TW202133881A - 對cd123具專一性之抗體和抗體-藥物共軛體及彼等之用途 - Google Patents
對cd123具專一性之抗體和抗體-藥物共軛體及彼等之用途 Download PDFInfo
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Abstract
本發明提供與CD123專一性結合之抗體。本發明進一步關於包含該等抗體之免疫共軛體(例如抗體-藥物共軛體或ADC)、編碼抗體之核酸及獲得該等抗體之方法。本發明進一步關於使用該等抗體及ADC以治療與表現CD123之細胞有關之病症(例如癌症或自體免疫性疾病)之治療方法。
Description
本發明關於抗體,例如與CD123專一性結合之全長抗體。本發明進一步關於包含CD123抗體之共軛體(例如抗體-藥物共軛體或「ADC」)、包含CD123抗體或彼等之共軛體之組成物及使用CD123抗體或彼等之共軛體治療與表現CD123之細胞有關之病症(例如癌症)之方法。
序列表的參照
本申請案係經EFS-Web以電子方式提出,包括以.txt格式之電子資料檢送之序列表。該.txt檔案包含標題為「PC72333_SEQ_LIST_ST25.txt」之序列表,建立日期2017年10月27日,檔案大小78 KB。此.txt檔中包含之序列表係本說明書之一部分,以參照方式整體納入此處。
CD123係介白素-3受體之α鏈(IL-3Rα或IL3RAa),其與常見β鏈CD131形成異二聚體以幫助傳遞IL-3的信號。IL-3的生物學角色是刺激多能性細胞的存活及增生。據信CD123涉及刺激急性骨髓性白血病(AML)細胞的增生且在腫瘤生物學上具有直接功能。CD123經常表現在白血病幹細胞(LSC)上,這種細胞群與病患復發相關。在正常人組織中,CD123表現大多限制在造血細胞,特別是漿細胞樣樹突細胞(pDC),其構成<0.4%的人周邊血液單核細胞。作為先天性免疫的組分,pDC因應病毒及細菌性刺激產製大量第1型干擾素(IFN-α/β)。重要的是,CD123不表現在造血幹細胞上。
預期白血病、淋巴瘤及骨髓瘤之新病例將佔2017年在美國所診斷之1,688,780起預估新癌症病例的10.2%。CD123表現在多種血液惡性病的癌細胞上,包括急性骨髓性白血病(AML),其中其表現>80%。表現CD123之血液癌細胞實例包括母細胞及白血病幹細胞。與CD123表現相關之疾病包括AML、骨髓發育不良症候群(MDS;低及高風險)、急性淋巴球性白血病(ALL,所有亞型)、瀰漫性大型B細胞淋巴瘤(DLBCL)、慢性骨髓性白血病(CML)及母細胞性漿細胞樣樹突細胞腫瘤(BPDCN)。
目前,這些疾病的治療包括超過50種個別藥物,尚有其他正在進行試驗及臨床試驗。放射療法亦經常用於治療血液癌症,有時連同藥物療法一起投予。亦使用免疫療法、基因療法及個人化藥物。然而,這些療法可具有顯著副作用及不良反應。因此,有需要為表現CD123(IL-3Rα)之血液癌症提供新的及改善的治療。
在本文中揭示之本發明係關於與CD123結合之抗體及包含與CD123結合之抗體之共軛體,諸如抗體-藥物共軛體(ADC),以及製備及使用該等抗體及ADC以治療病症之方法。
本文中提供與CD123專一性結合之抗體。在一些實施態樣中,本發明提供一種單離抗體,其與CD123專一性結合,其中該抗體包含:重鏈可變區(VH)及輕鏈可變區(VL),該重鏈可變區包含三個互補決定區(CDR),該VH包含SEQ ID NO: 6、24、32、44、51或64之胺基酸序列,該輕鏈可變區包含三個CDR,該VL包含SEQ ID NO: 17、28、39、48、57或71之胺基酸序列。在一些實施態樣中,該VH可包含:(i) VH CDR1,其包含SEQ ID NO: 7、33、52或65之胺基酸序列;(ii) VH CDR2,其包含SEQ ID NO: 8、25、34、45、53或66之胺基酸序列;及(iii) VH CDR3,其包含SEQ ID NO: 9、35、46或67之胺基酸序列。在一些實施態樣中,該VL區可包含:(i) VL CDR1,其包含SEQ ID NO: 18、40、58或72之胺基酸序列;(ii) VL CDR2,其包含SEQ ID NO: 19、42、60或74之胺基酸序列;及(iii) VL CDR3,其包含SEQ ID NO: 20、42、60或74之胺基酸序列。在一些實施態樣中,該VH可包含:(i) VH CDR1,其包含SEQ ID NO: 7之胺基酸序列;(ii) VH CDR2,其包含SEQ ID NO:25之胺基酸序列;及(iii) VH CDR3,其包含SEQ ID NO:9之胺基酸序列。在一些實施態樣中,該VL可包含:(i) VL CDR1,其包含SEQ ID NO: 18之胺基酸序列;(ii) VL CDR2,其包含SEQ ID NO:19之胺基酸序列;及(iii) VL CDR3,其包含SEQ ID NO:20之胺基酸序列。在一些實施態樣中,該VH可包含如SEQ ID NO: 24或其在非CDR內之殘基經一或多個保守性胺基酸取代之變體所示之序列,及/或該VL可包含如SEQ ID NO: 28或其在非CDR內之胺基酸經一或多個胺基酸取代之變體所示之胺基酸序列。在一些實施態樣中,該抗體可包含輕鏈及重鏈,該輕鏈包含如SEQ ID NO: 30所示之序列,該重鏈包含如SEQ ID NO: 27所示之序列。
亦提供一種單離抗體,其與CD123專一性結合且包含由ATCC寄存編號PTA-124283之表現載體所產製之重鏈可變區及由ATCC寄存編號PTA-124284之表現載體所產製之輕鏈可變區。
亦提供與CD123專一性結合且與包含下列之抗體競爭與CD123結合之單離抗體:重鏈可變區(VH)及VL,該重鏈可變區包含三個CDR,該VH包含SEQ ID NO: 6、24、32、44、51或64之胺基酸序列;該VL包含三個CDR,該VL包含SEQ ID NO: 17、28、39、48、57或71之胺基酸序列。
亦提供單離CD123抗體,其包含:包含SEQ ID NO: 7、8及9之胺基酸序列的VH及包含SEQ ID NO: 18、19及20之胺基酸序列的VL。
亦提供單離CD123抗體,其包含:包含SEQ ID NO: 7、25及9之胺基酸序列的VH及包含SEQ ID NO: 18、19及20之胺基酸序列的VL。
亦提供單離CD123抗體,其包含:包含SEQ ID NO: 33、34及35之胺基酸序列的VH及包含SEQ ID NO: 40、41及42之胺基酸序列的VL。
亦提供單離CD123抗體,其包含:包含SEQ ID NO: 33、45及46之胺基酸序列的VH及包含SEQ ID NO: 40、41及42之胺基酸序列的VL。
亦提供單離CD123抗體,其包含:包含SEQ ID NO: 52、53及54之胺基酸序列的VH及包含SEQ ID NO: 58、59及60之胺基酸序列的VL。
亦提供單離CD123抗體,其包含:包含SEQ ID NO: 65、66及67之胺基酸序列的VH及包含SEQ ID NO: 72、73及74之胺基酸序列的VL。
在一些實施態樣中,如本文所述之CD123抗體可包含經工程改造於特定位點之含有醯基供體麩醯胺酸之標籤。在一些實施態樣中,該標籤可包含選自由下列所組成之群組的胺基酸序列:Q、LQG、LLQGG (SEQ ID NO:77)、LLQG (SEQ ID NO:78)、LSLSQG (SEQ ID NO: 79)、GGGLLQGG (SEQ ID NO: 80)、GLLQG (SEQ ID NO: 81)、LLQ、GSPLAQSHGG (SEQ ID NO: 82)、GLLQGGG (SEQ ID NO: 83)、GLLQGG (SEQ ID NO: 84)、GLLQ (SEQ ID NO: 85)、LLQLLQGA (SEQ ID NO: 86)、LLQGA (SEQ ID NO: 87)、LLQYQGA (SEQ ID NO: 88)、LLQGSG (SEQ ID NO: 89)、LLQYQG (SEQ ID NO: 90)、LLQLLQG (SEQ ID NO: 91)、SLLQG (SEQ ID NO: 92)、LLQLQ (SEQ ID NO: 93)、LLQLLQ (SEQ ID NO: 94)、LLQGR (SEQ ID NO: 95)、LLQGPP (SEQ ID NO: 96)、LLQGPA (SEQ ID NO: 97)、GGLLQGPP (SEQ ID NO: 98)、GGLLQGA (SEQ ID NO: 99)、LLQGPGK (SEQ ID NO: 100)、LLQGPG (SEQ ID NO: 101)、LLQGP (SEQ ID NO: 102)、LLQP (SEQ ID NO: 103)、LLQPGK (SEQ ID NO: 104)、LLQAPGK (SEQ ID NO: 105)、LLQGAPG (SEQ ID NO: 106)、LLQGAP (SEQ ID NO: 107)及LLQLQG (SEQ ID NO: 108)。在一些實施態樣中,該含有麩醯胺酸之標籤係LLQG (SEQ ID NO: 78)。
在一些實施態樣中,如本文所述之CD123抗體可包含位置222、340或370之胺基酸修飾。在一些實施態樣中,該胺基酸修飾可將離胺酸取代成精胺酸。在一些實施態樣中,該胺基酸修飾可為K222R。
在一些實施態樣中,如本文所述之CD123抗體可包含連接子。在一些實施態樣中,連接子可為可切割的。在一些實施態樣中,該連接子可選自由下列所組成之群組:Ac-Lys-Gly(乙醯基-離胺酸-甘胺酸)、胺基己酸、Ac-Lys-β-Ala(乙醯基-離胺酸-β-丙胺酸)、胺基-PEG2(聚乙二醇)-C2、胺基-PEG3-C2、胺基-PEG6-C2、Ac-Lys-Val-Cit-PABC(乙醯基-離胺酸-纈胺酸-瓜胺酸-對胺基苄氧羰基)、胺基-PEG6-C2-Val-Cit-PABC、胺基己醯基-Val-Cit-PABC、[(3R,5R)-1-{3-[2-(2-胺基乙氧基)乙氧基]丙醯基}哌啶-3,5-二基]雙-Val-Cit-PABC、[(3S,5S)-1-{3-[2-(2-胺基乙氧基)乙氧基]丙醯基}哌啶-3,5-二基]雙-Val-Cit-PABC、腐胺及Ac-Lys-腐胺。在一些實施態樣中,該連接子可為Ac-Lys-Val-Cit-PABC(乙醯基-離胺酸-纈胺酸-瓜胺酸-對胺基苄氧羰基)。
在一些實施態樣中,如本文所述之抗體包含恆定區。在一些實施態樣中,該抗體係人化抗體。在一些實施態樣中,該抗體係屬於人IgG1、IgG2或IgG2Δa、IgG3或IgG4亞型。在一些實施態樣中,該抗體係IgG1抗體。在一些實施態樣中,抗體包含N60G突變。
亦提供共軛體,其包含與劑共軛之如本文所述之CD123抗體。在一些實施態樣中,該劑可選自由下列所組成之群組:細胞毒性劑、免疫調節劑、顯影劑、治療蛋白質、生物聚合物及寡核苷酸。在一些實施態樣中,該劑可為細胞毒性劑。在一些實施態樣中,該細胞毒性劑可選自由下列所組成之群組:蒽環、耳抑素(auristatin)、喜樹鹼、考布他丁(combretastatin)、CBI二聚體、環丙基吡咯并吲哚啉(CPI)二聚體、CTI二聚體、海兔毒素(dolastatin)、雙聯黴素(duocarmycin)、烯二炔、膠達納黴素(geldanamycin)、吲哚啉并-苯并二氮呯二聚體、美坦素(maytansine)、嘌呤黴素(puromycin)、吡咯并苯并二氮呯二聚體、紫杉烷、長春花生物鹼、微管溶素(tubulysin)、半星芒體(hemiasterlin)、司普力西歐他汀(spliceostatin)、普拉二烯內酯(pladienolide)及彼等之立體異構物、同電子排列體、類似物或衍生物。在一些實施態樣中,該細胞毒性劑可為CPI二聚體。在一些實施態樣中,該CPI二聚體係CPI-8314。在一些實施態樣中,該CPI二聚體可具有下列結構:。
在一些實施態樣中,細胞毒性劑可具有IUPAC名稱:(8S)-8-(氯甲基)-6-[(3-{[(1S)-1-(氯甲基)-5-羥基-8-甲基-1,6-二氫吡咯并[3,2-e]吲哚-3(2H)-基]羰基}雙環[1.1.1]戊-1-基)羰基]-1-甲基-3,6,7,8-四氫吡咯并[3,2-e]吲哚-4-基二氫磷酸鹽。在一些實施態樣中,細胞毒性劑可為C31H31Cl2N4O7P或醫藥上可接受之鹽或溶劑合物。在一些實施態樣中,細胞毒性劑可為三氟乙酸(TFA)鹽形式:C31H31Cl2N4O7P.
C2HF3O2。
在其他實施態樣中,細胞毒性劑可為MMAD(單甲基耳抑素D)、0101(2-甲基丙胺醯基-N-
[(3R,
4S,
5S
)-3-甲氧基-1-{(2S
)-2-[(1R,
2R
)-1-甲氧基-2-甲基-3-側氧基-3-{[(1S
)-2-苯基-1-(1,3-噻唑-2-基)乙基]胺基}丙基]吡咯啶-1-基}-5-甲基-1-側氧基庚-4-基]-N-
甲基-L-纈胺醯胺)、3377(N,2-二甲基丙胺醯基-N-{(1S,2R)-4-{(2S)-2-[(1R,2R)-3-{[(1S)-1-羧基-2-苯基乙基]胺基}-1-甲氧基-2-甲基-3-側氧基丙基]吡咯啶-1-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)、0131(2-甲基-L-脯胺醯基-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(1S)-1-羧基-2-苯基乙基]胺基}-1-甲氧基-2-甲基-3-側氧基丙基]吡咯啶-1-基}-3-甲氧基-5-甲基-1-側氧基庚-4-基]-N-甲基-L-纈胺醯胺)或0121(2-甲基-L-脯胺醯基-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S)-1-甲氧基-1-側氧基-3-苯基丙-2-基]胺基}-1-甲氧基-2-甲基-3-側氧基丙基]吡咯啶-1-基}-3-甲氧基-5-甲基-1-側氧基庚-4-基]-N-甲基-L-纈胺醯胺)。
在一些實施態樣中,共軛體可包含下式:抗體-(含有醯基供體麩醯胺酸之標籤)-(連接子)-(細胞毒性劑)。在一些實施態樣中,含有醯基供體麩醯胺酸之標籤可包含胺基酸序列LLQG (SEQ ID NO: 78)且連接子可包含乙醯基-離胺酸-纈胺酸-瓜胺酸-對胺基苄氧羰基。在一些實施態樣中,該含有醯基供體麩醯胺酸之標籤可插入抗體位置E294至N297。在一些實施態樣中,共軛體可在根據卡巴(Kabat)之EU指數編號的抗體位置222處進一步包含由離胺酸成為精胺酸之胺基酸取代(K222R)。
亦提供醫藥組成物,其包含治療有效量之如本文所述之CD123抗體或如本文所述之CD123 ADC及醫藥上可接受之載劑。
亦提供單離多核苷酸,其包含編碼如本文所述之CD123抗體之核苷酸序列。亦提供載體,其包含該等多核苷酸。
亦提供單離宿主細胞,其重組產製如本文所述之CD123抗體之任一者。亦提供產製抗體之方法,其包含在導致產製該抗體之條件下培養該等宿主細胞及自該等宿主細胞或培養物單離該抗體。
亦提供治療個體之與表現CD123之細胞有關之病症之方法,其包含向有該治療需要之個體投予治療有效量之醫藥組成物,該醫藥組成物包含如本文所述之CD123抗體之任一者或抗體任一者之共軛體及醫藥上可接受之載劑。在一些實施態樣中,病症係癌症。在一些實施態樣中,癌症可為選自由下列所組成之群組之癌症:急性骨髓性白血病(AML)、急性淋巴球性白血病(ALL)、母細胞性漿細胞樣樹突細胞腫瘤(BPDCN)、髮樣細胞白血病、B細胞非霍奇金氏(non-Hodgkin’s)淋巴瘤(NHL)、多發性骨髓瘤、惡性漿細胞腫瘤、霍奇金氏淋巴瘤(Hodgkin’s lymphoma)、結節性淋巴細胞為主型霍奇金氏淋巴瘤、卡勒氏病(Kahler’s disease)及骨髓瘤病、漿細胞白血病、漿細胞瘤、B細胞前淋巴細胞白血病、慢性淋巴球性白血病(CLL)、慢性骨髓性白血病(CML)、濾泡性淋巴瘤、伯基特氏淋巴瘤(Burkitt’s lymphoma)、邊緣區淋巴瘤、外套細胞淋巴瘤、大細胞淋巴瘤、前體B淋巴母細胞淋巴瘤、骨髓性白血病、瓦登斯特隆巨球蛋白血症(Waldenstrom’s macroglobulienemia)、瀰漫性大型B細胞淋巴瘤、濾泡性淋巴瘤、邊緣區淋巴瘤、黏膜相關性淋巴組織淋巴瘤、小細胞淋巴球性淋巴瘤、外套細胞淋巴瘤、伯基特氏淋巴瘤(Burkitt lymphoma)、原發性縱隔(胸腺)大型B細胞淋巴瘤、淋巴漿細胞淋巴瘤、瓦登斯特隆巨球蛋白血症(Waldenström macroglobulinemia)、結內邊緣區B細胞淋巴瘤、脾邊緣區淋巴瘤、血管內大型B細胞淋巴瘤、原發性滲出性淋巴瘤、淋巴瘤樣肉芽腫病、富含T細胞/組織細胞大型B細胞淋巴瘤、原發性中樞神經系統淋巴瘤、原發性皮膚瀰漫性大型B細胞淋巴瘤(腿型)、老年人之EBV陽性瀰漫性大型B細胞淋巴瘤、發炎相關性瀰漫性大型B細胞淋巴瘤、血管內大型B細胞淋巴瘤、ALK陽性大型B細胞淋巴瘤、漿母細胞淋巴瘤、HHV8相關性多中心型克斯特曼病(HHV8-associated multicentric Castleman disease)產生之大型B細胞淋巴瘤、特徵介於瀰漫性大型B細胞淋巴瘤與伯基特氏淋巴瘤之間的未分類B細胞淋巴瘤、特徵介於瀰漫性大型B細胞淋巴瘤與典型霍奇金氏淋巴瘤之間的未分類B細胞淋巴瘤及其他B細胞相關性淋巴瘤。在一些實施態樣中,癌症係AML。
亦提供抑制具有表現CD123之惡性細胞的個體之腫瘤生長或進展之方法,其包含向有該抑制需要之個體投予治療有效量之醫藥組成物,該醫藥組成物包含如本文所提供之CD123抗體之任一者或抗體任一者之共軛體及醫藥上可接受之載劑。
亦提供抑制個體之表現CD123之惡性細胞轉移之方法,其包含向有該抑制需要之個體投予治療有效量之醫藥組成物,該醫藥組成物包含如本文所提供之CD123抗體之任一者或抗體任一者之共軛體及醫藥上可接受之載劑。
亦提供誘導具有表現CD123之惡性細胞的個體之腫瘤消退之方法,其包含向有該誘導需要之個體投予治療有效量之醫藥組成物,該醫藥組成物包含如本文所提供之CD123抗體之任一者或抗體任一者之共軛體及醫藥上可接受之載劑。
在另一態樣中,本發明提供有效量的組成物(例如醫藥組成物),該組成物包含用於治療有該治療需要之個體之與CD123表現相關之病症(例如癌症或自體免疫疾病)之如本文所述之CD123抗體或CD123 ADC。在一些實施態樣中,有效量的組成物(例如醫藥組成物)包含用於抑制具有表現CD123之惡性細胞的個體之腫瘤生長或進展之如本文所述之CD123抗體或CD123 ADC。在一些實施態樣中,提供有效量的組成物(例如醫藥組成物),該組成物包含用於抑制有該抑制需要之個體之表現CD123之惡性細胞的轉移之如本文所述之CD123抗體或CD123 ADC。在一些實施態樣中,有效量的組成物(例如醫藥組成物)包含用於誘導具有表現CD123之惡性細胞的個體之腫瘤消退之如本文所述之CD123抗體或CD123 ADC。
在另一態樣中,本發明提供用於治療有該治療需要之個體之與CD123表現相關之病症(例如癌症或自體免疫疾病)之如本文所述之CD123抗體或CD123 ADC。在一些實施態樣中,提供用於抑制具有表現CD123之惡性細胞的個體之腫瘤生長或進展之如本文所述之CD123抗體或CD123 ADC。在一些實施態樣中,提供用於抑制有該抑制需要之個體之表現CD123之惡性細胞的轉移之如本文所述之CD123抗體或CD123 ADC。在一些實施態樣中,提供用於誘導具有表現CD123之惡性細胞的個體之腫瘤消退之如本文所述之CD123抗體或CD123 ADC。
在另一態樣中,本發明提供如本文所述之CD123抗體或CD123 ADC於製造藥物之用途,該藥物用於治療與CD123表現相關之病症(例如癌症或自體免疫疾病)。在一些實施態樣中,提供如本文所述之CD123抗體或CD123 ADC於製造藥物之用途,該藥物用於抑制腫瘤生長或進展。在一些實施態樣中,提供如本文所述之CD123抗體或CD123 ADC於製造藥物之用途,該藥物用於抑制表現CD123之惡性細胞的轉移。在一些實施態樣中,提供如本文所述之CD123抗體或CD123 ADC於製造藥物之用途,該藥物用於誘導腫瘤消退。
