TW201512220A - 抗cd37抗體 - Google Patents
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- TW201512220A TW201512220A TW103121994A TW103121994A TW201512220A TW 201512220 A TW201512220 A TW 201512220A TW 103121994 A TW103121994 A TW 103121994A TW 103121994 A TW103121994 A TW 103121994A TW 201512220 A TW201512220 A TW 201512220A
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Abstract
嵌合及人化抗CD37抗體及含其之醫藥組合物可用於治療B細胞惡性腫瘤及病理學涉及B細胞之自體免疫及發炎疾病。
Description
本發明係關於基於B細胞去除之免疫療法。詳言之,本發明係關於用於該等療法(例如,治療B細胞惡性腫瘤及自體免疫病狀)中之抗CD37抗體分子。
使用單株抗體(mAb)之免疫療法已呈現為一種用於治療癌症及其他疾病之安全及選擇性方法。詳言之,自引入利妥昔單抗(rituximab)(Rituxan®)(針對B細胞表面上之CD20抗原之抗體)以來,單株抗體在基於B細胞去除之療法(例如,B細胞惡性腫瘤之治療)中的作用已得到擴展。大量研究已證實呈單一藥劑及組合療法形式之利妥昔單抗在輕度NHL(Hiddemann等人,2005a;Hiddemann等人,2005b;Hainsworth 2004;McLaughlin等人,1998)、套細胞淋巴瘤(Forstpointner等人,2004;Kahl等人,2006;Foran等人,2000;Howard等人,2002;Romaguera等人,2005)、彌漫性大細胞淋巴瘤(DLCL)(Coiffier等人,1998;Feugier等人,2005)及伯基特(Burkitt)白血病/淋巴瘤(Thomas等人,2006)中的功效。然而,僅一部分患者對療法起反應且其中大多數患者在利妥昔單抗治療後最終復發。因此,已尋求對B細胞惡性腫瘤療法而言比CD20潛在有效之新的B細胞治療標靶(Zhao等人,2007)。
CD37抗原為迄今為止尚未以與B細胞抗原CD20相同之程度被視
為B細胞惡性腫瘤之標靶的細胞表面抗原。
CD37(四跨膜蛋白(tetraspanin)超家族之成員)為具有四個跨膜域及兩個細胞外環之高度糖基化細胞表面分子。CD37幾乎僅在成熟B細胞上表現,其中在外周血B細胞上表現程度最高,在漿細胞上表現程度降低,且在骨髓中之CD10+前驅B細胞上表現程度不可偵測。亦已報導CD37在靜止性及活化T細胞、粒細胞及單核細胞上之表現程度低。在B細胞贅瘤中,主要在侵襲性非霍奇金氏淋巴瘤(non-Hodgkin's lymphoma,NHL)及慢性淋巴白血病(CLL)中觀測到CD37表現。亦在套細胞淋巴瘤(MCL)上發現高程度CD37表現。此表現模式使CD37成為抗體介導之癌症療法的吸引人之標靶。
CD37在1986年被首次描述且其特徵為鼠科單株抗體MB-1(Link等人,1986)。
CD37之生理學作用尚未知曉。雖然缺乏CD37之小鼠未展示淋巴器官之發育及細胞組成的變化,但其具有降低之IgG1含量及衰減的T細胞介導之免疫反應(Knobeloch等人,2000)。對CD37-/-T細胞之研究表明CD37在T細胞增殖中之作用(van Spriel等人,2004)。
已報導CD37在各種疾病之惡性B細胞上表現。CD37在大多數成熟B細胞惡性腫瘤(例如,伯基特淋巴瘤、濾泡性淋巴瘤及淋巴細胞性淋巴瘤)中表現(Link等人,1986)。已在毛細胞白血病及患有慢性淋巴細胞白血病(CLL)及不同亞型非霍奇金氏淋巴瘤(NHL)(包括套細胞淋巴瘤(MCL))之患者樣品中觀測到高程度CD37表現(Schwartz-Albiez等人,1988;Barrena等人,2005)。一個利用抗體微陣列進行免疫表型分類之報導聲稱CD37為惡性CLL細胞(高CD37表現)與正常外周血(PB)淋巴細胞(低CD37表現)之間的良好鑑別者(Belov等人,2001)。
CD37特異性mAb與癌細胞之結合可引發各種作用機制:首先,在抗體與CD37抗原之胞外域結合之後,其可活化補體級聯且溶解標
靶細胞。其次,抗CD37抗體可介導抗體依賴性細胞介導之細胞毒性(ADCC)至標靶細胞,此發生在所結合抗體之Fc部分藉由免疫系統之細胞毒性細胞上的合適受體識別之後。
第三,該抗體可改變B細胞對抗原或其他刺激起反應的能力。最終,抗CD37抗體可引發漸進式細胞死亡(細胞凋亡)。
在伯基特淋巴瘤裸小鼠模型中評估放射性標記及未標記之抗CD37抗體MB-1的抗腫瘤功效(Buchsbaum等人,1992)。在此實驗中,與放射性標記之對照抗體相比,100μg腹膜內(i.p.)單劑量之未標記MB-1 mAb延緩確定之Raji腫瘤的生長。
在B-NHL患者中,在兩個放射免疫療法試驗中評估抗CD37 mAb MB-1(B細胞非霍奇金氏淋巴瘤(B-cell non-Hodgkin's lymphoma);Press等人,1989;Kaminski等人,1992)。在一試驗中,向6名復發NHL之患者投與治療劑量之131I-MB-1,且所有6名患者均實現臨床完全緩解(CR),其中中位持續時間為7個月。值得注意地,6名患者中之2名在僅投與示蹤劑量之MB-1以後顯示臨床消退,此表明抗體自身具有直接抗腫瘤作用。在第二試驗中,應用放射性標記之MB-1以治療難治NHL患者且引起9名可評估患者中之3名具有有限持續時間之目標反應(Kaminski等人,1992)。在兩個試驗中,均報導在注射示蹤標記之MB-1抗體劑量後外周B細胞快速且瞬間去除。此等觀測支持MB-1獨立發揮細胞毒性活性之結論。概言之,此等臨床試驗強調對於B細胞惡性腫瘤而言靶向CD37之可行性且表明抗CD37療法之潛在臨床相關性。
關於CD37特異性抗體樣單鏈分子("小模塊免疫藥物"(Small Modular ImmunoPharmaceutical),SMIP)之實驗證據表明,用該分子治療誘發活體外細胞凋亡且延遲活體內異種移植模型中之伯基特淋巴瘤生長。近來,描述來自Trubion之重組抗CD37 SMIP Tru16.4之抗細
胞凋亡活性(Zhao等人,2004)。Tru 16.4在來自腫瘤患者之初級CLL細胞上誘發卡斯蛋白酶(caspase)非依賴性細胞凋亡。對此等細胞之細胞凋亡的誘發大於利妥昔單抗對此等細胞之細胞凋亡的誘發且可與阿來組單抗(Alemtuzumab)(CD52拮抗劑)對此等細胞之細胞凋亡的誘發相當。細胞凋亡誘發程度與CD37細胞表面表現成正比且可藉由與抗人類IgG抗體交聯而進一步得到增強。關於活體外細胞株,證明CD37表現與ADCC之相關性。在伯基特淋巴瘤小鼠模型(Raji)中,用抗CD37scFv治療展示治療功效(Zhao等人,2007)。此等資料首次證明靶向CD37為藉由誘發細胞凋亡及ADCC進行之靶向抗腫瘤療法的期望方法。
總之,已顯示CD37抗原通常在若干人類B細胞惡性腫瘤中之腫瘤細胞及成熟的正常B淋巴細胞上表現且基於抗CD37之療法可為用於治療B細胞惡性腫瘤之期望方法。不認為對CD37呈陽性之正常B細胞的去除為關鍵性的,此係因為來自大量患者之臨床資料顯示甚至用抗CD20 mAb長期去除B細胞達6個月亦不會顯著降低IgG血清含量或增加感染危險(Van der Kolk等人,2002)。
雖然上述抗CD37抗體或抗體樣分子(MB-1及SMIP Tru16.4)已顯示在B細胞惡性腫瘤中之抗腫瘤功效及靶向CD37之潛能,但仍對改良基於B細胞去除之療法的替代性抗CD37抑制劑存在需要。
本發明之一目標係提供用於治療B細胞惡性腫瘤及對CD37陽性B細胞之去除起反應的其他病症之新穎CD37拮抗劑。
此外,本發明之一目標係提供具有改良效應功能之抗CD37抗體。詳言之,本發明者試圖提供具有抗體依賴性細胞介導之細胞毒性(ADCC)之抗CD37 mAB。
為解決本發明潛在之問題,使用鼠科單株抗CD37抗體作為用於
產生可用於人類療法中之嵌合及人化抗CD37抗體的起始抗體。
在第一態樣中,本發明提供與人類CD37結合且衍生自以下抗體之抗體分子:a)鼠科單株抗體,其藉由以下定義:i)包含SEQ ID NO:2中所示之胺基酸序列之可變重鏈;及ii)包含SEQ ID NO:4中所示之胺基酸序列之可變輕鏈,或b)非人類抗體,其識別與a)中所定義之抗體相同的人類CD37抗原決定基,或識別與該抗原決定基相近或部分一致之抗原決定基;其中該抗體分子為嵌合或人化抗體。
在一較佳實施例中,嵌合或人化抗體分子衍生自a)中所定義之起始抗體。具有相關序列之抗體稱為G28.1且描述於WO 2005/017148中。
類別b)之起始抗體可(例如)選自表徵Third HLDA Workshop中的CD37抗原之CD37特異性抗體(如G28.1);此等抗體稱為HD28、HH1、BI14、F97-3G6(Ling及MacLennan,1987)。其他已描述之CD37特異性抗體包括RFB-7、Y29/55、MB-1、M-B371、M-B372及IPO-24。根據Moldenhauer,2000及Schwartz-Albiez等人,1988,所有此等抗體(包括G28.1)識別相同或部分一致或相近之CD37抗原決定基。Schwartz-Albiez等人,1988指示該抗原決定基位於CD37之碳水化合物部分中。大量以上抗體可購得,例如HH1(SantaCruz)、RFB-7(Biodesign)、Y29/55(Biogenesis)、M-B371(BD Biosciences)、M-B372(SantaCruz)及IPO-24(AbCam)。
其他CD37特異性抗體為S-B3(Biosys)、NMN46(Chemicon)及ICO-66(Bioprobe)。可藉由競爭性結合檢定或藉由如Moldenhauer等人,1987及Moldenhauer,2000所述之交叉抑制放射免疫檢定來確定抗體是否識別與G28.1相同之抗原決定基。
以實例說明,可在ELISA中,使用塗有CD37蛋白或CD37肽或CD37陽性細胞之盤(細胞ELISA)且量測在競爭候選抗體存在下生物素標記抗體之結合來測定競爭性結合。在競爭抗體或抗體衍生片段存在下,在抗體識別共同抗原決定基之狀況下,經生物素標記之G28.1(或已知識別相同抗原決定基之另一抗體)之結合減少。為鑑別G28.1抗原決定基肽,可合成或產生衍生自CD37序列之片段或短的多肽或重組蛋白且在ELISA檢定中量測G28.1與該等肽/多肽之結合。如實例中所述,亦可藉由FACS分析來測定競爭性結合。
b)中所定義之抗體可以與G28.1類似之方式用作起始抗體,以產生嵌合或人化抗體分子。
亦可藉由使用含有相關抗原決定基之肽或蛋白片段或編碼該等肽/片段之DNA分子重新產生類別b)之起始抗體,以分別進行免疫以獲得對與G28.1相同之抗原決定基具反應性的抗體。
藉由以載運相關抗原決定基之全細胞進行免疫亦可獲得起始抗體b);接著,篩檢由此獲得之融合瘤細胞的分泌抗體之競爭性結合。
術語"抗CD37抗體分子"包含抗CD37抗體及抗CD37抗體片段以及與抗體分子之接合物。在本發明之含義中,抗體包括嵌合單株抗體及人化單株抗體。術語"抗體"應包含完整免疫球蛋白(當其藉由淋巴細胞產生且例如存在於血清中時)、由融合瘤細胞株分泌之單株抗體、藉由在宿主細胞中重組表現所產生之多肽(其具有免疫球蛋白或單株抗體之結合特異性)及藉由修飾或進一步加工而自該等抗體衍生同時保留其結合特異性之分子。
在本發明之一實施例中,抗CD37抗體分子為由以下定義之嵌合抗體:i)包含SEQ ID NO:2中所示之胺基酸序列的可變重鏈;ii)包含SEQ ID NO:4中所示之胺基酸序列的可變輕鏈;
iii)具有人類起源之恆定重鏈及輕鏈。
嵌合小鼠/人類抗體之構築及產生在此項技術中熟知(Boulianne等人,1984)。非人類抗體之可變區通常與人類免疫球蛋白之免疫球蛋白恆定區的至少一部分(Fc)連接。可根據熟知之程序自多種人類細胞、較佳自永生化B細胞分離人類恆定區DNA序列(參見Kabat等人,1991;及WO 87/02671)。該等抗體分子可含有所有或僅一部分恆定區,只要其展示與CD37抗原及Fc受體之特異性結合即可。恆定區之類型及長度的選擇視是否需要效應功能(如補體結合或抗體依賴性細胞介導之毒性)及抗體分子之所欲藥理學性質而定。
在某些實施例中,本發明之抗體分子為嵌合CD37特異性抗體,其具有與人類重鏈恆定區IgG1融合之a)或b)中所定義的非人類抗體之重鏈可變區及與人類輕鏈恆定區κ融合之a)或b)中所定義的非人類抗體之輕鏈可變區。
在另一實施例中,抗體分子為嵌合CD37特異性抗體,其具有與人類重鏈恆定區IgG1(其為具有SEQ ID NO:24中所示序列之IgG1分子或自其衍生之突變IgG1分子)融合的SEQ ID NO:2中所示之重鏈可變區且其具有與SEQ ID NO:26中所示之人類輕鏈恆定區κ融合的SEQ ID NO:4中所示之輕鏈可變區。
用於嵌合a)或b)中所定義之非人類起始抗體之其他人類恆定區可為熟習此項技術者採用,例如IgG2、IgG3、IgG4、IgA、IgE或IgM(替代IgG1)或λ(替代κ)。恆定區亦可為嵌合的,例如重鏈IgG1/IgG2或IgG1/IgG3嵌合體。
在本發明之某些實施例中,抗CD37抗體分子為由以下定義之人化抗體:i.含於如SEQ ID NO:2中所示之可變重鏈內之CDR,及ii.含於如SEQ ID NO:4中所示之可變輕鏈內之CDR,
iii.支撐該等CDR之衍生自人類抗體之構架,iv.來自人類抗體之恆定重鏈及輕鏈。
