TW202309270A - 用於細胞療法的b細胞擴增之方法 - Google Patents
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Abstract
本文揭示之發明關於用於擴增細胞群,特別是B細胞群之經改善的方法。本發明進一步關於包含經改善之細胞培養基、其組成,以及使用該等經擴增之B細胞的方法。
Description
本文揭示之發明關於用於擴增細胞群,特別是B細胞群之經改善的方法。
B細胞為負責多種功能,包括協助身體抵抗感染和疾病之免疫細胞。它們能夠對被識別之抗原回應而分泌抗體、呈遞抗原,且亦分泌細胞因子。在癌症中,某些腫瘤周圍之三級淋巴結構(“TLS”)中已找到B細胞。TLS包含免疫細胞(包括T細胞和B細胞二者)之聚集體。腫瘤中存有TLS與較佳之患者預後有關。參見,例如Helmink, B.A.,
et al., Nature, 2020, 577(7791), 549-555;Petitprez F
et al., Nature, 2020, 577(7791), 556-560。
腫瘤內注射經LPS活化之脾細胞(包括B細胞)與檢查點抑制劑已被證明可產生抗腫瘤反應。Soldevilla
et al., Oncoimmunology, 2018, 7:8, e1450711。此外,鑑於B細胞呈遞抗原和分泌蛋白質之天然能力,其具有巨大潛力來作為靶向某些患病之細胞類型和分泌治療有效載荷(payload)的細胞療法。
然而,擴大製造該經工程處理之B細胞以用於細胞療法為具有挑戰性之過程。數十年來,B細胞在體外活化和增殖已透過表現CD40配體(“CD40L”)之飼養細胞層系統實現。Banchereau, J.
et al.(1991) Science 251: 70-72;Schultze, J.L.
et al.(1997) J. Clin. Invest. 100: 2757-2765;Liebig, T.M.
et al.(2009) J. Vis. Exp. 32: 1373。這些系統有共通之缺點,那就是其對表現CD40L之飼養細胞層的依賴性。飼養細胞之使用阻礙活化和增殖過程的標準化,且在實驗步驟準則中引入一個變量。
使用CD40L之B細胞擴增法已有描述,結果好壞參半。參見,例如Wennhold
et al., 2019, Transfus Med Hemother, 46:36-46。一些方法導致擴增產量低,所產生之B細胞的量不足以用於細胞工程,及將B細胞作為治療劑以投予患者。因此,需要經改善之B細胞擴增技術、生長培養基,等。
本發明大致上提供用於擴增細胞群,特別是B細胞群之改善方法。本發明進一步關於經改善之細胞培養基、其組成和使用該等經擴增之B細胞的方法。該新穎方法納入使用新穎之CD40L融合蛋白、交聯抗體和IL-4和/或IL-21。該等方法在本文中顯示出對有效活化和增殖經工程處理之B細胞而言至關重要,從而導致該經功能性擴增之B細胞的合需水準增加200倍。
本文提供之用於擴增B細胞的方法優於常規方法之處在於迄今為止,該常規擴增方法導致不合需之低度細胞擴增,且因此減少經工程處理之B細胞的產量。適當之細胞功能和產量在細胞療法、同種異體治療中至關重要,特別是在自體治療環境中,其中通常只有一次機會來收穫患者之細胞、培養、擴增、工程處理和投予該等細胞之有效劑量。
於各種實施態樣中,本發明關於治療有其需要之個體的疾病或病症之方法,其包含從來源獲得B細胞群、將該等B細胞培養在包含CD40L融合蛋白和CD40L交聯劑之培養基中、將該等B細胞工程處理以表現有效載荷、嵌合受體、或二者;及將該等B細胞投予該個體。於各種實施態樣中,該來源為哺乳動物。於各種實施態樣中,該來源為包含外周單核血細胞之生物樣品。
於各種實施態樣中,該CD40L融合蛋白包含與SEQ ID NO.3具有至少85%同一性之胺基酸序列。於各種實施態樣中,該CD40L包含與SEQ ID NO.3具有至少95%同一性之胺基酸序列。於各種實施態樣中,該CD40L融合蛋白包含SEQ ID NO.3融合蛋白之胺基酸序列。於各種實施態樣中,該CD40L交聯劑為抗體。於各種實施態樣中,該抗體包含輕鏈可變區和重鏈可變區,該輕鏈可變區包含與SEQ ID NO.5具有至少95%同一性之胺基酸序列,且該重鏈可變區包含與SEQ ID NO.7具有至少95%同一性之胺基酸序列。於各種實施態樣中,該抗體包含輕鏈可變區和重鏈可變區,該輕鏈可變區包含SEQ ID NO.5之胺基酸序列,且該重鏈可變區包含SEQ ID NO.7之胺基酸序列。
於各種實施態樣中,該B細胞係將該等B細胞培養在具有CD40L融合蛋白和CD40L交聯劑之培養基中之前經工程處理。於各種實施態樣中,該B細胞係將該等B細胞培養在具有CD40L融合蛋白和CD40L交聯劑之培養基中之後經工程處理。於各種實施態樣中,該方法涉及進一步在IL-4之存在下培養該等B細胞。於各種實施態樣中,該方法涉及進一步在IL-21之存在下培養該等B細胞。
於各種實施態樣中,該經培養之B細胞表現下列標記中至少一者:CD62L、CCR7、CD80、CD86、CD54、ICAM、CD58或CD27。於各種實施態樣中,該疾病或病症係選自由下列至少一者所組成之群組:癌症、心臟病、發炎性疾病、肌肉耗損疾病、或神經疾病。於各種實施態樣中,該癌症為下列至少一者:乳癌、結腸癌、直腸癌、食道癌、肺癌、胰臟癌、胃癌、肝癌、肝細胞癌、間質瘤,諸如GIST、膠質母細胞瘤和神經膠質瘤。於各種實施態樣中,至少約3x10
7個B細胞係經投予該個體。於各種實施態樣中,該B細胞群係培養至少14天。
於各種實施態樣中,本發明關於治療有其需要之個體中之疾病或病症之方法,其包含從來源獲得B細胞群;將該等B細胞培養在包含CD40L融合蛋白和CD40L交聯抗體之培養基中,其中該CD40L融合蛋白包含與SEQ ID NO.3之胺基酸序列具有至少95%同一性之胺基酸序列,而CD40L交聯抗體之輕鏈可變區與SEQ ID NO:5之胺基酸序列具有至少95%同一性,且其重鏈可變區與SEQ ID NO:7之胺基酸序列具有至少95%同一性;及將該等B細胞投予該個體。
於各種實施態樣中,該來源為哺乳動物。於各種實施態樣中,該CD40L融合蛋白包含SEQ ID NO.3之胺基酸序列。於各種實施態樣中,該抗體包含輕鏈可變區和重鏈可變區,該輕鏈可變區包含SEQ ID NO.5之胺基酸序列,且該重鏈可變區包含SEQ ID NO.7之胺基酸序列。於各種實施態樣中,本發明進一步包含將該等B細胞工程處理以表現有效載荷、嵌合受體、或二者。