在本文中亦提供用於共軛抗體與AcLysValCitPABC-DMAE-CO_CPI-000638314(AcLysPABC-CPI-8314)之方法。在一些實施態樣中,該方法包含製備組成物,該組成物包含抗體與AcLysPABC-CPI-8314於包含30至100 mM KPO4及150至200 mM NaCl之緩衝劑中;添加細菌性轉麩醯胺酸酶至該組成物;及培養該組成物以允許該抗體與該AcLysPABC-CPI-8314共軛。在一些實施態樣中,該組成物之pH係7。在一些實施態樣中,該組成物包含每mg抗體0.5至2單位(U)之細菌性轉麩醯胺酸酶。在一些實施態樣中,該組成物包含每mg抗體1 U之細菌性轉麩醯胺酸酶。在一些實施態樣中,AcLysPABC-CPI-8314係以對抗體10倍莫耳過量存在。在一些實施態樣中,組成物在25°C和持續混合下經隔夜培養。在一些實施態樣中,組成物進一步包含7.5% (v/v)二甲亞碸(DMSO)。在一些實施態樣中,緩衝劑包含30 mM KPO4及150 mM NaCl。在一些實施態樣中,緩衝劑包含100 mM KPO4及200 mM NaCl。在一些實施態樣中,抗體係抗腫瘤抗體。在一些實施態樣中,抗腫瘤抗體係CD123抗體。
發明詳細說明
本文揭示之發明提供與CD123(例如人CD123)專一性結合之抗體及抗體-藥物共軛體(ADC)。本發明亦提供編碼該等抗體之多核苷酸、包含該等抗體之組成物及製備及使用該等抗體之方法。本發明亦提供治療個體之與CD123表現相關之病症諸如癌症或自體免疫性疾病之方法。
一般技術
除非另外說明,本發明之實施將採用分子生物學(包括重組技術)、微生物學、細胞生物學、生物化學及免疫學之習用技術,這些技術係該領域之習知技藝。該等技術係於文獻中充分解釋,諸如Molecular Cloning: A Laboratory Manual, second edition (Sambrook et al., 1989) Cold Spring Harbor Press;Oligonucleotide Synthesis (M.J. Gait, ed., 1984);Methods in Molecular Biology, Humana Press;Cell Biology: A Laboratory Notebook (J.E. Cellis, ed., 1998) Academic Press;Animal Cell Culture (R.I. Freshney, ed., 1987);Introduction to Cell and Tissue Culture (J.P. Mather and P.E. Roberts, 1998) Plenum Press;Cell and Tissue Culture: Laboratory Procedures (A. Doyle, J.B. Griffiths, and D.G. Newell, eds., 1993-1998) J. Wiley and Sons;Methods in Enzymology (Academic Press, Inc.);Handbook of Experimental Immunology (D.M. Weir and C.C. Blackwell, eds.);Gene Transfer Vectors for Mammalian Cells (J.M. Miller and M.P. Calos, eds., 1987);Current Protocols in Molecular Biology (F.M. Ausubel et al., eds., 1987);PCR: The Polymerase Chain Reaction, (Mullis et al., eds., 1994);Current Protocols in Immunology (J.E. Coligan et al., eds., 1991);Short Protocols in Molecular Biology (Wiley and Sons, 1999);Immunobiology (C.A. Janeway and P. Travers, 1997);Antibodies (P. Finch, 1997);Antibodies: a practical approach (D. Catty., ed., IRL Press, 1988-1989);Monoclonal antibodies: a practical approach (P. Shepherd and C. Dean, eds., Oxford University Press, 2000);Using antibodies: a laboratory manual (E. Harlow and D. Lane (Cold Spring Harbor Laboratory Press, 1999);The Antibodies (M. Zanetti and J.D. Capra, eds., Harwood Academic Publishers, 1995)。
定義
「抗體」係免疫球蛋白分子,其可透過位於該免疫球蛋白分子之可變區的至少一個抗原辨認區專一性地與目標結合,諸如碳水化合物、多核苷酸、脂肪、多肽等。此處所使用之該用語不僅包含完整多株或單株抗體,但亦包含彼之抗原結合片段(諸如Fab、Fab’、F(ab’)2
、Fv)、單鏈抗體(ScFv)和結構域抗體(包括例如鯊魚及駱駝抗體)、包含抗體之融合蛋白,及任何其他包含抗原辨認區之免疫球蛋白分子之經修飾之構型。抗體包括任何類型之抗體,諸如IgG、IgA或IgM(或彼等之亞型),且該抗體不需要是任何特定類型。根據免疫球蛋白之重鏈的恆定區之抗體胺基酸序列,其可被分成不同類型。有五種主要的免疫球蛋白類型:IgA、IgD、IgE、IgG及IgM,其中某些類型可進一步分成亞型(同型),例如IgG1、IgG2、IgG3、IgG4、IgA1和IgA2。對應不同類型之免疫球蛋白的重鏈恆定區分別被稱為α、δ、ε、γ和μ。不同類型之免疫球蛋白的次單位結構及三維構型係廣為週知。
抗體之「抗原結合片段」或「抗原結合部位」用語在本文係指完整抗體之一或多個片段,該片段保留與給定抗原(例如CD123)專一性結合之能力。抗體之抗原結合功能可藉由完整抗體之片段實現。抗體之「抗原結合片段」用語所涵蓋之結合片段之實例包括Fab、Fab'、F(ab')2
、由重鏈可變區(VH)及CH1結構域組成之Fd片段、由抗體單臂之VL及VH結構域組成之Fv片段、單一結構域抗體(dAb)片段(Ward et aI., Nature 341 :544-546, 1989)及經單離之互補決定區(CDR)。
與標靶(例如CD123蛋白質)「優先結合」或「專一性結合」(在此處可互換使用)之抗體、ADC或多肽係該領域理解清楚之用語,且判定該等專一性或優先結合之方法亦為該領域所廣為周知。若分子與特定細胞或物質之交互反應或相連相較於與其他細胞或物質之交互反應或相連係更頻繁、更快速、更長時間及/或更高親和性,該分子被稱為展現「專一性結合」或「優先結合」。若抗體與標靶之結合相較於與其他物質之結合具有更高親和性、親合力(avidity)、更快速及/或更長時間,則該抗體與標靶「專一性結合」或「優先結合」。舉例來說,與CD123表位專一性或優先地結合之抗體係指相較於彼與其他CD123表位或非CD123表位結合時以更高之親和性、親合力、更快速及/或更長時間地與此表位結合之抗體。藉由閱讀此定義亦可了解,舉例來說,與第一標靶專一性或優先結合之抗體(或部分或表位)可能與第二標靶或不與第二標靶專一性或優先結合。因此,「專一性結合」或「優先結合」不一定需要(雖然可包括)排他性結合。一般來說(但不必然),所謂的結合係指優先結合。
抗體之「可變區」係指抗體輕鏈之可變區或抗體重鏈之可變區(不論單獨或組合指稱)。如該領域所知,重鏈及輕鏈之可變區各由四個架構區(FR)及連接該四個架構區之三個互補決定區(CDR)組成,CDR亦稱為超變異區。各鏈中之CDR藉由FR被拉近,且與另一鏈之CDR形成抗體之抗原結合部位。有至少兩種用於判定CDR的技術:(1)基於跨種序列變異性之方法(即Kabat et al. Sequences of Proteins of Immunological Interest, (5th ed., 1991, National Institutes of Health, Bethesda MD));及(2)基於抗原-抗體複合體之結晶學研究之方法(Al-lazikani et al., 1997, J. Molec. Biol. 273:927-948)。此處所使用之CDR係指以任一方法或兩種方法之組合所定義之CDR。
可變結構域之「CDR」係位於可變區內之胺基酸殘基,其識別係根據卡巴(Kabat)定義、柯西亞(Chothia)定義、卡巴及柯西亞之累積定義、AbM定義、接觸定義及/或構形定義,或該領域廣為周知之任何CDR界定方法。抗體CDR可能被識別為原本由卡巴等人所定義之超變異區。見例如Kabat et al., 1992, Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, NIH, Washington D.C.。CDR之位置亦可能被識別為最先由柯西亞等人所描述之結構性圈環結構。見例如Chothia et al., Nature 342:877-883, 1989。其他識別CDR之方法包括「AbM定義」,該法為卡巴法及柯西亞法之折衷,係源自利用牛津分子(Oxford Molecular)之AbM抗體模型軟體(現為Accelrys®),或如MacCallum et aI., J. Mol. BioI. 262:732-745, 1996所述之基於抗原接觸觀察之CDR的「接觸定義」。在此處稱為CDR之「構形定義」之另一方法中,CDR之位置可能被識別為對抗原結合造成焓貢獻之殘基。見例如Makabe et al., Journal of Biological Chemistry, 283:1156-1166, 2008。其他CDR邊界定義可能仍不嚴格遵守上述方法中之一者,但將與至少部分之卡巴CDR重疊,不過它們可能根據特定殘基或殘基群或甚至整個CDR不顯著影響抗原結合之預測或實驗結果被縮短或延長。此處所使用之CDR可能指由該領域已知之任何方法(包括多種方法之組合)所定義之CDR。此處所使用之方法可利用根據這些方法中任一者所定義之CDR。以包含超過一種CDR之任何給定實施態樣而言,該等CDR可根據卡巴、柯西亞、延長、AbM、接觸及/或構形定義中任一者加以定義。
用語「多肽」、「寡肽」、「肽」及「蛋白質」在此處可交換使用以指稱任何長度之胺基酸鏈,較佳地相對短(例如10至100個胺基酸)之胺基酸鏈。該鏈可為線性或分支,其可能包含經修飾之胺基酸及/或可能被非胺基酸中斷。該等用語亦包含經天然或人為干預修飾之胺基酸鏈;例如雙硫鍵形成、糖基化、脂化、乙醯化、磷酸化或任何其他操縱或修飾,諸如與標記成份共軛。該定義亦包括例如包含一或多個胺基酸類似物(包括例如非天然胺基酸等)之多肽,以及包含該領域習知之其他修飾之多肽。應了解的是該多肽可以單鏈或相連之鏈存在。
本發明之抗體可利用該領域廣為周知之技術製備,例如重組技術、噬菌體展示技術、合成技術或該等技術之組合、或該領域已知之其他技術(見例如Jayasena, S.D., Clin. Chem., 45: 1628-50, 1999及Fellouse, F.A., et al, J. MoI. Biol., 373(4):924-40, 2007)。
如該領域所知之「多核苷酸」或「核酸」在此處可交換使用,其係指任何長度之核苷酸之鏈,包括DNA及RNA。該核苷酸可為去氧核糖核苷酸、核糖核苷酸、經修飾之核苷酸或鹼基及/或彼等之類似物,或任何可藉由DNA或RNA聚合酶被納入鏈中之底物。多核苷酸可包含經修飾之核苷酸,諸如甲基化核苷酸及彼等之類似物。若存在的話,對核苷酸結構之修飾可在該鏈組合之前或之後進行。核苷酸之序列可被非核苷酸成份中斷。多核苷酸在聚合之後可進一步被修飾,諸如與標記成份共軛。其它類型之修飾包括例如「加蓋(caps)」、以類似物取代一或多個天然發生之核苷酸、核苷酸間修飾諸如舉例來說該些具有不帶電鍵結(例如甲基膦酸酯、磷酸三酯、磷酸醯胺化物、胺基甲酸酯等)及帶電鍵結(例如硫代磷酸酯、二硫代磷酸酯等)者、該些含有側基團者,諸如例如蛋白質(例如核酸酶、毒素、抗體、信號肽、聚離胺酸等)、該些具有嵌入劑(intercalator)者(例如吖啶、補骨脂素等)、該些含有螯合劑者(例如金屬、放射性金屬、硼、氧化性金屬等)、該些含有烷化劑者、該些具有經修飾之鍵結者(例如α異位性核酸等)以及未經修飾之多核苷酸形式。另外,任何通常存在於糖類中之羥基可能被例如膦酸基、磷酸基取代、被標準保護基保護或被活化以製備與其他核苷酸之額外鍵結,或可能與固體支持物共軛。該5’及3’端OH可被磷酸化或被胺類或自1至20個碳原子之有機加蓋基團取代。其他羥基亦可被衍生成為標準保護基。多核苷酸亦可包含該領域通常已知之核糖或去氧核糖糖類之類似形式,包括例如2’-O-甲基-核糖、2’-O-烯丙基核糖、2’-氟代-核糖、2’-疊氮基-核糖、碳環糖類似物、α或β異位性糖類、差向異構體糖類諸如阿拉伯糖、木糖或來蘇糖、吡喃糖糖類、呋喃糖糖類、景天酮庚糖、非環類似物及無鹼基核苷類似物諸如甲基核糖苷。一或多個磷酸二酯鍵結可被替代性連接基團取代。該些替代性連接基團包括但不限於其中磷酸鹽被P(O)S(「硫代鹽」)、P(S)S(「二硫代鹽」)、(O)NR2
(「醯胺化物」)、P(O)R、P(O)OR’、CO或CH2
(「甲縮醛」)取代之實施態樣,其中各R或R’係獨立地H或經取代或未經取代之烷基(1至20個碳),該烷基可選擇地含有醚 (-O-)鍵結、芳基、烯基、環烷基、環烯基或芳烷基。多核苷酸中之所有鍵結不需要完全相同。前面的敘述適用於此處提及之所有多核苷酸,包括RNA及DNA。
該技藝中所謂之抗體之「恆定區」係指單獨或經組合之抗體輕鏈之恆定區或抗體重鏈之恆定區。
此處所使用之「實質上純的」係指其為至少50%純的(也就是不含汙染物),更佳地至少90%純的,更佳地至少95%純的,甚至更佳地至少98%純的,且最佳地至少99%純的物質。
「宿主細胞」包括可以或已經接受載體以導入多核苷酸插入物之個別細胞或細胞培養物。宿主細胞包括單一宿主細胞之後代,且該後代可能因為天然、意外或蓄意突變而不一定與原始親代細胞完全相同(在形態學或基因學DNA互補性上)。宿主細胞包括經本發明之多核苷酸在活體內轉染之細胞。
如該領域所知,用語「Fc區」係用於定義免疫球蛋白重鏈之C端區域。該「Fc區」可能為天然序列Fc區或變體Fc區。雖然免疫球蛋白重鏈之Fc區的邊界可能不同,人IgG重鏈Fc區通常被定義為從Cys226或Pro230位置之胺基酸殘基至彼之羧基端之片段。Fc區中之殘基編號係如卡巴(Kabat)所述之EU指數。Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991。免疫球蛋白之Fc區通常包含兩個恆定區CH2及CH3。
此處關於抗體所使用之用語「競爭」係指第一抗體或彼之抗原結合片段(或部份)與表位結合之方式充份類似於第二抗體或彼之抗原結合部份之結合,使得第一抗體與彼之同源表位在第二抗體存在時之結合結果呈可偵測地降低,相較於第二抗體不存在時該第一抗體與彼之同源表位之結合。或者,該情況可為但不一定是該第二抗體與彼之表位之結合亦因第一抗體之存在而可偵測地降低。也就是說,第一抗體可抑制第二抗體與彼之表位之結合,但第二抗體不抑制該第一抗體與彼之個別表位之結合。然而,當各種抗體不論以相同、較高或較低程度可偵測地抑制另一抗體與彼之同源表位或配體結合時,該等抗體被稱為彼此「交叉競爭」與彼等個別表位之結合。本發明包含競爭抗體及交叉競爭抗體。不論該競爭或交叉競爭所藉以發生之機轉為何(例如空間位阻、構形變化或與共同表位或彼之部分結合),技藝人士將了解根據此處所提供之揭示,本發明包含競爭及/或交叉競爭抗體且彼等可被用於此處所揭示之方法。
「天然序列Fc區」包含與在天然中發現之Fc區的胺基酸序列完全相同之胺基酸序列。「變體Fc區」包含與天然序列Fc區有至少一個胺基酸修飾之差異的胺基酸序列,但仍保留該天然序列Fc區之至少一種效應功能。在一些實施態樣中,該變體Fc區相較於天然序列Fc區或親代多肽之Fc區具有至少一個胺基酸取代,例如在天然序列Fc區或親代多肽之Fc區中自約1至約10個胺基酸取代,且較佳地自約1至約5個胺基酸取代。此處之變體Fc區將較佳地具有與天然序列Fc區及/或與親代多肽之Fc區至少約80%之序列一致性,最佳地具有至少約90%之序列一致性,更佳地具有至少約95%、至少約96%、至少約97%、至少約98%、至少約99%之序列一致性。
此處所使用之用語「CD123」係指保留至少部分之CD123活性之任何形式之CD123及彼之變體。除非不同地指明諸如特別指涉人CD123,否則CD123包括所有哺乳動物物種之天然序列CD123,例如人、犬、貓、馬及牛。例示性CD123序列顯示於表1。
如本文中所使用,「CD123抗體」係指與CD123專一性結合且調節由CD123所媒介之生物活性及/或下游事件之抗體。在一些實施態樣中,CD123抗體係拮抗抗體。CD123拮抗抗體包含(以任何程度包括顯著地)阻斷、拮抗、抑制或減少CD123生物活性之抗體,該生物活性包括由CD123媒介之下游事件,諸如IL-3結合及/或下游傳訊、STAT5磷酸化及多能性細胞的存活。CD123抗體及CD123抗體-藥物共軛體(「CD123 ADC」)之實例提供於本文中。
此處所使用之「治療」係指得到有益或所欲臨床結果之方法。就本發明之目的而言,有益或所欲臨床結果包括但不限於下列一或多者:減少(或摧毀)腫瘤或癌細胞之增生、抑制腫瘤性細胞轉移、緩解CD123相關疾病(例如癌症或自體免疫性疾病)、降低CD123相關疾病(例如癌症或自體免疫性疾病)所致之症狀、增加罹患CD123相關疾病(例如癌症或自體免疫性疾病)者之生活品質、降低治療CD123相關疾病(例如癌症或自體免疫性疾病)所需之其他藥物的劑量、延緩CD123相關疾病(例如癌症或自體免疫性疾病)的進展、治癒CD123相關疾病(例如癌症或自體免疫性疾病)及/或延長具有CD123相關疾病(例如癌症或自體免疫性疾病)之個體的存活期。
「改善(Ameliorating)」係指相較於未投予CD123抗體或CD123 ADC,減輕或改善一或多種症狀。「改善」亦包括縮短或減少症狀之持續時間。
此處所使用之藥物、化合物或醫藥組成物之「有效劑量」或「有效量」係指足以影響任一或多種有益或所欲結果之量。就預防性用途而言,有益或所欲結果包括消除或減少風險、減輕嚴重性或延遲疾病之開始,包括疾病之生化學、組織學及/或行為學之症狀、彼之併發症及在疾病發展期間所表現之中間病理學表型。就治療性用途而言,有益或所欲結果包括諸如下列臨床結果:減少發生或改善多種CD123相關疾病或病症(諸如例如但不限於癌症)的一或多種症狀、降低治療該疾病所需之其他藥物之劑量、提高其他藥物之效應及/或延緩個體之CD123相關疾病之進展。有效劑量可分一或多次投予。就本發明之目的而言,藥物、化合物或醫藥組成物之有效劑量係足以直接或間接完成預防性或治療性治療之量。如在臨床上所了解的,藥物、化合物或醫藥組成物之有效劑量可能與或可能不與另一藥物、化合物或醫藥組成物組合達成。因此,「有效劑量」可在投予一或多種治療劑之情況中被考慮,且可考慮給予有效量之單一劑(配合一或多種其他劑),若可能或能達成所欲之結果。
「個體(individual或subject)」係哺乳動物,更佳者係人。哺乳動物亦包括但不限於農場動物、競賽動物、寵物、靈長動物、馬、犬、貓、小鼠及大鼠。
此處所使用之「載體(vector)」係指建構物,其能在宿主細胞中遞送及較佳地表現一或多種感興趣之基因或序列。載體之實例包括但不限於病毒性載體、裸DNA或RNA表現載體、質體載體、黏質體載體、噬菌體載體、與陽離子縮合劑有關之DNA或RNA表現載體、包封於脂質體中之DNA或RNA表現載體及某些真核細胞諸如生產細胞。
此處使用之「表現控制序列(expression control sequence)」係引導核酸轉錄之核酸序列。表現控制序列可為啟動子,諸如組成性或誘導性啟動子或增強子。表現控制序列係可操作地與所欲轉錄之核酸序列連接。
此處所使用之「醫藥上可接受之載劑(pharmaceutically acceptable carrier)」或「醫藥上可接受之賦形劑(pharmaceutical acceptable excipient)」包括任何當與活性成分組合時能使該成分保留生物活性且不與個體之免疫系統反應之任何物質。實例包括但不限於任何標準醫藥載劑諸如磷酸鹽緩衝鹽水溶液、水、乳液諸如油/水乳液及各種類型之潤濕劑。較佳之用於氣霧劑或腸胃外投予之稀釋劑係磷酸鹽緩衝鹽水(PBS)或生理(0.9%)鹽水。包含該等載劑之組成物係由眾所周知之習知方法調製(見例如Remington's Pharmaceutical Sciences, 18th edition, A. Gennaro, ed., Mack Publishing Co., Easton, PA, 1990;及Remington, The Science and Practice of Pharmacy 21st Ed. Mack Publishing, 2005)。