人化形式之非人類抗體(例如,鼠科、大鼠或兔抗體)為含有衍生自非人類免疫球蛋白之最小序列的免疫球蛋白、免疫球蛋白鏈或其片段(諸如,Fv、Fab、Fab'、F(ab')2或具有抗體子序列之其他抗原結合分子)。
人化抗體包括其中來自受體抗體之互補判定區(CDR)的殘基經來自非人類物種(供體抗體)(諸如,小鼠、大鼠或兔)之CDR之具有所欲特異性、親和力及能力的殘基置換之人類免疫球蛋白(來自受體抗體)。在一些情況下,人類免疫球蛋白之Fv構架殘基經相應非人類殘基置換。
在本發明之人化抗體中,已將編碼a)或b)中所定義之非人類起始抗體之CDR的序列移植至人類免疫球蛋白重鏈及輕鏈之各別基因中。
根據Kabat等人,1991以及Chothia及Lesk(1987),應瞭解單株抗體之"互補判定區"(CDR)為涉及特異性抗原結合之彼等胺基酸序列。根據如SEQ ID NO:2及SEQ ID NO:4中所示之可變區序列,通常可藉由針對序列特徵搜索Kabat序列資料庫來確定CDR序列。
用於獲得人化抗體之技術通常可由熟習此項技術者採用,該等技術已描述於US 5,225,539、US 6,548,640及US 6,982,321中。
可將CDR移植抗體之合適構架殘基回復至鼠科殘基以改良結合親和力。如上所述,根據與此項技術相關之方法,專家知道如何自給定之非人類抗體獲得CDR,選擇及獲得適當人類免疫球蛋白基因,將CDR移植至此等基因中,修飾所選構架殘基,在適當宿主細胞(例如,中國倉鼠卵巢(CHO)細胞)中表現CDR移植抗體,及測試所得重組抗體之結合親和力及特異性。
為獲得人化抗體,將由重鏈CDR及輕鏈CDR形成之抗原結合位點
自分泌齧齒動物(鼠科)單株抗體之細胞的DNA切除且移植至編碼人類抗體構架之DNA中。
或者對於CDR移植而言,如US 5,639,641中所述,可藉由所謂的"表面重整"技術來人化非人類、尤其鼠科抗CD37抗體,藉此除表面暴露之殘基外,齧齒動物構架保留無變化。
在另一態樣中,本發明係關於含有具有SEQ ID NO:6中所示序列之可變重鏈及具有選自SEQ ID NO:12、SEQ ID NO:14、SEQ ID NO:16、SEQ ID NO:18、SEQ ID NO:20及SEQ ID NO:22中所示序列之序列的可變輕鏈之人化抗體。
在另一態樣中,本發明係關於含有具有SEQ ID NO:8中所示序列之可變重鏈及具有選自SEQ ID NO:12、SEQ ID NO:14、SEQ ID NO:16、SEQ ID NO:18、SEQ ID NO:20及SEQ ID NO:22中所示序列之序列的可變輕鏈之人化抗體。
在另一態樣中,本發明係關於含有具有SEQ ID NO:10中所示序列之可變重鏈及具有選自SEQ ID NO:12、SEQ ID NO:14、SEQ ID NO:16、SEQ ID NO:18、SEQ ID NO:20及SEQ ID NO:22中所示序列之序列的可變輕鏈之人化抗體。
以上所定義之人化抗體顯示於表1中。
在某些實施例中,人化抗體具有人類重鏈恆定區IgG1及人類輕鏈恆定區κ。如上文關於嵌合抗體所述,恆定區可選自其他種類及亞類。
在某些實施例中,在本發明之人化抗體中,人類恆定重鏈IgG1為具有SEQ ID NO:24中所示序列之IgG1分子或自其衍生之突變IgG1分子,且人類輕鏈恆定區κ具有SEQ ID NO:26中所示序列。
本發明之抗CD37抗體分子亦可為由序列表中所示胺基酸序列定義之抗體的變異體。使用通常可用之技術,熟習此項技術者將能夠製
備、測試及利用以上所定義之抗體的功能變異體。實例為CDR及/或構架中至少一個位置改變之變異抗體、在偏離生殖系序列之構架區中具有單一胺基酸取代之變異抗體、具有保守胺基取代之抗體、藉由在嚴格條件下與編碼抗體可變鏈的呈現於序列表中之DNA分子雜交的DNA分子編碼之抗體。
在給定個別胺基酸性質之情況下,可進行合理取代以獲得保存起始抗體之整個分子結構的抗體變異體。可(例如)基於各別胺基酸之極性、電荷、溶解度、疏水性、親水性及/或兩性性質之相似性進行胺基酸取代,意即"保守取代"。熟習此項技術者熟悉通常實施之胺基酸取代(舉例而言,如WO 2007/042309中所述)及用於獲得由此修飾之抗體的方法。在給定遺傳密碼及重組及合成DNA技術之情況下,通常可設計編碼具有一或多個保守胺基酸交換之變異抗體的DNA分子且易於獲得各別抗體。
與如藉由序列表中所示之可變鏈所定義的抗體相比,本發明所包含之抗體變異體在CDR區中具有至少60%、更佳至少70%或80%、更佳至少90%及最佳至少95%之序列一致性。較佳抗體亦在CDR區中具有至少80%、更佳90%及最佳95%之序列相似性。較佳抗體變異體在可變區中具有至少60%、更佳至少70%或80%、更佳至少90%及最佳至少95%之序列一致性。較佳抗體亦在可變區中具有至少80%、更佳90%及最佳95%之序列相似性。
兩個多肽序列之間的"序列一致性"指示序列之間一致之胺基酸的百分比。"序列相似性"指示一致或代表保守胺基酸取代之胺基酸的百分比。
亦可使用具有如序列表中所示之確定序列之抗體作為用於使一或多個胺基酸殘基、較佳地一或多個CDR中之胺基酸殘基最佳化及多樣化的起點,且篩檢所得抗體變異體集合中具有改良性質之變異體,藉
此來獲得變異體。已證明可變輕鏈CDR3、可變重鏈CDR3、可變輕鏈CDR1及/或可變重鏈CDR2中一或多個胺基酸殘基之多樣化為有用的。多樣化可藉由此項技術中已知之方法(例如,WO 2007/042309中提及之所謂TRIM技術)進行。
在另一實施例中,本發明之抗CD37抗體分子為"親和力成熟"抗體。
"親和力成熟"抗CD37抗體為衍生自具有序列表中所示序列之抗體的抗CD37抗體,其在一或多個CDR中具有一或多個改變,該等改變引起與各別原始未成熟抗體相比對抗原親和力之改良。一種用於產生該等抗體突變體之程序包括噬菌體呈現(Hawkins等人,1992;及Lowman等人,1991)。簡言之,使若干高變區位點(例如,6-7個位點)突變以在各位點產生所有可能之胺基酸取代。由此產生之抗體突變體自絲狀噬菌體顆粒以單價方式呈現為與封裝於各顆粒中之M13之基因III產物的融合體。接著,篩檢噬菌體呈現之突變體的如本文所揭示之生物活性(例如,結合親和力)。
親和力成熟抗體亦可藉由如以下所述之方法來產生:例如,Marks等人,1992(藉由可變重鏈(VH)及可變輕鏈(VL)域改組實現親和力成熟);或Barbas等人,1994;Shier等人,1995;Yelton等人,1995;Jackson等人,1995;及Hawkins等人,1992(CDR及/或構架殘基之隨機突變誘發)。較佳之親和力成熟抗體將對標靶抗原具有奈莫耳或甚至皮莫耳之親和力。
在另一實施例中,本發明之抗CD37抗體分子為"去免疫"抗體。
"去免疫"抗CD37抗體為衍生自具有序列表中所示序列之人化或嵌合抗體的抗體,其在胺基酸序列中具有一或多個改變,該等改變引起與各別原始非去人化抗體相比抗體免疫原性減少。一種用於產生該等抗體突變體之程序包括鑑別及移除抗體分子之T-細胞抗原決定基
(Baker及Jones,2007)。在第一步驟中,可藉由如文獻(Jones等人,2004;Jones等人,2005;Reche等人,2004;Hertz等人,2006)中所述之若干方法,例如藉由活體外測定T-細胞抗原決定基或模擬預測(in silico prediction)該等抗原決定基來測定抗體分子之免疫原性。一旦已鑑別T-細胞抗原決定基功能之關鍵殘基,則可進行突變以移除免疫原性且保留抗體活性(Jones等人,2005;Tangri等人,2005)。用於將突變引入蛋白中之方法在此項技術中熟知,例如藉由交迭PCR技術。
因為產生大量重要功能能力(其稱為"效應功能")之抗體的Fc區與大量Fc受體相互作用,所以在某些實施例中,該抗體為全長抗體或含有一部分Fc區之抗體,後者只要抗體展示與抗原相關部分及Fc受體均特異性結合即可。恆定區之類型及長度的選擇視效應功能(如補體結合或抗體依賴性細胞介導之細胞毒性)是否為所欲特徵及抗體蛋白之所欲藥理學性質而定。
在本發明之一實施例中,抗CD37抗體為具有Fc區或其相關部分之嵌合或人化抗體,該Fc區或其相關部分已經工程化以調節效應功能,尤其增強抗體與一或多個Fc受體之結合,藉此增強效應功能ADDC。與未經Fc工程化之親本抗體相比,Fc區之工程化在效應細胞存在下更有效地介導抗體之效應功能。在一實施例中,該抗體變異體介導比親本抗體介導之ADCC大的ADCC。(在下文中,若未另外說明,則在抗體分子之情形中或在IgG或Fc區之情形中術語"親本"分別指未經工程化之抗體分子、Fc區或IgG,自其衍生突變(工程化)分子)。
多種Fc區之修飾已在此項技術(科學文獻及專利文獻)中提出,例如在EP 0307434、WO 9304173、WO 9734631、WO 9744362、WO 9805787、WO 9943713、WO 9951642、WO 9958572、WO 02060919、WO 03074679、WO 2004016750、WO 2004029207、WO
2004063351、WO 2004074455、WO 2004035752、WO 2004099249、WO 2005077981、WO 2005092925、WO 2006019447、WO 2006031994、WO 2006047350、WO 2006053301、WO 2006088494及WO 2007041635中提出。
在較佳實施例中,本發明之抗體為在位置332及/或239及/或236具有胺基酸取代之Fc變異體。在較佳實施例中,本發明之抗體在Fc域中具有選自以下之群之突變:i)在位置332單一取代,較佳I332E;ii)在位置239及332的取代之組合,較佳S239D/I332E;iii)在位置236及332的取代之組合,較佳G236A/I332E;iv)在位置236、239及332的取代之組合,較佳G236A/S239D/I332E。
以上所定義之取代(例如)已藉由Lazar等人,2006描述且描述於WO 2004029207及WO 2007041635中。
本發明抗體中之Fc變異體係根據其包含之胺基酸修飾來定義。因此,舉例而言,I332E為相對於親本Fc多肽具有I332E取代之Fc變異體。同樣,S239D/I332E定義相對於親本Fc多肽具有取代S239D及I332E之Fc變異體,且S239D/I332E/G236A定義相對於親本Fc多肽具有取代S239D、I332E及G236A之Fc變異體。
編號係根據EU編號方案(Kabat等人,1991),EU編號方案係指EU抗體之編號(Edelman等人,1969)。熟習此項技術者將瞭解此等慣例由免疫球蛋白序列之特異性區中的非序列編號組成,使得能夠歸一化提及免疫球蛋白家族之保守位置。
在以上所定義之抗體中,經取代之位置236、239及332分別對應於SEQ ID NO:24中描繪的IgG1重鏈之位置119、122及215。(在SEQ ID NO:28、32、36及40中所示之抗體A2、A4、B2及B4之重鏈的全長
序列中,經取代之胺基酸在位置235、238及331處)。
在某些實施例中,本發明之Fc變異體係基於人類IgG序列,且因此將人類IgG序列用作與其他序列相比較之"基礎"序列。對於本發明之抗體而言,工程化Fc區較佳為IgG、尤其IgG1,但其亦可為IgG2或來自其他免疫球蛋白種類(諸如,IgA、IgE、IgGD、IgM)或兩種或兩種以上免疫球蛋白種類之嵌合型式(例如,IgG2/IgG1)之變異序列及其類似物。雖然在一個親本IgG之情形中將本發明之Fc變異體工程化,但該等變異體亦可在另一第二親本IgG情形下經工程化或"轉移"至另一第二親本IgG情形。此係藉由通常基於第一IgG序列與第二IgG序列之間的序列或結構同源性確定第一IgG與第二IgG之間的"等效"或"相應"殘基及取代來進行。為確定同源性,將本文所概述之第一IgG之胺基酸序列直接與第二IgG之序列相比。在對準該等序列之後,使用此項技術中已知的一或多個同源性對準程式,允許必需之插入及缺失以維持對準(亦即,避免經由任意缺失及插入而消除保守殘基),從而確定與第一Fc變異體之初始序列中之特定胺基酸等效的殘基。無論如何確定等效或相應殘基,且無論製造IgG之親本IgG的一致性如何,均意欲說明本發明中所用之Fc變異體可工程化為與Fc變異體具有顯著序列或結構同源性之任何第二親本IgG。因此,舉例而言,若藉由使用上述方法或用於確定等效殘基之其他方法來產生親本抗體為人類IgG1之變異抗體,則可在(例如)人類1gG2親本抗體、人類IgA親本抗體中將變異抗體工程化(參見WO 2007041635)。
本發明之抗體靶向抗原CD37,在CD37表現程度高於CD20表現程度之疾病中靶向抗原CD37可比靶向CD20有利,舉例而言,如在慢性淋巴細胞白血病(其中樣品已顯示與CD20 mRNA之低程度表現相比,CD37 mRNA表現程度高)中。
已顯示關於拉莫斯(Ramos)細胞上之ADCC活性、全血中之正常B
細胞去除及拉莫斯伯基特淋巴瘤細胞去除,本發明抗體優於利妥昔單抗(登記之抗CD20抗體)。如可在本發明之實驗中所示,本發明之抗體(未經Fc工程化及經Fc工程化之抗體)具有優於利妥昔單抗之B細胞去除活性的B細胞去除活性。具有突變Fc區之抗體顯示如與利妥昔單抗相比增加約10倍之B細胞去除活性(圖11B)。
本發明之CD37抗體之代表在未交聯之情況下顯示有效的促細胞凋亡活性;在此方面,具有此性質之抗體優於在未交聯情況下不顯示細胞凋亡之抗CD37 SMIP Tru16.4(Zhao等人,2007)。在未交聯情況下誘發細胞凋亡(其可由經Fc工程化或未經Fc工程化之本發明抗體顯示)在活體內缺乏交聯劑(例如,具有Fcγ受體之效應細胞)之情況下或在低密度標靶抗原CD37(例如,具有CD37低表現程度之腫瘤細胞)下為有利的。在未交聯情況下誘發細胞凋亡之抗體可能仍引起細胞死亡,而依賴於交聯之抗體不會引起細胞死亡。