於各種實施態樣中,該B細胞係將該等B細胞培養在具有CD40L融合蛋白和CD40L交聯抗體之培養基中之前經工程處理。於各種實施態樣中,該B細胞係將該等B細胞培養在具有CD40L融合蛋白和CD40L交聯抗體之培養基中之後經工程處理。於各種實施態樣中,本發明進一步包含在IL-4之存在下培養該等B細胞。於各種實施態樣中,本發明進一步包含在IL-21之存在下培養該等B細胞。於各種實施態樣中,該等經培養之B細胞表現下列標記中至少一者:CD62L、CCR7、CD80、CD86、CD54、ICAM、CD58、或CD27。於各種實施態樣中,該疾病或病症係選自由下列至少一者所組成之群組:癌症、心臟病、發炎性疾病、肌肉耗損疾病、或神經疾病。於各種實施態樣中,該癌症為下列至少一者:乳癌、結腸癌、直腸癌、食道癌、肺癌、胰臟癌、胃癌、肝癌、肝細胞癌、間質瘤,諸如GIST、膠質母細胞瘤和神經膠質瘤。於各種實施態樣中,至少約3x10
7個B細胞係經投予該個體。於各種實施態樣中,該B細胞群係培養至少14天。
於各種實施態樣中,本發明關於用於製造經工程處理之B細胞之方法,該方法包含從來源獲得B細胞群、將該等B細胞培養在包含CD40L融合蛋白和CD40L交聯劑之培養基中;及將該等B細胞工程處理以表現有效載荷、嵌合受體、或二者。於各種實施態樣中,該來源為哺乳動物。於各種實施態樣中,該來源為包含外周單核血球之生物樣品。
於各種實施態樣中,該CD40L融合蛋白包含與SEQ ID NO.3具有至少85%同一性之胺基酸序列。於各種實施態樣中,該CD40L融合蛋白包含與SEQ ID NO.3具有至少95%同一性之胺基酸序列。於各種實施態樣中,該CD40L融合蛋白包含SEQ ID NO.3之胺基酸序列。於各種實施態樣中,該CD40L交聯劑為抗體。於各種實施態樣中,該抗體包含輕鏈可變區和重鏈可變區,該輕鏈可變區包含與SEQ ID NO.5具有至少95%同一性之胺基酸序列,且該重鏈可變區包含與SEQ ID NO.7具有至少95%同一性之胺基酸序列。於各種實施態樣中,該抗體包含輕鏈可變區和重鏈可變區,該輕鏈可變區包含SEQ ID NO.5之胺基酸序列,且該重鏈可變區包含SEQ ID NO.7之胺基酸序列。
於各種實施態樣中,該B細胞係將該等B細胞培養在具有CD40L融合蛋白和CD40L交聯劑之培養基中之前經工程處理。於各種實施態樣中,該B細胞係將該等B細胞培養在具有CD40L融合蛋白和CD40L交聯劑之培養基中之後經工程處理。於各種實施態樣中,該方法涉及進一步在IL-4之存在下培養該等B細胞。於各種實施態樣中,該方法包涉及進一步在IL-21之存在下培養該等B細胞。於各種實施態樣中,該等經培養之B細胞表現下列標記至少一者:CD62L、CCR7、CD80、CD86、CD54、ICAM、CD58、或CD27。於各種實施態樣中,該來源為哺乳動物。於各種實施態樣中,該來源為包含外周單核血球之生物樣品。
於各種實施態樣中,該CD40L融合蛋白包含與SEQ ID NO.3具有至少85%同一性之胺基酸序列。於各種實施態樣中,該CD40L融合蛋白包含與SEQ ID NO.3具有至少95%同一性之胺基酸序列。於各種實施態樣中,該CD40L融合蛋白包含SEQ ID NO.3之胺基酸序列。於各種實施態樣中,該CD40L交聯劑為抗體。於各種實施態樣中,該抗體包含輕鏈可變區和重鏈可變區,該輕鏈可變區包含與SEQ ID NO.5具有至少95%同一性之胺基酸序列,且該重鏈可變區包含與SEQ ID NO.7具有至少95%同一性之胺基酸序列。於各種實施態樣中,該抗體包含輕鏈可變區和重鏈可變區,該輕鏈可變區包含SEQ ID NO.5之胺基酸序列,且該重鏈可變區包含SEQ ID NO.7之胺基酸序列。
於各種實施態樣中,該方法進一步包含在IL-4之存在下培養該等B細胞。於各種實施態樣中,該方法進一步包含在IL-21之存在下培養該等B細胞。於各種實施態樣中,該等經培養之B細胞表現下列標記至少一者:CD62L、CCR7、CD80、CD86、CD54、ICAM、CD58、或CD27。於各種實施態樣中,獲得至少約3x10
7個B細胞。於各種實施態樣中,該B細胞群係培養至少14天。
於各種實施態樣中,提供用於製造經工程處理之B細胞之方法,該方法包含從來源獲得B細胞群;在包含CD40L和CD40L交聯抗體之培養基中培養該等B細胞,其中該CD40L融合蛋白包含與SEQ ID NO.3之胺基酸序列具有至少95%同一性之胺基酸序列,而該CD40L交聯抗體之輕鏈可變區與SEQ ID NO.5之胺基酸序列具有至少95%同一性,且CD40L交聯抗體之重鏈可變區與SEQ ID NO.7之胺基酸序列具有至少95%同一性;及將該等B細胞投予該個體。於各種實施態樣中,該來源為哺乳動物。於各種實施態樣中,該CD40L融合蛋白包含SEQ ID NO.3之胺基酸序列。於各種實施態樣中,該抗體包含輕鏈可變區和重鏈可變區,該輕鏈可變區包含SEQ ID NO.5之胺基酸序列,該重鏈可變區包含SEQ ID NO.7之胺基酸序列。
於各種實施態樣中,該方法進一步包含將該等B細胞工程處理以表現有效載荷、嵌合受體、或二者。於各種實施態樣中,該B細胞係將該等B細胞培養在具有CD40L和CD40L交聯劑之培養基中之前經工程處理。於各種實施態樣中,該B細胞係將該等B細胞培養在具有CD40L和CD40L交聯劑之培養基中之後經工程處理。於各種實施態樣中,該方法進一步包含在IL-4之存在下培養該等B細胞。於各種實施態樣中,該方法進一步包含在IL-21之存在下培養該等B細胞。於各種實施態樣中,該等經培養之B細胞表現下列標記中至少一者:CD62L、CCR7、CD80、CD86、CD54、ICAM、CD58、或CD27。於各種實施態樣中,獲得至少約3x10
7個B細胞。於各種實施態樣中,該B細胞群係經培養至少14天。
於各種實施態樣中,本發明關於包含CD40L融合蛋白之B細胞擴增培養基,其中該CD40L融合蛋白包含與SEQ ID NO.3具有至少95%同一性之胺基酸序列及CD40L交聯抗體,該CD40L交聯抗體之輕鏈可變區與SEQ ID NO.5之胺基酸序列具有至少95%同一性且該CD40L交聯抗體之重鏈可變區與SEQ ID NO.7之胺基酸序列具有至少95%同一性;及將該等B細胞投予該個體。
於各種實施態樣中,該CD40L融合蛋白包含SEQ ID NO.3之胺基酸序列。於各種實施態樣中,該抗體包含輕鏈可變區和重鏈可變區,該輕鏈可變區包含SEQ ID NO.5之胺基酸序列且該重鏈可變區包含SEQ ID NO.7之胺基酸序列。於各種實施態樣中,該培養基進一步包含IL-4。於各種實施態樣中,該培養基進一步包含IL-21。
應理解的是,本文之描述僅用於示例和解釋,而非用於限制本發明申請專利之範圍。在本申請案中,除非另有明確說明,否則單數之使用包括複數。
I.
