌合抗原受體(CAR)存在。經過此類接觸或工程改造後,然後可以將細胞引入需要治療之癌症患者中。癌症患者可以患有如本文揭示之任何類型之癌症。細胞(例如,T細胞)可為例如腫瘤浸潤性T淋巴細胞、CD4+T細胞、CD8+T細胞或其組合,但不限於此。
在一些實施例中,該細胞係自癌症患者自身分離的。在一些實施例中,該細胞由供體或細胞庫提供。當自癌症患者中分離出細胞時,不期望的免疫反應可以被最小化。
癌症之非限制性實例包括膀胱癌、乳癌、結腸直腸癌、子宮內膜癌、食道癌、頭頸癌、腎癌、白血病、肝癌、肺癌、淋巴瘤、黑色素瘤、胰臟癌、前列腺癌及甲狀腺癌。在一些實施例中,癌症係胃癌、胰臟癌、食道癌、卵巢癌及肺癌中之一種或多種。
可以用本揭示之抗體或其變體或衍生物治療、預防、診斷及/或預後的、與細胞存活增加有關的其他疾病或病症包括但不限於:惡性腫瘤及相關病症之進展及/或轉移,惡性腫瘤及相關病症諸如為白血病(包括急性白血病(例如,急性淋巴細胞白血病、急性髓性白血病(包括骨髓母細胞性、早幼粒細胞性、髓單核細胞性、單核細胞性及紅細胞性白血病))及慢性白血病(例如,慢性髓性(粒細胞性白血病及慢性淋巴細胞性白血病))、真性紅細胞增多症、淋巴瘤(例如霍奇金氏病及非霍奇金氏病)、多發性骨髓瘤、瓦爾登斯特倫巨球蛋白血症(Waldenstrom's macroglobulinemia)、重鏈病及實體瘤,實體瘤包括但不限於肉瘤及癌瘤,例如纖維肉瘤、黏液肉瘤、脂肪肉瘤、軟骨肉瘤、骨原肉瘤、脊索瘤、血管肉瘤、內皮肉瘤、淋巴管肉瘤、淋巴管內皮肉瘤、滑膜瘤、間皮瘤、尤文氏腫瘤(Ewing's tumor)、平滑肌肉瘤、橫紋肌肉瘤、結腸癌、胰臟癌、乳癌、卵巢癌、前列腺癌、鱗狀細胞癌、基底細胞癌、腺癌、汗腺癌、皮脂腺癌、乳頭狀癌、乳頭狀腺癌、囊腺癌、髓樣癌、支氣管癌、腎細胞癌、肝癌、膽管癌、絨毛膜癌、精原細胞瘤、胚胎性癌、威爾姆氏腫瘤(Wilm's tumor)、宮頸癌、睾丸腫瘤、肺癌、小細胞肺癌、膀胱癌、上皮癌、神經膠質瘤、星形細胞瘤、髓母細胞瘤、顱咽管瘤、室管膜瘤、松果體瘤、血管母細胞瘤、聽神經瘤、少突膠質細胞瘤、腦膜瘤(menangioma)、黑色素瘤、神經母細胞瘤及視網膜母細胞瘤。
用於任何特定患者之具體劑量及治療方案將取決於多種因素,包括所使用之特定抗體、其變體或衍生物、患者之年齡、體重、總體健康狀況、性別、飲食、及給藥時間、排泄率、聯合用藥及正在治療之特定疾病之嚴重程度。醫療護理人類員對此等因素之判斷在本領域普通技術範疇內。該量亦將取決於待治療之個體患者、給藥途徑、製劑類型、所用化合物之特性、疾病之嚴重程度及所需之效果。所使用之量可以藉由此項技術中熟知之藥理學及藥代動力學原理確定。
抗體或變體之投與方法包括但不限於皮內、肌內、腹膜內、靜脈內、皮下、鼻內、硬膜外及經口途徑。抗原結合多肽或組合物可以藉由任何方便之途徑投與,例如藉由輸注或團注,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)吸收,並且可以與其他生物活性劑一起投與。因此,含有本揭示之抗原結合多肽之醫藥組合物可以經口、經直腸、非經腸、腦池內、陰道內、腹膜內、局部(如藉由粉劑、軟膏、滴劑或透皮貼劑)、經頰給藥,或作為口腔或鼻腔噴霧劑。
如本文所用之術語「非經腸」係指投與方式,包括靜脈內、肌內、腹膜內、胸骨內、皮下及關節內注射及輸注。
給藥可以係全身的或局部的。此外,可能需要藉由任何合適之途徑(包括腦室內及鞘內注射)將本揭示之抗體引入中樞神經系統;腦室內注射可以藉由腦室內導管來促進,例如,連接至儲液器(諸如Ommaya儲液器)之腦室內導管。亦可以採用肺部給藥,例如,藉由使用吸入器或霧化器,及與霧化劑一起調配。
可能需要將本揭示之抗原結合多肽或組合物局部投與至需要治療之區域;其可以藉由例如但不限於手術期間局部輸注、局部應用(例如手術後與傷口敷料結合)、藉由注射、藉由導管、藉由栓劑或藉由植入物來實現,該植入物係多孔、無孔或凝膠狀材料,包括膜,例如唾液酸膜或纖維。較佳地,當投與本揭示之蛋白質(包括抗體)時,必須注意使用不吸收該蛋白質之材料。
可以藉由標準臨床技術確定可有效治療、抑制及預防炎性、免疫或惡性疾病、病症或病狀之本揭示抗體之量。另外,可以視情況地採用活體外測定來幫助確定最佳劑量範圍。製劑中採用之精確劑量亦取決於給藥途徑及疾病、病症或病狀之嚴重性,並且應根據從業者之判斷及每個患者之情況來決定。有效劑量可以自來自活體外或動物模型測試系統之劑量反應曲線中推斷出來。
作為一般建議,投與至患者之本揭示之抗原結合多肽之劑量通常為0.1 mg/kg至100 mg/kg患者體重,0.1 mg/kg至20 mg/kg患者體重,或1 mg/kg至10 mg/kg患者體重。通常,由於對外源多肽之免疫反應,人類抗體比來自其他物種之抗體在人類活體內具有更長的半衰期。因此,較低劑量之人類抗體及較低頻率之給藥通常係可能的。進一步地,本揭示抗體之給藥劑量及頻率可以藉由修飾(例如脂化)以增強抗體之吸收及組織滲透(例如,進入腦中)來降低。
在另外的實施例中,本揭示之組合物與細胞介素聯合投與。可以與本揭示之組合物一起投與之細胞介素包括但不限於IL-2、IL-3、IL-4、IL-5、IL-6、IL-7、IL-10、IL-12、IL-13、IL-15、抗CD40、CD40L及TNF-α。
在另外的實施例中,本揭示之組合物與其他治療或預防方案(例如放射療法)聯合投與。
診斷方法
在某些腫瘤樣本中觀察到CCR8之過表現,並且具有CCR8過表現細胞之患者可能對用本揭示之抗CCR8抗體之治療有反應。因此,本揭示之抗體亦可以用於診斷及預後目的。
可自患者獲得較佳包括細胞之樣本,該患者可為癌症患者或需要診斷之患者。該細胞係腫瘤組織或腫瘤塊、血液樣本、尿液樣本或來自患者之任何樣本之細胞。在對樣本進行視情況預處理之後,可以在允許抗體與樣本中可能存在之CCR8蛋白相互作用之條件下,將樣本與本揭示之抗體一起孵育。可以使用諸如ELISA的方法,利用抗CCR8抗體,來偵測樣本中CCR8蛋白之存在。
樣本中CCR8蛋白之存在(視情況以一定之量或濃度存在)可以用於診斷癌症,作為患者適合用抗體治療之指示,或作為患者對癌症治療有(或沒有)反應之指示。對於預後方法,可以在開始癌症治療後,在某個階段進行一次、兩次或多次偵測,以指示治療進展。
組合物
本揭示亦提供了醫藥組合物。此類組合物包含有效量之抗體及可接受之載劑。在一些實施例中,該組合物進一步包括第二抗癌劑(例如,免疫檢查點抑制劑)。
在具體實施例中,術語「醫藥學上可接受之」係指由聯邦或州政府之監管機構批准或在美國藥典或其他公認之藥典中列出之用於動物的,更特別地係人類的。進一步地,「醫藥學上可接受之載劑」通常為任何類型之無毒固體、半固體或液體填充劑、稀釋劑、封裝材料或製劑助劑。
術語「載劑」係指與治療劑一起投與之稀釋劑、輔助劑、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、植物或合成來源之彼等者,例如花生油、大豆油、礦物油、芝麻油等。當醫藥組合物靜脈內給藥時,水係較佳之載劑。鹽溶液及葡萄糖水溶液及甘油溶液亦可以用作液體載劑,特別是用於注射溶液。合適之藥物賦形劑包括澱粉、葡萄糖、乳糖、蔗糖、明膠、麥芽、大米、麵粉、白堊、矽膠、硬脂酸鈉、單硬脂酸甘油酯、滑石、氯化鈉、脫脂奶粉、甘油、丙烯、乙二醇、水、乙醇等。若需要,該組合物亦可以含有少量之濕潤劑或乳化劑,或pH緩衝劑,諸如乙酸鹽、檸檬酸鹽或磷酸鹽。亦設想了抗菌劑,諸如苯甲醇或對羥基苯甲酸甲酯;抗氧化劑,諸如抗壞血酸或亞硫酸氫鈉;螯合劑,諸如乙二胺四乙酸;及用於調節張度(tonicity)之試劑,諸如氯化鈉或右旋糖(dextrose)。此等組合物可以採取溶液、懸浮液、乳劑、錠劑、丸劑、膠囊、粉劑、緩釋製劑等形式。該組合物可以與傳統之黏合劑及載劑(例如甘油三酯)一起配製成栓劑。口服製劑可以包括標準載劑,諸如藥用級之甘露醇、乳糖、澱粉、硬脂酸鎂、糖精鈉、纖維素、碳酸鎂等。合適之醫藥載劑之實例在E. W. Martin之Remington's Pharmaceutical Sciences中有描述,其以引用之方式併入本文中。此類組合物將包含治療有效量之抗原結合多肽,較佳地以純化形式,及適量之載劑,以提供用於向患者適當投與之形式。該製劑應適合於給藥方式。可以將非經腸製劑封裝在玻璃或塑料製成之安瓿、一次性注射器或多劑量小瓶中。
在一個實施例中,根據常規程序將該組合物配製成適於靜脈內投與至人類之醫藥組合物。通常,用於靜脈內給藥之組合物係在無菌等滲水性緩衝液中之溶液。必要時,該組合物亦可以包括增溶劑及局部麻醉劑,諸如利多卡因(lignocaine),以減輕注射部位之疼痛。通常,將成分以單位劑型單獨提供或混合提供,例如,作為乾燥之凍乾粉或無水濃縮物提供在密閉容器中,諸如指示活性劑之量之安瓿或小藥囊中。在組合物將藉由輸注投與之情況下,可以用裝有無菌藥用級水或鹽水之輸液瓶分配。在組合物藉由注射投與之情況下,可以提供一安瓿之無菌注射用水或鹽水,以使得可以在投與之前將成分混合。
本揭示之化合物可以配製成中性或鹽形式。醫藥學上可接受之鹽包括彼等與陰離子形成之鹽,例如彼等衍生自鹽酸、磷酸、乙酸、草酸、酒石酸等之鹽,及彼等與陽離子形成之鹽,例如衍生自氫氧化鈉、氫氧化鉀、氫氧化銨、氫氧化鈣、氫氧化鐵、異丙胺、三乙胺、2-乙基胺基乙醇、組胺酸、普魯卡因等之鹽。
實例 實例 1 :針對人類 CCR8 之鼠類單株抗體之產生
用人類CCR8蛋白免疫不同品系之小鼠,並相應產生雜交瘤。選擇CCR8陽性結合子並次選殖。隨後,進行活體外結合及功能篩選,並鑑定具有最高結合親和力及最強功能效力之先導抗體。
下表提供了先導鼠類抗體之VH/VL序列。
表 1. 先導鼠類抗體之 VH/VL 序列
實例 2. 與 U2OS 細胞上之 CCR8 結合
名稱 | 序列 (CDR 有下劃線) | SEQ ID NO: |
137D1H10 VH | EVQLVESGGGLVQPKGSLKLSCTASGFTFN TYAMN WVRQAPGKGLEWVA RIRSKANNYATYYADSVKD RFTISRDDSQRILYLQMNNLKAEDTAMYYCVR DRSRGEDYAMDY WGQGTSVTVSS | 1 |
137D1H10 VL | DIVMTQAAPSVPVTPGESVSISC RSSKSLLHSNGNTYLY WFLQRPGQSPQLLIY RMSNLAS GVPDRFSGSGSGTAFTLRISRVEAEDVGVYYC MQHLEYPFT FGAGTKLELK | 2 |
88D2C6 VH | EVQLVETGGGLVQPKGSLKLSCAASGFTFN PNAMN WVRQAPGKGLEWVA RIRSKSNNYATYYADSVKD RFTISRDDSQSMLYLQMNNLKTEDTAMYYCVR GKDDGYRHYAMDY WGQGTSVTVSS | 3 |
88D2C6 VL | DIVMTQAAPSVPVTPGESVSISC RSSKSLLHSNGNTYLY WFLQRPGQSPQLLIY RMSNLAS GVPDRFSGSGSGTAFTLRISRVEAEDVGVYYC MQHLEYPFT FGAGTKLELK | 2 |
89B6F8 VH | DVKLVESGGGLVKPGGSLKLSCAASGFTFS SYTMS WVRQTPEKRLEWVA TISSGDSYTYYPDSVKG RFTISRDNAKNTLYLRMSSLKSEDTAMYYCTR DHYRYDVYAMDY WGQGTSVTVSS | 4 |
89B6F8 VL | DIVMTQSPSSLTVTAGEKVTMSC KSSQSLLNSGNQKNYLT WYQQKPGQPPKLLIY WASTRES GVPDRFTGSGSGTDFTLTISSVQAEDLAVYYC QNDYSYPLT FGAGTKLELK | 5 |
132H8E10 VH | QVQLKESGPGLVAPSQSLSITCTVSGFSLT GYAVN WVRQPTGKGLEWLG MIWGDGSTDYNSALKS RLSISKDNSKSQVFLKMNSLQTDDTARYYCAR DSLYGNYPAY WGQGTLVTVSA | 6 |
132H8E10 VL | DIQMTQSPSSLSASLGGKVTITC KASQDINKYMA WYQHKPGKGPRLLIH STSTLQP GIPSRFSGSGSGRDYSFSISNLEPEDIATYYC LQYDNLLT FGGGTKLEIK | 7 |