在另一態樣中,本發明之抗CD37抗體分子為衍生自根據本發明之人化或嵌合CD37特異性抗體之抗體片段。為獲得抗體片段,例如Fab片段,可藉助於常規技術(例如,使用木瓜蛋白酶)來實現消化。木瓜蛋白酶消化之實例描述於WO 94/29348及US 4,342,566中。抗體之木瓜蛋白酶消化通常產生兩個一致之抗原結合片段(所謂的Fab片段),各片段具有單一抗原結合位點及殘餘Fc片段。胃蛋白酶處理產生具有兩個抗原結合位點且仍能夠與抗原交聯之F(ab')2片段。
藉由抗體消化獲得之Fab片段亦含有輕鏈恆定域及重鏈之第一恆定域(CH1)。Fab'片段與Fab片段不同,其不同之處在於其在重鏈CH1域之羧基末端含有其他殘基,包括一或多個來自抗體鉸鏈區的半胱胺酸。Fab'-SH在本文中表示恆定域之半胱胺酸殘基帶有游離硫醇基之Fab'。F(ab')2抗體片段最初以其間具有鉸鏈半胱胺酸之Fab'片段對的形式產生。抗體片段亦可藉由產生各別編碼性DNA片段之分子生物學
方法而產生。
抗體分子通常為由兩個輕鏈/重鏈對組成之四聚體,但亦可為二聚體,亦即,由輕鏈/重鏈對組成(例如,Fab或Fv片段),或其可為單體單鏈抗體(scFv;Johnson及Bird,1991)、微型抗體或雙功能抗體。
抗CD37抗體分子亦可呈接合物形式,亦即,與細胞毒性劑、尤其誘發腫瘤細胞之細胞毒性(例如,細胞凋亡或有絲分裂停滯)之細胞毒性劑化學偶合的抗體分子。由於正常藥理學清除機制,藥物接合物("免疫接合物")中所用之抗體僅以有限量與標靶細胞接觸且結合。因此,接合物中所用之細胞毒性劑必須具有高度細胞毒性,使得出現足夠細胞殺死以引起治療效應。如US 2004/0241174中所述,該等細胞毒性劑之實例包括紫杉烷(taxane)(參見例如WO 01/38318及WO 03/097625)、DNA烷基化劑(例如,CC-1065類似物)、蒽環黴素(anthracycline)、土布力辛(tubulysin)類似物、多卡米辛(duocarmycin)類似物、羥道諾紅黴素(doxorubicin)、阿瑞他汀E(auristatinE)、篦麻毒素A毒素及包含反應性聚乙二醇部分之細胞毒性劑(參見例如Sasse等人,2000;Suzawa等人,2000;Ichimura等人,1991;Francisco等人,2003;US 5,475,092、US 6,340,701、US 6,372,738及US 6,436,931、US 2001/0036923、US 2004/0001838、US 2003/0199519及WO 01/49698)。
在一較佳實施例中,細胞毒性劑為美登素類化合物(maytansinoid)(亦即,美登素(maytansine)之衍生物(CAS 35846538)),美登素類化合物為此項技術中已知,包括美登素、美登醇(maytansinol)、美登醇之C-3酯及其他美登醇類似物及衍生物(參見例如US 5,208,020及US 6,441,163)。
可如WO 2007077173中關於抗FAP免疫接合物所述來設計及合成抗CD37抗體免疫接合物。
在另一實施例中,本發明之抗CD37分子可經放射性標記以形成放射免疫接合物,此為一種關於抗CD37抗體MB-1所提出之方法(Buchsbaum等人,1992,參見上文)。具有有利放射性質之放射性核素在此項技術中已知,實例為磷-32、鍶-89、釔-90、碘-131、釤-153、鉺-169、鐿-175、錸-188,其已成功且穩定地與MAb偶合。可使用如US 6,241,961中所述之此項技術中已知之直接標記或間接標記方法,以各種放射性核素標記本發明之抗CD37抗體分子。關於用於產生及應用適用於本發明之新穎放射性標記的抗體接合物之技術的評論由Goldenberg及Sharkey,2007給出。
本發明之抗體分子(無論Fc經工程化或未經工程化)亦可具有雙特異性,亦即,抗體分子與兩個不同標靶結合,標靶之一為CD37,另一者係選自(例如)T細胞表現之表面抗原,例如CD3、CD16及CD56。
本發明亦係關於編碼本發明之嵌合或人化抗CD37抗體分子之DNA分子。編碼本發明之抗體分子之可變重鏈的序列顯示於SEQ ID NO:1、SEQ ID NO:5、SEQ ID NO:7及SEQ ID NO:9中。編碼本發明之抗體分子之可變輕鏈的序列顯示於SEQ ID NO:3、SEQ ID NO:11、SEQ ID NO:13、SEQ ID NO:15、SEQ ID NO:17、SEQ ID NO:19、SEQ ID NO:21中。
可藉由標準方法以化學方式及酶方式(PCR擴增)合成編碼輕鏈及重鏈之核酸分子。首先,可藉由此項技術中已知之方法(例如Gait,1984)合成合適之寡核苷酸,該等寡核苷酸可用於產生合成基因。自寡核苷酸產生合成基因之方法在此項技術中已知(例如,Stemmer等人,1995;Ye等人,1992;Hayden et Mandecki,1988;Frank等人,1987)。
本發明之DNA分子包括(但不限於)序列表中所示之DNA分子。因此,本發明亦係關於如WO 2007/042309中所定義在高嚴格結合及洗
滌條件下與序列表中所述之DNA分子雜交的核酸分子,其中該等核酸分子編碼具有等效於或優於序列表中所示序列所編碼之抗體之性質的抗體或其功能片段。較佳分子(自mRNA角度)為與本文所述之一種DNA分子具有至少75%或80%(較佳至少85%,更佳至少90%且最佳至少95%)同源性或序列一致性的彼等分子。
在本發明之範疇內的另一類DNA變異體可根據其編碼之多肽來定義。此等DNA分子在序列方面偏離序列表中描繪之彼等DNA分子,但由於遺傳密碼之簡並而編碼具有一致胺基酸序列之抗體。以實例說明,鑒於在真核細胞中表現抗體,序列表中所示之DNA序列已經設計以匹配真核細胞中之密碼子使用。若希望在大腸桿菌(E.coli)中表現抗體,則可使此等序列變化以匹配大腸桿菌密碼子使用。舉例而言,如WO 2007/042309中所述,可以若干不同方式構築本發明之DNA分子之變異體。
為產生本發明之重組抗CD37抗體分子,將編碼全長輕鏈及重鏈或其片段之DNA分子插入表現載體中,使得該等序列可操作地連接於轉錄及轉譯控制序列。
為製造本發明之抗體,熟習此項技術者可自此項技術中熟知之多種表現系統進行選擇,例如Kipriyanow及Le Gall,2004評述之彼等表現系統。
表現載體包括質體、反轉錄病毒、黏質體、EBV衍生之游離體及其類似物。表現載體及表現控制序列係經選擇以與宿主細胞相容。抗體輕鏈基因及抗體重鏈基因可插入單獨載體中。在某些實施例中,將兩個DNA序列插入同一表現載體中。適宜之載體為編碼功能完整之人類CH或CL免疫球蛋白序列者,其具有經工程化之適當限制位點以使任何VH或VL序列可易於如上所述般插入及表現。對於抗體輕鏈而言,恆定鏈通常為κ或λ,對於抗體重鏈而言,恆定鏈可為(不限於)任
何IgG同型(IgG1、IgG2、IgG3、IgG4)或其他免疫球蛋白,包括對偶基因變異體。
重組表現載體亦可編碼促進自宿主細胞分泌抗體鏈之信號肽。可將編碼抗體鏈之DNA選殖至載體中,使得信號肽同框連接於成熟抗體鏈DNA之胺基末端。信號肽可為免疫球蛋白信號肽或來自非免疫球蛋白之異源肽。或者,編碼抗體鏈之DNA序列可已含有信號肽序列。
除編碼抗體鏈之DNA序列以外,重組表現載體亦攜帶調節序列,包括啟動子、強化子、終止及多聚腺嘌呤信號及控制抗體鏈在宿主細胞中的表現之其他表現控制元件。啟動子序列之實例(關於哺乳動物細胞中之表現所例示)為衍生自(CMV)(諸如,CMV猴病毒40(SV40)(諸如,SV40啟動子/強化子))、腺病毒(例如,腺病毒主要晚期啟動子(AdMLP))、多形瘤之啟動子及/或強化子及強哺乳動物啟動子,諸如原生免疫球蛋白及肌動蛋白啟動子。多聚腺嘌呤信號之實例為BGH polyA、SV40晚期或早期polyA;或者,可使用免疫球蛋白基因之3'UTR等。
重組表現載體亦可攜帶調節宿主細胞中之載體複製之序列(例如,複製起點)及可選標記基因。可根據此項技術中熟知之轉染方法,包括脂質體介導之轉染、聚陽離子介導之轉染、原生質體融合、微注射、磷酸鈣沈澱、電穿孔或藉由病毒載體轉移,將編碼抗CD37抗體的重鏈或其抗原結合部分及/或輕鏈或其抗原結合部分之核酸分子及包含此等DNA分子之載體引入宿主細胞(例如細菌細胞或高級真核細胞,例如哺乳動物細胞)中。
編碼重鏈及輕鏈之DNA分子較佳存在於共轉染至宿主細胞、較佳哺乳動物細胞中之兩個載體上。
可用作用於表現之宿主的哺乳動物細胞株在此項技術中熟知且包括中國倉鼠卵巢(CHO,CHO-DG44)細胞、NSO、SP2/0細胞、海拉細
胞(HeLa cell)、幼倉鼠腎(BHK)細胞、猴腎細胞(COS)、人類癌細胞(例如,Hep G2)、A549細胞、3T3細胞或任何該細胞株之衍生物/子代。可使用其他哺乳動物細胞,包括(但不限於)人類、小鼠、大鼠、猴及齧齒動物細胞株;或其他真核細胞,包括(但不限於)酵母、昆蟲及植物細胞;或原核細胞,諸如細菌。藉由培養宿主細胞歷時足以允許抗體分子在宿主細胞中表現之一段時間來產生本發明之抗CD37抗體分子。
抗體分子較佳以分泌多肽形式自培養基回收,或若(例如)在無分泌信號之情況下表現,則其可自宿主細胞溶解產物回收。有必要使用用於重組蛋白及宿主細胞蛋白之標準蛋白純化方法,以獲得大體上同源抗體製劑之方式來純化抗體分子。以實例說明,適用於獲得本發明之抗CD37抗體分子的目前技術水平之純化方法包括自培養基或溶解產物移除細胞及/或微粒細胞碎片作為第一步驟。接著,(例如)藉由在免疫親和或離子交換管柱上進行分級分離、乙醇沈澱、逆相HPLC、Sephadex層析、二氧化矽或陽離子交換樹脂上之層析而自污染之可溶性蛋白、多肽及核酸純化抗體。作為獲得抗CD37抗體分子製劑之過程中的最後步驟,可如下文關於治療應用所述來乾燥經純化之抗體分子,例如冷凍乾燥。
在另一態樣中,本發明係關於含有本發明之抗CD37抗體分子作為活性成份的醫藥組合物。
為用於療法中,將抗CD37抗體包括在適於促進向動物或人類投與之醫藥組合物中。可藉由將抗CD37抗體分子與生理學上可接受之載劑、賦形劑或穩定劑混合而以冷凍乾燥或以其他方式乾燥之調配物或水溶液或水性或非水性懸浮液形式製備抗CD37抗體分子之典型調配物。載劑、賦形劑、改質劑或穩定劑在所用劑量及濃度下為無毒的。其包括:緩衝系統,諸如磷酸鹽、檸檬酸鹽、乙酸鹽及其他無機
酸或有機酸及其鹽;抗氧化劑,包括抗壞血酸及甲硫胺酸;防腐劑(諸如,氯化十八烷基二甲基苄基銨;氯化六羥季銨(hexamethonium chloride);氯苄烷銨(benzalkonium chloride);苯酚;丁醇或苄醇;對羥基苯甲酸烷基酯,諸如對羥基苯甲酸甲酯或對羥基苯甲酸丙酯;兒茶酚;間苯二酚;環己醇;3-戊醇;及間甲酚);蛋白,諸如血清白蛋白、明膠或免疫球蛋白;親水性聚合物,諸如聚乙烯吡咯啶酮或聚乙二醇(PEG);胺基酸,諸如甘胺酸、麩胺醯胺、天冬醯胺酸、組胺酸、精胺酸或離胺酸;單醣、雙醣、寡醣或多醣及其他碳水化合物,包括葡萄糖、甘露糖、蔗糖、海藻糖、糊精或葡聚糖(dextran);螯合劑,諸如EDTA;糖醇,諸如甘露糖醇或山梨糖醇;成鹽平衡離子,諸如鈉;金屬錯合物(例如,Zn-蛋白錯合物);及/或離子型或非離子型界面活性劑,諸如TWEENTM(聚山梨醇酯)、PLURONICSTM或脂肪酸酯、脂肪酸醚或糖酯。抗體調配物中亦可含有有機溶劑,諸如乙醇或異丙醇。賦形劑亦可具有釋放改良或吸收改良功能。
抗CD37抗體分子亦可經乾燥(冷凍乾燥、噴霧乾燥、噴霧冷凍乾燥、藉由近或超臨界氣體乾燥、真空乾燥、空氣乾燥),沈澱或結晶或包埋於(例如)藉由凝聚技術或藉由界面聚合(例如)分別使用羥甲基纖維素或明膠及聚(甲基丙烯酸甲酯)而製備之微膠囊中,包埋於膠狀藥物傳遞系統(例如,脂質體、白蛋白微球體、微乳液、奈米顆粒及奈米膠囊)中,包埋於巨乳液中,或(例如)藉由pcmc技術(蛋白塗覆微晶)而沈澱或固定於載劑或表面上。該等技術揭示於Remington:The Scienceand Practice of Pharmacy,第21版,Hendrickson R.編中。
自然地,待用於活體內投與之調配物必須無菌;可藉由習知技術(例如,藉由經由無菌過濾膜過濾)來實現殺菌。
可適用的是增加抗CD37抗體濃度以達到所謂的高濃度液體調配物(HCLF);已描述產生該等HCLF之各種方式。
抗CD37抗體分子亦可含於持續釋放製劑中。該等製劑包括疏水性或親水性聚合物之固體、半固體或液體基質,且可呈成形物品形式,例如薄膜、條狀物或微膠囊,且可經由應用裝置來應用。持續釋放基質之實例包括聚酯、水凝膠(例如,聚(2-羥基乙基-甲基丙烯酸酯)或蔗糖乙酸丁酸酯或聚(乙烯醇))、聚交酯(US 3,773,919)、L-麩胺酸與γ-L-麩胺酸乙酯之共聚物、不可降解之乙烯-乙酸乙烯酯、可降解之乳酸-乙醇酸共聚物(諸如,LUPRON DEPOTTM(由乳酸-乙醇酸共聚物及乙酸亮丙瑞林(leuprolide acetate)組成之可注射微球體))及聚-D-(-)-3-羥基丁酸。雖然諸如乙烯-乙酸乙烯酯及乳酸-乙醇酸之聚合物使分子能夠釋放超過100天,但某些水凝膠釋放蛋白歷時較短時段。當經囊封之抗體長時間保留於體內時,其因暴露於37℃下之水分而可能變性或聚集,從而導致生物活性損失且使免疫原性可能變化。視所涉及之機制而定,可設計合理策略以達成穩定。舉例而言,若發現凝集機制係經由硫基-二硫化物互換而形成分子間S-S鍵,則可藉由使巰基殘基改質、自酸性溶液凍乾(例如,如WO 89/011297中所述)、控制水分含量、使用適當添加劑及形成特定聚合物基質組合物來達成穩定。
亦可用於本發明之抗CD37抗體分子之調配物描述於US 7,060,268及US 6,991,790中。
CD37抗體分子亦可併入其他應用形式中,諸如併入分散液、懸浮液或脂質體、錠劑、膠囊、散劑、噴霧劑、具有或不具有滲透增強裝置之經皮或皮內貼片或乳膏、糯米紙囊劑、經鼻、經頰或經肺調配物中,或可藉由植入之細胞或在基因療法後藉由個體的自身細胞來產生。