概述
應理解的是,本發明關於產生、擴增和/或分離經工程處理之B細胞群的方法。例如,本方法可依2020年9月2日提交之美國臨時專利申請案編號63/073799和2020年3月31日提交之美國臨時專利申請案編號63/003120中之描述來產生,例如各種經工程處理之B細胞。這些包括,但不限於:
1) 已使用,例如結合結構域,諸如scFv、抗體、配體、受體或其片段修飾以歸巢至所欲部位/標靶之B細胞;
2) 已使用歸巢結構域修飾之B細胞,其進一步包含活化,及視需要地,共刺激結構域,從而使該B細胞可歸巢並在與合需之標靶交互作用時活化;
3) 經工程處理以能夠產生合需之蛋白質有效載荷,諸如抗體、治療性蛋白質、多肽、核酸序列(例如RNAi),等之B細胞;
4) 經工程處理之包含歸巢/結合結構域、活化結構域、可選擇之共刺激結構域的經工程處理之B細胞,其進一步經工程處理以表現合需之蛋白質有效載荷,諸如抗體、治療性蛋白質、多肽、核酸序列(諸如RNAi),等;
5) 已經過修飾以表現整合素、歸巢抗體、蛋白質或受體之B細胞,此使得該B細胞被吸引至在特定部位之特定配體、趨化因子或引誘劑/所欲標靶(例如歸巢組織處),且可藉此歸巢至所欲之部位/標靶,例如以遞送合需之有效載荷;
6) 已經過修飾以表現免疫抑制分子之B細胞,從而使該定位於所欲部位/標靶之B細胞的發炎和自體免疫活性降低,從而導致正向治療反應;
7) 已使用化合物或其衍生物處理之B細胞,從而藉由表現特定之B細胞整合素和/或歸巢受體來改變該等B細胞之運輸;
8) 已(i)使用Toll樣受體(TLR)激動劑處理和/或(ii)經工程處理以表現組成上活性之TLR的B細胞,以增強B細胞和/或產生有效之效應B細胞以增加個體之免疫反應;
9) 已使用編碼特定之所欲抗原的mRNA進行電穿孔之B細胞,該mRNA係與溶酶體蛋白之靶向信號融合,從而使該等B細胞可同時且有效地將所欲之特定抗原和/或抗原衍生之表位呈遞在HLA第I類和第II類分子中;
10) 已使用編碼上述第1至9部分中提及之任何項目的自行擴增RNA進行電穿孔的B細胞。
應理解的是,本申請案之經工程處理或修飾之B細胞的各種實施態樣並不交互排斥,且除非明確指出,可以任何方式彼此組合,而無任何限制,以實現促進本文考慮之任何結果和/或治療反應。
更具體地說,本方法可作為製造技術以在下列B細胞實施態樣之製造方法中產生經改善之B細胞擴增。這些描述於2020年9月2日提交之美國臨時專利申請案第63/073799號和2020年3月31日提交之美國臨時專利申請案第63/003120號中(其全文以引用方式併入本文)。用於製造本發明之構建體和經工程處理之免疫細胞的某些方法描述於PCT申請案PCT/US2015/14520中(其全文以引用方式併入本文)。製造該等構建體和細胞之其他方法可在美國臨時專利申請案編號62/244,036中找到(其全部內容進一步以引用方式併入本文)。
本發明亦關於使用藉由本文描述之方法產生之經工程處理的B細胞來治療疾病或病症之方法。適合治療之疾病或病症的實例包括,但不限於癌症、心臟病、發炎性疾病、肌肉萎縮疾病、神經疾病,等。
Ⅱ . 定義
本文使用之章節標題僅用於組織目的,而不應被解釋為限制所描述之主題。本申請案中引用之所有文件或文件部分,包括,但不限於專利案、專利申請案、文章、書籍和論文之全文以引用方式明確併入本文以用於任何目的。除非另有說明,否則根據本揭示所使用之下列術語應被理解為具有下列含義:
本申請案中,除非另有說明,否則
“ 或 ”之使用係指
“ 和 / 或 ”。此外,術語
“ 包括 (including) ”,以及其他形式,諸如
“ 包括 (includies) ”和
“ 包括 (included) ”之用途並非限制。此外,除非另有明確說明,否則諸如
“ 元件 ”或
“ 組分 ”之類的術語包含含有多於一個之次單位的單位,以及元件和組分。
術語
“ 多核苷酸 ”、
“ 核苷酸 ”或
“ 核酸 ”同時包括單股和雙股核苷酸聚合物。包含核苷酸之多核苷酸可為核糖核苷酸或去氧核糖核苷酸或任一類型之核苷酸的經修飾形式。該修飾包括鹼基修飾,諸如溴尿苷和肌苷衍生物、核糖修飾,諸如2',3'-二去氧核糖,及核苷酸間鍵聯修飾,諸如硫代磷酸酯、二硫代磷酸酯、硒代磷酸酯、二硒代磷酸酯、苯胺基硫代磷酸酯、胺苯基磷酸酯和磷醯胺酸酯。
術語
“ 寡核苷酸 ”係指包含200個或更少個核苷酸之多核苷酸。寡核苷酸可為單股或雙股的,例如用於構建突變基因。寡核苷酸可為有義或反義寡核苷酸。寡核苷酸可包括用於檢測分析之標記,包括放射性標記、螢光標記、半抗原或抗原標記。寡核苷酸可用於,例如作為PCR引物、選殖引物或雜交探針。
術語
“ 控制序列 ”係指可影響與其連接之編碼序列的表現和加工的多核苷酸序列。該等控制序列之性質可取決於該宿主生物。於特定之實施態樣中,用於原核生物之控制序列可包括啟動子、核醣體結合部位和轉錄終止序列。例如,用於真核生物之控制序列可包括包含一或多個轉錄因子之識別部位的啟動子、轉錄增強子序列和轉錄終止序列。“控制序列”可包括前導序列(信號肽)和/或融合伴侶序列。
如本文所使用之
“ 可操作地連接 ”係指該術語所適用之組分處於允許其在合適條件下執行其固有功能的關係。
術語
“ 載體 ”係指用於將蛋白質編碼信息轉移入宿主細胞中的任何分子或實體(例如核酸、質粒、噬菌體或病毒)。術語“表現載體”或“表現構建體”係指適合用於將宿主細胞轉形且含有核酸序列的載體,該核酸序列指導和/或控制(與宿主細胞聯合)可操作地連接至其上的一或多種異源編碼區之表現。表現構建體可包括,但不限於影響或控制轉錄、轉譯之序列,且若存有內含子時,影響與其可操作地連接之編碼區的RNA剪接。
術語
“ 宿主細胞 ”係指已使用核酸序列轉形或能夠被核酸序列轉形,且藉此表現所欲基因之細胞。該術語包括親代細胞之子代,無論該子代在形態或遺傳組成上是否與原始親代細胞相一致,只要存在該所欲之基因即可。
術語
“ 轉形 ”係指細胞遺傳特性中之變化,且當細胞已經過修飾以含有新DNA或RNA時,該細胞已被轉形。例如,當經由轉染、轉導或其他技術將新的遺傳物質引入細胞中使細胞從其天然狀態進行遺傳修飾時,該細胞被轉形。在轉染或轉導之後,該轉形DNA可藉由物理方式整合入細胞之染色體中而與該細胞之DNA重組,或可暫時以游離基因形元件形式保持而不被複製,或者可以質粒形式獨立複製。當該轉形DNA隨著細胞分裂而複製時,該細胞被認為已經“穩定轉形”。
術語
“ 轉染 ”係指由細胞攝入外來或外源DNA。許多轉染技術為本技藝中眾所周知且揭示於本文中。參見