10F11B2 VH | QVQLKESGPGLVQPSQTLSLTCTVSGFSLT SYSVH WVRQHSGKTLVWMG RLWSDGDTSYNSAFTS RLSISRDTSKSQVFLKMNSLQTEDTGTYYCAR KAPNGGAFDY WGQGVMVTVSS | 8 |
10F11B2 VL | QVVLTQPKSVSTSLESTVKLSC KLNSGNIGSYYVH WYQQHEGRSPTNMIY RDDKRPD GVPDRFSGSIDSSSNSAFLTINNVQTEDEAIYFC HSSDSSIKCI FGGGTKLTVL | 9 |
40H10F3 VH | QVQLKESGPGLVQPSQTLSLTCTVSGFSLT SYNVH WVRQPPGKGLEWMG RMRYYGDTSFSSALKS RLSISRDTSKNQVFLKMSSLQTDDTGTYYCTR GPPSYYRGDFFDY WGQGVMVAVSS | 10 |
40H10F3 VL | DIQMTQSPSLLSASVGDRVTINC KASLNINNYLN WYQQKLGEAPKLLID NTNNLQT GIPSRFSGSGSGTDYTLTISNLQPEDFGTYFC FQHNGWPLT FGSGTKLEIK | 11 |
53D6A9 VH | EVQLVESGGSLVQPGRSLKLSCAASGFTYN NYVMA WVRRAPTKGLEWVA SISTDGVSTQYRDSVKG RFTISRDNAKTSLFLHMDSLRSEDTATYYCAK DAARGLYGQGGYFDF WGQGVMVTVSS | 12 |
53D6A9 VL | DIQMTQSPASLSASLGETVSIEC LASEGISNDLA WYQQKSGKSPQLLIY AATRLEG GVPSRFSGSGSGTRFSLKISGMQFEDEADYFC QQSYKYPWT FGGGTKLELK | 13 |
352H11C11 VH | EVQLVETGGGLVQPKGSLKLSCAASGFTFN TNAMN WVRQAPGKGLEWVA RIRSKSNNYATYYADSVKD RFTISRDDSQSILYLQMNNLKTEDTAMYYCVR GGPIYHMDC WGQGTSVTVSS | 14 |
352H11C11 VL | DIVMTQAAPSVPVTPGESVSISC RSSKSLLHSNGNTYLY WFLQRPGQSPQLLIY RMSNLAS GVPDRFSGSGSGTAFTLRISRVEAEDVGVYYC MQHLEYPFT FGSGTKLEIK | 15 |
362G7D3 VH | EVQLVETGGGLVQPKGSLKLSCAASGFTFN TNAMN WVRQAPGKGLEWVA RIRSKSNNYATYYADSVKD RFTISRDDSQSMLYLQMNNLKTEDTAMYYCVR DPGLRQGMDY WGQGTSVTVSS | 16 |
362G7D3 VL | DIVMTQAAPSVPVTPGESVSISC RSSKSLLHSNGNTYLY WFLQRPGQSPQLLIY RMSNLAS GVPDRFSGSGSGTAFTLRISRVEAEDVGVYYC MQHLEYPFT FGSGTKLEIK | 15 |
362H10A3 VH | EVQLVESGGGLVQPKGSLKLSCAASGFTFN TYAMN WVRQAPGKGLEWVA RIRSKSNNYATYYADSVKD RFTISRDDSQSMLYLQMNNLKTEDTAMYYCVR GGGNYRGDYFDY WGQGTTLTVSS | 17 |
362H10A3 VL | DIVMTQAAPSVPVTPGESVSISC RSSKSLLHSNGNTYLY WFLQRPGQSPQLLIY RMSNLAS GVPDRFSGSGSGTAFTLRISRVEAEDVGVYYC MQHLEYPFT FGSGTKLEIK | 15 |
367D10E7 VH | EVQLVESGGGLVQPKGSLKLSCAASGFTFN TYAMN WVRQAPGKGLEWVA RIRSKSNNYATYYADSVKD RFTISRDDSQSMLYLQMNNLKTEDTAMYYCVR YDRSYAMDY WGQGTSVTVSS | 18 |
367D10E7 VL v1 | QIVLTQSPAIMSASPGEKVTITC SASSSVSYMH WFQQKPGTSPKLWIY STSNLAS GVPARFSGSGSGTSYSLTISRMEAEDAATYYC QQRSSYPLT FGAGTKLELK | 19 |
367D10E7 VL v2 | DIVMTQAAPSVPVTPGESVSISC RSSKSLLHSNGNTYLY WFLQRPGQSPQLLIY RMSNLAS GVPDRFSGSGSGTAFTLRISRVEAEDVGVYYC MQHLEYPFT FGAGTKLELK | 2 |
370D2C10 VH | EVQLIETGGGLVQPKGSLKLSCAASGFTFN TNAMN WVRQAPGKDLEWVS RIRTKSNNYATYYADSVKD RFTISRDDSQSMLYLQMNNLKTEDTAMYYCVT GTTVVAKEFAY WGQGTLVTVSA | 20 |
370D2C10 VL | DIVMTQAAPSVPVTPGESVSISC RSSKSLLHSNGNTYLY WFLQRPGQSPHLLIY RMSNLAS GVPDRFSGSGSGTAFTLRISRVEAEDVGVYYC MQHLEYPFT FGSGTKLEIK | 21 |
此實例測試了抗體與U2OS細胞上表現之人類CCR8蛋白結合之活性。
一些上述鑑定之鼠類抗體之嵌合抗體(與人類IgG1恆定區融合)由cDNA表現。將抗體與表現人類CCR8之U2OS細胞一起孵育。在測試之抗體中,88D2C6及137D1H10以劑量依賴性方式表現出比其他抗體高得多的親和力(
圖 1)。
實例 3. ADCC 量測
用過表現CCR8之CHO K1及U2OS細胞量測88D2C6及137D1H10及370D2C10 (均與人類IgG1恆定區融合,在Fc中具有ADCC活化突變)在介導ADCC中之效力。所有三種抗體均表現出高ADCC活性(
圖 2)。
所有三種抗體均表現出有效之ADCC活性。然而,其中,88D2C6具有相當高之效力(對CHO細胞之EC50為0.01743 nM及對U2OS細胞之EC50為0.1108)。
實例 4. 小鼠 mAb 之人源化
88D2C6及352H11C11之鼠類抗體可變區基因用於創建人源化mAb。將mAb之VH及VL之胺基酸序列與人類Ig基因序列之可用數據庫進行比較,以找到總體最佳匹配之人類種系Ig基因序列。然後將鼠類抗體之CDR移植至匹配之人類序列中。合成cDNA並用於生產人源化抗體。然後將來自鼠類抗體之某些回復突變引入回人源化抗體。某些胺基酸被突變以減少轉譯後修飾之機會。
下面提供了人源化抗體之胺基酸序列。
人源化序列 A. 88D2C6 表 2A. 88D2C6 之人源化 –VH
表 2B. CDR 序列
表 2C. 88D2C6 之人源化 –VL
表 2D. CDR 序列
表 2E. 人源化抗體
B. 137D1H10 表 3A. 137D1H10 之人源化 –VH
表 3B. CDR 序列
表 3C. 137D1H10 之人源化 –VL
表 3D. CDR 序列
表 3E. 人源化抗體
實例 5. 人源化抗體測試
名稱 | 序列 | SEQ ID NO: |
88D2C6 VH | EVQLVETGGGLVQPKGSLKLSCAASGFTFN PNAMNWVRQAPGKGLEWVA RIRSKSNNYATYYADSVKDRFTISRDDSQSMLYLQMNNLKTEDTAMYYCVR GKDDGYRHYAMDYWGQGTSVTVSS | 3 |
V1 (CRD移植) | EVQLVESGGGLVQPGGSLKLSCAASGFTFN PNAMNWVRQASGKGLEWVG RIRSKSNNYATYYADSVKDRFTISRDDSKNTAYLQMNSLKTEDTAVYYCTR GKDDGYRHYAMDYWGQGTTVTVSS | 29 |
V2 (具有回復突變) | EVQLVESGGGLVQPGGSLKLSCAASGFTFN PNAMNWVRQASGKGLEWVG RIRSKSNNYATYYADSVKDRFTISRDDSKNTAYLQMN N LKTEDTAVYYC V R GKDDGYRHYAMDYWGQGTTVTVSS | 30 |
V3 (具有回復突變) | EVQLVESGGGLVQPGGSLKLSCAASGFTFN PNAMNWVRQASGKGLEWV A RIRSKSNNYATYYADSVKDRFTISRDDSKNT L YLQMN N LKTEDTAVYYC V R GKDDGYRHYAMDYWGQGTTVTVSS | 31 |
CDR | 序列 | SEQ ID NO: |
CDR-H1 | PNAMN | 22 |
CDR-H2 | RIRSKSNNYATYYADSVKD | 23 |
CDR-H3 | GKDDGYRHYAMDY | 24 |
名稱 | 序列 | SEQ ID NO: |
88D2C6 VL | DIVMTQAAPSVPVTPGESVSISC RSSKSLLHSNGNTYLYWFLQRPGQSPQLLIY RMSNLASGVPDRFSGSGSGTAFTLRISRVEAEDVGVYYC MQHLEYPFTFGAGTKLELK | 2 |
V1 (CRD移植) | DIVMTQSPLSLPVTPGEPASISC RSSKSLLHSN ANTYLY WYLQKPGQSPQLLIY RMSNLASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYC MQHLEYPFTFGGGTKVEIK | 32 |
V2 (具有回復突變) | DIVMTQSPLSLPVTPGEPASISC RSSKSLLHSN ANTYLY W F LQKPGQSPQLLIY RMSNLASGVPDRFSGSGSGT A FTLKISRVEAEDVGVYYC MQHLEYPFTFGGGTKVEIK | 33 |
V3 (具有回復突變) | DIVMTQ A PLSLPVTPGEP V SISC RSSKSLLHSN ANTYLY W F LQKPGQSPQLLIY RMSNLASGVPDRFSGSGSGT A FTLKISRVEAEDVGVYYC MQHLEYPFTFGGGTK L EIK | 34 |
CDR | 序列 | SEQ ID NO: |
CDR-L1 | RSSKSLLHSNGNTYLY | 28 |
CDR-L1 (PM 位點突變) | RSSKSLLHSN A NTYLY | 25 |
CDR-L2 | RMSNLAS | 26 |
CDR-L3 | MQHLEYPFT | 27 |
VL | VL v1 | VL v2 | VL v3 | |
VH | 88-xi | |||
VH v1 | 88-H1L2 | 88-H1L3 | ||
VH v2 | 88-H2L2 | 88-H2L3 | ||
VH v3 | 88-H3L2 | 88-H2L3 |
名稱 | 序列 | SEQ ID NO: |
137D1H10 VH | EVQLVESGGGLVQPKGSLKLSCTASGFTFN TYAMNWVRQAPGKGLEWVA RIRSKANNYATYYADSVKDRFTISRDDSQRILYLQMNNLKAEDTAMYYCVR DRSRGEDYAMDYWGQGTSVTVSS | 1 |
V1 (CRD移植) | EVQLVESGGGLVQPGGSLKLSCAASGFTFN TYAMNWVRQASGKGLEWVG RIRSKANNYATYYADSVKDRFTISRDDSKNTAYLQMNSLKTEDTAVYYCTS DRSRGEDYAMDYWGQGTLVTVSS | 38 |
V2 (具有回復突變) | EVQLVESGGGLVQPGGSLKLSCAASGFTFN TYAMNWVRQASGKGLEWVG RIRSKANNYATYYADSVKDRFTISRDDSKNTAYLQMN N LKTEDTAVYYC VR DRSRGEDYAMDYWGQGTLVTVSS | 39 |
V3 (具有回復突變) | EVQLVESGGGLVQPGGSLKLSCAASGFTFN TYAMNWVRQASGKGLEWV A RIRSKANNYATYYADSVKDRFTISRDDSKNT L YLQMN N LKTEDTAVYYC VR DRSRGEDYAMDYWGQGTLVTVSS | 40 |