抗CD37抗體分子亦可由化學基團(諸如,聚乙二醇(PEG)、甲基或乙基或碳水化合物基團)衍生。此等基團可用於改良抗體之生物學特徵,例如增加血清半衰期或增加組織結合。
較佳應用模式為藉由輸注或注射(靜脈內、肌肉內、皮下、腹膜內、皮內)進行非經腸應用,但諸如藉由吸入、經皮、鼻內、經頰、經口之其他應用模式亦可為適用的。
為預防或治療疾病,抗體之適當劑量將視待治療之疾病類型、疾病之嚴重程度及過程、投與抗體為達成預防或治療目的、先前療法、患者病史及對抗體之反應以及主治醫師之判斷而定。合適地,一次性或經一系列治療向患者投與抗體。
視疾病之類型及嚴重程度而定,無論(例如)藉由一或多次分開投與或藉由連續輸注,約0.01μg/kg至40mg/kg(例如,0.1mg/kg-20mg/kg)之抗體為向患者投與之最初候選劑量。對於經數天或更長時間之重複投藥而言,視病狀而定,持續治療直至出現疾病症狀之所需抑制作用。然而,其他給藥方案亦可為有用的。此療法之進程易於藉由習知技術及檢定來監測,例如藉由測定B細胞去除之程度(例如,使用流式細胞儀)來監測。
待投與之抗體之"治療有效量"為預防、改善或治療疾病或病症所需之最低量。
本發明之抗CD37抗體分子及含其之醫藥組合物可用於去除在表面上表現CD37且引起癌症或自體免疫/發炎疾病之B細胞。
在第一態樣中,本發明之醫藥組合物可用於治療癌症,尤其任何CD37陽性惡性腫瘤。
B細胞惡性腫瘤包括(但不限於)B細胞淋巴瘤(例如,各種形式之霍奇金氏病(Hodgkin's disease)、B細胞非霍奇金氏淋巴瘤(NHL)及相關淋巴瘤(例如,瓦爾登斯特倫巨球蛋白血症(Waldenström's macroglobulinaemia)(亦稱為淋巴漿細胞淋巴瘤或免疫細胞瘤))或中樞神經系統淋巴瘤)、白血病(例如,急性淋巴母細胞白血病(ALL)、慢性淋巴細胞白血病(CLL;亦稱為B細胞慢性淋巴細胞白血病BCLL)、
毛細胞白血病及慢性肌胚細胞白血病)及骨髓瘤(例如,多發性骨髓瘤)。其他B細胞惡性腫瘤包括小淋巴細胞淋巴瘤、B細胞前淋巴細胞性白血病、淋巴漿細胞淋巴瘤、脾邊緣區淋巴瘤、漿細胞骨髓瘤、骨孤立性漿細胞瘤、骨外漿細胞瘤、黏膜相關(MALT)淋巴組織之結外邊緣區B細胞淋巴瘤、結邊緣區B細胞淋巴瘤、濾泡性淋巴瘤、套細胞淋巴瘤、彌漫性大B細胞淋巴瘤、縱隔(胸腺)大B細胞淋巴瘤、血管內大B細胞淋巴瘤、原發性滲出性淋巴瘤、伯基特氏淋巴瘤/白血病、灰區淋巴瘤、未定惡性腫瘤潛能之B細胞增殖、淋巴瘤樣肉芽腫病及移植後淋巴組織增生病症。
在另一態樣中,含有抗CD37抗體之醫藥組合物可用於治療病理學涉及B細胞之自體免疫及發炎疾病。
該等疾病包括(但不限於):關節炎、類風濕性關節炎、幼年型類風濕性關節炎、骨關節炎、多軟骨炎、牛皮癬性關節炎、牛皮癬、皮炎、多發性肌炎/皮肌炎、包涵體肌炎、發炎性肌炎、中毒性表皮壞死溶解、全身性硬皮病及硬化症、CREST徵候群、與發炎性腸病相關之反應、克羅恩氏病(Crohn's disease)、潰瘍性結腸炎、呼吸窘迫症候群、成人呼吸窘迫症候群(ARDS)、腦膜炎、腦炎、葡萄膜炎、結腸炎、絲球體腎炎、過敏病狀、濕疹、哮喘、包含T細胞浸潤及慢性發炎反應之病狀、動脈粥樣硬化、自體免疫心肌炎、白血球黏著缺乏、全身性紅斑狼瘡(SLE)、亞急性皮膚性紅斑狼瘡、盤狀狼瘡、狼瘡性脊髓炎、狼瘡性大腦炎、幼年發作型糖尿病、多發性硬化症、過敏性腦脊髓炎、視神經脊髓炎、風濕熱、西登哈姆氏舞蹈病(Sydenham's chorea)、與藉由細胞因子及T-淋巴細胞介導之急性及延遲性過敏相關的免疫反應、結核病、肉狀瘤病、肉牙腫病(包括韋格納氏肉牙腫病(Wegener's granulomatosis)及丘-施二氏疾病(Churg-Strauss disease))、顆粒性球缺乏症、血管炎(包括過敏性血管炎(vasculitis/angiitis)、
ANCA及類風濕性血管炎)、再生障礙性貧血、戴-布二氏貧血(Diamond Blackfan anemia)、免疫性溶血性貧血(包括自體免疫性溶血性貧血(AIHA))、惡性貧血、純紅血球發育不全(PRCA)、因子VIII缺乏、A型血友病、自體免疫嗜中性球減少症、全部血球減少症、白血球減少症、涉及白血球滲出之疾病、中樞神經系統(CNS)發炎病症、多發性器官損傷徵候群、重症肌無力、抗原抗體複合物介導之疾病、抗腎小球基底膜疾病、抗磷脂抗體徵候群、過敏性神經炎、貝切特氏病(Behcet disease)、卡斯特爾曼氏徵候群(Castleman's syndrome)、古德帕斯徹氏徵候群(Goodpasture's syndrome)、蘭姆博特-伊頓二氏重症肌無力症候群(Lambert-Eaton Myasthenic Syndrome)、雷諾氏徵候群(Reynaud's syndrome)、休格連氏徵候群(Sjorgen's syndrome)、史蒂芬-瓊森症候群(Stevens-Johnson syndrome)、實體器官移植排斥反應、移植物抗宿主疾病(GVHD)、大皰性類天疱瘡、天疱瘡、自體免疫多內分泌病變、血清陰性脊椎關節病、萊特爾氏病(Reiter's disease)、全身肌強直徵候群、巨細胞性動脈炎、免疫複合物腎炎、IgA腎病、IgM多發性神經病或IgM介導之神經病、特發性血小板減少性紫癜(ITP)、血栓性血小板減少性紫癜(TTP)、亨-舍二氏紫癜(Henoch-Schonlein purpura)、自體免疫血小板減少症、睪丸及卵巢之自體免疫疾病(包括自體免疫睪丸炎及卵巢炎)、原發性甲狀腺功能低下、自體免疫內分泌疾病(包括自體免疫甲狀腺炎)、慢性甲狀腺炎(橋本甲狀腺炎(Hashimoto's Thyroiditis))、亞急性甲狀腺炎、特發性甲狀腺功能低下、阿狄森氏病(Addison's disease)、格雷氏病(Grave's disease)、自體免疫多腺體徵候群(或多腺體內分泌病徵候群)、I型糖尿病(亦稱為胰島素依賴性糖尿病(IDDM))及席漢氏症候群(Sheehan's syndrome)、自體免疫肝炎、淋巴組織間質性肺炎(HIV)、閉塞性細支氣管炎(非移植)對NSIP、格-巴二氏徵候群(Guillain-Barre' Syndrome)、大血管血
管炎(包括風濕性多肌痛及巨細胞(高安氏(Takayasu's))動脈炎)、中血管血管炎(包括川崎氏病(Kawasaki's disease)及結節性多動脈炎)、結節性多動脈炎(PAN)、強直性脊椎炎、伯傑氏病(Berger's disease)(IgA腎病)、快速進行性絲球體腎炎、原發性膽汁性肝硬化、口炎性腹瀉(麩質腸病)、冷凝球蛋白血症、與肝炎相關之冷凝球蛋白血症、肌萎縮性側索硬化(ALS)、冠狀動脈疾病、家族性地中海熱(familial Mediterranean fever)、顯微性多血管炎、耳蝸前庭症候群(Cogan's syndrome)、維-奧二氏症候群(Whiskott-Aldrich syndrome)及閉塞性血栓血管炎(參見WO 2007014278)。
視待治療之病症而定,本發明之抗CD37抗體分子可單獨使用或與一或多種其他治療劑組合使用,該或該等其他治療劑尤其選自DNA破壞或微管蛋白結合劑或抑制癌細胞中的血管生成、信號轉導路徑或有絲分裂檢查點之治療活性化合物。
其他治療劑可視情況作為同一醫藥製劑之組份與抗CD37抗體分子同時投與,或在抗CD37抗體分子投與之前或之後投與。
在某些實施例中,其他治療劑可為(但不限於)一或多種選自以下之群之抑制劑:EGFR家族、VEGFR家族、IGF-1R、胰島素受體、AuroraA、AuroraB、PLK及PI3激酶、FGFR、PDGFR、Raf、KSP或PDK1之抑制劑。
其他治療劑之其他實例為CDK、Akt、Src、Bcr-Abl、cKit、cMet/HGF、c-Myc、Flt3、HSP90之抑制劑、hedgehog拮抗劑、JAK/STAT、Mek、mTor、NFκB、蛋白酶體、Rho之抑制劑、Wnt信號轉導或Notch信號轉導之抑制劑或泛素化路徑抑制劑。
Aurora抑制劑之實例為(但不限於)PHA-739358、AZD-1152、AT-9283、CYC-116、R-763、VX-667、MLN-8045、PF-3814735、SNS-314、VX-689、GSK-1070916、TTP-607、PHA-680626、MLN-8237及
ENMD-2076。
PLK抑制劑之實例為GSK-461364。
raf抑制劑之實例為BAY-73-4506(亦為VEGFR抑制劑)、PLX-4032、RAF-265(亦為VEGFR抑制劑)、索拉非尼(sorafenib)(亦為VEGFR抑制劑)、XL-281及Nevavar(亦為VEGFR之抑制劑)。
KSP抑制劑之實例為伊平絲博(ispinesib)、ARRY-520、AZD-4877、CK-1122697、GSK-246053A、GSK-923295、MK-0731、SB-743921、LY-2523355及EMD-534085。
src及/或bcr-abl抑制劑之實例為達沙替尼(dasatinib)、AZD-0530、伯舒替尼(bosutinib)、XL-228(亦為IGF-1R抑制劑)、尼羅替尼(nilotinib)(亦為PDGFR及cKit抑制劑)、伊馬替尼(亦為cKit抑制劑)、NS-187、KX2-391、AP-24534(亦為EGFR、FGFR、Tie2、Flt3之抑制劑)、KM-80及LS-104(亦為Flt3、Jak2之抑制劑)。
PDK1抑制劑之一實例為AR-12。
Rho抑制劑之一實例為BA-210。
PI3激酶抑制劑之實例為PX-866、PX-867、BEZ-235(亦為mTor抑制劑)、XL-147及XL-765(亦為mTor抑制劑)、BGT-226、CDC-0941。
cMet或HGF抑制劑之實例為XL-184(亦為VEGFR、cKit、Flt3之抑制劑)、PF-2341066、MK-2461、XL-880(亦為VEGFR之抑制劑)、MGCD-265(亦為VEGFR、Ron、Tie2之抑制劑)、SU-11274、PHA-665752、AMG-102、AV-299、ARQ-197、MetMAb、CGEN-241、BMS-777607、JNJ-38877605、PF-4217903、SGX-126、CEP-17940、AMG-458、INCB-028060及E-7050。
c-Myc抑制劑之一實例為CX-3543。
Flt3抑制劑之實例為AC-220(亦為cKit及PDGFR之抑制劑)、KW-2449、LS-104(亦為bcr-abl及Jak2之抑制劑)、MC-2002、SB-1317、來
妥替尼(lestaurtinib)(亦為VEGFR、PDGFR、PKC之抑制劑)、TG-101348(亦為JAK2之抑制劑)、XL-999(亦為cKit、FGFR、PDGFR及VEGFR之抑制劑)、舒尼替尼(sunitinib)(亦為PDGFR、VEGFR及cKit之抑制劑)及坦度替尼(tandutinib)(亦為PDGFR及cKit之抑制劑)。
HSP90抑制劑之實例為坦螺旋黴素(tanespimycin)、阿螺旋黴素(alvespimycin)、IPI-504、STA-9090、MEDI-561、AUY-922、CNF-2024及SNX-5422。
JAK/STAT抑制劑之實例為CYT-997(亦與微管蛋白相互作用)、TG-101348(亦為Flt3抑制劑)及XL-019。
Mek抑制劑之實例為ARRY-142886、AS-703026、PD-325901、AZD-8330、ARRY-704、RDEA-119及XL-518。
mTor抑制劑之實例為泰西羅莫司(temsirolimus)、德福羅莫司(deforolimus)(其亦用作VEGF抑制劑)、依維莫司(everolimus)(此外,VEGF抑制劑)、XL-765(亦為PI3激酶抑制劑)及BEZ-235(亦為PI3激酶抑制劑)。
Akt抑制劑之實例為哌立福新(perifosine)、GSK-690693、RX-0201及曲西立濱(triciribine)。
cKit抑制劑之實例為馬賽替尼(masitinib)、OSI-930(亦用作VEGFR抑制劑)、AC-220(亦為Flt3及PDGFR之抑制劑)、坦度替尼(亦為Flt3及PDGFR之抑制劑)、阿西替尼(axitinib)(亦為VEGFR及PDGFR之抑制劑)、舒尼替尼(亦為Flt3、PDGFR、VEGFR之抑制劑)及XL-820(亦用作VEGFR及PDGFR之抑制劑)、伊馬替尼(imatinib)(亦為bcr-abl抑制劑)、尼羅替尼(亦為bcr-abl及PDGFR之抑制劑)。
hedgehog拮抗劑之實例為IPI-609、CUR-61414、GDC-0449、IPI-926及XL-139。
CDK抑制劑之實例為塞力絲伯(seliciclib)、AT-7519、P-276、ZK-
CDK(亦抑制VEGFR2及PDGFR)、PD-332991、R-547、SNS-032、PHA-690509、PHA-848125及SCH-727965。
蛋白酶體抑制劑之實例為硼替佐米(bortezomib)、卡菲佐米(carfilzomib)及NPI-0052(亦為NFκB之抑制劑)。
蛋白酶體抑制劑/NFκB路徑抑制劑之實例為硼替佐米、卡菲佐米、NPI-0052、CEP-18770、MLN-2238、PR-047、PR-957、AVE-8680及SPC-839。
泛素化路徑抑制劑之實例為HBX-41108。