此處所使用之用語「含有醯基供體麩醯胺酸之標籤(acyl donor glutamine-containing tag)」或「麩醯胺酸標籤(glutamine tag)」係指含有一或多個作為轉麩醯胺酸酶胺受體之Gln殘基之多肽或蛋白質。見例如PCT公開號WO2012059882及WO2015015448,彼等全文以引用方式併入本文中。
此處所使用之用語「kon
」係指抗體與抗原締合之速率常數。特別地,該等速率常數(kon
及koff
)及平衡解離常數係利用IgG及CD123蛋白質(例如CD123-Fc融合蛋白質)測量。
此處所使用之用語「koff
」係指抗體自抗體/抗原複合物解離之速率常數。
此處所使用之用語「KD
」係指抗體-抗原交互作用之平衡解離常數。
在此處提及「約」某數值或參數時,其包括(且描述)與該數值或參數本身相關之實施態樣。例如,「約X」之敘述包括「X」之敘述。數字範圍包含界定該範圍之數字。
如本文中所使用,CPI係指1,2,8,8a-四氫環丙[c]吡咯并[3,2-e]吲哚-4(5H)-酮或其經取代或衍生形式。CPI亦可指CPI之seco形式或seco‑CPI,其亦稱為8-(氯甲基)-1-甲基-3,6,7,8-四氫吡咯并[3,2-e]吲哚-4-醇或其經取代或衍生形式(或多種形式)。
應了解的是,只要此處之實施態樣係以用語「包含」描述,其亦提供其他以「由...組成」及/或「實質上由...組成」之用語所描述之類似實施態樣。
本發明之態樣或實施態樣係以馬庫西群組或其他選擇性形式之群組描述,本發明不僅包含被標示為整體之整個群組,但亦包含該群組之個別成員及該主要群組中所有可能之亞群,且亦包含不含其中一或多個群組成員之主要群組。本發明亦設想明確排除該申請專利之發明中任何群組成員之一或多者。
除非另行定義,此處所使用之所有技術及科學用語和本發明所屬領域之一般技藝人士所通常瞭解之意義相同。若發生衝突,以本說明書(包括定義)為主。在本說明書及申請專利範圍中,用語「包含(comprise)」或變化用語諸如「包括(comprises)」或「含有(comprising)」將被理解為意指包括被敘述之整體或整體之群,但不排除任何其他整體或整體之群。除非上下文另外要求,單數用語應包括複數意義且複數用語應包括單數意義。
示範性方法及材料係於此處敘述,不過與此處所述之方法及材料類似或相等者亦可被用於實施或檢測本發明。該等材料、方法及實施態樣僅用來示例而非意圖限制。
CD123抗體及抗體-藥物共軛體
本發明提供與CD123(例如人CD123(例如SEQ ID NO: 1))結合之抗體及包含抗CD123抗體之共軛體(諸如抗體-藥物共軛體或ADC),彼等可由下列特徵之任一或多者表徵:(a)治療、預防、改善與個體之表現CD123之惡性細胞有關之病症(例如癌症諸如但不限於AML、B-ALL、HCL等)的一或多種症狀;(b)抑制個體之腫瘤生長或進展(該個體具有表現CD123之惡性腫瘤);(c)抑制個體之表現CD123之癌(惡性)細胞的轉移(該個體具有一或多種表現CD123之惡性細胞);(d)誘導表現CD123之腫瘤消退(例如長期消退);及(e)在表現CD123之惡性細胞中發揮細胞毒性活性。
本發明所使用之抗體可包含單株抗體、多株抗體、抗體片段(例如Fab、Fab’、F(ab’)2
、Fv、Fc等)、嵌合抗體、雙專一性抗體、異源共軛抗體、單鏈抗體(ScFv)、彼等之突變物、包含抗體部位之融合蛋白(例如結構域抗體)、人化抗體及任何其他含有該所需專一性之抗原辨認區的免疫球蛋白分子之經修飾之構型,包括抗體之糖基化變體、抗體之胺基酸序列變體及經共價修飾之抗體。該抗體可為小鼠、大鼠、人或任何其他來源(包括嵌合或人化抗體)。在一些實施態樣中,此處所述之CD123抗體係單株抗體。舉例來說,CD123抗體可為人化單株抗體、人抗體或嵌合性單株抗體。
在一些實施態樣中,該抗體可包含經修飾之恆定區,諸如但不限於具有增加之引發免疫反應潛力之恆定區。舉例來說,該恆定區可經修飾為對Fc γ受體(例如FcγRI、FcγRIIA或FcγIII)具有增加之親和性。在一些實施態樣中,該抗體包含免疫惰性之恆定區,即具有減少之引發免疫反應潛力之恆定區。在一些實施態樣中,該恆定區係經如Eur. J. Immunol., 29:2613-2624, 1999;PCT申請案PCT/GB99/01441及/或英國專利申請案98099518所述之修飾。該Fc可為人IgG1、人IgG2、人IgG3或人IgG4。該Fc可為含有突變A330P331至S330S331 (IgG2Δa)之人IgG2,其中該胺基酸殘基係參考野生型IgG2序列編號。Eur. J. Immunol., 29:2613-2624, 1999。在一些實施態樣中,該抗體包含有下列突變之IgG4
之恆定區(Armour et al., Molecular Immunology 40 585-593, 2003):E233F234L235至P233V234A235(IgG4Δc),其中該編號參考野生型IgG4。在另一實施態樣中,該Fc係人IgG4 E233F234L235至P233V234A235並刪除G236 (IgG4Δb)。在另一實施態樣中,該Fc係包含絞鏈穩定突變S228至P228之任何人IgG4 Fc (IgG4、IgG4Δb或IgG4Δc) (Aalberse et al., Immunology 105, 9-19, 2002)。在另一實施態樣中,該Fc可為非糖基化Fc。
在一些實施態樣中,該恆定區可為藉由使該寡醣連接殘基(諸如Asn297)及/或該恆定區中屬於糖基化辨認序列之部份的側翼殘基突變而去糖基化。在一些實施態樣中,該恆定區之N-連接糖基化係經酵素去糖基化。該恆定區之N-連接糖基化可經酵素去糖基化或藉由在糖基化缺陷之宿主細胞中表現以去糖基化。
判定抗體與CD123之結合親和性的一個方法係測量該抗體之單官能性Fab片段的結合親和性。為了得到單官能性Fab片段,抗體(例如IgG)可經木瓜酶剪切或經重組表現。抗體之CD123 Fab片段的親和性可藉由裝設預先固定之鏈黴抗生物素蛋白感測晶片(SA)或抗小鼠Fc或抗人Fc之表面電漿共振(BiacoreTM
3000TM
表面電漿共振(SPR)系統,BiacoreTM
, INC, Piscataway NJ)使用HBS-EP運行緩衝液(0.01M HEPES,pH 7.4,0.15 NaCl,3 mM EDTA,0.005% v/v界面活性劑P20)判定。經生物素化或Fc融合之人CD123可經HBS-EP緩衝液稀釋至濃度低於0.5 μg/mL,並利用不同的接觸時間注射經過各別晶片通道以達到兩種抗原密度範圍,即用於詳細動力學試驗之50至200反應單位(RU)或用於篩選測定之800至1,000 RU。再生試驗顯示含25 mM NaOH之25體積%乙醇有效地移除經結合之Fab同時保持晶片上之CD123供超過200次注射的活性。通常,經純化之Fab樣本的連續稀釋液(濃度自0.1至10倍之預估KD
濃度)係以100 μL/分鐘注射1 min,並允許最高2小時之解離時間。Fab蛋白之濃度係藉由使用已知濃度(如胺基酸分析判定)之Fab作為標準物之ELISA及/或SDS-PAGE電泳判定。使用BIAevaluation程式將資料完整帶入1:1 Langmuir結合模型(Karlsson, R. Roos, H. Fagerstam, L. Petersson, B. (1994). Methods Enzymology 6. 99-110)以同時得到動力學締合速率(kon
)及解離速率(koff
)。平衡解離常數(KD
)數值係以koff
/kon
計算。此方法適合用於判定抗體與任何CD123包括人CD123、另一哺乳動物之CD123(諸如小鼠CD123、大鼠CD123或靈長動物CD123)以及不同形式之CD123(例如糖基化CD123)之結合親和性。抗體結合親和性通常在25°C下測量,但亦可在37°C下測量。如本文所述之CD123抗體對CD123諸如人CD123(例如SEQ ID NO: 1)之結合親和性(KD
)可為約0.002 nM至約6500 nM。在一些實施態樣中,結合親和性係約6500 nm、6000 nm、5986 nm、5567 nm、5500 nm、4500 nm、4000 nm、3500 nm、3000 nm、2500 nm、2134 nm、2000 nm、1500 nm、1000 nm、750 nm、500 nm、400 nm、300 nm、250 nm、200 nM、193 nM、100 nM、90 nM、50 nM、45 nM、40 nM、35 nM、30 nM、25 nM、20 nM、19 nm、18 nm、17 nm、16 nm、15 nM、10 nM、8 nM、7.5 nM、7 nM、6.5 nM、6 nM、5.5 nM、5 nM、4 nM、3 nM、2 nM、1 nM、0.5 nM、0.3 nM、0.1 nM、0.01 nM或0.002 nM之任一者。在一些實施態樣中,結合親和性係小於約6500 nm、6000 nm、5500 nm、5000 nm、4000 nm、3000 nm、2000 nm、1000 nm、900 nm、800 nm、250 nM、200 nM、100 nM、50 nM、30 nM、20 nM、10 nM、7.5 nM、7 nM、6.5 nM、6 nM、5 nM、4.5 nM、4 nM、3.5 nM、3 nM、2.5 nM、2 nM、1.5 nM、1 nM或0.5 nM之任一者。
此處所述之CD123抗體可由該領域中習知之任何方法製備。就雜交瘤細胞系之產製而言,免疫接種宿主動物之途徑及時程通常與已建立及習知之抗體刺激及產製技術一致,如此處進一步描述。用於產製人及小鼠抗體之通用技術係該領域已知及/或係於此處描述。
在一些實施態樣中,CD123抗體可包含重鏈可變區(VH),該重鏈可變區包含三個CDR,該VH包含SEQ ID NO: 6、24、32、44、51或64之胺基酸序列。在本發明之一些態樣中,抗體包含輕鏈可變區(VL),該輕鏈可變區包含三個CDR,該VL包含SEQ ID NO: 17、28、39、48、57或71之胺基酸序列。在本發明之一些態樣中,抗體包含VH及VL,該VH包含三個CDR,該VH包含SEQ ID NO: 6、24、32、44、51或64之胺基酸序列,該VL包含三個CDR,該VL包含SEQ ID NO: 17、28、39、48、57或71之胺基酸序列。在其他實施態樣中,CD123抗體可包含:包含SEQ ID NO: 7、8及9之胺基酸序列的VH及包含SEQ ID NO: 18、19及20之胺基酸序列的VL。在其他實施態樣中,CD123抗體可包含:包含SEQ ID NO: 7、25及9之胺基酸序列的VH及包含SEQ ID NO: 18、19及20之胺基酸序列的VL。在其他實施態樣中,CD123抗體可包含:包含SEQ ID NO: 33、34及35之胺基酸序列的VH及包含SEQ ID NO: 40、41及42之胺基酸序列的VL。在其他實施態樣中,CD123抗體可包含:包含SEQ ID NO: 33、45及46之胺基酸序列的VH及包含SEQ ID NO: 40、41及42之胺基酸序列的VL。在其他實施態樣中,CD123抗體可包含:包含SEQ ID NO: 52、53及54之胺基酸序列的VH及包含SEQ ID NO: 58、59及60之胺基酸序列的VL。在其他實施態樣中,CD123抗體可包含:包含SEQ ID NO: 65、66及67之胺基酸序列的VH及包含SEQ ID NO: 72、73及74之胺基酸序列的VL。
代表性CD123抗體重鏈可變區及輕鏈可變區可分別包含SEQ ID NO: 6、24、32、44、51及64及SEQ ID NO: 17、28、39、48、57及71之胺基酸序列。代表性CD123抗體重鏈及輕胺基鏈可分別包含SEQ ID NO: 15、27、37、47、55及69及SEQ ID NO: 23、30、43、49、62及76之胺基酸序列。代表性CD123抗體序列顯示於表2.0。
本文提供之例示性CD123抗體包括表2.1顯示之18G3、人化18G3 (h18G3)、16D6、人化16D6 (h16D6)、3D1及20D7。表2.1顯示之序列係胺基酸序列(除非另外指明)。
取代變體是指該抗體分子中之至少一個胺基酸殘基被移除且在該位置插入不同之殘基。最受到關注之取代性突變形成之位置包括超變異區,但亦可考慮架構之改變。保守性取代係顯示於表3中標題「保守性取代」之欄。若該等取代導致生物活性改變,則更顯著之改變(表3稱為「示範性取代」)或如下參照胺基酸分類進一步描述者可被導入,然後篩選該產物。
抗體之生物特性的顯著修飾係藉由選擇在維持下列特性之效應上有顯著差異之取代加以完成:(a)取代區之多肽骨架結構,例如β摺板狀或螺旋構形,(b)標靶部位之分子的帶電或疏水性,或(c)側鏈之主體。天然發生之殘基基於常見之側鏈性質分成下列群組:
(1)非極性:正白胺酸、Met、Ala、Val、Leu、Ile;
(2)不帶電極性:Cys、Ser、Thr、Asn、Gln;
(3)酸性(帶負電):Asp、Glu;
(4)鹼性(帶正電):Lys、Arg;
(5)影響鏈方向性之殘基:Gly、Pro;及
(6)芳香性:Trp、Tyr、Phe、His。
非保守性取代係以上述分類中之一個分類的成員交換另一分類之成員達成。
可能被製造之一種取代舉例來說係改變抗體中一或多個半胱胺酸,其可能對另一殘基諸如但不限於丙胺酸或絲胺酸具化學反應性。舉例來說,可發生非典型半胱胺酸之取代。該取代可發生於抗體之可變結構域之CDR或架構區或恆定區中。在一些實施態樣中,該半胱胺酸係典型半胱胺酸。任何與維持抗體之適當構型無關之半胱胺酸殘基亦可被取代(通常以絲胺酸取代),以增進該分子之氧化穩定性及防止異常交聯。相反地,半胱胺酸鍵可被加入抗體以增進抗體之穩定性,特別是當該抗體係抗體片段諸如Fv片段時。
本發明亦提供一種如此處所述之CD123抗體或彼之抗原結合片段之共軛體,其中該抗體係直接或間接經由連接子與劑(例如細胞毒性劑)共軛以用於靶向性免疫療法(例如抗體-藥物共軛體或ADC)。舉例來說,細胞毒性劑可如此處所述與該CD123抗體連接或共軛以用於靶向性局部遞送該細胞毒性劑部分至腫瘤(例如表現CD123之腫瘤)。
用於共軛細胞毒性劑或其他治療劑與抗體之方法已於許多文獻中說明。舉例來說,抗體之化學修飾可經由離胺酸側鏈胺或藉由還原鏈間雙硫鍵而被活化之半胱胺酸氫硫基進行,以使共軛反應得以發生。見例如Tanaka et al., FEBS Letters 579:2092-2096, 2005及Gentle et al., Bioconjugate Chem. 15:658-663, 2004。亦已描述經工程改造於抗體之特定位點之反應性半胱胺酸殘基,該等殘基用於以經定義之化學計量進行特定藥物共軛。見例如Junutula et al., Nature Biotechnology, 26:925-932, 2008。在轉麩醯胺酸酶及胺(例如包含或連接至反應性胺之細胞毒性劑)存在時,使用藉由多肽工程改造之含有醯基供體麩醯胺酸之標籤或使成反應性之內源性麩醯胺酸(即形成共價鍵以作為醯基供體之能力)之共軛亦描述於國際專利申請案WO2012/059882及WO2015015448,彼等全文以引用方式併入本文中。轉麩醯胺酸酶係蛋白質-麩醯胺酸γ-麩胺醯基轉化酶(EC 2.3.2.13),其一般而言催化麩醯胺酸殘基與離胺酸殘基之pH依賴性轉醯胺作用。本文所述之本發明所使用之轉麩醯胺酸酶可獲自或自多種來源製造或經工程改造以催化一或多個內源性麩醯胺酸殘基與一或多個離胺酸殘基或含有一或多種反應性胺之胺供體劑的轉醯胺作用。使用轉麩醯胺酸酶以製備ADC之方法係描述於例如美國專利申請公開案20170043033,其全文在本文中以引用方式併入本文中。
ADC包含通常經由使用連接子與藥物劑共軛的抗體組分。在一些實施態樣中,在本文中揭示之ADC包含經由工程改造之含有麩醯胺酸之標籤、內源性麩醯胺酸(即未經工程改造之天然麩醯胺酸,諸如可變結構域、CDR等中之麩醯胺酸)及/或反應性內源性麩醯胺酸與胺供體劑(例如以胺供體單元與連接子偶合之小分子)定點共軛之抗體。
藉由修飾抗體中之一或多個胺基酸(例如胺基酸刪除、插入、取代或突變)、藉由酶的去糖基化或藉由與經工程改造之轉麩醯胺酸酶反應,可使內源性麩醯胺酸具有反應性(即在胺及轉麩醯胺酸酶存在下形成共價鍵作為醯基供體的能力)。因此,在一態樣中,提供包含下式之抗體-藥物共軛體(ADC):抗體-(T-(X-Y-Za
)b
)c
,其中:T係1)經工程改造於特定位點之含有麩醯胺酸之標籤,2)內源性麩醯胺酸及/或3)藉由抗體工程改造或經工程改造之轉麩醯胺酸酶而具有反應性之內源性麩醯胺酸;X係胺供體單元;Y係連接子;且Z係劑部份;X-Y-Z係與含有麩醯胺酸之標籤、內源性麩醯胺酸及/或反應性內源性麩醯胺酸定點共軛之胺供體劑;a係1至6的整數;b係1至6的整數;c係1至20的整數;且其中a、b及c之乘積(藥物-抗體比例)至少為約1。本文所述之抗體上之含有麩醯胺酸之標籤、內源性麩醯胺酸及/或反應性麩醯胺酸以及胺供體劑(X-Y-Z)兩者皆為轉麩醯胺酸酶之受質,且介於含有麩醯胺酸之標籤及/或內源性/反應性麩醯胺酸與胺供體劑之間之鍵聯具有式CH2
-CH2
-CO-NH-,其中NH-與連接子及劑部份連接。
在一些實施態樣中,此處描述之CD123抗體或共軛體包含經工程改造於抗體之特定位點(例如CD123抗體之羧基端、胺基端或另一位點)之含有醯基供體麩醯胺酸之標籤。在一些實施態樣中,標籤包含胺基酸麩醯胺酸(Q)或胺基酸序列LQG、LLQGG (SEQ ID NO:77)、LLQG (SEQ ID NO:78)、LSLSQG (SEQ ID NO: 79)、GGGLLQGG (SEQ ID NO: 80)、GLLQG (SEQ ID NO: 81)、LLQ、GSPLAQSHGG (SEQ ID NO: 82)、GLLQGGG (SEQ ID NO: 83)、GLLQGG (SEQ ID NO: 84)、GLLQ (SEQ ID NO: 85)、LLQLLQGA (SEQ ID NO: 86)、LLQGA (SEQ ID NO: 87)、LLQYQGA (SEQ ID NO: 88)、LLQGSG (SEQ ID NO: 89)、LLQYQG (SEQ ID NO: 90)、LLQLLQG (SEQ ID NO: 91)、SLLQG (SEQ ID NO: 92)、LLQLQ (SEQ ID NO: 93)、LLQLLQ (SEQ ID NO: 94)、LLQGR (SEQ ID NO: 95)、LLQGPP (SEQ ID NO: 96)、LLQGPA (SEQ ID NO: 97)、GGLLQGPP (SEQ ID NO: 98)、GGLLQGA (SEQ ID NO: 99)、LLQGPGK (SEQ ID NO: 100)、LLQGPG (SEQ ID NO: 101)、LLQGP (SEQ ID NO: 102)、LLQP (SEQ ID NO: 103)、LLQPGK (SEQ ID NO: 104)、LLQAPGK (SEQ ID NO: 105)、LLQGAPG (SEQ ID NO: 106)、LLQGAP (SEQ ID NO: 107)及LLQLQG (SEQ ID NO: 108)。
在一些實施態樣中,含有醯基供體麩醯胺酸之標籤包含例如LLQG (SEQ ID NO: 78),其取代抗體重鏈中之胺基酸殘基E294至N297。
本發明亦提供一種單離抗體,其包含含有醯基供體麩醯胺酸之標籤及該抗體之位置222、340或370(EU編號系統)之胺基酸修飾,其中該修飾係胺基酸刪除、插入、取代、突變或任何彼等之組合。在一些實施態樣中,該胺基酸修飾係將離胺酸取代成精胺酸(例如K222R、K340R或K370R)。
可與本發明之CD123抗體或抗原結合片段共軛之劑包括但不限於細胞毒性劑、免疫調節劑、顯影劑、治療性蛋白質、生物聚合物或寡核苷酸。