CDR | 序列 | SEQ ID NO: |
CDR-H1 | TYAMN | 35 |
CDR-H2 | RIRSKANNYATYYADSVKD | 36 |
CDR-H3 | DRSRGEDYAMDY | 37 |
名稱 | 序列 | SEQ ID NO: |
137D1H10 VL | DIVMTQAAPSVPVTPGESVSISC RSSKSLLHSNGNTYLYWFLQRPGQSPQLLIY RMSNLASGVPDRFSGSGSGTAFTLRISRVEAEDVGVYYC MQHLEYPFTFGAGTKLELK | 2 |
V1(CRD移植) | DIVMTQSPLSLPVTPGEPASISC RSSKSLLHSN ANTYLY WYLQKPGQSPQLLIY RMSNLASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYC MQHLEYPFTFGQGTKLEIK | 41 |
V2 (具有回復突變) | DIVMTQSPLSLPVTPGEPASISC RSSKSLLHSN ANTYLY W F LQKPGQSPQLLIY RMSNLASGVPDRFSGSGSGT A FTLKISRVEAEDVGVYYC MQHLEYPFTFGQGTKLEIK | 42 |
V3 (具有回復突變) | DIVMTQSPLSLPVTPGEP V SISC RSSKSLLHSN ANTYLY W F LQKPGQSPQLLIY RMSNLASGVPDRFSGSGSGT A FTLKISRVEAEDVGVYYC MQHLEYPFTFGQGTKLEIK | 43 |
CDR | 序列 | SEQ ID NO: |
CDR-L1 | RSSKSLLHSNGNTYLY | 28 |
CDR-L1 (PM 位點突變) | RSSKSLLHSN A NTYLY | 25 |
CDR-L2 | RMSNLAS | 26 |
CDR-L3 | MQHLEYPFT | 27 |
VL | VL v1 | VL v2 | VL v3 | |
VH | 137-xi | |||
VH v1 | ||||
VH v2 | 137-H2L2 | 137-H2L3 | ||
VH v3 | 137-H3L2 | 137-H3L3 |
此實例測試了一些人源化抗體對CCR8之結合親和力及其誘導ADCC之能力。
實驗程序類似於實例2至3。
圖 3顯示了88D2C6之人源化抗體之親和力。顯然,其均具有高親和力(亦參見
表 4)。
表 4A. 與 CHO-K1 細胞表現之 CCR8 之結合
表 4B. 與 U2OS 細胞表現之 CCR8 之結合
88-H1L2 | 88-H1L3 | 88-H2L2 | 88-H2L3 | 88-H3L2 | 88-H3L3 | 88-xi | |
最小反應 | 2669 | 2143 | 2494 | 2276 | 3937 | 3474 | 3631 |
最大反應 | 32782 | 31947 | 32830 | 31610 | 32495 | 32214 | 33947 |
LogEC50 | -0.7515 | -0.5189 | -0.6391 | -0.5461 | -0.6861 | -0.5826 | -0.6548 |
希爾斜率 | 1.502 | 1.377 | 1.404 | 1.408 | 1.382 | 1.345 | 1.480 |
EC50 | 0.1772 | 0.3028 | 0.2296 | 0.2844 | 0.2060 | 0.2615 | 0.2214 |
跨度 | 30113 | 29804 | 30336 | 29334 | 28557 | 28740 | 30316 |
88-H1L2 | 88-H1L3 | 88-H2L2 | 88-H2L3 | 88-H3L2 | 88-H3L3 | 88-xi | |
最小反應 | 2106 | 1542 | 2756 | 1530 | 2826 | 1623 | 1027 |
最大反應 | 28891 | 27635 | 28329 | 25780 | 27435 | 27421 | 29659 |
LogEC50 | -0.6779 | -0.5797 | -0.7241 | -0.5119 | -0.6841 | -0.6289 | -0.6921 |
希爾斜率 | 1.409 | 1.387 | 1.524 | 1.450 | 1.521 | 1.378 | 1.097 |
EC50 | 0.2099 | 0.2632 | 0.1888 | 0.3077 | 0.2070 | 0.2350 | 0.2032 |
跨度 | 26785 | 26092 | 25574 | 24250 | 24609 | 25798 | 28632 |
圖 4顯示了137D1H10之人源化抗體之親和力(數據見表5)。
表 5A. 與 CHO-K1 細胞表現之 CCR8 之結合
表 5B. 與 U2OS 細胞表現之 CCR8 之結合
137-H2L2 | 137-H2L3 | 137-H3L2 | 137-H3L3 | 137-xi | |
最小反應 | 2548 | 2244 | 4264 | 3820 | 3032 |
最大反應 | 29347 | 30182 | 33198 | 33389 | 34947 |
LogEC50 | -0.7893 | -0.5055 | -0.6843 | -0.7538 | -0.7792 |
希爾斜率 | 1.141 | 1.272 | 1.592 | 1.449 | 1.581 |
EC50 | 0.1625 | 0.3123 | 0.2069 | 0.1763 | 0.1663 |
跨度 | 26799 | 27937 | 28934 | 29569 | 31915 |
137-H2L2 | 137-H2L3 | 137-H3L2 | 137-H3L3 | 137-xi | |
最小反應 | 915.4 | 1322 | 2065 | 2098 | 2172 |
最大反應 | 26251 | 27254 | 32257 | 31927 | 33430 |
LogEC50 | -0.8422 | -0.4841 | -0.6897 | -0.7169 | -0.6052 |
希爾斜率 | 1.171 | 1.122 | 1.351 | 1.492 | 1.422 |
EC50 | 0.1438 | 0.3280 | 0.2043 | 0.1919 | 0.2482 |
跨度 | 25336 | 25932 | 30192 | 29829 | 31258 |
就ADCC (
圖 5)而言,令人類驚訝的係,所有人源化抗體均表現出比嵌合對應物更高(約5至10倍)的ADCC誘導活性。
實例 6. 基於細胞之抗體結合
此實例將137-H3L2 (LM-108)與參考抗體在基於細胞之結合方面進行了比較。
使用流動式細胞量測術評估了LM-108及參考抗體(根據WO2020138489合成)對過表現人類CCR8之細胞(HEK293/H_CCR8)之基於細胞之結合。將過表現人類CCR8之HEK293 (HEK293/H_CCR8)及親本HEK293細胞與滴定之LM-108、參考抗體及其同型對照(200 nM,4倍稀釋,12個點)在4℃下孵育60分鐘。將細胞用FACS緩衝液洗滌兩次,然後用螢光結合之第二抗體(Alexa Fluor® 647羊抗人類IgG,Jackson,109-605-098)在4℃下染色60分鐘。細胞洗滌兩次後,藉由流動式細胞量測術進行分析。
LM-108及參考抗體均以劑量依賴性方式有效結合HEK293/H_CCR8細胞,EC50分別為1.03 nM及0.99nM (
圖 6a及
表 6A)。對於LM-108沒有觀察到非特異性結合,但參考抗體對親本HEK293細胞顯示出輕微之非特異性結合(
圖 6b及
表 6B)。
表 6A. 與表現 CCR8 之 HEK293 細胞之結合
表 6B. 與不表現 CCR8 之 HEK293 細胞之結合
抗體 | EC50 (nM) | 最大值(MFI) |
LM-108 | 1.028 | 76795 |
參考抗體 | 0.9938 | 86817 |
同型 | 不適用 | 192 |
抗體 | EC50 (nM) | 最大值(MFI) |
LM-108 | 不適用 | 108 |
參考抗體 | 不適用 | 472 |
同型 | 不適用 | 145 |
使用流動式細胞量測術評估了LM-108對具有高CCR8表現量之細胞之基於細胞之結合。所使用之細胞係U2OS(U2OS/H_CCR8)。如
圖 7及
表 7所示,LM-108能夠以劑量依賴之方式有效結合U2OS/H_CCR8細胞,其中EC50為0.25 nM。
表 7. 與高表現 CCR8 之 U2OS 細胞之結合
抗體 | EC50 (nM) | 最大值(MFI) |
LM-108 | 0.2503 | 43087 |
同型 | 不適用 | 215 |
亦使用流動式細胞量測術評估了LM-108對具有低CCR8表現量之細胞之基於細胞之結合。所使用之細胞為Jurkat工程改造細胞(Jurkat/H_CCR8)。如
圖 8及
表 8所示,LM-108能夠以劑量依賴之方式有效結合Jurkat/H_CCR8細胞,其中EC50為0.21 nM。
表 8. 與低表現 CCR8 之 Jurkat 細胞之結合
實例 7. ADCC 報告基因分析
抗體 | EC50 (nM) | 最大值(MFI) |
LM-108 | 0.2124 | 1423 |
同型 | 不適用 | 134 |
此實例顯示了靶向不同表現CCR8之細胞之ADCC報告基因分析之結果。
靶向 U2OS/H_CCR8 之 ADCC 報告基因分析
LM-108之ADCC活性係用報告基因分析評價的,表現CD16a(158v)之Jurkat/NFAT-luc報告細胞作為效應細胞。過表現人類CCR8之U2OS細胞用作目標細胞。U2OS/H_CCR8細胞以每孔1E4細胞之密度接種至96孔板中過夜,然後與每孔1.5×10
5個效應細胞、滴定之LM-108及同型對照按最終濃度10 µg/ml,5倍稀釋,10個點共培養。37℃孵育6小時後,加入One-Glo (Promega)進行發光偵測。
結果顯示於
圖 9中。用Jurkat/CD16a/NFAT-luc報告細胞靶向U2OS/H_CCR8細胞,LM-108表現出有效之ADCC效應(EC50=0.00605nM)。
靶向 Jurkat/H_CCR8 之 ADCC 報告基因測定
LM-108之ADCC活性藉由報告基因測定評價,用表現CD16a (158v)之Jurkat/NFAT-luc報告細胞作為效應細胞。產生低表現人類CCR8之Jurkat細胞作為目標細胞以模擬腫瘤相關Treg之表現量。
效應細胞(Jurkat報告細胞)及目標細胞(Jurkat/H_CCR8)以3:1之比例與滴定之LM-108及同型對照混合(最終濃度200 nM,5倍稀釋,11個點)。37℃孵育6小時後,加入One-Glo (Promega)進行發光偵測。如
圖 10所示,LM-108具有劑量依賴性ADCC效應,EC
50=0.14 nM。
LM-108 對過表現人類 CCR8 之 HEK293(HEK293/H_CCR8) 及 HEK293 細胞與原代人類 PBMC 之 ADCC 作用
效應細胞(hPBMC)及目標細胞(HEK293/H_CCR8或HEK293)以50:1之比例與滴定之LM-108及同型對照(最終濃度10 nM,7倍稀釋,12個點)混合。在37℃下孵育6小時後,藉由細胞毒性偵測試劑盒(Roche,04744934001)分析每孔中之50 µl上清液。
如
圖 11A所示,LM-108以劑量依賴性方式對表現CCR8之HEK293細胞表現出特異性及強之ADCC效應,EC
50為0.002nM(
圖 6a)。對親本HEK293細胞未觀察到非特異性殺傷(
圖 11B)。
實例 8. 抗體依賴性細胞吞噬作用 (ADCP) 之測試
在該實例中,LM-108對過表現人類CCR8之CHO-K1細胞之抗體依賴性細胞吞噬作用(ADCP)係藉由FACS用單核細胞衍生之巨噬細胞(MDM)評價的。
在100 ng/mL人類M-CSF存在下,自分離自人類PBMC之單核細胞誘導效應細胞MDM,持續7天。目標細胞係CHO-K1 (陰性對照)及過表現人類CCR8之CHO-K1細胞,其標記為CFSE。將效應細胞、CFSE標記之目標細胞及滴定之測試抗體LM-108或其同型對照在37℃、5% CO