抗血管生成劑之實例為FGFR、PDGFR及VEGF(R)之抑制劑及沙力度胺(thalidomide),該等藥劑係選自(但不限於)貝伐單抗(bevacizumab)、莫替尼伯(motesanib)、CDP-791、SU-14813、替拉替尼(telatinib)、KRN-951、ZK-CDK(亦為CDK抑制劑)、ABT-869、BMS-690514、RAF-265、IMC-KDR、IMC-18F1、IMiD、沙力度胺、CC-4047、來那度胺(lenalidomide)、ENMD-0995、IMC-D11、Ki-23057、布瑞伐尼(brivanib)、西地尼布(cediranib)、1B3、CP-868596、IMC-3G3、R-1530(亦為Flt3抑制劑)、舒尼替尼(亦為cKit及Flt3之抑制劑)、阿西替尼(axitinib)(亦為cKit抑制劑)、來妥替尼(lestaurtinib)(亦為Flt3及PKC之抑制劑)、凡塔藍尼(vatalanib)、坦度替尼(亦為Flt3及cKit之抑制劑)、帕佐尼布(pazopanib)、PF-337210、阿柏西普(aflibercept)、E-7080、CHIR-258、索拉非尼甲苯磺酸鹽(亦為Raf之抑制劑)、範得他尼(vandetanib)、CP-547632、OSI-930、AEE-788(亦為EGFR及Her2之抑制劑)、BAY-57-9352(亦為Raf抑制劑)、BAY-73-4506(亦為Raf抑制劑)、XL-880(亦為cMet抑制劑)、XL-647(亦為EGFR及EphB4之抑制劑)、XL-820(亦為cKit之抑制劑)、尼羅替尼(亦為cKit及brc-abl之抑制劑)、CYT-116、PTC-299、BMS-584622、CEP-11981、多福替尼(dovitinib)、CY-2401401及ENMD-
2976。
其他治療劑亦可選自EGFR抑制劑,該等EGFR抑制劑可為小分子EGFR抑制劑或抗EGFR抗體。抗EGFR抗體之實例為(但不限於)西妥昔單抗(cetuximab)、盤尼圖單抗(panitumumab)、尼妥珠單抗(nimotuzumab)、劄魯目單抗(zalutumumab);小分子EGFR抑制劑之實例為吉非替尼(gefitinib)、埃羅替尼(erlotinib)及範得他尼(亦為VEGFR抑制劑)。EGFR調節劑之另一實例為EGF融合毒素。
可用於與本發明之抗CD37抗體分子組合的其他EGFR及/或Her2抑制劑為拉帕替尼(lapatinib)、曲妥珠單抗(trastuzumab)、帕妥珠單抗(pertuzumab)、XL-647、奈拉替尼(neratinib)、BMS-599626、ARRY-334543、AV-412、mAB-806、BMS-690514、JNJ-26483327、AEE-788(亦為VEGFR抑制劑)、AZD-8931、ARRY-380 ARRY-333786、IMC-11F8、Zemab、TAK-285、AZD-4769。
其他藥物亦可選自靶向IGF-1R及胰島素受體路徑之藥劑。該等藥劑包括與IGF-1R結合之抗體(例如,CP-751871、AMG-479、IMC-A12、MK-0646、AVE-1642、R-1507、BIIB-022、SCH-717454、rhu Mab IGFR)及靶向IGF1-R之激酶域的新穎化學實體(例如,OSI-906或BMS-554417、XL-228、BMS-754807)。
可在療法中與本發明之抗CD37抗體分子有利組合的其他藥劑為靶向CD20之分子,包括CD20特異性抗體(例如利妥昔單抗、LY-2469298、歐克利單抗(ocrelizumab)、MEDI-552、IMMU-106、GA-101(=R7159)、XmAb-0367、歐伐吐單抗(ofatumumab))、放射性標記之CD20抗體(例如托絲吐單抗(tositumumab)及替坦異貝莫單抗(ibritumomab tiuxetan))或其他針對CD20之蛋白,例如SMIP Tru015、PRO-131921、FBT-A05、伐吐珠單抗(veltuzumab)、R-7159。
CD37抗體可與白血球上表現之其他表面抗原之抑制劑、尤其抗
體或抗體樣分子組合,例如抗CD2(希普利珠單抗(siplizumab))、抗CD4(紮木單抗(zanolimumab))、抗CD19(MT-103、MDX-1342、SAR-3419、XmAb-5574)、抗CD22(依帕珠單抗(epratuzumab))、抗CD23(魯昔單抗(lumiliximab))、抗CD30(伊莫單抗(iratumumab))、抗CD32B(MGA-321)、抗CD38(HuMax-CD38)、抗CD40(SGN40)、抗CD52(阿來組單抗)、抗CD80(加利昔單抗(galiximab))。本發明之抗體亦可與另一CD37拮抗劑(例如,TRU-016)組合。
待與CD37抗體組合之其他藥劑為免疫毒素(例如BL-22(抗CD22免疫毒素))、伊妥珠單抗奧唑米星(inotuzumab ozogamicin)(抗CD23抗體-刺孢黴素(calicheamicin)接合物)、RFT5.dgA(抗CD25篦麻毒素A鏈)、SGN-35(抗CD30阿瑞他汀E接合物)及吉妥珠單抗奧唑米星(gemtuzumab ozogamicin)(抗CD33刺孢黴素接合物)、MDX-1411(抗CD70接合物)或放射性標記之抗體(例如90Y-依帕珠單抗(抗CD22放射免疫接合物))。
此外,抗CD37抗體亦可與免疫調節劑組合,該等免疫調節劑例如誘發細胞凋亡或修飾信號傳遞路徑之抗體,例如TRAIL受體調節劑馬帕妥單抗(mapatumumab)(TRAIL-1受體促效劑)、來沙木單抗(lexatumumab)(TRAIL-2受體促效劑)、替加妥珠單抗(tigatuzumab)、阿泊單抗(Apomab)、AMG-951及AMG-655;抗HLA-DR抗體(例如1D09C3)、抗CD74、破骨細胞分化因子配位體抑制劑(例如狄諾塞單抗(denosumab))、BAFF拮抗劑(例如AMG-623a)或Toll樣受體促效劑(例如,TLR-4或TLR-9)。
可與本發明之抗CD37抗體分子組合使用的其他藥物係選自(但不限於)激素、激素類似物及抗激素(例如,他莫昔芬(tamoxifen)、托瑞米芬(toremifene)、雷諾昔酚(raloxifene)、氟維司群(fulvestrant)、乙酸甲地孕酮(megestrol acetate)、氟他胺(flutamide)、尼魯胺
(nilutamide)、比卡魯胺(bicalutamide)、乙酸環丙孕酮(cyproterone acetate)、非那雄安(finasteride)、乙酸布舍瑞林(buserelin acetate)、氟氫可的松(fludrocortinsone)、氟甲睪酮(fluoxymesterone)、甲羥孕酮(medroxyprogesterone)、己酸羥孕酮(hydroxyprogesterone caproate)、己烯雌酚(diethylstilbestrol)、丙酸睪酮(testosterone propionate)、氟甲睪酮(fluoxymesterone)/等效物、奧曲肽(octreotide)、阿佐普芬(arzoxifene)、帕瑞肽(pasireotide)、伐普肽(vapreotide)、腎上腺類固醇(adrenocorticosteroid)/拮抗劑、潑尼松(prednisone)、地塞米松(dexamethasone)、胺魯米特(ainoglutethimide));芳香酶抑制劑(例如,安美達錠(anastrozole)、來曲唑(letrozole)、利阿唑(liarozole)、依西美坦(exemestane)、阿他美坦(atamestane)、福美司坦(formestane));LHRH促效劑及拮抗劑(例如,乙酸戈舍瑞林(goserelin acetate)、亮丙立德(leuprolide)、阿巴瑞克(abarelix)、西曲瑞克(cetrorelix)、地洛瑞林(deslorelin)、組胺瑞林(histrelin)、曲普瑞林(triptorelin));抗代謝物(例如,抗葉酸物,例如甲胺喋呤(methotrexate)、三甲曲沙(trimetrexate)、培美曲唑(pemetrexed);嘧啶類似物,例如5-氟尿嘧啶(5-fluorouracil)、氟脫氧尿苷(fluorodeoxyuridine)、卡西他濱(capecitabine)、地西他濱(decitabine)、奈拉濱(nelarabine)、5-氮胞苷(5-azacytidine)及吉西他濱(gemcitabine);嘌呤及腺苷類似物(諸如,巰嘌呤(mercaptopurine)、硫鳥嘌呤(thioguanine)、咪唑硫嘌呤(azathioprine)、克拉屈濱(cladribine)及噴司他丁(pentostatin)、阿糖胞苷(cytarabine)、氟達拉濱(fludarabine)、氯法拉濱(clofarabine));抗腫瘤抗生素(例如,蒽環黴素,例如羥道諾紅黴素、道諾黴素(daunorubicin)、表柔比星(epirubicin)及伊達比星(idarubicin)、絲裂黴素-C(mitomycin-C)、博萊黴素(bleomycin)、放線菌素D(dactinomycin)、普卡黴素(plicamycin)、
絲普卡黴素(splicamycin)、阿替莫黴素D(actimomycin D)、米托蒽醌(mitoxantrone)、米托蒽醌伊達比星(mitoxantroneidarubicin)、皮克蒽醌(pixantrone)、鏈脲佐菌素(streptozocin)、阿非迪黴素(aphidicolin));鉑衍生物(例如,順鉑(cisplatin)、奧賽力鉑(oxaliplatin)、卡波鉑(carboplatin)、洛鉑(lobaplatin)、撒塔鉑(satraplatin));烷基化劑(例如,雌莫司汀(estramustine)、司莫司汀(semustine)、氮芥(mechlorethamine)、美法侖(melphalan)、苯丁酸氮芥(chlorambucil)、馬利蘭(busulphan)、達卡巴嗪(dacarbazine)、環磷醯胺(cyclophosphamide)、異環磷醯胺(ifosfamide)、羥基脲(hydroxyurea)、替莫唑胺(temozolomide)、亞硝基脲(nitrosourea)(諸如,卡莫司汀(carmustine)及洛莫司汀(lomustine))、塞替派(thiotepa));抗有絲分裂劑(例如,長春花鹼(vinca alkaloid),例如長春鹼(vinblastine)、長春花鹼醯胺(vindesine)、長春瑞賓(vinorelbine)、長春氟寧(vinflunine)及長春新鹼(vincristine);及紫杉烷,例如紫杉醇(paclitaxel)、多烯紫杉醇(docetaxel)及其調配物拉若他西(larotaxel);絲莫他西(simotaxel)及埃坡黴素(epothilone),例如伊沙匹隆(ixabepilone)、帕妥匹隆(patupilone)、ZK-EPO);拓撲異構酶抑制劑(例如,表鬼臼素(epipodophyllotoxin),例如依託泊苷(etoposide)及磷酸依託泊苷(etopophos)、替尼泊甙(teniposide)、安吖啶(amsacrine)、拓朴替康(topotecan)、伊立替康(irinotecan)、巴諾蒽醌(banoxantrone)、喜樹鹼(camptothecin));及混雜化學治療劑,諸如視黃酸衍生物、胺磷汀(amifostine)、阿那格雷(anagrelide)、干擾素α、干擾素β、干擾素γ、介白素-2(interleukin-2)、丙卡巴肼(procarbazine)、N-甲肼(N-methylhydrazine)、米托坦(mitotane)及卟吩姆(porfimer)、貝瑟羅汀(bexarotene)、賽利克西(celecoxib)、乙烯亞胺(ethylenemine)/甲基三聚氰胺、三乙烯三聚氰胺
(triethyienemelamine)、三乙烯硫代磷醯胺(triethylene thiophosphoramide)、六甲基三聚氰胺(hexamethylmelamine)及酶L-天冬醯胺酶、L-精胺酸酶及甲硝噠唑(metronidazole)、米索硝唑(misonidazole)、去甲基醚醇硝唑(desmethylmisonidazole)、哌莫硝唑(pimonidazole)、依他硝唑(etanidazole)、尼莫唑(nimorazole)、RSU 1069、EO9、RB6145、SR4233、菸鹼醯胺(nicotinamide)、5-溴脫氧尿苷(5-bromodeozyuridine)、5-碘脫氧尿苷(5-iododeoxyuridine)、溴去氧胞苷(bromodeoxycytidine)、赤式羥基壬基腺嘌呤(erythrohydroxynonyl-adenine)、蒽二酮(anthracenedione)、GRN-163L(競爭性端粒酶模板拮抗劑)、SDX-101(PPAR促效劑)、他拉伯特(talabostat)(DPP抑制劑)、福羅地辛(forodesine)(PNP抑制劑)、阿他塞泊(atacicept)(靶向TNF家族成員BLyS及APRIL之可溶性受體)、TNF-α中和劑(恩博(Enbrel)、胡米拉(Humira)、雷米卡德(Remicade))、XL-844(CHK1/2抑制劑)、VNP-40101M(DNA烷基化劑)、SPC-2996(反義bcl2抑制劑)、歐巴妥拉(obatoclax)(bcl2抑制劑)、恩絲他瑞(enzastaurin)(PKCβ調節劑)、沃瑞塞特(vorinistat)(HDAC抑制劑)、羅米地辛(romidepsin)(HDAC抑制劑)、AT-101(Bcl-2/Bcl-xL抑制劑)、普利地辛(plitidepsin)(多作用縮肽)、SL-11047(多元胺代謝調節劑)。
在某些實施例中,將抗CD37抗體分子與"CHOP"(環磷醯胺、羥道諾紅黴素、長春新鹼及潑尼松之組合)一起應用。