細胞毒性劑之實例包括但不限於蒽環、耳抑素(auristatin)、海兔毒素(dolastatin)、考布他丁(combretastatin)、雙聯黴素(duocarmycin)、吡咯并苯并二氮呯二聚體、吲哚啉并-苯并二氮呯二聚體、烯二炔、膠達納黴素(geldanamycin)、美坦素(maytansine)、嘌呤黴素(puromycin)、紫杉烷、長春花生物鹼、喜樹鹼、微管溶素(tubulysin)、半星芒體(hemiasterlin)、司普力西歐他汀(spliceostatin)、普拉二烯內酯(pladienolide)及彼等之立體異構物、同電子排列體、類似物或衍生物。
在一些態樣中,藥物/劑係環丙基吡咯并吲哚啉(CPI)二聚體、CTI二聚體或CBI二聚體。CPI二聚體誘導股間DNA交聯及有效的細胞毒性。PCT國際專利公開號WO2015/110935(其全文以引用方式併入本文中)揭示可用於本發明之CD123 ADC之CPI及CBI二聚體且提供產生CPI及CBI二聚體之方法。例如,劑(8S)-8-(氯甲基)-6-[(3-{[(1S)-1-(氯甲基)-5-羥基-8-甲基-1,6-二氫吡咯并[3,2-e]吲哚-3(2H)-基]羰基}雙環[1.1.1]戊-1-基)羰基]-1-甲基-3,6,7,8-四氫吡咯并[3,2-e]吲哚-4-基二氫磷酸鹽(又名「CPI-8314二聚體」)具有下列結構:
具有式C31H31Cl2N4O7P。
蒽環係源自鏈黴菌屬(Strepomyces
)之細菌,已被用於治療多種癌症,諸如白血病、淋巴瘤、乳癌、子宮癌、卵巢癌及肺癌。例示性蒽環包括但不限於道諾黴素、多柔比星(doxorubicin)(即阿黴素(adriamycin))、表柔比星(epirubicin)、伊達比星(idarubicin)、戊柔比星(valrubicin)及米托蒽醌(mitoxantrone)。
海兔毒素(dolastatin)及彼等之肽類似物及衍生物耳抑素係高度有效之抗有絲分裂劑,已被顯示具有抗癌及抗真菌活性。見例如美國專利第5,663,149號及Pettit et al.,Antimicrob. Agents Chemother
. 42:2961-2965, 1998。例示性海兔毒素及耳抑素包括但不限於海兔毒素10、耳抑素E、耳抑素EB (AEB)、耳抑素EFP (AEFP)、MMAD(單甲基耳抑素D或單甲基海兔毒素10)、MMAF(單甲基耳抑素F或N-甲基纈胺酸-纈胺酸-海兔異白胺酸(dolaisoleuine)-海兔脯胺酸(dolaproine)-苯丙胺酸)、MMAE(單甲基耳抑素E或N-甲基纈胺酸-纈胺酸-海兔異白胺酸-海兔脯胺酸-降麻黃鹼)、5-苯甲醯基戊酸-AE酯(AEVB)及其他新穎之耳抑素(諸如美國專利申請案2013/0129753中所述者)。在一些實施態樣中,耳抑素係0101(2-甲基丙胺醯基-N-
[(3R,
4S,
5S
)-3-甲氧基-1-{(2S
)-2-[(1R,
2R
)-1-甲氧基-2-甲基-3-側氧基-3-{[(1S
)-2-苯基-1-(1,3-噻唑-2-基)乙基]胺基}丙基]吡咯啶-1-基}-5-甲基-1-側氧基庚-4-基]-N-
甲基-L-纈胺醯胺),其具有下列結構:。
在一些實施態樣中,耳抑素係3377(N,2-二甲基丙胺醯基-N-{(1S,2R)-4-{(2S)-2-[(1R,2R)-3-{[(1S)-1-羧基-2-苯基乙基]胺基}-1-甲氧基-2-甲基-3-側氧基丙基]吡咯啶-1-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),其具有下列結構:
在一些實施態樣中,耳抑素係0131-OMe(N,2-二甲基丙胺醯基-N-[(3R,4S,5S)-3-甲氧基-1-{(2S)-2-[(1R,2R)-1-甲氧基-3-{[(2S)-1-甲氧基-1-側氧基-3-苯基丙-2-基]胺基}-2-甲基-3-側氧基丙基]吡咯啶-1-基}-5-甲基-1-側氧基庚-4-基]-N-甲基L-纈胺醯胺),其具有下列結構:
在其他實施態樣中,耳抑素係0131(2-甲基-L-脯胺醯基-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(1S)-1-羧基-2-苯基乙基]胺基}-1-甲氧基-2-甲基-3-側氧基丙基]吡咯啶-1-基}-3-甲氧基-5-甲基-1-側氧基庚-4-基]-N-甲基-L-纈胺醯胺),其具有下列結構:
在其他實施態樣中,耳抑素係0121(2-甲基-L-脯胺醯基-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S)-1-甲氧基-1-側氧基-3-苯基丙-2-基]胺基}-1-甲氧基-2-甲基-3-側氧基丙基]吡咯啶-1-基}-3-甲氧基-5-甲基-1-側氧基庚-4-基]-N-甲基-L-纈胺醯胺),其具有下列結構:
喜樹鹼係細胞毒性喹啉生物鹼,其抑制酶拓撲異構酶I。喜樹鹼及其衍生物之實例包括但不限於托泊替康(topotecan)及伊立替康(irinotecan)及彼等之代謝物諸如SN-38。
考布他丁係具有腫瘤血管破壞特性之天然酚類。例示性考布他丁及彼等之衍生物包括但不限於考布他丁A-4 (CA-4)及奧瑞布林(ombrabulin)。
雙聯黴素(duocarmycin)及CC-1065係具有細胞毒性效力之DNA烷化劑。見Boger and Johnson,PNAS
92:3642-3649 (1995)。例示性雙聯黴素及CC-1065包括但不限於(+)-雙聯黴素A及(+)-雙聯黴素SA、(+)-CC-1065及如國際專利申請案PCT/IB2015/050280所揭示之化合物,包括但不限於N~2~-乙醯基-L-離胺醯基-L-纈胺醯基-N~5~-胺甲醯基-N-[4-({[(2-{[({(1S)-1-(氯甲基)-3-[(5-{[(1S)-1-(氯甲基)-5-(膦醯氧基(phosphonooxy))-1,2-二氫-3H-苯并[e]吲哚-3-基]羰基}噻吩-2-基)羰基]-2,3-二氫-1H-苯并[e]吲哚-5-基}氧基)羰基](甲基)胺基}乙基)(甲基)胺甲醯基]氧基}甲基)苯基]-L-鳥胺酸醯胺,其具有下列結構:、
N~2~-乙醯基-L-離胺醯基-L-纈胺醯基-N~5~-胺甲醯基-N-[4-({[(2-{[({(8S)-8-(氯甲基)-6-[(3-{[(1S)-1-(氯甲基)-8-甲基-5-(膦醯氧基(phosphonooxy))-1,6-二氫吡咯并[3,2-e]吲哚-3(2H)-基]羰基}雙環[1.1.1]戊-1-基)羰基]-1-甲基-3,6,7,8-四氫吡咯并[3,2-e]吲哚-4-基}氧基)羰基](甲基)胺基}乙基)(甲基)胺甲醯基]氧基}甲基)苯基]-L-鳥胺酸醯胺,其具有下列結構:
N~2~-乙醯基-L-離胺醯基-L-纈胺醯基-N~5~-胺甲醯基-N-[4-({[(2-{[({(8S)-8-(氯甲基)-6-[(4-{[(1S)-1-(氯甲基)-8-甲基-5-(膦醯氧基(phosphonooxy))-1,6-二氫吡咯并[3,2-e]吲哚-3(2H)-基]羰基}五環[4.2.0.0~2,5~.0~3,8~.0~4,7~]辛-1-基)羰基]-1-甲基-3,6,7,8-四氫吡咯并[3,2-e]吲哚-4-基}氧基)羰基](甲基)胺基}乙基)(甲基)胺甲醯基]氧基}甲基)苯基]-L-鳥胺酸醯胺,其具有下列結構:
烯二炔(Enediyne)係一類抗腫瘤細菌產物,其特徵為具有九元及十元環或有經共軛之三鍵-雙鍵-三鍵之環狀系統存在。例示性烯二炔包括但不限於卡利奇黴素(calicheamicin)、埃斯培拉黴素(esperamicin)、恩西拉黴素(uncialamicin)、達內黴素(dynemicin)及彼等之衍生物。
膠達納黴素(geldanamycin)係與Hsp90(熱休克蛋白90)結合之苯醌安莎黴素(ansamycin)抗生素,其已被用來作為抗腫瘤藥。例示性膠達納黴素包括但不限於17-AAG(17-N-烯丙基胺基-17-去甲氧基膠達納黴素)及17-DMAG(17-二甲基胺基乙基胺基-17-去甲氧基膠達納黴素)。
半星芒體及其類似物(例如HTI-286)與微管蛋白結合、破壞正常微管動力學且以化學計量之量去極化微管。
美坦素(Maytansine)或彼等之衍生物類美坦素(maytansinoid)抑制細胞增生,其藉由在有絲分裂時經由抑制微管蛋白之聚合而抑制微管形成。見Remillard et al., Science 189:1002-1005, 1975。例示性美坦素及類美坦素包括但不限於美登素(mertansine) (DM1)、美登素之衍生物及安絲菌素(ansamitocin)。
吡咯并苯并二氮呯二聚體(PBD)及吲哚啉并-苯并二氮呯二聚體(IGN)係含有一或多個與雙螺旋DNA結合之亞胺(immine)官能基或彼等之等效物之抗腫瘤劑。PBD及IGN分子係基於天然產物安麯黴素(athramycin)且與DNA以序列選擇性方式交互作用,較佳者為嘌呤-鳥嘌呤-嘌呤序列。例示性PBD及彼等之類似物包括但不限於SJG-136。
司普力西歐他汀及普拉二烯內酯係抗腫瘤化合物,彼等抑制剪接且與剪接體SF3b交互作用。司普力西歐他汀之實例包括但不限於司普力西歐他汀A、FR901464及(2S,3Z)-5-{[(2R,3R,5S,6S)-6-{(2E,4E)-5-[(3R,4R,5R,7S)-7-(2-肼基-2-側氧基乙基)-4-羥基-1,6-二氧雜螺[2.5]辛-5-基]-3-甲基戊-2,4-二烯-1-基}-2,5-二甲基四氫-2H-哌喃-3-基]胺基}-5-側氧基戊-3-烯-2-基乙酸酯,其具有下列結構:。
普拉二烯內酯之實例包括但不限於普拉二烯內酯B、普拉二烯內酯D或E7107。
紫杉烷(taxane)係作為抗微管蛋白劑或有絲分裂抑制劑之二萜。例示性紫杉烷包括但不限於太平洋紫杉醇(paclitaxel)(例如TAXOL®
)及多西紫杉醇(docetaxel) (TAXOTERE®
)。
微管溶素係單離自黏球菌菌株之天然產物,已顯示可去極化微管且誘導有絲分裂停止。例示性微管溶素包括但不限於微管溶素A、微管溶素B及微管溶素D。
長春花生物鹼亦為抗微管蛋白劑。例示性長春花生物鹼包括但不限於長春新鹼(vincristine)、長春鹼(vinblastine)、長春地辛(vindesine)及長春瑞濱(vinorelbine)。
在一些實施態樣中,細胞毒性劑係選自由由下列所組成之群組:MMAD(單甲基耳抑素D)、0101(2-甲基丙胺醯基-N-
[(3R,
4S,
5S
)-3-甲氧基-1-{(2S
)-2-[(1R,
2R
)-1-甲氧基-2-甲基-3-側氧基-3-{[(1S
)-2-苯基-1-(1,3-噻唑-2-基)乙基]胺基}丙基]吡咯啶-1-基}-5-甲基-1-側氧基庚-4-基]-N-
甲基-L-纈胺醯胺)、3377(N,2-二甲基丙胺醯基-N-{(1S,2R)-4-{(2S)-2-[(1R,2R)-3-{[(1S)-1-羧基-2-苯基乙基]胺基}-1-甲氧基-2-甲基-3-側氧基丙基]吡咯啶-1-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)、0131(2-甲基-L-脯胺醯基-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(1S)-1-羧基-2-苯基乙基]胺基}-1-甲氧基-2-甲基-3-側氧基丙基]吡咯啶-1-基}-3-甲氧基-5-甲基-1-側氧基庚-4-基]-N-甲基-L-纈胺醯胺)、0131-OMe(N,2-二甲基丙胺醯基-N-[(3R,4S,5S)-3-甲氧基-1-{(2S)-2-[(1R,2R)-1-甲氧基-3-{[(2S)-1-甲氧基-1-側氧基-3-苯基丙-2-基]胺基}-2-甲基-3-側氧基丙基]吡咯啶-1-基}-5-甲基-1-側氧基庚-4-基]-N-甲基L-纈胺醯胺)、0121(2-甲基-L-脯胺醯基-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S)-1-甲氧基-1-側氧基-3-苯基丙-2-基]胺基}-1-甲氧基-2-甲基-3-側氧基丙基]吡咯啶-1-基}-3-甲氧基-5-甲基-1-側氧基庚-4-基]-N-甲基-L-纈胺醯胺)及(2S,3Z)-5-{[(2R,3R,5S,6S)-6-{(2E,4E)-5-[(3R,4R,5R,7S)-7-(2-肼基-2-側氧基乙基)-4-羥基-1,6-二氧雜螺[2.5]辛-5-基]-3-甲基戊-2,4-二烯-1-基}-2,5-二甲基四氫-2H-哌喃-3-基]胺基}-5-側氧基戊-3-烯-2-基乙酸酯。
在一些實施態樣中,該劑係免疫調節劑。免疫調節劑之實例包括但不限於更昔洛韋(gancyclovier)、依那西普(etanercept)、他克莫司(tacrolimus)、西羅莫司(sirolimus)、伏環孢素(voclosporin)、環孢靈(cyclosporine)、雷帕黴素(rapamycin)、環磷醯胺(cyclophosphamide)、硫唑嘌呤(azathioprine)、黴酚酸酯(mycophenolate mofetil)、甲胺喋呤(methotrexate)、糖皮質素、糖皮質素類似物、細胞介素、幹細胞生長因子、淋巴毒素、腫瘤壞死因子(TNF)、造血因子、介白素(例如介白素-1 (IL-1)、IL-2、IL-3、IL-6、IL-10、IL-12、IL-18及IL-21)、集落刺激因子(例如顆粒球集落刺激因子(G-CSF)及顆粒球巨噬細胞集落刺激因子(GM-CSF))、干擾素(例如干擾素-α、干擾素-β及干擾素-γ)、命名為「S1因子」之幹細胞生長因子、紅血球生成素、血小板生成素或彼等之組合。
在一些實施態樣中,劑部份係顯影劑(例如螢光團或螯合劑),諸如螢光素、玫瑰紅、鑭系元素磷光體及彼等之衍生物或鍵合至螯合劑之放射性同位素。螢光團之實例包括但不限於螢光素異硫氰酸酯(FITC)(例如5-FITC)、螢光素胺基磷酸酯(fluorescein amidite) (FAM)(例如5-FAM)、伊紅素、羧基螢光素、紅螢素(erythrosine)、Alexa Fluor®
(例如Alexa 350、405、430、488、500、514、532、546、555、568、594、610、633、647、660、680、700或750)、羧基四甲基玫瑰紅(TAMRA)(例如5,-TAMRA)、四甲基玫瑰紅(TMR)及磺基玫瑰紅(SR)(例如SR101)。螯合劑之實例包括但不限於1,4,7,10-四氮雜環十二烷-N,N',N'',N'''-四乙酸(DOTA)、1,4,7-三氮雜環壬烷-1,4,7-三乙酸(NOTA)、1,4,7-三氮雜環壬烷、1-戊二酸-4,7-乙酸(去鐵胺)、二伸乙三胺五乙酸(DTPA)及1,2-雙(鄰胺基苯氧基)乙烷-N,N,N',N'-四乙酸) (BAPTA)。
螢光團之實例包括但不限於螢光素異硫氰酸酯(FITC)(例如5-FITC)、螢光素胺基磷酸酯(fluorescein amidite)(FAM)(例如5-FAM)、伊紅素、羧基螢光素、紅螢素(erythrosine)、Alexa Fluor®
(例如Alexa 350、405、430、488、500、514、532、546、555、568、594、610、633、647、660、680、700或750)、羧基四甲基玫瑰紅(TAMRA)(例如5,-TAMRA)、四甲基玫瑰紅(TMR)及磺基玫瑰紅(SR)(例如SR101)。
在一些實施態樣中,治療性或診斷性放射性同位素或其他標記(例如PET或SPECT標記)可被納入與此處所述之CD123抗體或抗原結合片段共軛之劑中。放射性同位素或其他標記之實例包括但不限於3
H、11
C、13
N、14
C、15
N、15
O、35
S、18
F、32
P、33
P、47
Sc、51
Cr、57
Co、58
Co、59
Fe、62
Cu、64
Cu、67
Cu、67
Ga、68
Ga、75
Se、76
Br、77
Br、86
Y、89
Zr、90
Y、94
Tc、95
Ru、97
Ru、99
Tc、103
Ru、105
Rh、105
Ru、107
Hg、109
Pd、111
Ag、111
In、113
In、121
Te、122
Te、123
I、124
I、125
I、125
Te、126
I、131
I、131
In、133
I、142
Pr、143
Pr、153
Pb、153
Sm、161
Tb、165
Tm、166
Dy、166
H、167
Tm、168
Tm、169
Yb、177
Lu、186
Re、188
Re、189
Re、197
Pt、198
Au、199
Au、201
Tl、203
Hg、211
At、212
Bi、212
Pb、213
Bi、223
Ra、224
Ac或225
Ac。
在一些實施態樣中,該劑係治療性蛋白質,包括但不限於毒素、荷爾蒙、酶及生長因子。
毒素蛋白質(或多肽)之實例包括但不限於白喉毒素(例如白喉毒素A鏈)、假單胞菌外毒素及內毒素、蓖麻毒蛋白(ricin)(例如蓖麻毒蛋白A鏈)、相思豆毒素(abrin)(例如相思豆毒素A鏈)、莫迪素(modeccin)(例如莫迪素A鏈)、α-次黃嘌呤(sarcin)、油桐(Aleurites fordii)蛋白質、石竹素(dianthin)蛋白質、核糖核酸酶(RNase)、DNA酶I、葡萄球菌腸毒素A、商陸(pokeweed)抗病毒蛋白、白樹毒素(gelonin)、白喉毒素、美洲商陸(Phytolaca americana)蛋白質(PAPI、PAPII及PAP-S)、苦瓜(momordica charantia)抑制劑、瀉果素(curcin)、巴豆素(crotin)、肥皂草(Sapaonaria officinalis)抑制劑、絲裂膠素(mitogellin)、局限曲菌素(restrictocin)、酚黴素(phenomycin)、伊諾黴素(enomycin)、新月毒素(tricothecene)、抑制劑胱胺酸結(ICK)肽(例如角毒素(ceratotoxin))及芋螺毒素(conotoxin)(例如KIIIA或SmIIIa)。
在一些實施態樣中,該劑係生物相容性聚合物。此處所述之CD123抗體或抗原結合片段可與生物相容性聚合物共軛以增加血清半衰期及生物活性及/或延長體內半衰期。生物相容性聚合物之實例包括水溶性聚合物,諸如聚乙二醇(PEG)或彼之衍生物及含有兩性離子之生物相容性聚合物(例如含有磷醯膽鹼之聚合物)。
在一些實施態樣中,該劑係寡核苷酸,諸如反義寡核苷酸。
在另一態樣中,本發明提供如此處所述之抗體之共軛體,其中該共軛體包含下式:抗體-(含有醯基供體麩醯胺酸之標籤)-(連接子)-(細胞毒性劑),其中該含有醯基供體麩醯胺酸之標籤係經工程改造於抗體之特定位置(例如重鏈或輕鏈之羧基端、在抗體重鏈之殘基T135之後或另一位點),其中該標籤係與連接子共軛(例如含有一或多個反應性胺(例如一級胺NH2
)之連接子)且其中該連接子係與細胞毒性劑(例如MMAD或其他耳抑素諸如0101、0131或3377)共軛。
含有一或多個反應性胺之連接子之實例包括但不限於:Ac-Lys-Gly(乙醯基-離胺酸-甘胺酸)、胺基己酸、Ac-Lys-β-Ala(乙醯基-離胺酸-β-丙胺酸)、胺基-PEG2(聚乙二醇)-C2、胺基-PEG3-C2、胺基-PEG6-C2(或胺基PEG6-丙醯基)、Ac-Lys-Val-Cit-PABC(乙醯基-離胺酸-纈胺酸-瓜胺酸-對胺基苄氧羰基)、胺基-PEG6-C2-Val-Cit-PABC、胺基己醯基-Val-Cit-PABC、[(3R,5R)-1-{3-[2-(2-胺基乙氧基)乙氧基]丙醯基}哌啶-3,5-二基]雙-Val-Cit-PABC、[(3S,5S)-1-{3-[2-(2-胺基乙氧基)乙氧基]丙醯基}哌啶-3,5-二基]雙-Val-Cit-PABC、腐胺或Ac-Lys-腐胺。
在一些實施態樣中,(連接子)-(細胞毒性劑)係N2
-乙醯基-L-離胺醯基-L-纈胺醯基-N5
-胺甲醯基-N-[4-({[(2-{[({(8S)-8-(氯甲基)-6-[(3-{[(1S)-1-(氯甲基)-8-甲基-5-(膦醯氧基(phosphonooxy))-1,6-二氫吡咯并[3,2-e]吲哚-3(2H)-基]羰基}雙環[1.1.1]戊-1-基)羰基]-1-甲基-3,6,7,8-四氫吡咯并[3,2-e]吲哚-4-基}氧基)羰基](甲基)胺基}乙基)(甲基)胺甲醯基]氧基}甲基)苯基]-L-鳥胺酸醯胺(分子式C63H82Cl2N13O15P),其具有下列結構:
在一些實施態樣中,(連接子)-(細胞毒性劑)係C63H82Cl2N13O15P之三氟乙酸鹽形式,其具有下列結構:
上述三氟乙酸鹽形式之式為C63H82Cl2N13O15P.