2之培養箱中孵育2小時。將細胞用FACS緩衝液(1 × DPBS + 2% FBS)洗滌,然後用APC結合之人類CD14抗體染色以鑑定巨噬細胞。用FACS緩衝液洗滌兩次後,藉由流動式細胞量測術分析樣本。吞噬指數確定為CD14-APC+/CFSE+雙陽性細胞占總CD14+陽性細胞之百分比。
如
圖 12A-B所示,LM-108對過表現人類CCR8之CHO-K1細胞具有特異性及劑量依賴性吞噬作用,但對對照細胞沒有。
LM-108與單核細胞衍生之巨噬細胞(MDM)之ADCP亦由Operetta測定。在100 ng/mL人類M-CSF存在下,自分離自人類PBMC之單核細胞誘導效應細胞MDM,持續6天。然後將效應細胞以2 × 10
4計數/孔接種至具有透明底部之黑色96孔板中,並繼續培養2天以進行黏附。目標細胞為Jurkat (陰性對照)及過表現人類CCR8之Jurkat細胞(Jurkat/H_CCR8)。將CFSE標記之目標細胞及測試抗體LM-108或其同型對照加入含有巨噬細胞之平板中,並在37℃、5% CO
2培養箱中孵育2小時。效應細胞:目標細胞比例為1:2。洗滌細胞並用APC結合之人類CD14抗體染色以鑑定巨噬細胞。洗滌兩次後,用4%多聚甲醛(PFA)稀釋液固定細胞,並在藉由Operetta拍照前在4℃冰箱中避光保存。
如
圖 13所示,LM-108對過表現人類CCR8之Jurkat細胞誘導ADCP,而其同型對照則沒有。LM-108及同型對照均未對Jurkat細胞誘導明顯之吞噬作用。
實例 9. 活體內功效
在該實例中,進行了LM-108或其小鼠替代物之活體內功效研究。
第一個實驗係用LM-108m (LM-108之替代抗體(surrogate antibody))在CT26同基因模型上進行的。在本研究中,每隻小鼠在右側腋窩(外側)皮下接種0.1 ml PBS中之CT26腫瘤細胞(5×10
5),用於腫瘤發展。在細胞接種後之第三天將動物隨機分為4組(n=7),然後開始治療。PBS組作為媒劑,LM-108m及mPD-1抗體以10 mg/kg之劑量在第0天、第3天、第7天、第10天、第14天及第17天藉由腹腔(i.p.)作為單一藥劑給藥或聯合給藥。由於對照組之平均腫瘤體積超過2000 mm
3,實驗在第18天終止。
使用卡尺在二維方向上每週量測腫瘤大小三次,並使用以下公式表示體積(以mm
3計):V = 0.5
a × b
2 其中
a及
b分別係腫瘤之長徑及短徑。然後將腫瘤大小用於計算T/C(%)值。T/C(%)使用以下公式計算:T/C % = (T
i-T
0)/(V
i-V
0)×100,T
i為治療組在規定日之平均腫瘤體積,T
0為治療組在治療第一天之平均腫瘤體積,Vi係媒劑對照組在與T
i同一天之平均腫瘤體積,V
0係媒劑組在治療第一天之平均腫瘤體積。使用以下公式計算每組之TGI:TGI (%) = [100-T/C]。
圖 14顯示了CT26荷瘤Balb/c小鼠在投與LM-108m及抗mPD-1 Ab後之腫瘤生長曲線。LM-108m作為單一藥劑或與mPD-1抗體聯合顯示出強之抗腫瘤活性(表9)。數據點代表組(n=7)平均值,誤差條代表平均值之標準誤差(SEM)。與使用PBS之媒劑對照相比,藉由t-檢驗基於腫瘤大小計算p值。
表 9. 活體內功效 (CT26 同基因模型 )
治療後天數 T/C(%) | 0 | 3 | 6 | 9 | 12 | 15 | 18 |
G2: LM-108m 10mpk | - | 72.161 | 86.504 | 54.453 | 47.024 | 35.639 | 28.219 |
G3: 抗mPD-1 Ab 10mpk | - | 59.926 | 70.322 | 44.463 | 38.057 | 35.773 | 38.326 |
G4: LM-108m+mPD-1 Ab | - | 70.506 | 60.774 | 35.973 | 27.413 | 20.386 | 15.292 |
治療後天數 TGI(%) | 0 | 3 | 6 | 9 | 12 | 15 | 18 |
G2: LM-108m 10mpk | - | 27.839 | 13.496 | 45.547 | 52.976 | 64.361 | 71.781 |
G3: 抗mPD-1 Ab 10mpk | - | 40.074 | 29.678 | 55.537 | 61.943 | 64.227 | 61.674 |
G4: LM-108m+mPD-1 Ab | - | 29.494 | 39.226 | 64.027 | 72.587 | 79.614 | 84.708 |
治療後天數 P 值 | 0 | 3 | 6 | 9 | 12 | 15 | 18 |
G2: LM-108m 10mpk | - | 0.053 | 0.385 | 0.024 | 0.026 | 0.025 | 0.023 |
G3: 抗mPD-1 Ab 10mpk | - | 0.024 | 0.073 | 0.007 | 0.008 | 0.026 | 0.044 |
G4: LM-108m+mPD-1 Ab | - | 0.037 | 0.017 | 0.002 | 0.006 | 0.01 | 0.012 |
第二個實驗使購自從BIOCYTOGEN之人類CCR8 ki小鼠。每隻hCCR8 ki小鼠在右側腋窩(外側)皮下接種在0.1 ml PBS中之MC38腫瘤細胞(1×10
6),用於腫瘤發展。在細胞接種後之第三天將動物隨機分組,然後開始治療以進行功效研究。在第0天、第3天、第7天、第10天藉由腹腔(i.p.)投與10 mg/kg劑量之LM-108。當對照組之平均腫瘤體積超過2000 mm
3時終止實驗。
使用卡尺在二維方向上每週量測腫瘤大小三次,並使用以下公式表示體積(以mm
3計):V = 0.5
a×
b
2 ,其中
a及
b分別係腫瘤之長徑及短徑。然後將腫瘤大小用於計算T/C(%)值。T/C(%)使用以下公式計算:T/C % = (T
i-T
0)/(V
i-V
0)×100,T
i為治療組在規定日之平均腫瘤體積,T
0為治療組在治療第一天之平均腫瘤體積,Vi係媒劑對照組在與T
i同一天之平均腫瘤體積,V
0係媒劑組在治療第一天之平均腫瘤體積。使用以下公式計算每組之TGI:TGI (%) = [100-T/C]。數據點代表組(n=8)平均值,誤差條代表平均值之標準誤差(SEM)。與媒劑對照相比,藉由t-檢驗基於腫瘤大小計算p值。
圖 15顯示了MC38荷瘤小鼠在投與LM-108後之腫瘤生長曲線,數據彙總於表10中。LM-108顯示出有效之腫瘤抑制效果。
表 10. 活體內功效 (MC38 同基因模型 )
實例 10. 細胞毒性評估
P 值 | 治療後天數 | |||||||
0 | 2 | 4 | 7 | 9 | 11 | 14 | ||
LM-108 相較於媒劑 | - | 0.985 | 0.503 | 0.042 | 0.002 | 0 | 0.001 | |
T/C(%) | 治療後天數 | |||||||
0 | 3 | 5 | 7 | 10 | 12 | 14 | ||
LM-108 相較於媒劑 | - | 99.68 | 95.326 | 73.673 | 47.349 | 34.464 | 31.23 | |
TGI(%) | 治療後天數 | |||||||
0 | 3 | 5 | 7 | 10 | 12 | 14 | ||
LM-108 相較於媒劑 | - | 0.32 | 4.674 | 26.327 | 52.651 | 65.536 | 68.77 |
此實例評價了抗體-藥物結合物LM-108-vc-MMAE (單甲基奧瑞他汀E)對表現人類CCR8之HEK293細胞之細胞毒性。
為了評價LM-108是否可用於ADC開發,藉由共培養表現人類CCR8之HEK293細胞及LM-108-vc-MMAE之滴定ADC來評價MMAE結合之LM-108之細胞毒性。
HEK293/H_CCR8細胞以每孔1.5×10
4個細胞之密度接種至96孔板中過夜,然後與滴定之LM-108-vc-MMAE共培養,達到最終濃度100 nm,3倍稀釋,9個點。在37℃下孵育96小時後,加入Cell-Titer-Glo (Promega)進行細胞活力評價。
如
圖 16所示,MMAE結合之LM-108對表現人類CCR8之HEK293細胞具有有效之細胞毒性(IC50=0.5285nM)。
* * *
本揭示之範疇不受所描述之具體實施例之限制,該等具體實施例旨在作為本揭示之個別態樣之單一說明,並且任何在功能上等效之組合物或方法均在本揭示之範疇內。對熟習此項技術者明顯的係,在不脫離本揭示之精神或範疇之情況下,可以對本揭示的方法及組合物進行各種修改及變化。因此,本揭示旨在覆蓋本揭示之修改及變化,只要此等修改及變化落入所附申請專利範圍及其等效物之範疇內。
本說明書中提及之所有出版物及專利申請均以引用方式併入本文,其程度就如同每個單獨之出版物或專利申請被特別地及單獨地指示為以引用方式併入一樣。
圖 1顯示具有鼠類VH/VL之嵌合抗體之CCR8結合親和力。
圖 2顯示三種嵌合抗體之ADCC活性。
圖 3顯示人源化88D2C6抗體具有高親和力。
圖 4顯示人源化137D1H10抗體具有高親和力。
圖 5顯示,與嵌合抗體相比,人源化抗體具有顯著更高之ADCC活性。
圖 6顯示LM-108及參考抗體與人類CCR8藉由流動式細胞量測術之基於細胞之結合之結果。上圖:LM-108在表現人類CCR8之HEK293上之FACS結合。下圖:LM-108在HEK293細胞上之FACS結合。
圖 7顯示LM-108與高表現人類CCR8之U2OS細胞藉由流動式細胞量測術之基於細胞之結合。
圖 8顯示LM-108與低表現人類CCR8之Jurkat細胞藉由流動式細胞量測術之基於細胞之結合。
圖 9顯示用Jurkat/CD16a(158v)/NFAT-luc細胞、靶向高表現CCR8之U2OS細胞進行之LM-108的ADCC報告基因分析之結果。
圖 10顯示用Jurkat/CD16a(158v)/NFAT細胞、靶向低表現CCR8之Jurkat細胞進行之LM-108的ADCC報告基因分析之結果。
圖 11顯示用hPBMC靶向表現CCR8之細胞(上圖)或對照細胞(下圖)之LM-108的ADCC檢驗結果。
圖 12顯示LM-108與單核細胞衍生之巨噬細胞藉由FACS之ADCP。上圖:LM-108 LM-108對過表現人類CCR8之CHO-K1細胞之ADCP。下圖:LM-108 LM-108對對照CHO-K1細胞之ADCP。
圖 13顯示LM-108與單核細胞衍生之巨噬細胞藉由Operetta之ADCP成像結果。
圖 14顯示在LM-108m對BALB/c小鼠之CT26同基因模型之活體內功效研究中,在投與LM-108m及抗mPD-1 Ab後CT26荷瘤小鼠之腫瘤生長曲線。
圖 15顯示在LM-108對hCCR8 ki小鼠之MC38同基因模型之活體內功效研究中,在投與LM-108m及媒劑後MC38荷瘤小鼠之腫瘤生長曲線。
圖 16顯示LM-108-vc-MMAE對表現hCCR8之細胞之細胞毒性評價結果。