本發明之抗CD37抗體分子亦可與其他療法組合使用,該等療法包括外科手術、放射療法、內分泌療法、生物反應改質劑、高溫及冷凍療法及減弱任何不利影響之藥劑(例如,止吐藥)、G-CSF、GM-CSF、光敏劑(諸如,血卟啉衍生物、Photofrin®、苯并卟啉衍生物、Npe6、錫本卟啉、苯博瑞德a(pheoboride-a)、細菌葉綠素a(bacteriochlorophyll-a)、萘酞菁(naphthalocyanine)、酞菁
(phthalocyanine)、鋅酞菁)。
單株抗體顯示靈敏的抗原特異性且通常僅與人類標靶抗原反應,而不與來自動物物種之同源蛋白反應。為支持治療抗體之研製,可需要用於評估活體內毒性及藥效行為之適當動物模型。活體內模型之一種可能性為內源標靶抗原經人類同源物置換之轉殖基因小鼠("基因剔除/基因敲入"小鼠)。詳言之,為研製治療性抗CD37抗體,可由人類CD37基因置換鼠科CD37基因。此可藉由構築含有側接未轉譯序列之人類CD37基因之編碼性基因組序列的靶向載體來實現。此靶向載體可用於使用小鼠ES細胞進行同源重組。用於人類CD37表現之同型接合之轉殖基因動物可用以(例如)藉由監測抗體應用後外周B細胞的數目來評估抗體關於人類CD37之藥效作用。或者,彼等小鼠可用於研究在靜脈內(i.v.)應用後人類CD37特異性抗體之潛在毒性作用。
在缺乏單株抗體之動物交叉反應性之狀況下,另一可能性為產生所謂的替代抗體。替代抗體為與可用於研究藥效及毒性作用之相關動物物種(例如,小鼠或石蟹獼猴)之同源蛋白反應的抗體。在CD37之狀況下,分別研製對獼猴CD37或小鼠CD37具特異性之單株抗體。理想地,此類替代抗體應具有與研製抗體類似之結合及功能性質。此可藉由使用檢定系統來研究,該等檢定系統利用獼猴或小鼠的表現CD37之細胞作為標靶細胞,例如對於結合而言,可使用FACS Scatchard分析、ADCC及細胞凋亡檢定。最終,可根據活體外獼猴或小鼠血液中之B細胞去除活性來選擇替代抗體。
圖1:藉由FACS競爭檢定所測定,嵌合抗體A0特異性識別CD37抗原。
圖2:藉由FACS所測定,A0之人化型式與細胞CD37抗原結合。
圖3:藉由FACS所測定,A0之人化型式與細胞CD37抗原結合。
圖4:藉由FACS scatchard分析所測定,A0之人化型式對細胞CD37抗原具有親和力。
圖5:A0之人化型式對拉莫斯細胞之ADCC活性。
圖6:A0之人化型式對拉莫斯細胞之促細胞凋亡活性。
圖7:mAb A0之Fc工程化型式對拉莫斯細胞之ADCC活性。
圖8:mAb B0之Fc工程化型式對拉莫斯細胞之ADCC活性。
圖9:mAb A0及B0之促細胞凋亡活性。
圖10:mAb A0之Fc工程化型式之促細胞凋亡活性。
圖11A:全血檢定中與利妥昔單抗相比,藉由Fc工程化之抗體A2及B2對正常人類B細胞進行之去除。
圖11B:與利妥昔單抗相比,Fc工程化後抗體之B細胞去除活性優良。
圖12:與利妥昔單抗相比,Fc工程化後ADCC活性優良。
圖13:全血檢定中與利妥昔單抗相比,藉由Fc工程化之抗體A2及B2對拉莫斯伯基特淋巴瘤細胞進行之去除。
圖14:藉由Fc工程化之抗體A2及B2對裸小鼠中拉莫斯異種移植腫瘤之活體內腫瘤生長抑制。
圖15:CD37在多發性骨髓瘤細胞上之表現。
圖16:抗體A2及B2在多發性骨髓瘤細胞上之ADCC活性。
實例1
嵌合及人化抗CD37抗體之產生
a)嵌合抗體A0之產生
基於SEQ ID NO:2及SEQ ID NO:4中所示之可變重鏈及輕鏈胺基酸序列,應用關於哺乳動物細胞最佳化之密碼子使用(GeneArt,Regensburg,Germany),在5'末端添加HindIII選殖位點及在3'末端添加
BamH1選殖位點,藉此合成相應DNA序列。合成之DNA分子經HindIII及BamHI消化,且基於分別編碼人類IgG1恆定區及人類κ輕鏈恆定區(SEQ ID NO:24及SEQ ID NO:26)之表現載體,將所得DNA片段(SEQ ID NO:1及SEQ ID NO:3加上限制位點)選殖至pcDNA3.1中。製備EndoFree質體製劑(Qiagen),且根據供應商之方案,將重鏈及輕鏈質體以各質體1mg/L之濃度共轉染至HEK 293自由式細胞(Invitrogen)中。72小時後,採集上清液且藉由ELISA測定IgG濃度。將所得嵌合抗CD37抗體(稱為A0)在改良之蛋白A管柱(GE Healthcare)上純化,溶離至檸檬酸鹽緩衝液中,接著在PBS中透析。
b)嵌合抗體A0之人化型式之產生
使用如(例如)US 5,225,539、US 6,548,640、US 6,982,321中所述之CDR移植方法,執行如a)中獲得之嵌合mAb A0之人化。
為建立mAb A0 VL域之結構模型,自布魯克哈芬國家實驗室(Brookhaven National Laboratory)之蛋白資料庫(PDB)中選擇結構模板。自鼠科單株抗體輸入"1KB5"選擇具有88%序列一致性/81%相似性及2.5Å解析度之VL域。對於mAb A0 VH域,選擇具有90%序列一致性及91%相似性之同一小鼠單株抗體結構"1KB5"作為主要模型化模板。發現人類Vκ1(hVK1)及人類VH1(hVH1)類型與人類一致構架達到最佳配合。作為替代性設計,選擇最穩定人類一致域hVK3及hVH3之移植物。為進行移植,將mAb A0_VL及mAb A0_VH模型與人類一致域模型hVK1、hVK3、hVH1A及hVH3組合,且將其組合以產生Fv模型。藉由將鼠科mAb A0 CDR區包埋至人類抗體構架中來執行環移植,且合成人化鏈構築體之DNA分子。
在如表1所示之重鏈及輕鏈序列的組合中,合成各別人化可變區且將其選殖至免疫球蛋白表現載體中且在如a)中所述之HEK 293自由式表現系統(Invitrogen)中瞬間表現,且在蛋白A管柱上進行純化。
c)Fc工程化之嵌合及人化抗CD37抗體的產生
如Lazar等人,2006所述,執行Fc突變體之產生。將所得Fc工程化之重鏈序列引入表現載體pAD-CMV1(EP 393 438中所述)中且與含有輕鏈編碼序列之質體一起共轉染至CHO-DG44細胞中。在轉染後5至7天自細胞培養基採集抗體,且經由蛋白A層析進行純化,將其溶離至檸檬酸鹽緩衝液中,接著在PBS中透析。經由蛋白A HPLC來測定樣品之蛋白含量,經由Kinetic-QCL動力學顯色檢定(Kinetic Chromogenic Assay,Lonza)來測定內毒素含量。藉由HP-SEC來測定樣品之單體含量,用於功能測試之所有樣品均顯示單體含量>95%。
表2嵌合及人化抗CD37抗體之可變重鏈及輕鏈序列及Fc突變(抗體A0、B0、C0等與表1中之抗體A及B、C等一致)。一些突變抗體藉由其重鏈及輕鏈之全長序列來例示。
實例2
嵌合mAb A0特異性識別CD37抗原
在FACS競爭檢定中,在拉莫斯伯基特淋巴瘤細胞(ATCC #CRL-1596)上測試MAb A0對細胞CD37之特異性。使細胞在使用補充有10%經熱失活之胎牛血清、12.5mM HEPES、1mM丙酮酸鈉、1% MEM非必需胺基酸之RPMI-1640+GlutaMAX作為培養基的組織培養燒瓶(175cm2)中生長。在濕潤氣氛中,於37℃及5% CO2下以3×105個細胞/毫升之初始密度將細胞培養3天。藉由一週2-3次用新鮮培養基以1:6之比率進行轉種,將培養物維持在3×105與1.8×106/ml之間的細胞濃度
下。對於FACS競爭分析而言,使用濃度為1μg/ml之直接經藻紅素(PE)標記的CD37特異性mAb HH1(Santa Cruz)。在4℃下,以所指示之莫耳比率將抗體用未標記之競爭抗體A0預培育10min。此後,將1×105個拉莫斯細胞用抗體混合物在冰上培育30min。此後,將細胞在磷酸鹽緩衝生理食鹽水(PBS)中洗滌兩次,再懸浮於FACS緩衝液中且在BD FACS Canto上進行量測。此類檢定之結果顯示於圖1中。以20倍莫耳過量添加對照人類IgG1抗體(Sigma IgG1κ)並未顯著降低拉莫斯細胞之平均螢光強度(MFI)。以20倍莫耳過量添加未標記之HH1抗體或A0抗體幾乎完全廢除直接標記之HH1抗體的結合。此表明A0及HH1抗體識別拉莫斯細胞上之一致或相似抗原決定基且競爭與細胞CD37抗原之結合。
實例3
mAb A0之人化型式與細胞CD37抗原之結合
藉由FACS分析來測試A0之人化型式與細胞CD37抗原之結合。以所指示之濃度將抗體添加至拉莫斯細胞中且使其在4℃下結合30min。此後,用PE標記之山羊抗人類IgG抗體(Sigma)偵測結合抗體,將細胞用PBS洗滌2次,且此後使細胞再懸浮於FACS緩衝液中且藉由FACS在BD FACS Canto上進行分析。實例顯示於圖2及3中(分別為抗體A、B、C、D、I或A、H、I、J、K、L及M;參見表1)。數個A0人化型式顯示與拉莫斯細胞之結合與親本抗體A0相似,表明人化不會降低與細胞CD37抗原之結合。
實例4
嵌合mAb A0之人化型式的FACS scatchard分析
藉由如其他文獻(Brockhoff等人,1994)所述之FACS scatchard分析來測定抗體A0之人化型式(稱為B、C、D、H、I及K;參見表1)對細胞CD37抗原之親和力。簡言之,在96孔盤中製備抗體稀釋液,在
第一孔中以100-400nM開始(80μl),接著11個稀釋步驟(1:2,40+40μl)。將50μl mAb稀釋液添加至FACS管中,將150μl細胞(0.8×106/ml=1.2×105個細胞/管)添加至各FACS管中。將細胞輕輕混合且在冰上培育1h。此後,添加50μl FITC接合之二次抗體(濃度為15μg/ml;小鼠mAb抗hu IgG所有亞類,Zymed 05-4211),使其混合且在冰上培育30min。此後添加4ml含有0.02%酸之PBS(ph 7.2),將細胞粒化且再懸浮於300μl PBS(pH 7.2)中且經受使用BD FACS Canto之FACS分析。所有實驗步驟均在濕冰上執行,所有抗體稀釋液均在PBS/0.5% BSA+0.02%酸中製成。使用Quantum FITC MESF(Premix)高含量珠粒(Bangs Laboratories)來執行FACS校準。所有樣品均使用相同FACS參數來量測。根據不同抗體濃度下之MFI值來計算結合IgG對游離IgG之比率,且將其展示為scatchard墨點。圖4顯示數個A0人化變異體之MFI/抗體濃度關係。結果顯示一些人化型式與拉莫斯細胞之結合與起始抗體相似,其中解離常數(Kd)在2.15至4.90奈莫耳/公升之範圍內。
實例5
嵌合mAb A0之人化型式之ADCC活性
使用拉莫斯細胞作為標靶細胞及使用IL2刺激之人類PBMC作為效應細胞,來評估A0之人化型式(稱為B、C、D、H、J、K;參見表1)介導抗體依賴性細胞介導之細胞毒性(ADCC)的能力。拉莫斯細胞(伯基特淋巴瘤;ATCC #CRL-1596)自ATCC購得。使細胞在使用補充有10%經熱失活之胎牛血清、12.5mM HEPES、1mM丙酮酸鈉、1% MEM非必需胺基酸之RPMI-1640+GlutaMAX作為培養基的組織培養燒瓶(175cm2)中生長。在濕潤氣氛中,於37℃及5% CO2下以3×105個細胞/毫升之初始密度將細胞培養3天。藉由一週2-3次用新鮮培養基以1:6之比率進行轉種,將培養物維持在3×105與1.8×106/ml之間的細胞
濃度下。將細胞密度在1.5×106/ml與1.8×106/ml之間且處於生長對數期之細胞培養物的等分試樣離心(200×g,亦即1000rpm)10min。將細胞用洗滌培養基(不含L-麩胺醯胺之RPMI 1640)洗滌一次且粒化(200×g,亦即1000rpm;10min)。使細胞小球再懸浮於檢定培養基[於不含L-麩胺醯胺之RPMI中之1% BSA]中且測定細胞數。將細胞濃度調整至2×105/ml。
自健康供體抽出約50-80ml全血,將其用於PBMC之分離。在50ml管中,將10ml全血用26ml HBSS(不含鈣及鎂之漢克平衡鹽溶液(Hanks' Balanced Salt Solution w/o calcium and magnesium))以1:3.6稀釋。在50ml管中,使18ml經稀釋之全血在12ml Lymphoprep(Nycomed Pharma)上分層,且以370×g(1400rpm)離心35min。自界面吸出單核細胞且首先用HBSS洗滌(750×g,亦即1900rpm;10min),接著用HBSS進行第二次洗滌(300×g,亦即1200rpm;10min)且最終用HBSS洗滌(160×g,亦即900rpm;10min)。使用移液管使粒化細胞輕輕再懸浮於培養基/檢定培養基(於不含L-麩胺醯胺之RPMI 1640中的10%經熱失活之人類AB血清)中,且在細胞計數器中測定細胞數。將PBMC濃度調整至1×107/ml。將剛分離之PBMC(5×105/ml)維持在37℃下、CO2恆溫箱中之組織培養燒瓶(75cm2)中的培養基(不含L-麩胺醯胺之補充有10%人類AB血清的RPMI 1640)中隔夜。第二天,用最終濃度為1U/ml之hIL-2刺激細胞,歷時另外3天。在Lymphoprep梯度上,自細胞碎片分離經IL-2刺激之PBMC。使經純化之經IL-2刺激之PBMC以1×107/ml之濃度懸浮於培養基/檢定培養基中。
在96孔圓底微量滴定盤中,在每孔最終體積為200μl之檢定培養基中,雙重複或三次重複地執行效應細胞與標靶細胞在特異性或非特異性抗體存在下之共培養,其中檢定培養基由1:1比率之RPMI中的
10%人類AB血清及1% BSA組成。首先,塗上效應細胞(於每孔100μl於RPMI中之10%人類AB血清中的剛分離之PBMC細胞),接著塗上標靶細胞及在50μl於RPMI中之1% BSA中稀釋的抗體溶液。作為對照,在單獨檢定培養基中培養效應細胞(效應細胞對照),且在單獨檢定培養基(自發溶解)或在補充有1% Triton X-100之檢定培養基(最大溶解)中培養標靶細胞。將共培養物在潮濕CO2恆溫箱中於37℃下培育3小時。在培育結束時,在室溫下藉由離心(200×g,亦即1000rpm;10min)自培養基移除細胞。將不含細胞之上清液(每孔100μl)轉移至96孔平底盤之相應孔中。為測定此等上清液中之LDH活性,將100μl反應混合物(將250μl催化劑與11.25ml染料溶液新鮮混合)添加至各孔中且在室溫下在黑暗中培育30min。接著,如下所述來量測吸光度。