C2HF3O2。
在一些實施態樣中,ADC係1)抗體-LLQG (SEQ ID NO: 78)-Ac-Lys-Val-Cit-PABC-CPI-8314。在一些實施態樣中,含有醯基供體麩醯胺酸之標籤包含例如LLQG (SEQ ID NO: 78),其取代抗體重鏈中之胺基酸殘基E294至N297。在一些實施態樣中,ADC包含位置K222之胺基酸修飾(在絞鏈中)。在一些實施態樣中,修飾係K222R。抗體之實例包括但不限於h18G3、18G3、h18G3、16D6、h16D6、3D1及20D7。
在一些實施態樣中,本發明包含組成物(包括醫藥組成物),該組成物包含此處所述之抗體或ADC或藉由此處所述之方法產製且具有此處所述之特徵之抗體或ADC。如本文中所使用,組成物包含一或多種與CD123結合之抗體或ADC。該等組成物可進一步包含適當之賦形劑,諸如醫藥上可接受之賦形劑,包括該領域眾所周知之緩衝劑。
使用CD123抗體及其ADC之方法
本發明之抗體及ADC可用於許多應用,包括但不限於治療性處理方法及診斷性處理方法。
在一態樣中,本發明提供一種治療與個體之CD123表現有關之病症之方法。在一些實施態樣中,該治療與個體之CD123表現有關之病症之方法包含向需要治療之個體投予有效量之組成物(例如醫藥組成物),該組成物包含如此處所述之CD123抗體或CD123 ADC。與CD123表現有關之病症包括但不限於不正常之CD123表現、經改變或異常之CD123表現、表現CD123之惡性細胞及增生性疾病(例如癌症)或自體免疫疾病。
因此,在一些實施態樣中,提供一種治療個體之癌症之方法,該方法包含向需要治療之個體投予有效量之組成物,該組成物包含如此處所述之CD123抗體或CD123 ADC。如本文中所使用,癌症可為例如但不限於:多發性骨髓瘤、惡性漿細胞腫瘤、霍奇金氏淋巴瘤(Hodgkin’s lymphoma)、結節性淋巴細胞為主型霍奇金氏淋巴瘤、卡勒氏病(Kahler’s disease)及骨髓瘤病、漿細胞白血病、漿細胞瘤、B細胞前淋巴細胞白血病、髮樣細胞白血病(HCL)、B細胞非霍奇金氏(non-Hodgkin’s)淋巴瘤(NHL)、急性骨髓性白血病(AML)、慢性淋巴球性白血病(CLL)、急性淋巴球性白血病(ALL, B-ALL)、慢性骨髓性白血病(CML)、濾泡性淋巴瘤、伯基特氏淋巴瘤(Burkitt’s lymphoma)、邊緣區淋巴瘤、外套細胞淋巴瘤、大細胞淋巴瘤、前體B淋巴母細胞淋巴瘤、母細胞性漿細胞樣樹突細胞腫瘤(BPDCN)、骨髓性白血病、瓦登斯特隆巨球蛋白血症(Waldenstrom’s macroglobulienemia)、瀰漫性大型B細胞淋巴瘤、濾泡性淋巴瘤、邊緣區淋巴瘤、黏膜相關性淋巴組織淋巴瘤、小細胞淋巴球性淋巴瘤、外套細胞淋巴瘤、伯基特氏淋巴瘤(Burkitt lymphoma)、原發性縱隔(胸腺)大型B細胞淋巴瘤、淋巴漿細胞淋巴瘤、瓦登斯特隆巨球蛋白血症(Waldenström macroglobulinemia)、結內邊緣區B細胞淋巴瘤、脾邊緣區淋巴瘤、血管內大型B細胞淋巴瘤、原發性滲出性淋巴瘤、淋巴瘤樣肉芽腫病、富含T細胞/組織細胞大型B細胞淋巴瘤、原發性中樞神經系統淋巴瘤、原發性皮膚瀰漫性大型B細胞淋巴瘤(腿型)、老年人之EBV陽性瀰漫性大型B細胞淋巴瘤、發炎相關性瀰漫性大型B細胞淋巴瘤、血管內大型B細胞淋巴瘤、ALK陽性大型B細胞淋巴瘤、漿母細胞淋巴瘤、HHV8相關性多中心型克斯特曼病(HHV8-associated multicentric Castleman disease)產生之大型B細胞淋巴瘤、特徵介於瀰漫性大型B細胞淋巴瘤與伯基特氏淋巴瘤之間的未分類B細胞淋巴瘤、特徵介於瀰漫性大型B細胞淋巴瘤與典型霍奇金氏淋巴瘤之間的未分類B細胞淋巴瘤及其他B細胞相關性淋巴瘤。在一些實施態樣中,癌症係AML、B-ALL、BPDCN、NHL或HCL。
在一些實施態樣中,提供一種抑制具有表現CD123之惡性細胞的個體之腫瘤生長或進展之方法,該方法包含向需要抑制之個體投予有效量之組成物,該組成物包含如此處所述之CD123抗體或CD123 ADC。在其他實施態樣中,本發明提供一種抑制個體之表現CD123之轉移細胞之方法,該方法包含向需要抑制之個體投予有效量之組成物,該組成物包含如此處所述之CD123抗體或CD123 ADC。在其他實施態樣中,本發明提供一種誘導個體之惡性細胞腫瘤消退之方法,該方法包含向需要誘導之個體投予有效量之組成物,該組成物包含如此處所述之CD123抗體或CD123 ADC。
在一些實施態樣中,提供一種治療個體之自體免疫病症之方法,該方法包含向需要治療之個體投予有效量之組成物,該組成物包含如此處所述之CD123抗體或CD123 ADC。
如本文中所使用,自體免疫病症包括但不限於:全身性紅斑性狼瘡、類風濕性關節炎、糖尿病(第一型)、多發性硬化症、Addison氏病、乳糜瀉、皮肌炎、Graves氏病、橋本氏甲狀腺炎、橋本氏腦病變、重症肌無力、惡性貧血、反應性關節炎、Sjogren氏症候群、急性瀰漫性腦脊髓炎、γ球蛋白缺乏症、肌萎縮性脊髓側索硬化、關節黏連性脊椎炎、抗磷脂症候群、抗合成酶症候群、異位性過敏、異位性皮膚炎、自體免疫性腸病變、自體免疫溶血性貧血、自體免疫性肝炎、自體免疫性內耳疾病、自體免疫性淋巴細胞增生症候群、自體免疫性週邊神經病、自體免疫性胰臟炎、自體免疫性多內分泌腺病症候群、自體免疫性黃體酮皮膚炎、自體免疫性血小板減少紫瘢病、自體免疫性蕁麻疹、自體免疫性葡萄膜炎、Bechet氏病、Castleman氏病、冷凝集素症、克隆氏病、皮肌炎、嗜酸性筋膜炎、胃腸道類天皰瘡、Goodpasture氏症候群、Guillain-Barré症候群、化膿性汗腺炎、自發性血小板減少紫瘢病、猝睡症、尋常天皰瘡、惡性貧血、多發性肌炎、原發性膽道性肝硬化、復發性多軟骨炎、風濕熱、顳動脈炎、橫貫性脊髓炎、潰瘍性結腸炎、未分化結締組織疾病、血管炎及Wegener氏肉芽腫病。
在另一態樣中,本發明提供有效量的組成物(例如醫藥組成物),該組成物包含用於治療有該治療需要之個體之與CD123表現相關之病症(例如癌症或自體免疫疾病)之如本文所述之CD123抗體或CD123 ADC。在一些實施態樣中,提供有效量的組成物(例如醫藥組成物),該組成物包含用於抑制具有表現CD123之惡性細胞的個體之腫瘤生長或進展之如本文所述之CD123抗體或CD123 ADC。在一些實施態樣中,提供有效量的組成物(例如醫藥組成物),該組成物包含用於抑制有該抑制需要之個體之表現CD123之惡性細胞的轉移之如本文所述之CD123抗體或CD123 ADC。在一些實施態樣中,提供有效量的組成物(例如醫藥組成物),該組成物包含用於誘導具有表現CD123之惡性細胞的個體之腫瘤消退之如本文所述之CD123抗體或CD123 ADC。
在另一態樣中,本發明提供用於治療有該治療需要之個體之與CD123表現相關之病症(例如癌症或自體免疫疾病)之如本文所述之CD123抗體或CD123 ADC。在一些實施態樣中,提供用於抑制具有表現CD123之惡性細胞的個體之腫瘤生長或進展之如本文所述之CD123抗體或CD123 ADC。在一些實施態樣中,提供用於抑制有該抑制需要之個體之表現CD123之惡性細胞的轉移之如本文所述之CD123抗體或CD123 ADC。在一些實施態樣中,提供用於誘導具有表現CD123之惡性細胞的個體之腫瘤消退之如本文所述之CD123抗體或CD123 ADC。
在另一態樣中,本發明提供如本文所述之CD123抗體或CD123 ADC於製造藥物之用途,該藥物用於治療與CD123表現相關之病症(例如癌症或自體免疫疾病)。在一些實施態樣中,提供如本文所述之CD123抗體或CD123 ADC於製造藥物之用途,該藥物用於抑制腫瘤生長或進展。在一些實施態樣中,提供如本文所述之CD123抗體或CD123 ADC於製造藥物之用途,該藥物用於抑制表現CD123之惡性細胞的轉移。在一些實施態樣中,提供如本文所述之CD123抗體或CD123 ADC於製造藥物之用途,該藥物用於誘導腫瘤消退。
在另一態樣中,本發明提供一種檢測、診斷及/或監測與CD123表現有關之病症之方法。舉例來說,此處所述之CD123抗體可經可檢測之部份標記,諸如顯影劑及酶-受質標記。此處所述之抗體亦可被用於體內診斷性試驗,諸如體內顯影(例如PET或SPECT)或染色試劑。
在一些實施態樣中,此處描述之方法另包含以其他形式之療法治療個體之步驟。在一些實施態樣中,該其他形式之療法係其他抗癌療法,包括但不限於化學療法、放射療法、手術、荷爾蒙療法及/或其他免疫療法。
在一些實施態樣中,該其他形式之療法包含投予一或多種除了此處所述之CD123抗體或CD123 ADC以外之治療劑。一或多種治療劑可為例如但不限於:第二抗體(例如,抗VEGF(血管內皮生長因子)抗體(例如AVASTIN®
)、抗HER2抗體(例如HERCEPTIN®
)、抗CD25抗體、抗CD33抗體、抗CD20抗體(例如RITUXAN®
)、抗黏液素樣糖蛋白抗體、抗TNF抗體、抗PD-1或PD-L1抗體及/或表皮生長因子受體(EGFR)抗體(例如ERBITUX®
))、血管生成抑制劑、細胞毒性劑(例如蒽環(例如道諾黴素、多柔比星、表柔比星、伊達比星、戊柔比星及米托蒽醌)、紫杉烷(例如太平洋紫杉醇及多西他賽)、海兔毒素、雙聯黴素、烯二炔、膠達納黴素、美坦素、嘌呤黴素、長春花生物鹼(例如長春新鹼)、拓撲異構酶抑制劑(例如依托泊苷)、微管溶素、嘧啶類似物(例如氟尿嘧啶)、含鉑劑(例如順鉑、卡鉑及奧沙利鉑)、烷化劑(例如美法侖、環磷醯胺或卡莫司汀)及半星芒體)、免疫調節劑(例如潑尼松)、消炎劑(例如地塞米松)、芳香酶抑制劑(例如阿那曲唑、依西美坦、來曲唑、伏氯唑、福美坦或睪內酯)、蛋白酶體抑制劑(例如硼替佐米諸如VELCADE®
([(1R)-3-甲基-1-[[(2S)-1-側氧基-3-苯基-2-[(吡基羰基)胺基]丙基]胺基]丁基]硼酸)及其他劑諸如它莫西芬。
例如,在一些實施態樣中,提供一種治療AML之方法,該方法包含向需要治療之個體投予有效量的組成物,該組成物包含如本文所述之CD123抗體或CD123 ADC及一種其他治療劑諸如化學治療劑或沙利度胺或其衍生物(例如,來那度胺(lenalidomide))。在一些實施態樣中,一種其他治療劑選自由下列所組成之群組:硼替佐米(例如VELCADE®
)、美法侖、潑尼松、多柔比星、來那度胺、沙利度胺、潑尼松、卡莫司汀、依托泊苷、順鉑、環磷醯胺及長春新鹼。在一些實施態樣中,其他治療劑係硼替佐米(例如VELCADE®
)、美法侖或潑尼松。在一些實施態樣中,個體復發或為先前AML療法所難治。
CD123抗體或CD123 ADC可經由任何適當之途徑對個體投予。該領域之技藝人士應了解的是,此處所描述之實例不應意圖限制而是可用技術之示例。因此,在一些實施態樣中,CD123抗體或CD123 ADC係根據已知方法對個體投予,諸如靜脈內投予例如快速濃注或在一段時間內連續輸注、肌肉內、腹腔內、腦脊髓腔內、顱內、經皮、皮下、關節內、舌下、滑膜內、經噴入、脊椎鞘內、經口、吸入或局部途徑。投予可為系統性例如靜脈內投予或局部投予。自商業途徑獲得之液體調製劑噴霧器(包括噴射噴霧器及超音波噴霧器)可用於投予。液體調製劑可經直接噴霧,冷凍乾燥之粉末可在重構後經噴霧投予。替代地,CD123抗體或CD123 ADC可利用氟碳調製劑及定量吸入器加以氣霧化或以經冷凍乾燥及磨細粉末之形式吸入。
在一實施態樣中,CD123抗體或CD123 ADC係經定點或靶向性局部遞送技術投予。定點或靶向性局部遞送技術之實例包括各種Trop抗體或CD123 ADC之植入式貯劑來源或局部遞送導管,諸如輸注導管、留置導管、或針頭導管、合成性移植物、外膜層包覆、分流器及支架或其他植入式裝置、定點載劑、直接注射或直接施用。見例如PCT公開號WO 00/53211及美國專利第5,981,568號。
CD123抗體或CD123 ADC之多種調製劑可被用於投予。在一些實施態樣中,CD123抗體或CD123 ADC可被用於單獨投予。在一些實施態樣中,CD123抗體(或CD123 ADC)及醫藥上可接受之賦形劑可為多種調製劑。醫藥上可接受之賦形劑係為該領域所知,且係有助於投予藥理有效物質之相對惰性物質。舉例來說,賦形劑可提供外形或稠度,或作為稀釋劑。適當之賦形劑包括但不限於安定劑、潤濕劑、乳化劑、用於改變滲透性之鹽類、包封劑、緩衝劑及皮膚穿透增進劑。用於腸胃外及非腸胃外藥物遞送之賦形劑以及調製劑係闡述於Remington, The Science and Practice of Pharmacy, 21st Ed., Mack Publishing, 2005。
在一些實施態樣中,該等劑係經調製為供注射投予(例如腹膜內、靜脈、皮下、肌肉內等)。因此,該等劑可與醫藥上可接受之載劑(諸如鹽水、林格(Ringer)氏液、葡萄糖溶液及該類似物)組合。特定給藥方案(即劑量、時間及重複性)將依特定個體及該個體之醫學病史而定。
此處所述之CD123抗體或CD123 ADC可利用任何適當之方法投予,包括注射(例如腹腔注射、靜脈注射、皮下注射、肌肉注射等)。CD123抗體或CD123 ADC亦可經此處所述之吸入投予。通常在投予CD123抗體及CD123 ADC時,初始候選劑量可為約2 mg/kg。就本發明之目的而言,典型之每日劑量可根據上述因子介於自約3微克/公斤至30微克/公斤、至300微克/公斤、至3毫克/公斤、至30毫克/公斤、至100毫克/公斤或至100毫克/公斤以上之任何範圍內。舉例來說,可使用約1毫克/公斤、約2.5毫克/公斤、約5毫克/公斤、約10毫克/公斤及約25毫克/公斤之劑量。視狀況而在數天或更久期間內重複投予時,該治療係持續進行直到發生所欲之症狀抑制或達成足夠之治療水準,例如抑制或延緩腫瘤生長/惡化或癌細胞轉移。一種例示性給藥方案包含投予初始劑量約2毫克/公斤之CD123抗體或CD123 ADC,隨後每週約1毫克/公斤之維持劑量,或隨後隔週約1毫克/公斤之維持劑量。另一種例示性給藥方案包含投予初始劑量每週或每三週約0.21、約0.5或約0.8 mg/kg。其他示範性給藥方案包含投予漸增之劑量(例如初始劑量1 mg/kg,逐漸增加至每周或更長期間給予一或多個更高之劑量)。其他給藥方案亦可根據醫師所希望達成之藥物動力學衰減模式使用。舉例來說,在一些實施態樣中,每週投藥一至四次係經考慮。在其他實施態樣中,每月投藥一次或隔月或每三個月投藥一次係經考慮。此治療之進展可藉由習知技術及檢測加以輕易地監測。給藥方案(包括所使用之CD123抗體或CD123 ADC)可隨時間而異。
就本發明之目的而言,CD123抗體或CD123 ADC之適當劑量將依所採用之CD123抗體或CD123 ADC(或彼等之組成物)、所欲治療之症狀的類型及嚴重性、該劑是否以治療性目的投予、先前治療、該個體之臨床病史及對該劑之反應、該個體清除該經投予之劑之速率及主治醫師之考量而定。通常醫師將投予CD123抗體或CD123 ADC直到達到可完成所欲結果之劑量。劑量及/或頻率可依治療療程而異。經驗性考量諸如半衰期通常將影響該劑量之決定。舉例來說,可相容於人免疫系統之抗體諸如人化抗體或全人抗體可被用以延長該抗體之半衰期及防止該抗體被宿主之免疫系統攻擊。投予頻率可在療程當中決定及調整,通常但不一定根據症狀之治療及/或抑制及/或改善及/或延緩,例如腫瘤生長之抑制或延緩等。替代地,CD123抗體或CD123 ADC之持續性連續釋放調製劑可為適當。各種用於達成持續釋放之調製劑及裝置係該領域所知。
在一實施態樣中,在已經接受過一或多次CD123抗體或其CD123 ADC投予之個體中,該CD123抗體或CD123 ADC之劑量可能憑經驗決定。給予個體漸增劑量之CD123抗體或CD123拮抗劑。為了評估療效,可追蹤疾病之指標。
根據本發明之方法投予CD123抗體或CD123 ADC可為連續性或間歇性,依例如接受者之生理狀況、該投藥之目的係治療性或預防性及該領域之技藝人士所知之其他因素而定。CD123抗體或CD123 ADC之投予可為實質上連續一段預先決定之時間,或可為一系列間隔劑量。
在一些實施態樣中,可能存在超過一種CD123抗體或CD123 ADC。可能存在至少一種、至少兩種、至少三種、至少四種、至少五種不同或更多種CD123抗體或CD123 ADC。通常,該等CD123抗體或CD123 ADC可能具有不會互相不良影響之互補活性。舉例來說,一或多種下列CD123抗體可被使用:針對CD123上之一種表位之第一CD123抗體及針對CD123上之不同表位之第二CD123抗體。
本發明所使用之CD123抗體或CD123 ADC之治療性調製劑係藉由混合具有所欲純度之抗體與可任意選擇之醫藥上可接受之載劑、賦形劑或安定劑(Remington, The Science and Practice of Pharmacy 21st Ed. Mack Publishing, 2005),以製備成供儲存之冷凍乾燥調製劑或水性溶液之形式。可接受之載劑、賦形劑或穩定劑在所採用之劑量及濃度下對接受者不具毒性,可能包括例如緩衝劑諸如磷酸鹽、檸檬酸鹽及其他有機酸;鹽諸如氯化鈉;抗氧化劑包括抗壞血酸及甲硫胺酸;保存劑(諸如十八基二甲基苄基氯化銨;氯化六烴季銨;苯紮氯銨、苄索氯銨;苯酚、丁醇或苄醇;烷基對羥基苯甲酸酯諸如甲基或丙基對羥基苯甲酸酯;兒茶酚;間苯二酚;環己醇;3-戊醇;及間甲酚);低分子量(小於約10個殘基)多肽;蛋白質諸如血清白蛋白、明膠或免疫球蛋白;親水性聚合物諸如聚乙烯吡咯啶酮;胺基酸諸如甘胺酸、麩醯胺酸、天冬醯胺酸、組胺酸、精胺酸或離胺酸;單醣、雙醣及其他碳水化合物包括葡萄糖、甘露糖或糊精;螯合劑諸如EDTA;糖諸如蔗糖、甘露醇、海藻糖或山梨醇;鹽形成反離子諸如鈉;金屬錯合物(例如Zn-蛋白質錯合物);及/或非離子界面活性劑諸如TWEENTM
、PLURONICSTM
或聚乙二醇(PEG)。
含有CD123抗體或CD123 ADC之脂質體係藉由該領域已知之方法製備,諸如Epstein, et al., Proc. Natl. Acad. Sci. USA 82:3688, 1985、Hwang, et al., Proc. Natl Acad. Sci. USA 77:4030, 1980及美國專利第4,485,045及4,544,545號所述。循環時間延長之脂質體係揭露於美國專利第5,013,556號。特別有用之脂質體可利用逆相蒸發方法以包含磷脂醯膽鹼、膽固醇及PEG-衍生性磷脂醯乙醇胺(PEG-PE)之脂質組成物產製。脂質體被擠壓通過定義孔徑大小之濾網以產生具有所欲直徑之脂質體。
該活性成分亦可被包封於藉由例如凝聚技術或藉由界面聚合化所製備之微膠囊中,例如分別於羥甲基纖維素或明膠微膠囊及聚-(異丁烯酸甲酯)微膠囊中、於膠體藥物遞送系統中(例如脂質體、白蛋白微球、微乳化液、奈米微粒及奈米微囊)或於巨乳化液中。該等技術係揭示於Remington, The Science and Practice of Pharmacy, 21st Ed., Mack Publishing, 2005。
持續釋放性製劑可被製備。持續釋放製劑之適當實例包括含有該抗體之固相疏水性聚合物之半透性基體,該基體係呈形狀物件之形式(例如膜或微膠囊)。持續釋放基質之實例包括聚酯、水凝膠(例如聚(2-羥乙基-甲基丙烯酸酯)或聚乙烯醇)、聚交酯(美國專利第3,773,919號)、L-麩胺酸及7乙基-L-麩胺酸鹽之共聚物、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-乙醇酸共聚物及柳菩林(leuprolide acetate)所組成之注射型微球)、蔗糖乙酸異丁酸酯及聚-D-(-)-3-羥丁酸。
欲用於體內投予之調製劑必須為無菌。此可輕易地藉由例如無菌過濾膜之過濾達成。治療性CD123抗體或CD123 ADC組成物通常被置放於具有無菌接口之容器中,例如具有可被皮下注射針穿刺之塞子的靜脈溶液袋或小瓶。
本發明之組成物可呈單位劑量形式,諸如錠劑、丸劑、膠囊、粉劑、顆粒劑、溶液、懸浮液或栓劑,以供口服、腸胃外或經直腸投予,或藉由吸入或噴入投予。
為了製備固體組成物諸如錠劑,主要活性成份係與醫藥載劑(例如習用之製錠成分諸如玉米澱粉、乳糖、蔗糖、山梨醇、滑石、硬脂酸、硬脂酸鎂、磷酸二鈣或膠)及其他醫藥稀釋劑(例如水)混合,以形成含有本發明之化合物或彼之非毒性醫藥上可接受之鹽的均質混合物之固體預調製組成物。當提到這些均質之預調製組成物,表示該活性成分係均勻分散於該組成物內,以使該組成物可被輕易地細分為同樣有效之單位劑量形式諸如錠劑、丸劑及膠囊。此固體預調製組成物接著被細分為上述類型之單位劑量形式,其含有自0.1至約500 mg之本發明之活性成份。該新穎組成物之錠劑或丸劑可經包覆或經其他方式複合以提供具有長效優點之劑型。舉例來說,該錠劑或丸劑可包含內部劑量及外部劑量成分,後者係呈包封前者之形式。該兩種成分可以腸溶層分開,該腸溶層用來抵抗胃中之崩解,以使該內部成分完整通過到達十二指腸或被延遲釋放。多種物質可被用於該腸溶層或包覆層,該等物質包括多種聚合酸及聚合酸與諸如蟲膠、鯨臘醇及醋酸纖維素之物質之混合物。