<![CDATA[<110> 中國大陸商禮新醫藥科技(上海)有限公司(LANOVA MEDICINES LIMITED)]]> <![CDATA[<120> 抗CCR8單株抗體及其用途]]> <![CDATA[<130> 70LG-322175-TW]]> <![CDATA[<160> 43 ]]> <![CDATA[<170> PatentIn version 3.5]]> <![CDATA[<210> 1]]> <![CDATA[<211> 123]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 1]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Lys Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Asn Thr Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Arg Ser Lys Ala Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp 50 55 60 Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Gln Arg Ile 65 70 75 80 Leu Tyr Leu Gln Met Asn Asn Leu Lys Ala Glu Asp Thr Ala Met Tyr 85 90 95 Tyr Cys Val Arg Asp Arg Ser Arg Gly Glu Asp Tyr Ala Met Asp Tyr 100 105 110 Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser 115 120 <![CDATA[<210> 2]]> <![CDATA[<211> 112]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 2]]> Asp Ile Val Met Thr Gln Ala Ala Pro Ser Val Pro Val Thr Pro Gly 1 5 10 15 Glu Ser Val Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser 20 25 30 Asn Gly Asn Thr Tyr Leu Tyr Trp Phe Leu Gln Arg Pro Gly Gln Ser 35 40 45 Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Ala Phe Thr Leu Arg Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln His 85 90 95 Leu Glu Tyr Pro Phe Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys 100 105 110 <![CDATA[<210> 3]]> <![CDATA[<211> 124]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 3]]> Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Lys Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Pro Asn 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Arg Ser Lys Ser Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp 50 55 60 Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Gln Ser Met 65 70 75 80 Leu Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Met Tyr 85 90 95 Tyr Cys Val Arg Gly Lys Asp Asp Gly Tyr Arg His Tyr Ala Met Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser 115 120 <![CDATA[<210> 4]]> <![CDATA[<211> 121]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 4]]> Asp Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Thr Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu Glu Trp Val 35 40 45 Ala Thr Ile Ser Ser Gly Asp Ser Tyr Thr Tyr Tyr Pro Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Arg Met Ser Ser Leu Lys Ser Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Thr Arg Asp His Tyr Arg Tyr Asp Val Tyr Ala Met Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Ser Val Thr Val Ser Ser 115 120 <![CDATA[<210> 5]]> <![CDATA[<211> 113]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 5]]> Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Thr Val Thr Ala Gly 1 5 10 15 Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser 20 25 30 Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Asn 85 90 95 Asp Tyr Ser Tyr Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu 100 105 110 Lys <![CDATA[<210> 6]]> <![CDATA[<211> 118]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 6]]> Gln Val Gln Leu Lys Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln 1 5 10 15 Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Gly Tyr 20 25 30 Ala Val Asn Trp Val Arg Gln Pro Thr Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Met Ile Trp Gly Asp Gly Ser Thr Asp Tyr Asn Ser Ala Leu Lys 50 55 60 Ser Arg Leu Ser Ile Ser Lys Asp Asn Ser Lys Ser Gln Val Phe Leu 65 70 75 80 Lys Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Arg Tyr Tyr Cys Ala 85 90 95 Arg Asp Ser Leu Tyr Gly Asn Tyr Pro Ala Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ala 115 <![CDATA[<210> 7]]> <![CDATA[<211> 106]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 7]]> Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Leu Gly 1 5 10 15 Gly Lys Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Ile Asn Lys Tyr 20 25 30 Met Ala Trp Tyr Gln His Lys Pro Gly Lys Gly Pro Arg Leu Leu Ile 35 40 45 His Ser Thr Ser Thr Leu Gln Pro Gly Ile Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Arg Asp Tyr Ser Phe Ser Ile Ser Asn Leu Glu Pro 65 70 75 80 Glu Asp Ile Ala Thr Tyr Tyr Cys Leu Gln Tyr Asp Asn Leu Leu Thr 85 90 95 Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 <![CDATA[<210> 8]]> <![CDATA[<211> 118]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 8]]> Gln Val Gln Leu Lys Glu Ser Gly Pro Gly Leu Val Gln Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr 20 25 30 Ser Val His Trp Val Arg Gln His Ser Gly Lys Thr Leu Val Trp Met 35 40 45 Gly Arg Leu Trp Ser Asp Gly Asp Thr Ser Tyr Asn Ser Ala Phe Thr 50 55 60 Ser Arg Leu Ser Ile Ser Arg Asp Thr Ser Lys Ser Gln Val Phe Leu 65 70 75 80 Lys Met Asn Ser Leu Gln Thr Glu Asp Thr Gly Thr Tyr Tyr Cys Ala 85 90 95 Arg Lys Ala Pro Asn Gly Gly Ala Phe Asp Tyr Trp Gly Gln Gly Val 100 105 110 Met Val Thr Val Ser Ser 115 <![CDATA[<210> 9]]> <![CDATA[<211> 111]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 9]]> Gln Val Val Leu Thr Gln Pro Lys Ser Val Ser Thr Ser Leu Glu Ser 1 5 10 15 Thr Val Lys Leu Ser Cys Lys Leu Asn Ser Gly Asn Ile Gly Ser Tyr 20 25 30 Tyr Val His Trp Tyr Gln Gln His Glu Gly Arg Ser Pro Thr Asn Met 35 40 45 Ile Tyr Arg Asp Asp Lys Arg Pro Asp Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Ile Asp Ser Ser Ser Asn Ser Ala Phe Leu Thr Ile Asn Asn 65 70 75 80 Val Gln Thr Glu Asp Glu Ala Ile Tyr Phe Cys His Ser Ser Asp Ser 85 90 95 Ser Ile Lys Cys Ile Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <![CDATA[<210> 10]]> <![CDATA[<211> 121]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 10]]> Gln Val Gln Leu Lys Glu Ser Gly Pro Gly Leu Val Gln Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr 20 25 30 Asn Val His Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Met 35 40 45 Gly Arg Met Arg Tyr Tyr Gly Asp Thr Ser Phe Ser Ser Ala Leu Lys 50 55 60 Ser Arg Leu Ser Ile Ser Arg Asp Thr Ser Lys Asn Gln Val Phe Leu 65 70 75 80 Lys Met Ser Ser Leu Gln Thr Asp Asp Thr Gly Thr Tyr