,例如Graham
et al.,1973,
Virology, 1973, 52:456;Sambrook
et al., Molecular Cloning: A Laboratory Manual, 2001, 如上述;Davis
et al., Basic Methods in Molecular Biology, 1986, Elsevier;Chu
et al., 1981, Gene, 13:197。
術語
“ 轉導 ”係指經由病毒載體將外源DNA引入細胞所憑藉之過程。參見,例如Jones
et al., Genetics: Principles and Analysis, 1998, Boston: Jones & Bartlett Publ。
術語
“ 多 肽 ”或
“ 蛋白質 ”係指具有蛋白質之胺基酸序列的大分子,包括從天然序列刪除、添加和/或取代一或多個胺基酸。具體地說,術語
“ 多 肽 ”和
“ 蛋白質 ”包含抗原結合分子、抗體或從抗原結合蛋白刪除、添加和/或取代一或多個胺基酸的序列。術語
“ 多 肽 片段 ”係指與全長天然蛋白質相比較,具有胺基端缺失、羧基端缺失和/或內部缺失之多肽。當與天然蛋白質相比較時,該等片段亦可含有經修飾之胺基酸。有用之多肽片段包括抗原結合分子之免疫功能片段。
術語
“ 經分離的 ”係指(i)不含至少一些通常會與其一起被發現的其他蛋白質,(ii)基本上不含來自相同來源,例如來自相同物種的其他蛋白質,(iii)與至少約50%之自然界中與之聯結的多核苷酸、脂質、碳水化合物或其他物質分開,(iv)與在自然界中不與之聯結的多肽可操作地聯結(藉由共價或非共價交互作用),或(v)不存在於自然界中。
多肽(例如抗原結合分子)之
“ 變體 ”包含相對於另一多肽序列而言,該胺基酸序列中被插入、刪除和/或取代一或多個胺基酸殘基的胺基酸序列。變體包括融合蛋白。
術語
“ 同一性 ”係指當藉由比對和比較序列來測定時,具有二或更多個多肽分子或二或更多個核酸分子的序列之間的關係。
“ 同一性百分比 ”係指在相比較之分子中的胺基酸或核苷酸之間的相同殘基之百分比,且係基於相比較分子中最小分子的大小計算。對於這些計算,比對中的間隙(若有的話)較佳為藉由特定之數學模型或電腦程式(即“算法”)來解決。
為了計算同一性百分比,相比較之序列通常以能在序列之間得到最大匹配的方式進行比對。可用於測定同一性百分比之電腦程式的一種實例為GCG程式包,其包括GAP (Devereux
et al.,
Nucl. Acid Res., 1984, 12, 387;Genetics Computer Group, University of Wisconsin, Madison, Wis.)。使用電腦演算法GAP來比對要測定序列同一性百分比的二個多肽或多核苷酸。比對序列以獲得各別胺基酸或核苷酸之最佳匹配(如藉由該算法測定之“匹配跨度”)。於某些實施態樣中,該算法意使用標準比較矩陣(參見,例如用於PAM 250比較矩陣之Dayhoff
et al., 1978, Atlas of Protein Sequence and Structure, 5:345-352;用於BLO-SUM 62比較矩陣之Henikoff
et al., 1992,
Proc. Natl. Acad. Sci. U.S.A., 89, 10915-10919)。
如本文所使用者,該二十種常規(例如天然存在的)胺基酸及其縮寫係遵循常規用法。參見,例如Immunology A Synthesis(2nd Edition, Golub and Green, Eds., Sinauer Assoc., Sunderland, Mass.(1991))(其以引用方式併入本文以用於任何目的)。該二十種常規胺基酸、非天然胺基酸,諸如α-,α-二取代之胺基酸、N-烷基胺基酸、乳酸及其他非常規胺基酸之立體異構體(例如D-胺基酸)亦可為本發明多肽之合適組分。非常規胺基酸之實例包括:4-羥基脯胺酸、γ-羧基-麩胺酸、ε-N,N,N-三甲基離胺酸、e-N-乙醯離胺酸、0-磷酸絲胺酸、N-乙醯絲胺酸、N-甲醯甲硫胺酸、3-甲基組胺酸、5-羥基離胺酸、σ-N-甲基精胺酸及其他類似之胺基酸和亞胺基酸(例如4-羥基脯胺酸)。按照標準使用和慣例,本文所使用之多肽符號中,左手方向為胺基端方向,右手方向為羧基端方向。
保守性胺基酸取代可包含非天然存在之胺基酸殘基,其通常藉由化學肽合成方法納入,而非藉由在生物系統中合成納入。這些包括肽模擬物及胺基酸部分之其他反轉或倒轉形式。天然存在之殘基可基於共通之側鏈性質分成幾類:
a) 疏水性:正白胺酸、Met、Ala、Val、Leu、Ile;
b) 中性親水性:Cys、Ser、Thr、Asn、Gln;
c) 酸性:Asp、Glu;
d) 鹼性:His、Lys、Arg;
e) 影響鏈取向之殘基:Gly、Pro;和
f) 芳香族:Trp、Tyr、Phe。
例如,非保守取代可涉及將這些類別其中一者之成員替換為另一類別之成員。
根據某些實施態樣,在對抗原結合分子、經工程處理之T細胞的共刺激或活化結構域進行改變時,可考慮胺基酸之親水指數。各胺基酸均已基於其疏水性和電荷特性而被指定親水指數。其為:異白胺酸(+4.5);纈胺酸(+4.2);白胺酸(+3.8);苯丙胺酸(+2.8);半胱胺酸/胱胺酸(+2.5);甲硫胺酸(+1.9);丙胺酸(+1.8);甘胺酸(-0.4);蘇胺酸(-0.7);絲胺酸(-0.8);色胺酸(-0.9);酪胺酸(-1.3);脯胺酸(-1.6);組胺酸(-3.2);麩胺酸(-3.5);麩胺醯胺
(-3.5);天冬胺酸(-3.5);天冬醯胺(-3.5);離胺酸(-3.9);和精胺酸(-4.5)。參見,例如Kyte
et al., 1982,
J. Mol. Biol., 157, 105-131。已知某些胺基酸可取代具有類似親水指數或分數的其他胺基酸且仍然保留類似之生物活性。本技藝亦理解相似胺基酸可基於親水性有效地進行取代,特別是當由此創建之生物學上的功能性蛋白質或肽係意圖用於免疫學實施態樣時(如同本案例中者)。示例性胺基酸取代列於表1中。
術語“
衍生物”係指包括除胺基酸(或核酸)之插入、缺失或取代以外的化學修飾之分子。於某些實施態樣中,衍生物包含共價修飾,包括,但不限於與聚合物、脂質或其他有機或無機部分化學鍵結。於某些實施態樣中,經化學修飾之抗原結合分子可具有較未經化學修飾之抗原結合分子更長的循環半衰期。於一些實施態樣中,衍生性抗原結合分子係經共價修飾以包括一或多種水溶性聚合物連接物,包括,但不限於聚乙二醇、聚氧基乙二醇或聚丙二醇。