適當之表面活性劑包括特別是非離子性劑,諸如聚氧乙烯去水山梨醇(例如TweenTM
20、40、60、80或85)及其他去水山梨醇(例如SpanTM
20、40、60、80或85)。含有表面活性劑之組成物將方便地包含自0.05至5%之表面活性劑,且可介於0.1至2.5%。將了解若需要的話其他成分可被添加,例如甘露醇或其他醫藥上可接受之載具。
適當之乳液可利用自商業途徑獲得之脂質乳液製備,如IntralipidTM
、LiposynTM
、InfonutrolTM
、LipofundinTM
及LipiphysanTM
。該活性成分可被溶解於預先混合之乳液組成物中,或者可被溶解於油中(例如大豆油、紅花籽油、棉花籽油、芝麻油、玉米油或杏仁油),再與磷脂(例如卵磷脂、大豆磷脂或大豆卵磷脂)及水混合以形成乳液。將瞭解的是可添加其他成分例如甘油或葡萄糖以調整該乳液之張力。適當之乳液通常將含有最高20%例如介於5至20%之油。該脂肪乳液可包含介於0.1至1.0 μm,特別是0.1至0.5 μm之脂肪液滴,且具有介於5.5至8.0之pH。
乳液組成物可為該些藉由混合CD123抗體或CD123 ADC與IntralipidTM
或彼之成份(大豆油、卵磷脂、甘油及水)所製備者。
用於吸入或噴入之組成物包括在醫藥上可接受之水性或有機溶劑中之溶液及懸浮液,或彼等之混合物,以及粉末。該液體或固體組成物可能包含如前述之適當之醫藥上可接受之賦形劑。在一些實施態樣中,該組成物係以經口或經鼻呼吸途徑投予以提供局部或系統性效應。在較佳無菌之醫藥上可接受之溶劑中之組成物可藉由使用氣體加以噴霧化。經噴霧化之溶液可從噴霧裝置直接吸入,或該霧化裝置可與面罩、帷幕或間歇性正壓呼吸器連接。溶液、懸浮液或粉末組成物可自裝置較佳地經口或經鼻投予,該裝置以適當方式遞送調製劑。
組成物
用於本發明之方法中之組成物包含有效量之此處所討論之CD123抗體或CD123 ADC。該等組成物之實例以及如何調製也被描述於較早段落及以下。在一些實施態樣中,該組成物包含一或多種CD123抗體或CD123 ADC。例如,CD123抗體辨識人CD123。在一些實施態樣中,CD123抗體係人抗體、人化抗體或嵌合性抗體。在一些實施態樣中,CD123抗體包含能引發所欲之免疫反應(諸如抗體媒介性溶解或ADCC)之恆定區。在其他實施態樣中,CD123抗體包含不引發非所需或非所欲之免疫反應(諸如抗體媒介性溶解或ADCC)之恆定區。在其他實施態樣中,CD123抗體包含抗體之一或多個CDR(諸如一、二、三、四、五或在一些實施態樣中所有六個CDR)。
應了解該等組成物可包含超過一種CD123抗體或CD123 ADC(例如辨識CD123之不同表位之CD123抗體之混合物)。其他例示性組成物包含超過一種辨識相同表位之CD123抗體或CD123 ADC,或與CD123(例如人CD123)之不同表位結合之不同物種的CD123抗體或CD123 ADC。
在一些實施態樣中,CD123抗體可與一或多種額外治療劑之投予組合投予。這些包括但不限於投予下列:化學治療劑、疫苗、基於CAR-T細胞之療法、放射療法、細胞介素療法、疫苗、CD123雙專一性抗體、其他免疫抑制途徑抑制劑、血管生成抑制劑、T細胞活化劑、代謝途徑抑制劑、mTOR抑制劑、腺苷途徑抑制劑、酪胺酸激酶抑制劑包括但不限於英立達(inlyta)、ALK抑制劑及舒尼替尼、BRAF抑制劑、表觀遺傳修飾劑、IDO1抑制劑、Treg細胞及/或骨髓來源抑制細胞之抑制劑或耗盡劑、JAK抑制劑、STAT抑制劑、週期蛋白依賴性激酶抑制劑、生物治療劑(包括但不限於抗VEGF、VEGFR、EGFR、Her2/neu、其他生長因子受體、CD20、CD40、CD-40L、CTLA-4、OX-40、4-1BB、CD123、PD-L1、TIGIT及ICOS之抗體)、免疫原性劑(例如減弱的癌細胞、腫瘤抗原、抗原呈現細胞諸如以腫瘤衍生抗原或核酸刺激之樹突細胞、免疫刺激細胞介素(例如IL-2、IFNα2、GM-CSF)及經編碼免疫刺激細胞介素諸如但不限於GM-CSF之基因轉染之細胞)。化學治療劑之實例包括烷化劑諸如塞替派(thiotepa)及環磷醯胺;烷基磺酸酯諸如白消安(busulfan)、英丙舒凡(improsulfan)及哌泊舒凡(piposulfan);氮丙啶類諸如苯佐替派(benzodopa)、卡波醌(carboquone)、美妥替派(meturedopa)和烏瑞替派(uredopa);乙烯亞胺和甲基蜜胺,包括六甲蜜胺、三伸乙基蜜胺、三伸乙基磷醯胺、三伸乙基硫代磷醯胺及三羥甲基蜜胺;番荔枝內酯(acetogenin)(尤其是布拉他辛(bullatacin)及布拉他辛酮(bullatacinone));喜樹鹼(包括合成的類似物托泊替康);苔蘚蟲素(bryostatin);海綿多聚乙醯(callystatin);CC-1065(包括其合成類似物阿多來新(adozelesin)、卡折來新(carzelesin)及比折來新(bizelesin));念珠藻素(尤其是念珠藻素1及念珠藻素8);海兔毒素;雙聯黴素(包括合成的類似物KW-2189及CBI-TMI);艾榴塞洛素(eleutherobin);水鬼蕉鹼(pancratistatin);匍枝珊瑚醇(sarcodictyin);海綿素(spongistatin);氮芥諸如苯丁酸氮芥、萘氮芥(chlornaphazine)、氯磷醯胺(cholophosphamide)、雌莫司汀、依弗醯胺、甲基二(氯乙基)胺、甲基二(氯乙基)胺氧化物鹽酸鹽、美法侖、新氮芥(novembichin)、膽甾醇苯乙酸氮芥(phenesterine)、松龍苯芥(prednimustine)、氯乙環磷醯胺(trofosfamide)、尿嘧啶氮芥;亞硝基脲(nitrosourea)諸如卡莫司汀、吡葡亞硝脲(chlorozotocin)、福莫司汀、洛莫司汀、尼氮芥(nimustine)、雷莫司汀;抗生素諸如烯二炔抗生素(例如卡利奇黴素,特別是卡利奇黴素γ1I及卡利奇黴素phiI1,見例如Agnew, Chem. Intl. Ed. Engl., 33:183-186 (1994);達內黴素(dynemicin),包括達內黴素A;雙膦酸鹽類,諸如氯屈膦酸鹽(clodronate);埃斯培拉黴素(esperamicin);以及新抑癌素(neocarzinostatin)發色團及相關色素蛋白烯二炔抗生素發色團)、阿克拉黴素(aclacinomysin)、放線菌素、安曲黴素(authramycin)、氮絲胺酸、博萊黴素、放線菌素C、卡拉星(carabicin)、洋紅黴素(caminomycin)、嗜癌素(carzinophilin)、色黴素(chromomycin)、放線菌素D、道諾黴素、地托比星、6-重氮基-5-側氧基-L-正白胺酸、多柔比星(包括N-嗎啉基-多柔比星、氰基N-嗎啉基-多柔比星、2-吡咯啉基-多柔比星及去氧多柔比星)、聚乙二醇化脂質體多柔比星、表柔比星、依索比星(esorubicin)、伊達比星、麻西羅黴素(marcellomycin)、絲裂黴素諸如絲裂黴素C、麥考酚酸、諾加黴素(nogalamycin)、橄欖黴素(olivomycin)、培洛黴素(peplomycin)、波弗黴素(potfiromycin)、嘌呤黴素、三鐵阿黴素(quelamycin)、羅多比星、鏈黑黴素、鏈佐星、殺結核菌素(tubercidin)、烏苯美司(ubenimex)、淨司他丁、佐柔比星;抗代謝物諸如甲胺蝶呤及5-氟尿嘧啶(5-FU);葉酸類似物諸如二甲葉酸(denopterin)、甲胺蝶呤、蝶羅呤、三甲喋呤;嘌呤類似物諸如氟達拉濱、6-巰嘌呤、硫咪嘌呤、硫鳥嘌呤;嘧啶類似物諸如安西他濱(ancitabine)、阿紮胞苷、6-硫唑脲嘧啶(6-azauridine)、卡莫氟、阿糖胞苷、二去氧尿苷、去氧氟尿苷(doxifluridine)、依諾他濱(enocitabine)、氟尿苷;雄性激素諸如卡普睪酮、丙酸屈他雄酮(dromostanolone propionate)、硫雄甾醇(epitiostanol)、美雄烷、睪內酯;抗腎上腺劑諸如胺魯米特(aminoglutethimide)、米托坦(mitotane)、曲洛司坦(trilostane);葉酸補充劑諸如亞葉酸;醋葡醛內酯;醛磷醯胺糖苷(aldophosphamide glycoside);胺基酮戊酸;恩尿嘧啶(eniluracil);安吖啶;貝斯特氮芥(bestrabucil);比生群(bisantrene);依達曲沙(edatrexate);得弗伐胺(defofamine);秋水仙胺(demecolcine);地吖醌(diaziquone);艾弗尼辛(elformithine);依利醋銨(elliptinium acetate);埃博黴素(epothilone);依托格鲁(etoglucid);硝酸鎵;羥基尿素;香菇糖(lentinan);氯尼達明;類美坦素(maytansinoid)諸如美坦素及安絲菌素(ansamitocin);米托胍腙(mitoguazone);米托蒽醌(mitoxantrone);莫哌達醇(mopidamol);二胺硝吖啶(nitracrine);噴司他丁(pentostatin);蛋胺氮芥(phenamet);吡柔比星(pirarubicin);洛索蒽醌(losoxantrone);鬼臼酸(podophyllinic acid);2-乙醯肼;甲基苄肼;雷佐生(razoxane);利索新(rhizoxin);西佐喃(sizofuran);鍺螺胺(spirogermanium);細交鏈孢菌酮酸(tenuazonic acid);三亞胺醌(triaziquone);2,2',2''-三氯三乙胺;新月毒素(特別是T-2毒素、韋拉庫林A (verracurin A)、桿孢菌素A (roridin A)及安奎定(anguidine));烏拉坦(urethan);長春地辛;達卡巴嗪;甘露莫司汀;二溴甘露醇;二溴衛矛醇;哌泊溴烷(pipobroman);伽托辛(gacytosine);阿糖胞苷(「Ara-C」);環磷醯胺;塞替派;類紫杉醇(taxoid),例如太平洋紫杉醇及多西他賽(doxetaxel);苯丁酸氮芥;吉西他濱;6-硫鳥嘌呤;巰嘌呤;甲胺蝶呤;鉑類似物諸如順鉑及卡鉑;長春鹼;鉑;依托泊苷(VP-16);依弗醯胺;米托蒽醌(mitoxantrone);長春新鹼;長春瑞濱;諾安托(novantrone);替尼泊苷;依達曲沙;柔紅黴素(daunomycin);胺喋呤;截瘤達(xeloda);伊班膦酸鹽(ibandronate);CPT-11;拓撲異構酶抑制劑RFS 2000;二氟甲基鳥胺酸(DMFO);維他命A酸類諸如視黃酸;卡培他濱;及上述任一者之醫藥上可接受之鹽、酸或衍生物。亦包括可作用以調節或抑制荷爾蒙對腫瘤之作用的抗荷爾蒙劑,諸如抗雌激素劑及選擇性雌激素受體調節劑(SERM),包括例如它莫西芬、雷洛昔芬、曲洛昔芬(droloxifene)、4-羥基它莫西芬、曲沃昔芬(trioxifene)、雷洛昔芬(keoxifene)、LY117018、奧那司酮(onapristone)及托瑞米芬(toremifene) (Fareston);抑制調節腎上腺之雌激素產生之芳香酶的芳香酶抑制劑,諸如例如4(5)-咪唑、胺魯米特(aminoglutethimide)、乙酸甲地孕酮(megestrol acetate)、依西美坦(exemestane)、福美司坦(formestane)、法屈唑(fadrozole)、伏羅唑(vorozole)、來曲唑(letrozole)及阿那曲唑(anastrozole);及抗雄激素劑,諸如氟他胺(flutamide)、尼魯米特(nilutamide)、比卡魯胺(bicalutamide)、亮丙立德(leuprolide)及戈舍瑞林(goserelin);及上述任一者之醫藥上可接受之鹽、酸或衍生物。
在一些實施態樣中,CD123抗體係與一或多種靶向免疫檢查點調節劑之其他治療劑組合使用,諸如例如但不限於靶向下列之劑:CD123、PD-1、PD-L1、CTLA-4、LAG-3、B7-H3、B7-H4、B7-DC (PD-L2)、B7-H5、B7-H6、B7-H8、B7-H2、B7-1、B7-2、ICOS、ICOS-L、TIGIT、CD2、CD47、CD80、CD86、CD48、CD58、CD226、CD155、CD112、LAIR1、2B4、BTLA、CD160、TIM1、TIM-3、TIM4、VISTA (PD-H1)、OX40、OX40L、GITR、GITRL、CD70、CD27、4-1BB、4-BBL、DR3、TL1A、CD40、CD40L、CD30、CD30L、LIGHT、HVEM、SLAM (SLAMF1、CD150)、SLAMF2 (CD48)、SLAMF3 (CD229)、SLAMF4 (2B4、CD244)、SLAMF5 (CD84)、SLAMF6 (NTB-A)、SLAMCF7 (CS1)、SLAMF8 (BLAME)、SLAMF9 (CD2F)、CD28、CEACAM1 (CD66a)、CEACAM3、CEACAM4、CEACAM5、CEACAM6、CEACAM7、CEACAM8、CEACAM1-3AS CEACAM3C2、CEACAM1-15、PSG1-11、CEACAM1-4C1、CEACAM1-4S、CEACAM1-4L、IDO、TDO、CCR2、CD39–CD73–腺苷途徑(A2AR)、BTKs、TIKs、CXCR2、CCR4、CCR8、CCR5、VEGF途徑、CSF-1或先天免疫反應調節劑。在一些實施態樣中,CD123抗體係與下列組合使用:例如,抗PD-L1拮抗劑抗體諸如例如BMS-936559(MDX-1105;CD123抗體諸如例如尼沃魯單抗(nivolumab)、派姆單抗(pembrolizumab)及匹利珠單抗(pidilizumab);抗CTLA-4拮抗劑抗體諸如例如伊匹單抗(ipilimumab);抗LAG-3拮抗劑抗體諸如BMS-986016及IMP701;抗TIM-3拮抗抗體;抗B7-H3拮抗抗體諸如例如MGA271;抗VISTA拮抗抗體;抗TIGIT拮抗抗體;抗CD28拮抗抗體;抗CD80抗體;抗CD86抗體;抗B7-H4拮抗抗體;抗ICOS拮抗抗體;抗CD28拮抗抗體;先天免疫反應調節劑(例如,TLR、KIR、NKG2A)及IDO抑制劑。在一些實施態樣中,CD123抗體係與4-1BB (CD137)促效劑組合使用,諸如例如PF-05082566或BMS-663513。在一些實施態樣中,CD123抗體係與OX40促效劑組合使用,諸如例如抗OX-40促效抗體。在一些實施態樣中,CD123抗體係與GITR促效劑組合使用,諸如抗GITR促效抗體,諸如例如但不限於TRX518。在一些實施態樣中,CD123抗體係與IDO抑制劑組合使用。在一些實施態樣中,CD123抗體係與細胞介素療法組合使用,諸如例如不限IL-15、CSF-1、MCSF-1等。
在一些實施態樣中,CD123抗體係與一或多種治療抗體組合使用,諸如例如但不限於靶向CD19、CD22、CD40、CD52或CCR4之抗體。
在一些實施態樣中,CD123抗體療法可在其他劑治療之前或之後相隔數分鐘至數週進行。在其中其他劑及/或蛋白質或多核苷酸分開投予之實施態樣中,通常會確保在各次遞送之間不會超過顯著時間期間,使得本發明之劑及該組成物仍然能夠對個體發揮有利的組合效應。在這種例子中,所考慮的是可將兩種方案在彼此投予的約12至24 h內且更佳的是在約6至12 h內投予。然而在一些情況下,所欲的可能是顯著延長投予的時間期間,其中在各別投予之間經過數天(2、3、4、5、6或7)至數週(1、2、3、4、5、6、7或8)。
在一些實施態樣中,CD123抗體組成物包含第二劑,其係選自克唑替尼(crizotinib)、帕博西尼(palbociclib)、吉西他濱、環磷醯胺、氟尿嘧啶、FOLFOX、亞葉酸、奧沙利鉑(oxaliplatin)、阿西替尼(axitinib)、舒尼替尼蘋果酸鹽(sunitinib malate)、托法替尼(tofacitinib)、貝伐珠單抗(bevacizumab)、利妥昔單抗(rituximab)及曲妥珠單抗(traztuzumab)。
在一些實施態樣中,CD123抗體組成物係與治療方案組合,該治療方案進一步包含選自由手術、放射療法、化學療法、靶向性療法、免疫療法、荷爾蒙療法、血管生成抑制及姑息療法所組成之群組之傳統療法。
本發明所使用之組成物可另包含醫藥上可接受之載劑、賦形劑或安定劑(Remington: The Science and practice of Pharmacy 21st Ed., 2005, Lippincott Williams and Wilkins, Ed. K. E. Hoover)以呈冷凍乾燥調製劑或水性溶液之形式。可接受之載劑、賦形劑或穩定劑在劑量及濃度下對接受者不具毒性,可能包括例如緩衝劑諸如磷酸鹽、檸檬酸鹽及其他有機酸;抗氧化劑包括抗壞血酸及甲硫胺酸;保存劑(諸如十八基二甲基苄基氯化銨;氯化六烴季銨;苯紮氯銨、苄索氯銨;苯酚、丁醇或苄醇;烷基對羥基苯甲酸酯諸如甲基或丙基對羥基苯甲酸酯;兒茶酚;間苯二酚;環己醇;3-戊醇;及間甲酚);低分子量(小於約10個殘基)多肽;蛋白質諸如血清白蛋白、明膠或免疫球蛋白;親水性聚合物諸如聚乙烯吡咯啶酮;胺基酸諸如甘胺酸、麩醯胺酸、天冬醯胺酸、組胺酸、精胺酸或離胺酸;單醣、雙醣及其他碳水化合物包括葡萄糖、甘露糖或葡聚糖;螯合劑諸如EDTA;糖諸如蔗糖、甘露醇、海藻糖或山梨醇;鹽形成反離子諸如鈉;金屬錯合物(例如Zn-蛋白質錯合物);及/或非離子界面活性劑諸如TWEENTM
、PLURONICSTM
或聚乙二醇(PEG)。醫藥上可接受之賦形劑另於此處說明。
多核苷酸、載體及宿主細胞
本發明亦提供編碼本發明之抗體之經分離之多核苷酸,及包含該多核苷酸之載體及宿主細胞。在另一態樣中,本發明提供包含本發明之任何多核苷酸之組成物(諸如醫藥組成物)。在一些實施態樣中,該組成物包含表現載體,該表現載體包含編碼此處所述之任何抗體之多核苷酸。在另一態樣中,本發明提供製備此處所述之任何多核苷酸之方法。
與任何該等序列互補之多核苷酸亦包含於本發明中。多核苷酸可能為單股(編碼或反義)或雙股,且可能為DNA (基因組、cDNA或合成性)或RNA分子。RNA分子包括HnRNA分子及mRNA分子,該HnRNA分子包含內含子且以一對一之方式對應DNA分子,該mRNA分子不包含內含子。其他編碼或非編碼序列可能(但不一定)存在於本發明之多核苷酸內,且多核苷酸可能(但不一定)與其他分子及/或支持物質連接。
多核苷酸可能包含天然序列(即編碼抗體或彼之部分之內源性序列)或可能包含該序列之變體。多核苷酸變體包含一或多個取代、添加、刪除及/或插入,以使該經編碼之多肽的免疫反應性相對於天然免疫反應性分子不被減少。對該經編碼之多肽的免疫反應性之影響通常係如此處所述檢測。變體較佳地展現與編碼天然抗體或彼之部分之多核苷酸序列具有至少約70%之一致性,更佳地至少約80%之一致性,甚至更佳地至少約90%之一致性及最佳地至少約95%之一致性。
若二個多核苷酸或多肽序列如下所述排比以得到最高對應性且該二個序列中之核苷酸或胺基酸序列相同,則該二個序列被稱為「一致(identical)」。兩序列之間的比較通常藉由在比較窗中比較序列加以進行,以識別及比較具有序列相似性之局部區域。此處所使用之「比較窗(comparison window)」係指至少約20個、通常30個至約75個、或40個至約50個連續位置之區段,在該窗中一序列可與具有相同連續位置數量之參考序列在該二序列經最佳排比後比較。