Tyr Cys Thr 85 90 95 Arg Gly Pro Pro Ser Tyr Tyr Arg Gly Asp Phe Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Val Met Val Ala Val Ser Ser 115 120 <![CDATA[<210> 11]]> <![CDATA[<211> 107]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 11]]> Asp Ile Gln Met Thr Gln Ser Pro Ser Leu Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Asn Cys Lys Ala Ser Leu Asn Ile Asn Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Leu Gly Glu Ala Pro Lys Leu Leu Ile 35 40 45 Asp Asn Thr Asn Asn Leu Gln Thr Gly Ile Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Asn Leu Gln Pro 65 70 75 80 Glu Asp Phe Gly Thr Tyr Phe Cys Phe Gln His Asn Gly Trp Pro Leu 85 90 95 Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys 100 105 <![CDATA[<210> 12]]> <![CDATA[<211> 124]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 12]]> Glu Val Gln Leu Val Glu Ser Gly Gly Ser Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Tyr Asn Asn Tyr 20 25 30 Val Met Ala Trp Val Arg Arg Ala Pro Thr Lys Gly Leu Glu Trp Val 35 40 45 Ala Ser Ile Ser Thr Asp Gly Val Ser Thr Gln Tyr Arg Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Ser Leu Phe 65 70 75 80 Leu His Met Asp Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys 85 90 95 Ala Lys Asp Ala Ala Arg Gly Leu Tyr Gly Gln Gly Gly Tyr Phe Asp 100 105 110 Phe Trp Gly Gln Gly Val Met Val Thr Val Ser Ser 115 120 <![CDATA[<210> 13]]> <![CDATA[<211> 107]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 13]]> Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ser Ala Ser Leu Gly 1 5 10 15 Glu Thr Val Ser Ile Glu Cys Leu Ala Ser Glu Gly Ile Ser Asn Asp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Ser Gly Lys Ser Pro Gln Leu Leu Ile 35 40 45 Tyr Ala Ala Thr Arg Leu Glu Gly Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Arg Phe Ser Leu Lys Ile Ser Gly Met Gln Phe 65 70 75 80 Glu Asp Glu Ala Asp Tyr Phe Cys Gln Gln Ser Tyr Lys Tyr Pro Trp 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Leu Lys 100 105 <![CDATA[<210> 14]]> <![CDATA[<211> 120]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 14]]> Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Lys Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Asn 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Arg Ser Lys Ser Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp 50 55 60 Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Gln Ser Ile 65 70 75 80 Leu Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Met Tyr 85 90 95 Tyr Cys Val Arg Gly Gly Pro Ile Tyr His Met Asp Cys Trp Gly Gln 100 105 110 Gly Thr Ser Val Thr Val Ser Ser 115 120 <![CDATA[<210> 15]]> <![CDATA[<211> 112]]> <![CDATA[<212>]]> PRT <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 15]]> Asp Ile Val Met Thr Gln Ala Ala Pro Ser Val Pro Val Thr Pro Gly 1 5 10 15 Glu Ser Val Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser 20 25 30 Asn Gly Asn Thr Tyr Leu Tyr Trp Phe Leu Gln Arg Pro Gly Gln Ser 35 40 45 Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Ala Phe Thr Leu Arg Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln His 85 90 95 Leu Glu Tyr Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys 100 105 110 <![CDATA[<210> 16]]> <![CDATA[<211> 121]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 16]]> Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Lys Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Asn 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Arg Ser Lys Ser Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp 50 55 60 Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Gln Ser Met 65 70 75 80 Leu Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Met Tyr 85 90 95 Tyr Cys Val Arg Asp Pro Gly Leu Arg Gln Gly Met Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Ser Val Thr Val Ser Ser 115 120 <![CDATA[<210> 17]]> <![CDATA[<211> 123]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 17]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Lys Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Arg Ser Lys Ser Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp 50 55 60 Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Gln Ser Met 65 70 75 80 Leu Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Met Tyr 85 90 95 Tyr Cys Val Arg Gly Gly Gly Asn Tyr Arg Gly Asp Tyr Phe Asp Tyr 100 105 110 Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser 115 120 <![CDATA[<210> 18]]> <![CDATA[<211> 120]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 18]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Lys Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Arg Ser Lys Ser Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp 50 55 60 Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Gln Ser Met 65 70 75 80 Leu Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Met Tyr 85 90 95 Tyr Cys Val Arg Tyr Asp Arg Ser Tyr Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Ser Val Thr Val Ser Ser 115 120 <![CDATA[<210> 19]]> <![CDATA[<211> 106]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 19]]> Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly 1 5 10 15 Glu Lys Val Thr Ile Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met 20 25 30 His Trp Phe Gln Gln Lys Pro Gly Thr Ser Pro Lys Leu Trp Ile Tyr 35 40 45 Ser Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Met Glu Ala Glu 65 70 75 80 Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Arg