肽類似物通常以具有類似於模板肽之性能的非肽藥物形式用於製藥工業中。這些類型之非肽化合物被稱為“
肽模擬物(
peptide mimetic)”或“
肽模擬物(
peptidomimetic)
”。Fauchere, J. L., 1986,
Adv. Drug Res., 1986, 15, 29;Veber, D. F. & Freidinger, R. M., 1985,
Trends in Neuroscience, 8, 392-396;和Evans, B. E.,
et al., 1987,
J. Med. Chem., 30, 1229-1239(其以引用方式併入本文以用於任何目的)。
術語“
治療有效量”係指經測定用於在哺乳動物中產生治療反應之免疫細胞或其他治療劑的量。該等治療有效量可輕易地由本技藝之一般技術人士確定。
術語“
患者”和“
個體”可互換使用且包括人類和非人類動物個體,以及患有經正式診斷之疾病的個體、不具有經正式診斷之疾病的個體、接受醫療護理之個體、處於發展出疾病之風險中的個體,等。
術語“
治療 (treat)”和“
治療 (treatment)”包括治療性治療、預防性治療,以及其中降低個體發展出疾病或其他風險因素之風險的應用。治療不需要完全治癒疾病且包含其中個體減輕症狀或潛在風險因素的實施態樣。“預防”一詞並不要求100%排除事件發生的可能性。相反地,其表示在化合物或方法存在之情況下,事件發生的可能性已降低。
標準技術可用於重組DNA、寡核苷酸合成以及組織培養和轉形(例如電穿孔、脂質轉染)。酶催化性反應和純化技術可根據製造商之說明書或依本技藝中通常熟練的或依本文之描述進行。前述技術和程序通常可根據本技藝所周知之常規方法進行及依本專利說明書全文中所引用和討論之各種一般和更具體的參考文獻中之描述執行。參見,例如Sambrook
et al., Molecular Cloning: A Laboratory Manual(2d ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.(1989))(其以引用方式併入本文以用於任何目的)。
如本文所使用之術語“
實質上 (substantially)”或“
本質上 (essentially)”係指與參考數量、水準、數值、數目、頻率、百分比、尺寸、大小、量、重量或長度相比較,約90%、91%、92%、93%、94%、95%、96%、97%、98%或99%更高之數量、水準、數值、數目、頻率、百分比、尺寸、大小、量、重量或長度。於一實施態樣中,術語“本實上相同”或“實質上相同”係指與參考數量、水準、數值、數目、頻率、百分比、尺寸、大小、量、重量或長度相比較,約為相同之數量、水準、數值、數目、頻率、百分比、尺寸、大小、量、重量或長度範圍。
如本文所使用者,術語“
實質上不含”和“
本質上不含”可互換使用,且當用於描述組成物,諸如細胞群或培養基時,係指不含具體指定之物質的組成物,諸如95%不含、96%不含、97%不含、98%不含、99%不含該具體指定之物質,或藉由常規方法測量時無法檢測到。類似之含義可應用於術語“
不存在”,其中指不存在組成物之特定物質或組分。
如本文所使用者,術語“
可感知的”係指藉由一或多種標準方法可輕易檢測到之數量、水準、數值、數目、頻率、百分比、尺寸、大小、量、重量或長度的範圍或事件。術語“
不可感知的 (not-appreciable)”和“
不可感知的 (not appreciable)”及其同等物係指藉由標準方法不易檢測或檢測不到之數量、水準、數值、數目、頻率、百分比、尺寸、大小、量、重量或長度的範圍或事件。於一實施態樣中,若事件發生少於該時間之5%、4%、3%、2%、1%、0.1%、0.001%或更少,則該事件是不可感知的。
在本專利說明書之全文中,除非上下文另有要求,否則詞語“
包含 (comprise)”、“
包含 (comprises)”和“
包含 (comprising)”將被理解為暗示包含該聲明之步驟或元件或一組步驟或元件,但不排除任何其他步驟或元件或一組步驟或元件。於特定之實施態樣中,使用之術語“包括”、“具有”、“含有”和“包含”為同義。
如本文所使用者,“
由……組成”係指包括,且限於短語“
由……
組成”之後的任何內容。因此,短語“
由……組成”表示所列之元件為必需的或為強制性的,且無其他元件可能存在。
“
本質上由……組成”係指包括列於該短語之後的任何元件,且限於不干擾或有助於本揭示中具體指明之該列出之元件的活性或作用的其他元件。因此,短語“本質上由……組成”表示所列之元件為必需的或強制性的,但沒有其他元件為可選擇的且根據其是否影響所列元件之活性或作用而可能存在或可能不存在。
本專利說明書全文中對“
一種實施態樣”、“
一實施態樣”、“
特定之實施態樣”、“
相關之實施態樣”、“
某種實施態樣”、“
另外之實施態樣”或“
進一步之實施態樣”或彼等之組合的引用意指針對該實施態樣所描述之特定特性、結構或特徵係包括在至少一種本發明之實施態樣中。因此,本專利說明書全文中各處出現之前述短語不一定都指同一實施態樣。此外,該特定特性、結構或特徵可以任何合適之方式組合在一或多個實施態樣中。
如本文所使用之術語“
約”或“
近似”係指變化高達參考數量、水準、數值、數目、頻率、百分比、尺寸、大小、量、重量或長度之30、25、20、15、10、9、8、7、6、5、4、3、2或1%的數量、水準、數值、數目、頻率、百分比、尺寸、大小、量、重量或長度。於特定之實施態樣中,當術語“約”或“近似”在數值之前表示該數值加或減15%、10%、5%或1%之範圍,或任何其居間範圍。
如本文所使用之術語“
引入”係指包含使細胞與多核苷酸、多肽或小分子接觸的過程。引入步驟亦可包含將多核苷酸或多肽顯微注射入細胞中、使用脂質體將多核苷酸或多肽遞送入細胞中、或將多核苷酸或多肽與細胞可滲透部分融合以將其引入細胞中。
Ⅲ . 用於細胞療法之 B 淋巴細胞群的擴增方法
於各種實施態樣中,思考經工程處理之B淋巴細胞群之經改良的擴增方法。該方法涉及透過包含CD40配體之細胞培養基將表現在B細胞上之CD40與交聯抗體交聯。已證明將CD40L與IL-4(其為已知之用於活化B細胞的生長因子)結合對B細胞之有效活化和增殖至關重要。Banchereau, J.
et al.(1991) Science 251: 70-72;Schultze, J.L.