使用細胞毒性偵測套組(LDH;Roche)來量測ADCC活性。細胞毒性之偵測係基於自質膜受破壞之細胞釋放的LDH酶活性之量測。釋放至培養物上清液中之LDH將來自套組之四唑鹽還原成甲臢(formazan)。相對於參考波長650nm,在ELISA盤式讀數器中量測490nm下甲臢染料之吸收最大值。為計算細胞介導之細胞毒性百分比,在各實驗設備中執行五個對照。
背景對照I(1):檢定培養基中所含之LDH活性,將其自值(3)及(5)減去。
背景對照II(2):檢定培養基中1% Triton-X100中所含之LDH活性,將其自最大LDH釋放值(4)減去。
自發LDH釋放(3):自單獨標靶細胞釋放之LDH活性。
最大LDH釋放(4):標靶細胞中最大可釋放之LDH活性。
效應細胞對照(5):自單獨效應細胞釋放之LDH活性。
為測定細胞介導之細胞毒性百分比,計算三次重複或雙重複實驗之平均吸光度,且根據製造商之說明減去背景。在圖5中,顯示使用
25:1之E:T比率及拉莫斯標靶細胞之ADCC檢定的結果。添加30ng/ml濃度之抗體。起始mAb及其人化型式展示關於拉莫斯細胞具有相似的ADCC活性。總之,抗CD37 mAb A之人化不會顯著改變其誘發ADCC之能力。
實例6
嵌合mAb A0之人化型式之促細胞凋亡活性
藉由在用mAb培育拉莫斯細胞之後量測AnnexinV/PI陽性細胞來評估mAb A0(=A)及其人化型式(B、C、D及I;參見表1)之促細胞凋亡活性。拉莫斯細胞(伯基特淋巴瘤;ATCC #CRL-1596)來源於ATCC。使細胞在使用補充有10%經熱失活之胎牛血清、12.5mM HEPES、1mM丙酮酸鈉、1% MEM非必需胺基酸之RPMI-1640+GlutaMAX作為培養基的組織培養燒瓶(175cm2)中生長。在濕潤氣氛中,於37℃及5% CO2下以3×105個細胞/毫升之初始密度將細胞培養3天。藉由一週2-3次用新鮮培養基以1:6之比率進行轉種,將培養物維持在3×105與1.8×106/ml之間的細胞濃度下。將細胞密度在1.5×106/ml與1.8×106/ml之間且處於生長對數期之細胞培養物的等分試樣離心(200×g,亦即1000rpm)10min。將細胞用洗滌培養基(不含L-麩胺醯胺之RPMI 1640)洗滌一次且粒化(200×g,亦即1000rpm;10min)。使細胞小球再懸浮於培養基中且測定細胞數。將細胞濃度調整至1×106/ml。將每孔100μl細胞懸浮液塗於96孔圓底盤中。在含有10% FBS之細胞培養基中稀釋抗體且每孔添加100μl抗體溶液。將細胞在CO2恆溫箱中於37℃下培育20至24小時,且此後以Vybrant細胞凋亡檢定套組#2染色。將Alexa Fluor 488標記之Annexin V及碘化丙啶溶液添加至細胞中且在黑暗中培育15min。此後,使細胞再懸浮於400μl AnnexinV結合緩衝液中且經受使用BD FACS Canto之FACS分析。使用FL1/FL2通道,以二維點漬墨法測定AnnexinV陽性/PI陰性細胞及AnnexinV/PI陽
性細胞之百分比。將同型匹配之未結合抗體(Sigma人類IgG1)用作陰性對照。
在圖6中,顯示mAb A之各種人化型式對拉莫斯細胞之促細胞凋亡作用。用10μg/ml之抗體將細胞培育24小時,展示AnnexinV陽性細胞(PI陽性及PI陰性)之總百分比。親本mAb A顯示有效促細胞凋亡活性。意外地,人化型式顯示與親本mAb A相比顯著減少之AnnexinV陽性細胞數目,表明人化抗體之促細胞凋亡活性改變。總之,在此實驗配置中,MAb A之人化引起其促細胞凋亡活性之降低。
實例7
嵌合mAb A0之Fc工程化型式之ADCC活性
使用拉莫斯細胞作為標靶細胞來評估mAb A0之Fc工程化型式(稱為A1、A2、A3、A4,參見表2)的ADCC活性。如上所述來執行ADCC檢定(實例5)。實驗結果顯示於圖7中。A0之Fc工程化型式清楚顯示與親本mAb A0相比經改良之效能及功效。某些Fc變異體顯示與親本mAb相比多達100%之最大溶解的改良及與親本mAb相比多達10倍之EC50的改良。總之,引入特異性Fc突變體強烈增加嵌合mAb A0之ADCC活性。
實例8
mAb B0之Fc工程化型式之ADCC活性
使用拉莫斯細胞作為標靶細胞來評估mAb B0之Fc工程化型式(稱為B1、B2、B3、B4;參見表2)的ADCC活性。如上所述來執行ADCC檢定(實例5)。B0之Fc工程化型式清楚顯示與親本mAb B0相比經改良之效能及功效。某些Fc變異體顯示與親本mAb相比多達80%之最大溶解的改良及與親本mAb相比多達20倍之EC50改良。總之,引入特異性Fc突變體強烈增加人化mAb B0之ADCC活性。實驗結果顯示於圖8中。
實例9
mAb A0及B0之促細胞凋亡活性
圖9中展示與抗IgG mAb交聯之前及之後mAb A0及B0對拉莫斯細胞之促細胞凋亡活性。如實例6中所述來執行細胞凋亡檢定,為進行抗體交聯,以1:1之比率將抗人類IgG抗體(γ-鏈特異性;Sigma)添加至抗體中且在37℃下培育15min,接著將其添加至標靶細胞中。在圖9中,以1μg/ml之濃度添加交聯及未交聯之CD37特異性mAb。嵌合mAb A0即使未交聯亦為細胞凋亡之有效誘發劑,此作用在mAb交聯之後顯著增強。意外地,未交聯之人化mAb B0完全缺乏促細胞凋亡活性,然而在與抗IgG Ab交聯之後顯示有效促細胞凋亡活性。總之,此實驗顯示mAb A0之人化型式之促細胞凋亡活性可在抗體交聯後恢復。
實例10
mAb A0之Fc工程化型式之促細胞凋亡活性
藉由如實例6中所述之AnnexinV/PI染色來評估嵌合mAb A0之Fc工程化型式對拉莫斯細胞的促細胞凋亡活性。在0.1至10.000ng/ml之濃度範圍內,對親本抗體A0及Fc工程化變異體A2及A4進行滴定。如圖10中可見,所有3個抗體均顯示相似的促細胞凋亡活性。總之,此實驗顯示mAb A0之Fc工程化不會改變其促細胞凋亡活性。
實例11
a)全血檢定中Fc工程化之抗體A2及B2之B細胞去除活性
使用全血檢定來評估自人類血液去除正常B細胞之功效及效能。在此檢定格式中,將測試抗體添加至來自健康個體之人類血液的經EDTA處理之樣品中,且接著在37℃下培育3至4小時後,藉由4色FACS檢定定量量測B細胞數目。藉由與緩衝液或IgG對照相比,可計算測試藥劑去除B細胞之程度。由於存在與活體內人類中之情況相似
的人類IgG含量及效應細胞,所以認為此檢定類型極適用於預測活體內測試抗體之作用。
使用定量FACS檢定來測定來源於健康個體之血液樣品中B細胞及/或所添加之拉莫斯細胞的數目。使用含有已知數目之螢光珠粒之BD Trucount管來執行定量分析,該等螢光珠粒用作定量相關細胞群體之內標。藉由4色分析,使用4種不同的CD標記(CD3/CD14/CD19/CD45)以及FSC/SSC分析來鑑別B細胞。
將每孔270μl新鮮血液與30μl抗體稀釋液(在PBS中)或PBS(緩衝液對照)一起在48孔盤中雙重複培育。將樣品在37℃下培育4h且此後立即將其置於冰上。將33μl CD標記母體混合物添加至Trucount管中且添加50μl血液-抗體混合物。使樣品渦旋且在室溫下培育15分鐘。此後,添加450μl溶解緩衝液,使其渦旋且在室溫下再培育15分鐘。將樣品置於冰上且立即經受使用BD FACS CantoTM流式細胞儀之FACS分析。使用BD FACSDiva軟體(5.0.2版)來執行資料評估。
Fc工程化之嵌合及人化mAb A2及B2顯示對正常B細胞去除之優良效能,其中EC50值在0.15至0.35nM之範圍內。正常B細胞去除程度在57%至65%之範圍內。同時測試利妥昔單抗(用於治療B-NHL之登記抗體)且在此檢定格式中,其產生顯著較低之B細胞去除(圖11A)。
b)Fc工程化引入與利妥昔單抗相比A0及B0之優良B細胞去除活性
如a)中所述來評估來源於健康個體之人類血液中mAb對B細胞去除之作用。類似於利妥昔單抗,未經Fc工程化之mAb A0及B0顯示介於13%至26%之範圍內的B細胞去除活性。Fc工程化引起對兩個mAb而言均顯著增加之B細胞去除活性,其中平均去除百分比為75%。此顯然證明與利妥昔單抗相比A2及B2之優越性(圖11B)。
實例12
Fc工程化引入與利妥昔單抗相比優良之ADCC活性
使用拉莫斯細胞作為標靶細胞來評估mAb A0之Fc工程化型式A2的ADCC活性。如上所述來執行ADCC檢定(實例5)。未經Fc工程化之抗體A0顯示拉莫斯標靶細胞之最大溶解次於利妥昔單抗(對CD20具特異性之抗體,其經批准用於治療罹患B細胞淋巴瘤之患者)。意外地,A0之Fc工程化引起A2與利妥昔單抗相比明顯經改良之效能及功效。此表明在拉莫斯細胞上CD20及CD37之相似抗原密度下,Fc工程化之抗CD37 mAb A2明顯顯示與利妥昔單抗相比經改良之ADCC活性(圖12)。
實例13
全血檢定中Fc工程化之抗體A2及B2之淋巴瘤細胞去除活性
使用如實例11中所述之全血檢定來評估去除拉莫斯細胞(來自人類血液之源自伯基特淋巴瘤之細胞株)之功效及效能。在該檢定之修改中,以與內源性B細胞相比約十倍過量向全血基質中添加拉莫斯腫瘤細胞,且亦藉由FACS分析來監測其去除。Fc工程化之嵌合及人化mAb A2及B2顯示對拉莫斯細胞去除之良好效能,其中EC50值在0.35至0.54nM之範圍內。拉莫斯細胞去除程度在36%至55%之範圍內。同時測試利妥昔單抗(用於治療B-NHL之登記抗體)且在此檢定格式中,其產生顯著較低之拉莫斯細胞去除(圖13)。
實例14
疾病相關模型中Fc工程化之抗體A2及B2之活體內功效
使用裸小鼠中之拉莫斯伯基特淋巴瘤模型來評估mAb A2及B2之活體內抗腫瘤功效。將CD37陽性拉莫斯細胞經皮下注射至動物腰窩中且當腫瘤形成時,開始靜脈內治療該等動物。選擇每週兩次之治療時程(q3/4d),同時測試兩種不同劑量(8mg/kg及25mg/kg)。兩種mAb均顯示顯著抗腫瘤功效,其中T/C值在0.2%至26%之範圍內。未觀測到兩種劑量水平之間及兩種抗體之間的顯著差異。然而,存在經大劑
量A2治療之動物中功效更佳之傾向,其中T/C為0.2%且5/10完全腫瘤消退。所有治療均良好耐受,無明顯重量減輕。總之,mAb A2及B2顯示在拉莫斯伯基特淋巴瘤模型中具有顯著抗腫瘤功效,其中在8mg/kg劑量水平下已獲得最大活性。該活性可與同時測試之利妥昔單抗之活性相當。必須注意的是,在Fc工程化之抗體A2及B2下觀測到之活體內活性可能被低估,此係因為此等mAb係關於與人類效應細胞而非鼠科效應細胞之相互作用而最佳化。此最佳化相互作用在使用人類效應細胞時引起強烈改良之活體外ADCC活性(實例8),但在所用小鼠模型中並未有所反映。然而,此實驗中獲得之資料(圖14中所示)提供活體內證據證明靶向CD37之概念且因此可用於評估人類之治療劑量。
實例15
小鼠中A2及B2之藥物動力學與藥效作用之相關性以評估人類之治療劑量
使用拉莫斯腫瘤異種移植模型,在小鼠中建立A2及B2之血清濃度與其藥效作用之間的相關性。此等研究證明在小鼠中使用標準q3或4d抗體給藥時程,8mg/kg A2及B2之劑量(調配於檸檬酸鹽緩衝液中:25mM檸檬酸鈉、115mM NaCl、0.04% Tween 80,pH 6.0)引起此侵襲性皮下腫瘤模型中腫瘤生長之顯著延緩,因此表明在整個給藥時間間隔中具有持續之活性。此外,亦建立同一劑量之藥物動力學資料。
使用小鼠中之此PK/PD關聯,可使用關於人類中人化抗體之清除率(CL)的公開資料(Lobo等人,2004)來計算所評估之人類劑量。
A2之完整計算:
‧單一劑量8mg/kg後,平均AUC(0-∞)=6099μg.h/mL
‧假定小鼠中AUC(0-∞)=小鼠中AUC(ss,τ),且
AUC(ss,τ)/τ=C(ave,ss)
‧小鼠中C(ave,ss)(τ=84小時)=73μg/mL,假定其等於人類C(ave,ss)(τ=168h)。
‧因為人類AUC(ss,τ)=D/CL,且使用Lobo等人,2004所報導之人類中的人化抗體清除率(CL)範圍:CL=7mL/h/70kg至15mL/h/70kg。
‧對於7mL/h/70kg:168h×7=1176mL×73μg=86mg。
‧對於15mL/h/70kg:168h×15=2520mL×73μg=184mg。
因此,對於70kg人類而言,經評估之A2每週劑量在86至184mg範圍內。使用與上述相同之假定,對於70kg人類而言,所計算之經評估之人類B2每週劑量為189至404mg。
實例16
抗體A2及B2顯示在多發性骨髓瘤細胞上之ADCC活性
藉由FACS分析,使用對CD37具特異性之抗體來評估CD37在一組多發性骨髓瘤細胞株上之表現。用直接螢光標記之抗CD37抗體或未標記之CD37特異性抗體培育細胞,接著用針對一次抗體之螢光標記之二次抗體培育細胞。用FACS Canto流式細胞儀(BD Biosciences)量測經標記細胞之螢光活性且使用FACS Diva軟體將螢光強度記錄為MFI。11個經測試之多發性骨髓瘤中的6個證明CD37之細胞表面表現(圖15)。接著,在如實例5中所述之ADCC檢定中使用CD37特異性抗體A2及B2來測試一種細胞株(RPMI 8226)。兩種抗體均證明在RPMI 8226細胞上具有有效ADCC活性,其中EC50值在25ng/ml範圍內且最大細胞溶解為約20%(圖16)。此實例證明使用CD37特異性mAb A2及B2使CD37陽性多發性骨髓瘤細胞易於進行ADCC介導之細胞溶解。
圖15顯示對用於CD37表現之源自多發性骨髓瘤之6個細胞株進行的FACS分析。空心曲線指示與CD37特異性抗體之反應性,填充曲線