供比較之序列的最佳排比可利用雷斯基(Lasergene)生物資訊套裝軟體中之邁佳來(Megalign)程式(威斯康辛州麥迪遜市DNASTAR公司)以內建參數進行。此程式具體化下列文獻中描述之數種排比法:Dayhoff, M.O., 1978, A model of evolutionary change in proteins - Matrices for detecting distant relationships. In Dayhoff, M.O. (ed.) Atlas of Protein Sequence and Structure, National Biomedical Research Foundation, Washington DC Vol. 5, Suppl. 3, pp. 345-358;Hein J., 1990, Unified Approach to Alignment and Phylogenes pp. 626-645 Methods in Enzymology vol. 183, Academic Press, Inc., San Diego, CA; Higgins, D.G. and Sharp, P.M., 1989, CABIOS 5:151-153;Myers, E.W. and Muller W., 1988, CABIOS 4:11-17;Robinson, E.D., 1971, Comb. Theor. 11:105;Santou, N., Nes, M., 1987, Mol. Biol. Evol. 4:406-425;Sneath, P.H.A. and Sokal, R.R., 1973, Numerical Taxonomy the Principles and Practice of Numerical Taxonomy, Freeman Press, San Francisco, CA;Wilbur, W.J. and Lipman, D.J., 1983, Proc. Natl. Acad. Sci. USA 80:726-730。
較佳地,「序列一致性之百分比(percentage of sequence identity)」係藉由在至少20個位置之比較窗中比較二個經最佳排比之序列加以決定,其中在比較窗中多核苷酸或多肽序列之部分相較於供二序列最佳排比之參考序列(其不包含添加或刪除)可能包含20%或低於20%、通常5%至15%、或10%至12%之添加或刪除(即缺口)。百分比之計算係藉由測定二個序列中出現相同之核酸鹼基或胺基酸殘基之位置的數目,以得到匹配位置之數目,將該匹配位置之數目除以參考序列之位置總數(即窗之大小),並將該結果乘以100以得到序列一致性百分比。
變體亦可能或選擇性地與天然基因或彼之部分或互補部分實質上同源。該等多核苷酸變體能在中度嚴謹度條件下與編碼天然抗體之天然發生之DNA序列(或互補序列)雜交。
合適的「中度嚴謹度條件(moderately stringent condition)」包括用5 X SSC、0.5% SDS、1.0 mM EDTA (pH 8.0)溶液預先洗滌;在50°C至65°C下以5 X SSC雜交整夜;隨後在65°C下用含有0.1 % SDS之2X、0.5X及0.2X SSC各洗滌二次20分鐘。
如本文中所使用,「高度嚴謹條件(highly stringent conditions)」或「高嚴謹度條件(high stringency conditions)」係指:(1)採用低離子強度及高溫洗滌,例如在50℃下0.015 M氯化鈉/0.0015 M檸檬酸鈉/0.1%十二基硫酸鈉;(2)在42℃下之雜交期間採用變性劑,諸如甲醯胺,例如具有0.1%牛血清白蛋白/0.1% Ficoll/0.1%聚乙烯基吡咯烷酮/含有750 mM氯化鈉、75 mM檸檬酸鈉之pH 6.5之50 mM磷酸鈉緩衝液之50%(體積/體積)甲醯胺;或(3)在42℃下採用50%甲醯胺、5倍SSC(0.75 M NaCl、0.075 M檸檬酸鈉)、50 mM磷酸鈉(pH 6.8)、0.1%焦磷酸鈉、5倍Denhardt氏溶液、經超音波化之鮭魚精子DNA (50 µg/ml)、0.1% SDS及10%硫酸葡聚糖,並在42℃下以0.2倍SSC(氯化鈉/檸檬酸鈉)洗滌且在55℃下以50%甲醯胺清洗,之後在55℃下以含有EDTA之0.1倍SSC進行高嚴謹度洗滌。該領域中具有通常知識者將認知當有需要時如何調整溫度、離子強度等條件以配合諸如探針長度及類似因子。
該領域之一般技藝人士將瞭解的是,由於基因密碼簡併之結果,有許多核苷酸序列編碼此處所描述之多肽。這些多核苷酸中有些與任何天然基因之核苷酸序列具有極低之同源性。然而,本發明特別考慮因為使用不同的密碼子而有所差異之多核苷酸。另外,包含此處所提供之多核苷酸序列之基因的等位基因係屬於本發明之範圍內。等位基因係因為一或多個突變,諸如核苷酸之刪除、添加及/或取代而被改變之內源性基因。該形成之mRNA及蛋白質可能但不一定具有經改變之結構或功能。等位基因可利用標準技術(諸如雜交、擴增及/或資料庫序列比較)加以識別。
本發明之多核苷酸可利用化學合成、重組方法或PCR獲得。化學多核苷酸合成之方法係該領域所廣為週知,不須在此詳細說明。該領域之技藝人士可利用此處所提供之序列及商用DNA合成儀產製所欲之DNA序列。
在利用重組方法製備多核苷酸時,包含所欲序列之多核苷酸可被插入適當之載體中,該載體接著可被導入適當之宿主細胞以供複製及擴增,在下面進一步討論。多核苷酸可藉由該領域所知之任何方法被插入宿主細胞中。細胞之轉形係藉由直接攝取、胞飲作用、轉染、F交配(F-mating)或電穿孔導入外源性多核苷酸。一旦導入後,該外源性多核苷酸可以非整合性載體(諸如質體)或整合至該宿主細胞之基因組中而被維持於該細胞內。經此放大之多核苷酸可利用該領域所熟習之方法自該宿主細胞分離。見例如Sambrook et al., 1989。
另外,PCR能複製DNA序列。PCR技術係該領域所廣為周知,於美國專利第4,683,195、4,800,159、4,754,065及4,683,202號及PCR: The Polymerase Chain Reaction, Mullis et al. eds., Birkauswer Press, Boston, 1994中描述。
RNA可藉由使用適當載體中經分離之DNA且將其插入適當之宿主細胞中獲得。當細胞複製且該DNA被轉錄成為RNA時,該RNA即可利用該領域之技藝人士所廣為週知之方法分離,例如於Sambrook et al., 1989(同上)所述。
適當之選殖載體可根據標準技術建構,或可選自該領域為數眾多之可用選殖載體。雖然該經選擇之選殖載體可能因所意圖使用之宿主細胞而異,適用之選殖載體通常具有自我複製之能力、可能具有特定限制內切酶之單一目標及/或可能帶有可用於選擇含有該載體之克隆的標誌基因。適當實例包括質體及細菌性病毒,例如pUC18、pUC19、Bluescript(例如pBS SK+)及其衍生物、mp18、mp19、pBR322、pMB9、ColE1、pCR1、RP4、噬菌體DNA及穿梭載體諸如pSA3及pAT28。這些及許多其他選殖載體可購自商業賣方諸如BioRad、Strategene及Invitrogen公司。
表現載體通常是可複製之多核苷酸建構物,其包含本發明之多核苷酸。這表示表現載體必需能在宿主細胞中以附加體或染色體DNA之組成部分被複製。適當之表現載體包括但不限於質體、病毒載體(包括腺病毒、腺病毒相關病毒、反轉錄病毒)、黏質體及PCT公開號WO 87/04462中所揭示之表現載體。載體組分通常包括但不限於下列一或多者:信號序列;複製起點;一或多個標誌基因;合適的轉錄控制元件(諸如啟動子、增強子及終止子)。就表現(即轉譯)而言,通常也需要一或多種轉譯控制元件,諸如核糖體結合位置、轉譯起始位置及終止密碼子。
含有感興趣之多核苷酸之載體可藉由任何適當之方法導入宿主細胞,包括電穿孔、使用氯化鈣、氯化銣、磷酸鈣、DEAE-葡聚糖或其他物質之轉染;微彈撞擊;脂質體轉染;及感染(例如該載體為感染性劑諸如牛痘病毒)。導入載體或多核苷酸之選擇通常將視該宿主細胞之特徵而定。
本發明亦提供包含此處所述之任何多核苷酸之宿主細胞。任何能過度表現異源性DNA之宿主細胞可被使用以分離編碼該感興趣之抗體、多肽或蛋白質之基因。哺乳動物宿主細胞之非限制性實例包括但不限於COS、HeLa及CHO細胞。亦見PCT公開號WO 87/04462。適當之非哺乳動物宿主細胞包括原核生物(諸如大腸桿菌(E. coli
)或枯草桿菌(B. subtillis
))及酵母菌(諸如啤酒釀母菌(S. cerevisae
)、分裂酵母(S. pombe
);或乳酸克魯維酵母菌(K. lactis
))。較佳地,該宿主細胞以相較於該對應之感興趣之內源性抗體或蛋白質若存在於宿主細胞中高出約5倍、更佳為高出10倍、甚至更佳為高出20倍之量表現cDNA。篩選與CD123專一性結合之宿主細胞係由免疫測定或FACS進行。過度表現感興趣之抗體或蛋白之細胞可被識別。
套組
本發明亦提供用於本快速方法之套組。本發明之套組包括一或多個含有此處所述之CD123抗體或CD123 ADC之容器及根據此處所述之本發明之任一方法使用之說明。通常,這些說明包含投予CD123抗體或CD123 ADC以用於上述治療性治療之描述。
有關使用如此處所述之CD123抗體或CD123 ADC之說明通常包括用於該意圖處理之劑量、投藥計畫及投予途徑之資訊。該等容器可為單位劑量、大量包裝(例如多劑量包裝)或次單位劑量。本發明之套組所提供之說明通常為在標籤或包裝仿單上之書面說明(例如包含在套組中之紙張),但機器讀取之說明(例如磁性或光學儲存磁碟上攜有之說明)亦可被接受。
本發明之套組係經適當包裝。適當包裝包括但不限於小瓶、瓶子、罐、可彎折之包裝(例如密封之美拉(Mylar)或塑膠袋)、及類似物。亦考慮的是與特殊裝置組合使用之包裝,諸如吸入器、經鼻投予裝置(例如霧化器)或輸注裝置諸如小型泵。套組可能具有無菌接口(例如該容器可能為具有可被皮下注射針穿刺之塞子的靜注溶液袋或小瓶)。該容器也可能具有無菌接口(例如該容器可能為具有可被皮下注射針穿刺之塞子的靜注溶液袋或小瓶)。該組成物中至少有一種活性劑係CD123抗體。該容器可能另包含第二醫藥活性劑。
套組可能可任意選擇地提供額外成份諸如緩衝劑及解說資訊。通常,該套組包含容器及在該容器上或與該容器相關之標籤或包裝仿單。
生物寄存
本發明之代表性材料係於2017年6月29日寄存於美國菌種保存中心(ATCC)。ATCC編號PTA-124283之載體係編碼人化CD123抗體重鏈序列之多核苷酸,且ATCC編號PTA-124284之載體係編碼人化CD123抗體輕鏈序列之多核苷酸。該等寄存係根據「國際承認用於專利程序及法規的微生物保存布達佩斯條約」(布達佩斯條約)之規定進行。此確保自寄存日開始30年內維持存活的寄存物培養物。該寄存物將依照布達佩斯條約之規定由ATCC提供,且將受限於輝瑞(Pfizer, Inc.)與ATCC之合約,該合約確保當頒發相關美國專利或公開任何美國或外國專利申請案時(以先到者為主),該寄存物之培養子代可永久且不受限制地供公眾使用,且確保由美國專利商標局局長依據35 U.S.C. 122節及該局長所依據之法則(包括37 C.F.R. 1.14節,特別參照886 OG 638)判定有權獲得該子代者之可得性。
本申請案之代理人同意,若該寄存中之材料的培養物在適當條件培養下死亡或遺失或毀損,一經通知應立即以另一相同材料取代該材料。不得將該寄存材料之可得性視為可藉以實施本發明而侵犯由任何政府機關依據該國專利法所授予之權利之許可。
實例
下列實施態樣僅作為示範之用,無意在任何方面限制本發明之範圍。事實上,除了在此處顯示及說明之修飾之外,本發明之許多修飾將為該領域之技藝人士自前述說明所顯而易見且屬於隨附之權利要求之範圍內。
實例1:CD123抗體-藥物共軛體的體外細胞毒性
此實例說明各種CD123 ADC之細胞毒性。
在本試驗中,使用2D體外細胞毒性測定在下列AML細胞系中測試各種CD123 ADC之細胞毒性:MOLM13、MV411、JVM3、Granata519、OCI-AML3、NB4及HL60。表4表明所使用之各個各別細胞的CD123表現水準。
第一群測試的ADC為用AcLysValCitPABC連接子與CPI共軛的CD123 ADC。這些ADC為:18G3-CPI、16D6-CPI、3D1-CPI及20D7-CPI,其各者具有約2的藥物:抗體比例(DAR)。CD123 ADC之製備係詳細描述於以下實例5。使用DAR約2的對照組IgG(不與CD123結合之IgG)(「Neg.8.8」)與CPI劑作為陰性對照組。
對2D體外細胞毒性測定而言,將AML細胞與下列劑量的ADC或對照組一起培養96小時:100 ng/ml、25 ng/ml、6.25 ng/ml、1.56 ng/ml、0.39 ng/ml、0.09 ng/ml、0.024 ng/ml、0.006 ng/ml、0.002 ng/ml及0.0004 ng/ml。用CelltiterGlo (Promega, Madison, WI)測量細胞存活性,並使用Victor板讀取儀(Perkin Elmer, Waltham, MA)判定發光。使用XLfit (IDBS, Boston, MA) 4參數曲線擬合產生50%抑制值(IC50)計算。結果摘列於表5。
結果顯示CD123-CPI對表現CD123之細胞具有細胞毒性,且彼等比起不具專一性之CP1 (Neg8.8-CPI)更具細胞毒性。例如,在MOLM13細胞中,CD123 ADC 18G3-CPI、16D6-CPI及3D1-CPI之IC50分別為0.25±0.04 ng/mL、0.22±0.05 ng/mL、0.33±0.06 ng/mL及0.32±0.14 ng/mL。相對地,Neg.8.8-CPI之IC50為>88.43±18.66(表5,最後一列)。DAR約2之Neg.8.8-CPI在最高測試劑量下實質上較不具活性(表5,最後一列)。表明之CD123 ADC的IC50值與細胞上的CD123表現水準有良好相關(表4及5)。例如,18G3-CPI在表現高水準CD123之MV411細胞中的IC50為0.41± 0.07。相對地,18G3-CPI在表現低水準CD123之NB4細胞中的IC50為63.92±36.08,且18G3-CPI在不表現CD123之HL60細胞中的IC50為>84.4±33.30。
CD123-18G3 ADC與不同的劑iPr-卡利奇黴素或CTI(葡萄糖醛酸苷)共軛具有類似的細胞毒性效應。18G3與iPr-卡利奇黴素(「iPr」)共軛之細胞毒性測定結果摘列於表6。18G3與CTI(葡萄糖醛酸苷)共軛之細胞毒性測定結果摘列於表7。
這些資料顯示DAR約2的CD123-ADC在表現CD123的癌細胞系中具有活性且誘導細胞死亡,但在不表現CD123的細胞中不具活性。此顯示這些ADC的效力及專一性。
實例2:介白素-3(IL-3)傳訊途徑及CD123抗體及ADC的細胞毒性
此實例說明CD123抗體阻斷IL-3傳訊的能力及CD123 ADC的細胞毒性。
進行此試驗以判定任何CD123抗體克隆是否競爭性地與表現CD123/IL-3Rα的TF-1細胞之IL-3結合位點結合。將表現CD123/IL-3Rα的TF-1細胞與20 ng/ml的IL-3及下列CD123抗體共培養:3D1、18G3及16D6,劑量為100 ng/ml、25 ng/ml、6.25 ng/ml、1.56 ng/ml、0.39 ng/ml、0.09 ng/ml、0.024 ng/ml、0.006 ng/ml、0.002 ng/ml及0.0004 ng/ml。使用CD123抗體7G3作為已顯示阻斷IL-3傳訊途徑之基準抗體,且使用Neg 8.8抗體作為陰性對照組。在測量細胞存活之CTG測定中,將細胞在37˚C下處理四天。在處理期之後,收集細胞並製備蛋白質。使用西方墨點轉漬法分析,分析STAT5、磷酸化STAT5及肌動蛋白水準。西方墨點轉漬法結果顯示於圖1。
下游傳訊蛋白質磷酸化STAT5(「磷酸化Stat5」)的存在表明活化IL-3傳訊途徑。用單獨IL-3或IL-3加上Neg.8.8對照抗體(「8.8」)處理TF-1細胞活化IL-3傳訊,如磷酸化Stat5存在所示(圖1)。用CD123抗體7G3處理阻斷IL-3傳訊。CD123抗體3D1亦阻斷此途徑。相對地,CD123抗體18G3及16D6不阻斷IL-3媒介之STAT5磷酸化。
CD123-18G3-CPI及CD123-16D6-CPI的細胞毒性在IL-3存在下仍維持(表8)。
實例3:CD123-ADC之體內療效
此實例說明CD123 ADC的體內療效。
使用急性骨髓性白血病(AML)細胞系異種移植模型,測試CD123 ADC的體內抗腫瘤活性。下述之各模型中,第一劑皆於第0天給予。每周至少測量一次腫瘤,彼等之體積係以下式計算:腫瘤體積(mm3
) = 0.5 x(腫瘤寬度2
)(腫瘤長度)。各治療組之平均腫瘤體積(± S.E.M.)係由包括10隻動物加以計算。所有動物實驗皆於經實驗動物管理評鑑協會(Association for Assessment of Laboratory Animal Care)認證的機構,遵守實驗動物照顧及使用委員會(Institutional Animal Care and Use Committee)準則及適當動物研究核准下進行。CD123 ADC在具有各種基因突變或過度表現基因及/或蛋白質的細胞系中以劑量依賴性方式顯示高度療效。
A. H.1 MOLM13 AML異種移植
CD123 ADC的抗腫瘤活性係於NOD/SCID免疫不全小鼠中以人腫瘤的體內生長評估。在皮下(sc) AML模型中,將5 X 106
個MOLM13細胞植入雌性小鼠脇部皮下。當腫瘤到達200 mm3
之平均體積時,將動物分期以確保在不同治療組之間的腫瘤大小之一致性。MOLM13 AML sc異種移植模型經每四天靜脈內給藥四次(Q4dx4):PBS媒劑、0.3 mg/kg或1 mg/kg之CD123-CPI(18G3、16D6或3D1)或0.3 mg/kg或1 mg/kg之對照組Neg-8.8-CPI。資料摘列於表9。
CD123-CPI相較於Neg.8.8-CPI顯著抑制腫瘤(表9)。在0.3 mg/kg之劑量下,所有三種CD123 ADC:18G3-CPI、16D6-CPI及3D1-CPI皆具細胞毒性。到第17天,各組中的十隻動物中有十隻顯示腫瘤消退。所有這些小鼠維持無腫瘤直到至少第60天,此時為試驗結束時。在1 mg/kg的CD123 ADC之劑量下,腫瘤消退發生較早(第12天)。
這些資料顯示,CD123-CPI抑制MOLM13 AML異種移植腫瘤的生長。
為了測試CD123-ADC在降低劑量下的療效,使用相同MOLM13模型執行體內療效試驗。動物的治療如上述進行。如下表10所示,0.1 mg/kg之CD123-CPI非常有效且以劑量依賴性方式抑制所有小鼠中的腫瘤生長(表10,中間欄「18G3-CPI」及「16D6-CPI」)。相對地,Neg. 8.8-CPI治療小鼠的腫瘤持續生長(表10,右側欄「Neg 8.8-CPI」)。
為了測試CD123-18G3-CTI的療效,使用相同MOLM13模型執行體內療效試驗。動物的治療如上述進行。如表11所示,CD123-18G3-CTI治療以劑量依賴性方式抑制小鼠中的腫瘤生長。相對地,Neg. 8.8-CTI治療小鼠的腫瘤持續生長。
B. H.2 MV4-11 AML異種移植
使用免疫不全小鼠評估CD123 ADC對人腫瘤生長的效應。在皮下(sc) AML模型中,將5 X 106
個MV4-11細胞植入雌性NOD-SCID小鼠脇部皮下。當腫瘤到達200 mm3
之平均體積時,將動物分期以確保在不同治療組之間的腫瘤大小之一致性。MV4-11 AML sc異種移植動物經每四天靜脈內給藥四次(Q4dx4):PBS媒劑、在下列劑量下的CD123-CPI或8.8-CPI:0.1、0.3及0.6 mg/kg。資料摘列於表12。將CD123-18G3-H16-CPI與Neg 8.8-CPI及PBS媒劑比較。
0.6 mg/kg劑量之CD123-CPI為此試驗測試之最有效的ADC,到第65天,仍在試驗中的10隻動物中有10隻維持無腫瘤。甚至在0.3 mg/kg劑量下,十隻小鼠中有九隻在約第25天顯示腫瘤消退,且維持無腫瘤直到試驗在第65天結束。資料顯示,CD123-CPI抑制MV4-11異種移植腫瘤的生長。
為了測試CD123-CTI的療效,使用相同MV4-11模型執行體內療效試驗。動物的治療如上述進行。如表13所示,CD123-CTI亦以劑量依賴性方式抑制小鼠的腫瘤生長,然而Neg. 8.8-CTI治療小鼠的腫瘤持續生長。
這些結果顯示,CD123 ADC高度有效地治療腫瘤。
實例4:CD123-ADC之體內療效
此實例使用AML病患衍生性散播型異種移植(AML PDX)說明CD123 ADC的體內療效。
CD123-CPI的效力係於免疫不全小鼠中,評估利用根據適當同意程序獲得之病患骨髓細胞所建立之散播型模型的體內生長。表14提供此試驗中使用之病患樣本的摘要。
在試驗中,將1.0 X 106