et al.(1997) J. Clin. Invest. 100: 2757-2765。同樣地,據報導,IL-21亦為B細胞活化和增殖之有效刺激物。然而,此外,IL-21驅動B細胞朝向漿細胞表型成熟。值得注意的是,本發明之各種實施態樣的細胞培養基和方法使經工程處理之B細胞能夠實現活化和增殖結果,此與經典的基於飼養細胞之NIH3T3/tCD40L方案相當。
1. CD-40 配體
於各種實施態樣中,該等經工程處理之B細胞係在包含CD40L序列和多聚化結構域之融合蛋白的存在下擴增。於各種實施態樣中,該多聚化結構域係衍生自肌腱蛋白(tenascin)。於各種實施態樣中,該多聚化結構域包含:
於較佳之實施態樣中,該CD40L融合蛋白包含與SEQ ID NO.3具有至少85%同一性之胺基酸序列。於各種實施態樣中,該CD40L融合蛋白包含與SEQ ID NO.3具有至少95%同一性之胺基酸序列。於各種實施態樣中,該CD40L融合蛋白包含SEQ ID NO.3之胺基酸序列。
2. 交聯劑
於各種實施態樣中,該抗體包含輕鏈可變區和重鏈可變區,該輕鏈可變區包含與SEQ ID NO.5具有至少95%之同一性的胺基酸序列,該重鏈可變區包含與SEQ ID NO.7具有至少95%之同一性的胺基酸序列。於各種實施態樣中,該抗體包含輕鏈可變區和重鏈可變區,該輕鏈可變區包含SEQ ID NO.5之胺基酸序列,該重鏈可變區包含SEQ ID NO.7之胺基酸序列。於各種實施態樣中,該抗體包含SEQ ID NO.4之輕鏈及SEQ ID NO.6之重鏈。於各種實施態樣中,該抗體包含輕鏈和重鏈,該輕鏈包含與SEQ ID NO.4具有至少85%之同一性的胺基酸序列,該重鏈包含與SEQ ID NO.6具有至少85%之同一性的胺基酸序列。於各種實施態樣中,該抗體包含輕鏈和重鏈,該輕鏈包含與SEQ ID NO.4具有至少95%之同一性的胺基酸序列,該重鏈包含與SEQ ID NO.6具有至少95%之同一性的胺基酸序列。
IV. 經工程處理之 B 細胞
如本文所使用者,術語“經工程處理之B細胞”係指已經過遺傳改造以表現合需之蛋白質或分子的B細胞。該等蛋白質或分子可為內源性受體或嵌合受體。該等經工程處理之B細胞可經遺傳改造以表現“歸巢”受體,該受體靶向具體指定之組織/器官類型或靶向腫瘤或具體指定之細胞類型。
1. 抗原
腫瘤抗原。於某些實施態樣中,B細胞之所欲部位/標靶為腫瘤抗原。本發明之抗原結合結構域(部分)的選擇將取決於待治療之特定癌症類型。一些腫瘤抗原可能為與膜結合的,而其他可能為分泌型的。例如,腫瘤抗原可能分泌出並積聚在細胞外基質中,或者該腫瘤抗原可能以MHC複合物之一部分表現。腫瘤抗原為本技藝所周知且可包括,例如CD19、KRAS、HGF、CLL、與神經膠質瘤相關之抗原、癌胚抗原(CEA);β-人絨毛膜促性腺激素、α胎兒蛋白(AFP)、凝集素(lectin)反應性AFP、甲狀腺球蛋白、RAGE-1、MN-CA IX、人端粒酶逆轉錄酶、RU1、RU2(AS)、腸羧基酯酶、mut hsp70-2、M-CSF、前列腺酶、前列腺特異性抗原(PSA)、PAP、NY-ESO-1、LAGE-1a、p53、蛋白質、PSMA、Her2/neu、生存素(survivin)和端粒酶(telomerase)、前列腺癌腫瘤抗原1(PCTA-1)、MAGE、ELF2M、中性粒細胞彈性蛋白酶、ephrinB2、CD22、胰島素生長因子(IGF)-I、IGF-II、IGF-I受體、間皮素(mesothelin)、EGFR、BCMA、KIT和IL-13。
傳染病抗原。於某些實施態樣中,所欲之部位/標靶為針對可能需要免疫反應之傳染病抗原。傳染病抗原為本技藝所周知且可包括,但不限於病毒、細菌、原生生物和寄生蟲抗原,諸如寄生蟲、真菌、酵母菌、支原體、病毒蛋白、細菌蛋白和碳水化合物,以及真菌蛋白和碳水化合物。另外,傳染病抗原之傳染病類型並無特別限定,可包括,但不限於病毒性傳染病中之頑固性疾病,諸如AIDS、B型肝炎、愛潑斯坦-巴爾病毒(Epstein-Barr virus)(EBV)感染、HPV感染、HCV感染,等。寄生蟲抗原可包括,但不限於瘧原蟲孢子體蛋白。
於某些實施態樣中,該等經修飾之B細胞表現經工程處理之B細胞受體(CAR-B),該B細胞受體(CAR-B)包含胞外結構域、跨膜結構域和胞內結構域。於某些實施態樣中,該胞外結構域包含結合結構域和鉸鏈域。
於某些實施態樣中,該胞外結構域包含結合結構域,諸如scFv、配體、抗體、受體或其片段,其允許該經修飾之B細胞藉由與表現在那些細胞表面上之蛋白質結合來靶向特定之靶細胞。於某些實施態樣中,該經修飾之腫瘤細胞靶向表現在腫瘤細胞表面上之蛋白質/抗原並與其結合。於某些實施態樣中,該經修飾之B細胞進一步表現有效載荷。於某些實施態樣中,該有效載荷能夠增加腫瘤中之交叉呈遞的樹突細胞(DC)之數量。於某些實施態樣中,該有效載荷能夠活化並吸引T細胞進入腫瘤中。於某些實施態樣中,該有效載荷能夠促進腫瘤中之三級淋巴結構(TLS)的形成。於本發明之某些實施態樣中,該經修飾之B細胞表現CAR-B和有效載荷二者。於某些實施態樣中,該CAR-B包含刺激性結構域,當其與表現在腫瘤細胞表面上之抗原或蛋白質結合時會活化該有效載荷之表現。
2. B 細胞中之嵌合抗原受體 (CAR-B) 的設計和結構域取向
於各種實施態樣中,本發明提供嵌合B細胞受體(CAR-B)。應瞭解的是,嵌合B細胞受體(CAR-B)為經遺傳工程處理之受體。根據本技藝已知之技術,這些經工程處理之受體可輕易地插入B細胞中並由B細胞表現。藉由CAR-B可對單一受體進行編程以識別表現在腫瘤細胞上之特定蛋白質或抗原,且當與該蛋白質或抗原結合時可引發抗腫瘤反應。於各種實施態樣中,該CAR-B係部分作為歸巢機制以將B細胞遞送至標靶組織。
應瞭解的是,相對於攜帶該受體之細胞,本發明之嵌合B細胞受體將包含胞外結構域(其將包含抗原結合結構域並可包含胞外信號傳導結構域和/或鉸鏈結構域)、跨膜結構域和胞內結構域。該胞內結構域包含至少一個活化結構域,其較佳為由CD79a(免疫球蛋白α)、CD79b(免疫球蛋白β)、CD40、CD19、CD137、Fcγr2a和/或MyD88所組成。應進一步理解的是,該抗原結合結構域係經工程處理,從而使其位於該分子/構建體之細胞外部分,從而能夠識別並與其標靶或標靶們結合。