表示陰性對照抗體。
實例17
轉殖基因小鼠模型之產生,其中內源性標靶抗原CD37經其人類同源物置換。
構築含有側接未轉譯序列之人類CD37(BAC(細菌人工染色體)ID:RP11-433N13、RP11-50I11)基因之編碼序列的靶向載體。接著,將此靶向載體用於使用小鼠ES細胞進行同源重組。為此,使C57BL/6N ES細胞株在包含含有20% FBS(PAN)之DMEM高葡萄糖培養基中之小鼠胚胎纖維母細胞(MEF)及1200u/mL白血病抑制因子(Millipore ESG 1107)的有絲分裂失活餵養層上生長。在240V及500F下,將1×107個細胞及30g線性化DNA載體電穿孔(Biorad Gene Pulser)。G418選擇(200g/mL)在第2天開始。用更昔洛韋(Gancyclovir)(2M)進行之反選擇在電穿孔後第5天開始。在第8天分離ES純系且在純系擴展及在液氮中冷凍後,根據標準程序,(例如)藉由使用對標靶基因具特異性之放射性標記之DNA探針,藉由南方墨點法進行分析。接著,藉由此項技術中已知之標準程序,例如藉由注射胚泡及隨後產生嵌合動物,產生轉殖基因動物。分別藉由嵌合及異型接合之動物的習知繁殖來獲得針對人類CD37之異型接合及同型接合之動物。使用標準程序,例如外周血淋巴細胞之FACS分析或組織切片之免疫組織化學分析,監測在蛋白層級下鼠科CD37基因之成功基因剔除及人類CD37基因之基因敲入。
實例18
替代抗體之產生
藉由使用獼猴CD37抗原之完整編碼序列(寄存編號ENSMMUT00000020744)對小鼠及兔進行基因免疫,產生獼猴CD37特異性單株抗體。例如,藉由標準ELISA或FACS技術,使用表現獼猴
CD37抗原之重組HEK293或CHO細胞來選擇特異性抗體。藉由PCR選殖來獲取此等抗體之可變重鏈及輕鏈編碼序列且將其用於產生具有來源於鼠科或兔起始抗體之VH及VL區及與本發明抗體(例如,A2或B2)之Fc部分一致之Fc部分的嵌合抗體(如實例1中所述)。可藉由使用檢定系統來研究結合及功能性質,該等檢定系統利用獼猴CD37表現性細胞作為標靶細胞,例如對於結合而言,可使用FACS、Scatchard分析、ADCC及細胞凋亡檢定。最終,根據活體外石蟹獼猴血液中之B細胞去除活性來選擇替代抗體。
實例19
對於產生抗體之純系的製備
為製備用於產生本發明抗體(例如,抗體A2、A4、B2或B4)之純系,將編碼分別具有SEQ ID NO:27、31、35或39中所示序列之完整重鏈的DNA分子插入稱為pBI-26之真核表現載體中,該載體亦編碼來自倉鼠之選擇標記二氫葉酸還原酶。
將編碼分別描繪於SEQ ID NO:29、33、37及41中之完整輕鏈的DNA分子插入稱為pBI-49之真核表現載體中,該載體亦編碼選擇標記新黴素磷酸轉移酶。將整個重鏈及輕鏈之DNA序列完全定序。
將在化學上確定之培養基中以懸浮狀態生長的倉鼠細胞株CHO-DG44與如上所述用於抗體重鏈及輕鏈之真核表現載體共轉染。在不含次黃嘌呤及胸苷且存在抗生素G418之培養基中選擇經轉染之細胞。接著,使用增加濃度之甲胺喋呤(MTX)使細胞經受逐步選擇及擴增。根據800nM MTX擴增步驟,基於旋轉器運行中之生長效能及抗體產生來選擇單一細胞株,且將其冷凍保存於安全細胞庫(Safety Cell Bank,SCB)中。
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Zhao XB, Lapalombella R, Joshi T, Cheney C, Gowda A, Hayden-Ledbetter MS, Baum PR, Lin TS, Jarjoura D, Lehman A, Kussewitt D, Lee RJ, Caligiuri MA, Tridandapani S, Muthusamy N, Byrd JC. Targeting CD37+ lymphoid malignancies with a novel engineered small modular immunopharmaceutical 2007; BLOOD, 2007年10月1日,第110卷,第7期(Epub ahead of print. Blood, 2007年4月17日)。
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Claims (53)
- 一種抗體,其與人類CD37結合且衍生自以下抗體:a)鼠科單株抗體,其藉由以下定義:i)包含SEQ ID NO:2中所示之胺基酸序列之可變重鏈;及ii)包含SEQ ID NO:4中所示之胺基酸序列之可變輕鏈,或b)非人類抗體,其識別與a)中所定義之抗體相同的人類CD37抗原決定基,或識別與該抗原決定基相近或重疊之抗原決定基;其中該抗體分子為嵌合或人化抗體。
- 如請求項1之抗體,其為由以下定義之嵌合抗體:i)包含SEQ ID NO:2中所示之胺基酸序列之可變重鏈;ii)包含SEQ ID NO:4中所示之胺基酸序列之可變輕鏈;iii)具有人類起源之恆定重鏈及輕鏈。
- 如請求項2之抗體,其中:i)該恆定重鏈為IgG1鏈;且ii)該恆定輕鏈為κ鏈。
- 如請求項3之抗體,其中該恆定重鏈i)包含SEQ ID NO:24中所示之胺基酸序列,且其中該恆定輕鏈ii)包含SEQ ID NO:26中所示之胺基酸序列。
- 如請求項1之抗體,其為由以下定義之人化抗體:a)含於如SEQ ID NO:2中所示之可變重鏈內的CDR;b)含於如SEQ ID NO:4中所示之可變輕鏈內的CDR;c)支撐該等CDR之來源於人類抗體之構架;d)來自人類抗體之恆定重鏈及輕鏈。
- 如請求項5之抗體,其包含具有SEQ ID NO:6中所示序列之可變 重鏈。
- 如請求項6之抗體,其包含具有SEQ ID NO:12、14、16、18、20或22中所示序列之可變輕鏈。
- 如請求項5之抗體,其包含具有SEQ ID NO:8中所示序列之可變重鏈。
- 如請求項10之抗體,其包含具有SEQ ID NO:12、14、16、18、20或22中所示序列之可變輕鏈。
- 如請求項5之抗體,其包含具有SEQ ID NO:10中所示序列之可變重鏈。
- 如請求項20之抗體,其包含具有SEQ ID NO:12、14、16、18、20或22中所示序列之可變輕鏈。
- 如請求項1至11中任一項之抗體,其中該抗體在Fc域中具有一或多個調節一或多種效應功能之突變。
- 如請求項12之抗體,其中該效應功能調節為抗體依賴性細胞介導之細胞毒性的增加。
- 如請求項12之抗體,其中該Fc域中之該一或多個突變為在根據Kabat EU編號索引編號之位置332的單一取代。
- 如請求項12之抗體,其中該Fc域中之該一或多個突變為在根據Kabat EU編號索引編號之位置239及332的取代之組合。
- 如請求項12之抗體,其中該Fc域中之該一或多個突變為在根據Kabat EU編號索引編號之位置236及332的取代之組合。
- 如請求項12之抗體,其中該Fc域中之該一或多個突變為在根據Kabat EU編號索引編號之位置236、239及332的取代之組合。
- 如請求項17之抗體,其中該等取代為I332E、S239D及G236A。
- 一種抗體,其與人類CD37結合且具有包含胺基酸序列SEQ ID NO:28之重鏈。
- 如請求項19之抗體,其具有包含胺基酸序列SEQ ID NO:30之輕鏈。
- 一種抗體,其與人類CD37結合且具有包含胺基酸序列SEQ ID NO:36之重鏈。
- 如請求項21之抗體,其具有包含胺基酸序列SEQ ID NO:38之輕鏈。
- 一種抗體,其與人類CD37結合且具有包含胺基酸序列SEQ ID NO:32之重鏈。
- 如請求項23之抗體,其具有包含胺基酸序列SEQ ID NO:34之輕鏈。
- 一種抗體,其與人類CD37結合且具有包含胺基酸序列SEQ ID NO:40之重鏈。
- 如請求項25之抗體,其具有包含胺基酸序列SEQ ID NO:42之輕鏈。
- 一種DNA分子,其包含編碼如請求項1至26中任一項之抗體之可變重鏈的區。
- 如請求項27之DNA分子,其中該編碼可變重鏈之區與編碼人類起源的恆定重鏈之區融合。
- 如請求項28之DNA分子,其中該人類恆定重鏈為IgG1。
- 如請求項29之DNA分子,其中該IgG1藉由SEQ ID NO:23中所示之序列編碼。
- 如請求項28至30中任一項之DNA分子,其中該人類恆定重鏈在Fc區中具有如請求項14至18中任一項中所定義之取代。
- 一種DNA分子,其包含編碼如請求項1至26中任一項之抗體之可變輕鏈的區。
- 如請求項32之DNA分子,其中該編碼可變輕鏈之區與編碼人類起 源的恆定輕鏈之區融合。
- 如請求項33之DNA分子,其中該恆定輕鏈為κ鏈。
- 如請求項34之DNA分子,其中該κ輕鏈藉由SEQ ID NO:25中所示之序列編碼。
- 一種表現載體,其含有如請求項27至31中任一項之DNA分子及/或如請求項32至35中任一項之DNA分子。
- 一種宿主細胞,其載運一或多個如請求項36之載體。
- 如請求項37之宿主細胞,其載運包含如請求項27至31中任一項之DNA分子的表現載體及包含如請求項32至35中任一項之DNA分子的第二載體。
- 如請求項37之宿主細胞,其為哺乳動物細胞。
- 一種用於產生如請求項1至26中任一項之抗體之方法,其包含以一或多個如請求項36之載體轉染哺乳動物宿主細胞,培養該宿主細胞,及回收且純化抗體分子。
- 一種醫藥組合物,其包含一或多種如請求項1至26中任一項之抗CD37抗體作為活性成份及醫藥學上可接受之載劑。
- 如請求項41之醫藥組合物,其進一步包含一或多種其他治療劑。
- 如請求項42之醫藥組合物,其中該一或多種其他治療劑係選自靶向除CD37以外的B細胞抗原之藥劑。
- 如請求項43之醫藥組合物,其中該B細胞抗原為CD20。
- 如請求項42之醫藥組合物,其中該一或多種其他治療劑係選自誘發細胞凋亡之藥劑。
- 如請求項45之醫藥組合物,其中該藥劑為TRAIL受體之調節劑。
- 如請求項41至46中任一項之醫藥組合物,其係用於去除在其表面上表現CD37之B細胞。
- 如請求項47之醫藥組合物,其係用於治療B細胞惡性腫瘤。
- 如請求項48之醫藥組合物,其中該B細胞惡性腫瘤係選自B細胞非霍奇金氏淋巴瘤(non-Hodgkins lymphoma)、B細胞慢性淋巴細胞白血病及多發性骨髓瘤。
- 如請求項47之醫藥組合物,其係用於治療病理學涉及B細胞之自體免疫及發炎疾病。
- 一種自細胞群體去除表現CD37之B細胞之方法,其包含向該細胞群體投與如請求項1至26中任一項之抗體或含有該抗體分子之醫藥組合物。
- 如請求項51之方法,其在活體外進行。
- 一種如請求項41至46中任一項之醫藥組合物之用途,其係用於製造用以治療罹患選自以下疾病之B細胞惡性腫瘤的患者之藥物:B細胞非霍奇金氏淋巴瘤、B細胞慢性淋巴細胞白血病及多發性骨髓瘤。
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TW097130378A TWI535733B (zh) | 2007-08-09 | 2008-08-08 | 抗cd37抗體 |
TW103121994A TW201512220A (zh) | 2007-08-09 | 2008-08-08 | 抗cd37抗體 |
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UA97469C2 (uk) | 2005-07-25 | 2012-02-27 | Емерджент Продакт Дівелопмент Сіетл, Елелсі | Гуманізована специфічна до cd37 зв'язувальна молекула імуноглобуліну |
NZ573646A (en) | 2006-06-12 | 2012-04-27 | Wyeth Llc | Single-chain multivalent binding proteins with effector function |
PE20090499A1 (es) * | 2007-08-09 | 2009-05-18 | Boehringer Ingelheim Int | Anticuerpos anti-cd37 |
JP2010540460A (ja) * | 2007-09-24 | 2010-12-24 | トラガラ ファーマシューティカルズ,インク. | COX‐2阻害薬と抗HER2[ErbB2]抗体の混合物又はCOX‐2阻害薬とHER2[ErbB2]受容体チロシンキナーゼ阻害薬の混合物を用いた癌の治療 |
NZ603059A (en) | 2008-04-11 | 2014-07-25 | Emergent Product Dev Seattle | Cd37 immunotherapeutic and combination with bifunctional chemotherapeutic thereof |
DK2516468T3 (en) * | 2009-12-23 | 2016-05-23 | Synimmune Gmbh | ANTI-FLT3 ANTIBODIES AND METHODS FOR USING THESE |
NO331080B1 (no) * | 2010-01-29 | 2011-09-26 | Nordic Nanovector As | Radioimmunkonjugater, farmasøytiske sammensetninger og kit omfattende det samme og anvendelse derav |
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