個病患骨髓細胞靜脈內注射至經輻照NSG小鼠的側尾靜脈。基於人CD45+/CD123+/CD33+細胞的植入(周邊血液中12至55%,如流式細胞分析染色所測量),將試驗分期並隨機分組。AML PDX小鼠每七天靜脈內給藥2次(Q7dx2):PBS媒劑或18G3-CPI。在第二次/最後一次劑量後約3至5天,自犧牲小鼠收集周邊血液及骨髓。犧牲動物之骨髓及血液中剩餘的腫瘤細胞藉由流動式細胞測量術分析。結果摘列於圖2之圖及表15。在表15中,數字代表周邊血液及骨髓中之剩餘腫瘤細胞的百分比。
各試驗中,每組具有約6至10隻小鼠。資料顯示,CD123 ADC以劑量依賴性方式有效減少周邊血液及骨髓中之腫瘤細胞數量(圖2及表15)。
為了判定CD123-18G3-CPI是否可增加荷瘤小鼠之整體存活期,當周邊血液顯示高度植入(即平均約32%)時,使用PDX2407執行存活性試驗。小鼠每七天靜脈內給藥2次(Q7dx2):PBS媒劑或CD123-CPI,且每天監測。當小鼠顯示臨床徵候,諸如疲倦及體重減輕(根據實驗動物管理評鑑協會,遵照實驗動物照顧及使用委員會準則),將小鼠安樂死。
結果摘列於圖3之圖。CD123-18G3-CPI治療以劑量依賴性方式延長荷瘤動物的整體存活期。具體而言,在0.1 mg/kg劑量下之CD123-18G3-CPI治療延長約25%的存活期,且在0.3 mg/kg劑量下之CD123-18G3-CPI治療大約使存活期長度加倍(圖3)。
這些結果顯示,CD123-ADC治療誘導AML消退且抑制進展,並延長存活期。
實例5:製備CD123抗體藥物共軛體(ADC)
此實例說明h18G3-AcLysValCitPABC-DMAE-CO_CPI-000638314(一種CD123 ADC,在本文中亦稱為「18G3-CPI」或「CD123-18G3-CPI」)的共軛及製備。
18G3-CPI是一種包含CD123人化mAb 18G3(見表2.0及2.1,同上,「h18G3」)、AcLysValCitPABC連接子及環丙基吡咯并吲哚啉(CPI)劑之ADC。K222R、E295L、Q295L、Y296Q、N297G突變係經導入上絞鏈及Fc,以使轉麩醯胺酸酶能夠催化CPI劑之定點共軛。CD123-18G3-H16-N60G-K222R人化IgG1抗體(在本文中稱為「h18G3」)之輕鏈及重鏈胺基酸序列如下:
輕鏈:
重鏈:
H16定點突變序列如上以粗體斜體字表示且包括五個H16定點轉麩醯胺酸酶突變K222R(在絞鏈中)、E294L、Q295L、Y296Q及N297G。LLQG序列係轉麩醯胺酸酶之辨識標籤,且連接子-劑係共軛在Q296。CDR-H2中之G(畫底線)係N60G突變。
連接子-劑(AcLysValCitPABC-DMAE-CO_CPI)係定點共軛於胺基酸Q296。AcLysValCitPABC-DMAE-CO_CPI-000638314連接子-劑結構如下所示。
h18G3與AcLysValCitPABC-DMAE-CO_CPI-000638314連接子-劑係經由使用細菌性轉麩醯胺酸酶(Sigma,45U/mg蛋白質)共軛。具體而言,將抗體交換至含有100 mM KPO4、200 mM NaCl pH 7之緩衝劑中。連接子-劑係在7.5% (v/v)二甲亞碸(DMSO)存在下以對抗體10倍莫耳過量添加。藉由每mg抗體添加1U的細菌性轉麩醯胺酸酶以起始酶反應且在25°C和持續混合下經隔夜培養。
將反應混合物在室溫下與15%異丙醇培養30 min。接著稀釋至4體積的1M KPO4緩衝劑且使用丁基-瓊脂糖HP管柱(GE Lifesciences)經由疏水性交互作用層析法(HIC)純化。該方法利用1M KPO4、50 mM Tris pH 7來結合,並以50 mM Tris, pH 7經10 CV洗提ADC。將經HIC純化的化合物透析至20mM組胺酸、85 mg/mL蔗糖pH 5.8之最終緩衝劑中。經由SEC進一步表徵ADC的純度,且經由逆相層析法計算藥物-抗體比例。蛋白質濃度係經由UV分光光度計測定。
前導抗體具有非常好的表現,在CHO池中評估至多700 mg/L,88%回收產率及三個純化步驟後99%純度。18G3的共軛執行得非常好,如達成DAR 1.9至2.0及純化後55至60%共軛產率所評估。所得之ADC(CD123-18G3-H16-N60G-K222R-hG1-(Q)AcLysValCitPABC-DMAE-CO_CPI)展現良好熱穩定性及分子完整性。
實例6:使用轉麩醯胺酸酶將抗體與AcLysValCitPABC-DMAE-CO_CPI-000638314共軛之方法
此實例說明抗體與連接子-劑(AcLysValCitPABC-DMAE-CO_CPI-000638314,在本文中亦稱為 AcLysPABC-CPI-8314)的共軛。CPI 連接子 - 細胞毒性劑的共軛
。AcLysPABC-CPI-8314(結構顯示於上之實例5)與抗體之H16位點的共軛藉由改變多種不同參數來優化,諸如體積莫耳濃度及鹽組成物、pH、酶濃度、時間及溫度(表16)。簡言之,將抗體用緩衝劑交換至表16所示之各種條件之適當緩衝劑及pH中。將10倍莫耳過量的AcLysPABC-CPI-8314連接子-劑添加至抗體,且添加5至10%二甲亞碸以使連接子-劑溶解於反應混合物中。在添加細菌性轉麩醯胺酸酶(0.5至5 U/mg抗體)之後,將反應混合物連續混合規定的時間及溫度。經由粒徑排阻層析法及/或疏水性交互作用層析法移除未反應的連接子-劑及轉麩醯胺酸酶。經由LCMS或RP-HPLC計算藥物-抗體比例。
在各種條件下藉由抗體-藥物比例(DAR)測量的共軛效率顯示於表16。例如,當抗體交換至含有30 mM KPO4、150 mM NaCl pH 7之緩衝劑時,達成DAR 1.6。
靶向CD33、CD123、Her2、PRLR、CD22及其他抗原(包括抗原)的抗體使用這些優化條件與連接子-劑AcLysValCitPABC-DMAE-CO_CPI-000638314共軛。
雖然本發明之揭示內容已藉由各種應用、方法、套組及組成物加以說明,應了解可進行各種改變及修飾而不背離此處之揭示內容及以下之申請專利範圍。前述之實施態樣係為了更清楚地說明本發明之揭示內容而提供,並無意限制本發明之範圍。雖然本發明已藉由該等示範性實施態樣說明,該領域之技藝人士將輕易了解可能針對該等示範性實施態樣進行許多變異及修飾而無須過度實驗。所有該等變異及修飾皆包含在本揭示發明之範圍內。
此處之引證文獻(包括專利、專利申請案、論文、教科書及該類似文獻)以及該等文獻中所引證之文獻若未經本發明參照,則以參照方式整體納入此處。若一或多篇該等納入文獻及類似材料與本申請案有不同或衝突之處,包括但不限於經定義之用語、用語之使用、經描述之技術或該類似物,以本申請案為主。
前述之詳細說明及實施方式詳細描述本發明之某些特定實施態樣,並說明發明人所考慮之最佳模式。然而應了解的是,不論前述內容說明得多詳細,本發明可以許多方式實施,且應根據該隨附之申請專利範圍及彼等之任何相等範圍被解讀。
圖1描繪用IL-3加上抗體(「Ab」)處理細胞之西方墨點轉漬法分析結果。7G3係基準抗體且3D1、18G3及16D6係CD123抗體;8.8係不與CD123結合之陰性對照組抗體。分析STAT5、磷酸化STAT5及肌動蛋白水準。
圖2描繪代表性流動式細胞測量術分析,其顯示在經媒劑或CD123-ADC(CD123-18G3-CPI)治療後的動物模型中,周邊血液(左圖)及骨髓(右圖)中剩餘的腫瘤細胞百分比。
圖3描繪的圖摘列經媒劑或所示劑量的CD123 ADC治療之動物的存活期長度(以天計)。
Claims (42)
- 一種單離抗體,其與CD123專一性結合,其中該抗體包含: 重鏈可變區(VH)及輕鏈可變區(VL),該VH包含(i) VH互補決定區(CDR)1,其包含SEQ ID NO: 33之胺基酸序列;(ii) VH CDR2,其包含SEQ ID NO: 45之胺基酸序列;及(iii) VH CDR3,其包含SEQ ID NO: 46之胺基酸序列,且該VL包含(i) VL CDR1,其包含SEQ ID NO: 40之胺基酸序列;(ii) VL CDR2,其包含SEQ ID NO: 41之胺基酸序列;及(iii) VL CDR3,其包含SEQ ID NO: 42之胺基酸序列; 重鏈可變區(VH)及輕鏈可變區(VL),該VH包含(i) VH互補決定區(CDR)1,其包含SEQ ID NO: 33之胺基酸序列;(ii) VH CDR2,其包含SEQ ID NO: 34之胺基酸序列;及(iii) VH CDR3,其包含SEQ ID NO: 35之胺基酸序列,且該VL包含(i) VL CDR1,其包含SEQ ID NO: 40之胺基酸序列;(ii) VL CDR2,其包含SEQ ID NO: 41之胺基酸序列;及(iii) VL CDR3,其包含SEQ ID NO: 42之胺基酸序列; 重鏈可變區(VH)及輕鏈可變區(VL),該VH包含(i) VH互補決定區(CDR)1,其包含SEQ ID NO: 52之胺基酸序列;(ii) VH CDR2,其包含SEQ ID NO: 53之胺基酸序列;及(iii) VH CDR3,其包含SEQ ID NO: 54之胺基酸序列,且該VL包含(i) VL CDR1,其包含SEQ ID NO: 58之胺基酸序列;(ii) VL CDR2,其包含SEQ ID NO: 59之胺基酸序列;及(iii) VL CDR3,其包含SEQ ID NO: 60之胺基酸序列;或 重鏈可變區(VH)及輕鏈可變區(VL),該VH包含(i) VH互補決定區(CDR)1,其包含SEQ ID NO: 65之胺基酸序列;(ii) VH CDR2,其包含SEQ ID NO: 66之胺基酸序列;及(iii) VH CDR3,其包含SEQ ID NO: 67之胺基酸序列,且該VL包含(i) VL CDR1,其包含SEQ ID NO: 72之胺基酸序列;(ii) VL CDR2,其包含SEQ ID NO: 73之胺基酸序列;及(iii) VL CDR3,其包含SEQ ID NO: 74之胺基酸序列; 其中該抗體包含連接子且其中該抗體與細胞毒性劑共軛。
- 如請求項1之抗體,其中該VH包含SEQ ID NO: 44之胺基酸序列或與SEQ ID NO: 44具有至少約90%序列一致性之胺基酸序列,且該VL包含SEQ ID NO: 48之胺基酸序列或與SEQ ID NO: 48具有至少約90%序列一致性之胺基酸序列。
- 如請求項2之抗體,其中該抗體包含輕鏈及重鏈,該輕鏈包含如SEQ ID NO: 49所示之序列或與SEQ ID NO: 49具有至少約90%序列一致性之胺基酸序列,且該重鏈包含如SEQ ID NO: 47所示之序列或與SEQ ID NO: 47具有至少約90%序列一致性之胺基酸序列。
- 如請求項1至3中任一項之抗體,其中該抗體包含經工程改造於特定位點之含有醯基供體麩醯胺酸之標籤。
- 如請求項4之抗體,其中該含有醯基供體麩醯胺酸之標籤包含選自由下列所組成之群組的胺基酸序列:Q、LQG、LLQGG (SEQ ID NO:77)、LLQG (SEQ ID NO:78)、LSLSQG (SEQ ID NO: 79)、GGGLLQGG (SEQ ID NO: 80)、GLLQG (SEQ ID NO: 81)、LLQ、GSPLAQSHGG (SEQ ID NO: 82)、GLLQGGG (SEQ ID NO: 83)、GLLQGG (SEQ ID NO: 84)、GLLQ (SEQ ID NO: 85)、LLQLLQGA (SEQ ID NO: 86)、LLQGA (SEQ ID NO: 87)、LLQYQGA (SEQ ID NO: 88)、LLQGSG (SEQ ID NO: 89)、LLQYQG (SEQ ID NO: 90)、LLQLLQG (SEQ ID NO: 91)、SLLQG (SEQ ID NO: 92)、LLQLQ (SEQ ID NO: 93)、LLQLLQ (SEQ ID NO: 94)、LLQGR (SEQ ID NO: 95)、LLQGPP (SEQ ID NO: 96)、LLQGPA (SEQ ID NO: 97)、GGLLQGPP (SEQ ID NO: 98)、GGLLQGA (SEQ ID NO: 99)、LLQGPGK (SEQ ID NO: 100)、LLQGPG (SEQ ID NO: 101)、LLQGP (SEQ ID NO: 102)、LLQP (SEQ ID NO: 103)、LLQPGK (SEQ ID NO: 104)、LLQAPGK (SEQ ID NO: 105)、LLQGAPG (SEQ ID NO: 106)、LLQGAP (SEQ ID NO: 107)及LLQLQG (SEQ ID NO: 108)。
- 如請求項5之抗體,其中該含有醯基供體麩醯胺酸之標籤係LLQG (SEQ ID NO: 78)。
- 如請求項5之抗體,其中該抗體進一步包含在位置222、340或370之胺基酸修飾。
- 如請求項7之抗體,其中該胺基酸修飾係將離胺酸取代成精胺酸。
- 如請求項8之抗體,其中該胺基酸修飾係K222R。
- 如請求項1之抗體,其中該連接子係可切割連接子。
- 如請求項10之抗體,其中該連接子係選自由下列所組成之群組:Ac-Lys-Gly(乙醯基-離胺酸-甘胺酸)、胺基己酸、Ac-Lys-β-Ala(乙醯基-離胺酸-β-丙胺酸)、胺基-PEG2(聚乙二醇)-C2、胺基-PEG3-C2、胺基-PEG6-C2、Ac-Lys-Val-Cit-PABC(乙醯基-離胺酸-纈胺酸-瓜胺酸-對胺基苄氧羰基)、胺基-PEG6-C2-Val-Cit-PABC、胺基己醯基-Val-Cit-PABC、[(3R,5R)-1-{3-[2-(2-胺基乙氧基)乙氧基]丙醯基}哌啶-3,5-二基]雙-Val-Cit-PABC、[(3S,5S)-1-{3-[2-(2-胺基乙氧基)乙氧基]丙醯基}哌啶-3,5-二基]雙-Val-Cit-PABC、腐胺及Ac-Lys-腐胺。
- 如請求項11之抗體,其中該連接子係Ac-Lys-Val-Cit-PABC(乙醯基-離胺酸-纈胺酸-瓜胺酸-對胺基苄氧羰基)。
- 一種如請求項1至12中任一項之抗體與細胞毒性劑共軛之共軛體。
- 如請求項13之共軛體,其中該細胞毒性劑係選自由下列所組成之群組:蒽環、耳抑素(auristatin)、喜樹鹼、考布他丁(combretastatin)、CBI二聚體、環丙基吡咯并吲哚啉(CPI)二聚體、CTI二聚體、海兔毒素(dolastatin)、雙聯黴素(duocarmycin)、烯二炔、膠達納黴素(geldanamycin)、吲哚啉并-苯并二氮呯二聚體、美坦素(maytansine)、嘌呤黴素(puromycin)、吡咯并苯并二氮呯二聚體、紫杉烷、長春花生物鹼、微管溶素(tubulysin)、半星芒體(hemiasterlin)、司普力西歐他汀(spliceostatin)及普拉二烯內酯(pladienolide)。
- 如請求項14之共軛體,其中該細胞毒性劑係CPI二聚體。
- 如請求項15之共軛體,其中該CPI二聚體係C31H31Cl2N4O7P或其醫藥上可接受之鹽,包括C31H31Cl2N4O7P. C2HF3O2。
- 如請求項13至16中任一項之共軛體,其中該共軛體包含下式:抗體-(含有醯基供體麩醯胺酸之標籤)-(連接子)-(細胞毒性劑)。
- 如請求項17之共軛體,其中該含有醯基供體麩醯胺酸之標籤包含胺基酸序列LLQG (SEQ ID NO: 78)且其中該連接子包含乙醯基-離胺酸-纈胺酸-瓜胺酸-對胺基苄氧羰基。
- 如請求項17之共軛體,其中該含有醯基供體麩醯胺酸之標籤係插入抗體位置E294至N297。
- 如請求項13至16中任一項之共軛體,其中該共軛體在根據卡巴(Kabat)之EU指數編號的抗體位置222處包含由離胺酸成為精胺酸之胺基酸取代。
- 一種醫藥組成物,其包含治療有效量之如請求項13至20中任一項之共軛體及醫藥上可接受之載劑。
- 一種單離多核苷酸,其包含編碼如請求項1至12中任一項之抗體的核苷酸序列。
- 如請求項22之單離多核苷酸,其包含與編碼天然抗體或彼之部分的多核苷酸序列至少約95%一致性。
- 一種載體,其包含如請求項22或23之多核苷酸。
- 一種單離宿主細胞,其包含如請求項24之載體。
- 一種產製如請求項1至12中任一項之抗體之方法,其包含在導致產製該抗體之條件下培養如請求項25之宿主細胞及自該宿主細胞或培養物單離該抗體。
- 一種如請求項21之醫藥組成物於製造藥物之用途,該藥物用於治療個體之與表現CD123之細胞有關之病症。
- 如請求項27之用途,其中該病症係癌症。
- 如請求項28之用途,其中該癌症係選自由下列所組成之群組之癌症:急性骨髓性白血病(AML)、急性淋巴球性白血病(ALL)、母細胞性漿細胞樣樹突細胞腫瘤(BPDCN)、髮樣細胞白血病、B細胞非霍奇金氏(non-Hodgkin’s)淋巴瘤(NHL)、多發性骨髓瘤、惡性漿細胞腫瘤、霍奇金氏淋巴瘤(Hodgkin’s lymphoma)、結節性淋巴細胞為主型之霍奇金氏淋巴瘤、卡勒氏病(Kahler’s disease)及骨髓瘤病、漿細胞白血病、漿細胞瘤、B細胞前淋巴細胞白血病、慢性淋巴球性白血病(CLL)、慢性骨髓性白血病(CML)、濾泡性淋巴瘤、伯基特氏淋巴瘤(Burkitt’s lymphoma)、邊緣區淋巴瘤、外套細胞淋巴瘤、大細胞淋巴瘤、前體B淋巴母細胞淋巴瘤、骨髓性白血病、瀰漫性大型B細胞淋巴瘤、黏膜相關性淋巴組織淋巴瘤、小細胞淋巴球性淋巴瘤、伯基特淋巴瘤(Burkitt lymphoma)、原發性縱隔大型B細胞淋巴瘤、淋巴漿細胞淋巴瘤、瓦登斯特隆巨球蛋白血症(Waldenström macroglobulinemia)、結內邊緣區B細胞淋巴瘤、脾邊緣區淋巴瘤、血管內大型B細胞淋巴瘤、原發性滲出性淋巴瘤、淋巴瘤樣肉芽腫病、富含T細胞/組織細胞大型B細胞淋巴瘤、原發性中樞神經系統淋巴瘤、原發性皮膚瀰漫性大型B細胞淋巴瘤、老年人之EBV陽性瀰漫性大型B細胞淋巴瘤、發炎相關性瀰漫性大型B細胞淋巴瘤、ALK陽性大型B細胞淋巴瘤、漿母細胞淋巴瘤、HHV8相關性多中心型克斯特曼病(HHV8-associated multicentric Castleman disease)產生之大型B細胞淋巴瘤、特徵介於瀰漫性大型B細胞淋巴瘤與伯基特淋巴瘤之間的未分類B細胞淋巴瘤、特徵介於瀰漫性大型B細胞淋巴瘤與典型霍奇金氏淋巴瘤之間的未分類B細胞淋巴瘤及其他B細胞相關性淋巴瘤。
- 如請求項29之用途,其中該癌症係AML。
- 一種如請求項21之醫藥組成物於製造藥物之用途,該藥物用於抑制具有表現CD123之惡性細胞之個體的腫瘤生長或進展。
- 一種如請求項21之醫藥組成物於製造藥物之用途,該藥物用於抑制個體之表現CD123之惡性細胞的轉移。
- 一種如請求項21之醫藥組成物於製造藥物之用途,該藥物用於誘導具有表現CD123之惡性細胞之個體的腫瘤消退。
- 如請求項34之方法,其中該組成物之pH係7。
- 如請求項34之方法,其中該組成物包含每mg該抗體0.5至2單位(U)之細菌性轉麩醯胺酸酶。
- 如請求項34至36中任一項之方法,其中該組成物包含每mg該抗體1 U之細菌性轉麩醯胺酸酶。
- 如請求項34至36中任一項之方法,其中該AcLysPABC-CPI-8314係以對該抗體10倍莫耳過量存在。
- 如請求項34至36中任一項之方法,其中該組成物在25℃和持續混合下經隔夜培養。
- 如請求項34至36中任一項之方法,其中該組成物進一步包含7.5% (v/v)二甲亞碸(DMSO)。
- 如請求項34至36中任一項之方法,其中該緩衝劑包含30 mM KPO4及150 mM NaCl。
- 如請求項34至36中任一項之方法,其中該緩衝劑包含100 mM KPO4及200 mM NaCl。
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CN113563470B (zh) * | 2020-04-29 | 2023-02-10 | 广州昂科免疫生物技术有限公司 | 结合tigit抗原的抗体及其制备方法与应用 |
BR112023023831A2 (pt) * | 2021-05-26 | 2024-01-30 | Oxford Biotherapeutics Ltd | Métodos, combinação farmacêutica, anticorpo ou porção de ligação ao antígeno do mesmo |
CN116018351A (zh) * | 2021-08-16 | 2023-04-25 | 上海优替济生生物医药有限公司 | 靶向cd123的抗体、嵌合抗原受体及其用途 |
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