於各種實施態樣中,嵌合B細胞受體係由胞外結構域、跨膜結構域和胞質結構域組成。於各種實施態樣中,該胞質結構域包含活化結構域。於各種實施態樣中,該胞質結構亦可包含共刺激結構域。於各種實施態樣中,該胞外結構域包含抗原結合結構域。於各種實施態樣中,該胞外結構域進一步包含介於該抗原結合結構域與跨膜結構域之間的鉸鏈區。
胞外結構域。本發明可使用之胞外結構域有許多。於各種實施態樣中,該胞外結構域包含抗原結合結構域。於各種實施態樣中,該胞外結構域亦可包含鉸鏈區和/或信號傳導結構域。於各種實施態樣中,該含有IgG1恆定結構域之胞外結構域亦可包含IgG1(孔)或IgG1(鈕)以促進定向之cBCR形成。
抗原結合結構域和結合結構域。如本文所使用者,“抗原結合結構域”、“抗原-結合結構域”或“結合結構域”係指該B-CAR能與表現在細胞表面上之抗原或蛋白質結合的一部分。於一些實施態樣中,該抗原-結合結構域與涉及過度增殖性疾病之細胞上的抗原或蛋白質結合。於較佳之實施態樣中,該抗原-結合結構域與表現在腫瘤細胞表面上之抗原或蛋白質結合。該抗原-結合分子可鑑於下列定義和描述進一步理解。
當該解離常數(K
d)為1x10
-7M時,抗原結合結構域被稱為與其標靶抗原或蛋白質“特異性結合”。當該K
d為1至5x10
-9M時,該抗原結合結構域以“高親和力”與抗原特異地結合,而當該K
d為1至5x10
-10M時,該抗原結合結構域以“非常高之親和力”與抗原特異地結合。於一實施態樣中,該抗原結合結構域之K
d為10
-9M。於一實施態樣中,該解離速率<1x10
-5。於其他實施態樣中,該抗原結合結構域將以介於約10
-7M至10
-13M之間的K
d與抗原或蛋白質結合,且再於另一實施態樣中,該抗原結合結構域將以1.0至5.0x
10之K
d結合。
當抗原結合結構域與一個標靶的結合較與第二個標靶的結合更緊密時,該抗原結合結構域被稱為“選擇性”。
術語“
中和”係指與配體結合並防止或降低該配體之生物學效果的抗原結合結構域。此可,例如藉由直接阻斷配體上之結合部位或透過間接方式藉由與配體結合並改變該配體之結合能力(諸如配體中之結構或能量改變)來完成。於一些實施態樣中,該術語亦可表示防止與其結合之蛋白質執行生物學功能之抗原結合結構域。
術語“
標靶”或“
抗原”係指能夠與抗原結合分子結合之分子或分子的一部分。於某些實施態樣中,標靶可具有一或多個表位。
術語“
抗體”係指所謂的免疫球蛋白,由免疫系統產生以識別特定抗原之Y形蛋白質。術語“抗體片段”係指抗體之抗原結合片段和Fc片段。抗原結合片段之類型包括:F(ab')2、Fab、Fab'和Fv分子。Fc片段完全從免疫球蛋白之重鏈恆定區產生。
胞外信號傳導結構域。該細胞外結構域有利於信號傳導及淋巴細胞對抗原之有效反應。本發明中具有特定用途之胞外結構域可源自(即,包含)CD28、CD28T(參見,例如美國專利申請案US2017/0283500A1)、OX40、4-1BB/CD137、CD2、CD7、CD27、CD30、CD40、程序性死亡-1(PD-1)、誘導性T細胞共刺激物(ICOS)、淋巴細胞功能相關之抗原-1(LFA-1、CD1-1a/CD18)、CD3γ、CD3δ、CD3ε、CD247、CD276(B7-H3)、LIGHT、(TNFSF14)、NKG2C、CD79a(免疫球蛋白α)、CD79b(免疫球蛋白β)、DAP-10、Fcγ受體、第1類MHC分子、TNF受體蛋白及免疫球蛋白、細胞因子受體、整合素、信號傳導淋巴細胞活化分子(SLAM蛋白)、活化NK細胞受體、BTLA、Toll配體受體、ICAM-1、B7-H3、CDS、ICAM-1、GITR、BAFFR、LIGHT、HVEM (LIGHTR)、KIRDS2、SLAMF7、NKp80(KLRF1)、NKp44、NKp30、NKp46、CD19、CD4、CD8α、CD8β、IL-2Rβ、IL-2Rγ、IL-7Rα、ITGA4、VLA1、CD49a、ITGA4、IA4、CD49D、ITGA6、VLA-6、CD49f、ITGAD、CD11d、ITGAE、CD103、ITGAL、CD1 la、LFA-1、ITGAM、CD1 1b、ITGAX、CD1 lc、ITGB1、CD29、ITGB2、CD18、LFA-1、ITGB7、NKG2D、TNFR2、TRANCE/RANKL、DNAM1(CD226)、SLAMF4 (CD244、2B4)、CD84、CD96(Tactile)、CEACAM1、CRT AM、Ly9(CD229)、CD160(BY55)、PSGL1、CD100 (SEMA4D)、CD69、SLAMF6(NTB-A、Ly108)、SLAM (SLAMF1、CD150、IPO-3)、BLAME(SLAMF8)、SELLPG (CD162)、LTBR、LAT、GADS、SLP-76、PAG/Cbp、CD19a、與CD83特異地結合之配體或彼等之任意組合。該胞外結構域可源自天然或合成來源。
鉸鏈結構域。如本文所描述者,胞外結構域通常包含鉸鏈部分。此為靠近細胞膜之胞外結構域的一部分。該胞外結構域可進一步包含間隔子區。根據本發明可使用各種鉸鏈,包括如上文討論之共刺激分子,以及免疫球蛋白(Ig)序列,3Xstrep II間隔子或其他合適分子,以實現與靶細胞之合需特殊距離。於一些實施態樣中,該整個胞外區包含一個鉸鏈區。於一些實施態樣中,該鉸鏈區包含如本文所描述之CD28或CD8或其部分之胞外結構域。
跨膜結構域。該B-CAR可經過設計以包含與該B-CAR之胞外結構域融合或以其他方式連接之跨膜結構域。其可以類似方法與B-CAR之胞內結構域融合。於一實施態樣中,使用與B-CAR中的結構域之一天然聯結的跨膜結構域。在一些情況下,可藉由胺基酸取代來選擇或修飾該跨膜結構域,以避免該等結構域與相同或不同表面膜蛋白之跨膜結構域結合以將與該受體複合物之其他成員的交互作用減至最少。該跨膜結構域可源自天然來源或合成來源。其中該來源為天然之情況下,該結構域可以源自任何膜結合或跨膜蛋白。