Ser Ser Tyr Pro Leu Thr 85 90 95 Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys 100 105 <![CDATA[<210> 20]]> <![CDATA[<211> 122]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 20]]> Glu Val Gln Leu Ile Glu Thr Gly Gly Gly Leu Val Gln Pro Lys Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Asn 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Asp Leu Glu Trp Val 35 40 45 Ser Arg Ile Arg Thr Lys Ser Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp 50 55 60 Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Gln Ser Met 65 70 75 80 Leu Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Met Tyr 85 90 95 Tyr Cys Val Thr Gly Thr Thr Val Val Ala Lys Glu Phe Ala Tyr Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ala 115 120 <![CDATA[<210> 21]]> <![CDATA[<211> 112]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 21]]> Asp Ile Val Met Thr Gln Ala Ala Pro Ser Val Pro Val Thr Pro Gly 1 5 10 15 Glu Ser Val Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser 20 25 30 Asn Gly Asn Thr Tyr Leu Tyr Trp Phe Leu Gln Arg Pro Gly Gln Ser 35 40 45 Pro His Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Ala Phe Thr Leu Arg Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln His 85 90 95 Leu Glu Tyr Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys 100 105 110 <![CDATA[<210> 22]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 22]]> Pro Asn Ala Met Asn 1 5 <![CDATA[<210> 23]]> <![CDATA[<211> 19]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 23]]> Arg Ile Arg Ser Lys Ser Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser 1 5 10 15 Val Lys Asp <![CDATA[<210> 24]]> <![CDATA[<211> 13]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 24]]> Gly Lys Asp Asp Gly Tyr Arg His Tyr Ala Met Asp Tyr 1 5 10 <![CDATA[<210> 25]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 25]]> Arg Ser Ser Lys Ser Leu Leu His Ser Asn Ala Asn Thr Tyr Leu Tyr 1 5 10 15 <![CDATA[<210> 26]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 26]]> Arg Met Ser Asn Leu Ala Ser 1 5 <![CDATA[<210> 27]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 27]]> Met Gln His Leu Glu Tyr Pro Phe Thr 1 5 <![CDATA[<210> 28]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 28]]> Arg Ser Ser Lys Ser Leu Leu His Ser Asn Gly Asn Thr Tyr Leu Tyr 1 5 10 15 <![CDATA[<210> 29]]> <![CDATA[<211> 124]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 29]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Pro Asn 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Ser Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly Arg Ile Arg Ser Lys Ser Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp 50 55 60 Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr 65 70 75 80 Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr 85 90 95 Tyr Cys Thr Arg Gly Lys Asp Asp Gly Tyr Arg His Tyr Ala Met Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <![CDATA[<210> 30]]> <![CDATA[<211> 124]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 30]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Pro Asn 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Ser Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly Arg Ile Arg Ser Lys Ser Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp 50 55 60 Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr 65 70 75 80 Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr 85 90 95 Tyr Cys Val Arg Gly Lys Asp Asp Gly Tyr Arg His Tyr Ala Met Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <![CDATA[<210> 31]]> <![CDATA[<211> 124]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 31]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Pro Asn 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Ser Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Arg Ser Lys Ser Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp 50 55 60 Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr 65 70 75 80 Leu Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr 85 90 95 Tyr Cys Val Arg Gly Lys Asp Asp Gly Tyr Arg His Tyr Ala Met Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <![CDATA[<210> 32]]> <![CDATA[<211> 112]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 32]]> Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly 1 5 10 15 Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser 20 25 30 Asn Ala Asn Thr Tyr Leu Tyr Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln His 85 90 95 Leu Glu Tyr Pro Phe Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110 <![CDATA[<210> 33]]> <![CDATA[<211> 112]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 33]]> Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly 1 5 10 15 Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser 20 25 30 Asn Ala Asn Thr Tyr Leu Tyr Trp Phe Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Ala Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln His 85 90 95 Leu Glu Tyr Pro Phe Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110 <![CDATA[<210> 34]]> <![CDATA[<211> 112]]> <![CDATA[<212> P]]>RT <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 34]]> Asp Ile Val Met Thr Gln Ala Pro Leu Ser Leu Pro Val Thr Pro Gly 1 5 10 15 Glu Pro Val Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser 20 25 30 Asn Ala Asn Thr Tyr Leu Tyr Trp Phe Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Ala Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln His 85 90 95 Leu Glu Tyr Pro Phe Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110 <![CDATA[<210> 35]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 35]]> Thr Tyr Ala Met Asn 1 5 <![CDATA[<210> ]]> 36 <![CDATA[<211> 19]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 36]]> Arg Ile Arg Ser Lys Ala Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser 1 5 10 15 Val Lys Asp <![CDATA[<210> 37]]> <![CDATA[<211> 12]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 37]]> Asp Arg Ser Arg Gly Glu Asp Tyr Ala Met Asp Tyr 1 5 10 <![CDATA[<210> 38]]> <![CDATA[<211> 123]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 38]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Ser Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly Arg Ile Arg Ser Lys Ala Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp 50 55 60 Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr 65 70 75 80 Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr 85 90 95 Tyr Cys Thr Ser Asp Arg Ser Arg Gly Glu Asp Tyr Ala Met Asp Tyr 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <![CDATA[<210> 39]]> <![CDATA[<211> 123]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 39]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Ser Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly Arg Ile Arg Ser Lys Ala Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp 50 55 60 Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr 65 70 75 80 Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr 85 90 95 Tyr Cys Val Arg Asp Arg Ser Arg Gly Glu Asp Tyr Ala Met Asp Tyr 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <![CDATA[<210> 40]]> <![CDATA[<211> 123]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 40]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Ser Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Arg Ser Lys Ala Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp 50 55 60 Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr 65 70 75 80 Leu Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr 85 90 95 Tyr Cys Val Arg Asp Arg Ser Arg Gly Glu Asp Tyr Ala Met Asp Tyr 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <![CDATA[<210> 41]]> <![CDATA[<211> 112]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 41]]> Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly 1 5 10 15 Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser 20 25 30 Asn Ala Asn Thr Tyr Leu Tyr Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln His 85 90 95 Leu Glu Tyr Pro Phe Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 110 <![CDATA[<210> 42]]> <![CDATA[<211> 112]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 42]]> Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly 1 5 10 15 Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser 20 25 30 Asn Ala Asn Thr Tyr Leu Tyr Trp Phe Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Ala Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln His 85 90 95 Leu Glu Tyr Pro Phe Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 110 <![CDATA[<210> 43]]> <![CDATA[<211> 112]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 43]]> Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly 1 5 10 15 Glu Pro Val Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser 20 25 30 Asn Ala Asn Thr Tyr Leu Tyr Trp Phe Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Ala Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln His 85 90 95 Leu Glu Tyr Pro Phe Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 110
Claims (17)
- 一種對人類趨化因子(C-C模體)受體8 (CCR8)蛋白具有結合特異性之抗體或其片段,其中該抗體或其片段包含重鏈可變區及輕鏈可變區,該重鏈可變區包含重鏈互補決定區CDRH1、CDRH2及CDRH3,該輕鏈可變區包含輕鏈互補決定區CDRL1、CDRL2及CDRL3,並且其中: (a) 該CDRH1包含SEQ ID NO: 35之胺基酸序列, 該CDRH2包含SEQ ID NO: 36之胺基酸序列, 該CDRH3包含SEQ ID NO: 37之胺基酸序列, 該CDRL1包含SEQ ID NO: 25或28之胺基酸序列, 該CDRL2包含SEQ ID NO: 26之胺基酸序列,且 該CDRL3包含SEQ ID NO: 27之胺基酸序列,或 (b) 該CDRH1包含SEQ ID NO: 22之胺基酸序列, 該CDRH2包含SEQ ID NO: 23之胺基酸序列, 該CDRH3包含SEQ ID NO: 24之胺基酸序列, 該CDRL1包含SEQ ID NO: 25或28之胺基酸序列, 該CDRL2包含SEQ ID NO: 26之胺基酸序列,且 該CDRL3包含SEQ ID NO: 27之胺基酸序列。
- 如請求項1之抗體或其片段,其中該CDRH1包含SEQ ID NO: 35之胺基酸序列,該CDRH2包含SEQ ID NO: 36之胺基酸序列,該CDRH3包含SEQ ID NO: 37之胺基酸序列,該CDRL1包含SEQ ID NO: 25之胺基酸序列,該CDRL2包含SEQ ID NO: 26之胺基酸序列,並且該CDRL3包含SEQ ID NO: 27之胺基酸序列。
- 如請求項2之抗體或其片段,其中該重鏈可變區包含選自由SEQ ID NO: 38-40組成之群的胺基酸序列,並且該輕鏈可變區包含選自由SEQ ID NO: 32-34及41-43組成之群的胺基酸序列。
- 如請求項2之抗體或其片段,其中該重鏈可變區包含SEQ ID NO: 40之胺基酸序列,並且該輕鏈可變區包含SEQ ID NO: 42之胺基酸序列。
- 如請求項1之抗體或其片段,其中該CDRH1包含SEQ ID NO: 22之胺基酸序列,該CDRH2包含SEQ ID NO: 23之胺基酸序列,該CDRH3包含SEQ ID NO: 24之胺基酸序列,該CDRL1包含SEQ ID NO: 25之胺基酸序列,該CDRL2包含SEQ ID NO: 26之胺基酸序列,並且該CDRL3包含SEQ ID NO: 27之胺基酸序列。
- 如請求項5之抗體或其片段,其中該重鏈可變區包含選自由SEQ ID NO: 29-31組成之群的胺基酸序列,並且該輕鏈可變區包含選自由SEQ ID NO: 32-34及41-43組成之群的胺基酸序列。
- 如請求項5之抗體或其片段,其中該重鏈可變區包含SEQ ID NO: 29之胺基酸序列,並且該輕鏈可變區包含SEQ ID NO: 33之胺基酸序列。
- 如請求項1至7中任一項之抗體或其片段,其係人源化的。
- 一種抗體或其片段,其對人類趨化因子(C-C模體)受體8 (CCR8)蛋白具有結合特異性,並且與如請求項1之抗體或其片段結合CCR8蛋白上之相同抗原決定基,或與如請求項1之抗體或其片段競爭結合CCR8蛋白。
- 如請求項1至9中任一項之抗體或其片段,其能夠介導抗體依賴性細胞毒性(ADCC)。
- 如請求項10之抗體或其片段,其係未去岩藻糖基化的。
- 如請求項1至11中任一項之抗體或其片段,其進一步對第二目標蛋白具有結合特異性。
- 一種組合物,其包含如請求項1至12中任一項之抗體或其片段及醫藥學上可接受之載劑。
- 如請求項13之組合物,其進一步包含對腫瘤抗原具有特異性之第二抗體。
- 一種治療有需要患者之癌症的方法,其包含向該患者投與如請求項1至12中任一項之抗體或其片段。
- 一種如請求項1至12中任一項之抗體或其片段在製備用於治療癌症之藥物中之用途。
- 如請求項15之方法或如請求項16之用途,其中該癌症選自由以下組成之群:膀胱癌、肝癌、結腸癌、直腸癌、子宮內膜癌、白血病、淋巴瘤、胰臟癌、小細胞肺癌、非小細胞肺癌、乳癌、尿道癌、頭頸癌、胃腸癌、胃癌、食道癌、卵巢癌、腎癌、黑色素瘤、前列腺癌及甲狀腺癌。
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