本發明中具特定用途之跨膜區可源自(即,包含)CD28、CD28T、OX-40、4-1BB/CD137、CD2、CD7、CD27、CD30、CD40、程序性死亡-1(PD-1)、誘導性T細胞共刺激物(ICOS)、淋巴細胞功能相關之抗原-1(LFA-1、CD1-1a/CD18)、CD3γ、CD3δ、CD3ε、CD247、CD276(B7-H3)、LIGHT、(TNFSF14)、NKG2C、CD79a(免疫球蛋白α)、CD79b(免疫球蛋白β)、DAP-10、Fcγ受體、第1類MHC分子、TNF受體蛋白、免疫球蛋白、細胞因子受體、整合素、信號傳導淋巴細胞活化分子(SLAM蛋白)、活化NK細胞受體、BTLA、Toll配體受體、ICAM-1、B7-H3、CDS、ICAM-1、GITR、BAFFR、LIGHT、HVEM(LIGHTR)、KIRDS2、SLAMF7、NKp80 (KLRF1)、NKp44、NKp30、NKp46、CD19、CD4、CD8α、CD8β、IL-2Rβ、IL-2Rγ、IL-7Rα、ITGA4、VLA1、CD49a、ITGA4、IA4、CD49D、ITGA6、VLA-6、CD49f、ITGAD、CD11d、ITGAE、CD103、ITGAL、CD1 la、LFA-1、ITGAM、CD1 1b、ITGAX、CD1 lc、ITGB1、CD29、ITGB2、CD18、LFA-1、ITGB7、NKG2D、TNFR2、TRANCE/RANKL、DNAM1(CD226)、SLAMF4 (CD244、2B4)、CD84、CD96(Tactile)、CEACAM1、CRT AM、Ly9(CD229)、CD160(BY55)、PSGL1、CD100 (SEMA4D)、CD69、SLAMF6(NTB-A、Ly108)、SLAM (SLAMF1、CD150、IPO-3)、BLAME(SLAMF8)、SELLPG (CD162)、LTBR、LAT、GADS、SLP-76、PAG/Cbp、CD19a、與CD83特異地結合之配體或彼等之任意組合。
視需要地,短連接子可在B-CAR之胞外、跨膜和胞內結構域其中任一或某些結構域之間形成連接。
於某些實施態樣中,本發明之B-CAR中的跨膜結構域為CD28跨膜結構域。於一實施態樣中,本發明之B-CAR中的跨膜結構域為CD8跨膜結構域。
胞內 ( 細胞質 ) 結構域。本發明之B-CAR受體的胞內(IC或細胞質)結構域可活化該免疫細胞之正常效應子功能至少一者。
應理解的是,合適之細胞內分子包括,但不限於CD79a(免疫球蛋白α)、CD79b(免疫球蛋白β)、CD40、CD19、CD137、Fcγr2a和MyD88。細胞內分子可進一步包括CD28、CD28T、OX40、4-1BB/CD137、CD2、CD7、CD27、CD30、CD40、程序性死亡-1(PD-1)、誘導性T細胞共刺激物(ICOS)、淋巴細胞功能相關之抗原
-1(LFA-1、CD1-1a/CD18)、CD3γ、CD3δ、CD3ε、CD247、CD276(B7-H3)、LIGHT、(TNFSF14)、NKG2C、Igα(CD79a)、DAP-10、Fcγ受體、第1類MHC分子、TNF受體蛋白、免疫球蛋白、細胞因子受體、整合素、信號傳導淋巴細胞活化分子(SLAM蛋白)、活化NK細胞受體、BTLA、Toll配體受體、ICAM-1、B7-H3、CDS、ICAM-1、GITR、BAFFR、LIGHT、HVEM(LIGHTR)、KIRDS2、SLAMF7、NKp80(KLRF1)、NKp44、NKp30、NKp46、CD19、CD4、CD8α、CD8β、IL-2Rβ、IL-2Rγ、IL-7Rα、ITGA4、VLA1、CD49a、ITGA4、IA4、CD49D、ITGA6、VLA-6、CD49f、ITGAD、CD11d、ITGAE、CD103、ITGAL、CD1 la、LFA-1、ITGAM、CD1 lb、ITGAX、CD1 lc、ITGB1、CD29、ITGB2、CD18、LFA-1、ITGB7、NKG2D、TNFR2、TRANCE/RANKL、DNAM1 (CD226)、SLAMF4(CD244、2B4)、CD84、CD96 (Tactile)、CEACAM1、CRT AM、Ly9(CD229)、CD160 (BY55)、PSGL1、CD100(SEMA4D)、CD69、SLAMF6 (NTB-A、Ly108)、SLAM(SLAMF1、CD150、IPO-3)、BLAME (SLAMF8)、SELPLG(CD162)、LTBR、LAT、GADS、SLP-76、PAG/Cbp、CD19a、與CD83特異地結合之配體或彼等之任何組合。本發明之CAR-B的細胞質信號傳導部分內的細胞質信號傳導序列可以隨機或具體指定之順序彼此連接。
如本所使用之術語“
共刺激”結構域或分子係指用於擴增或抵消細胞之初始活化信號的細胞表面分子之異質基團。
於一較佳之實施態樣中,該細胞質結構域係經過設計以包含hCD19之信號傳導結構域。於另一實施態樣中,該細胞質結構域係經過設計以包含hCD40之信號傳導結構域。於另一實施態樣中,該細胞質結構域係經過設計以包含hCD40和hCD79b之信號傳導結構域。於另一實施態樣中,該細胞質結構域係經過設計以包含hCD40和hCD137之信號傳導結構域。於另一實施態樣中,該細胞質結構域係經過設計以包含hCD40和hFcγr2a之信號傳導結構域。於另一實施態樣中,該細胞質結構域係經過設計以包含hCD40和hMyd88之信號傳導結構域。於另一實施態樣中,該細胞質結構域係經過設計以包含hCD79a之信號傳導結構域。於另一實施態樣中,該細胞質結構域係經過設計以包含hCD79b之信號傳導結構域。這些實施態樣較佳為源自人類,但可源自其他物種。
B. 表現有效載荷之經修飾的 B 細胞。
於本發明之各種實施態樣中,提供能夠表現有效載荷之經修飾的B細胞。如本文所使用之術語“
有效載荷”係指作為治療劑之胺基酸序列、編碼肽或蛋白質之核酸序列或RNA分子。於某些實施態樣中,該有效載荷係用於遞送至腫瘤或腫瘤微環境。於某些實施態樣中,B細胞將能夠,例如增加腫瘤中交叉呈遞樹突細胞(DC)之數量的有效載荷遞送至腫瘤或腫瘤微環境是合需的。交叉呈遞DC將允許改善腫瘤抗原之呈遞。於各種實施態樣中,該有效載荷可能能夠活化T細胞並將其吸引入腫瘤中。活化腫瘤中更多之T細胞將補充交叉呈遞DC以重塑該腫瘤環境,使其具有更強之抗腫瘤免疫能力。有效載荷亦可能促進腫瘤中之三級淋巴結構(TLS)形成。臨床研究表明B細胞、TLS和對免疫檢查點阻斷的反應之間存在關係。
本發明之有效載荷的非排他性實例包括:IL-1、IL-7、IL-8、IL-10、IL-12、IL-13、IL-17、IL-18、IL-21、干擾素α、干擾素β、干擾素γ、TSLP、CCL21、FLT3L、XCL1、LIGHT(TNFSF14)、OX40L、CD137L、CD40L、ICOSL、抗CD3抗體、CD47、TIM4-FC、CXCL13、CCL21、CD80、CD40L、IFNα A2、LIGHT、4-1BBL、MDGF(C19orf10)、FGF10、PDGF、集聚蛋白(agrin)、TNF-α、GM-CSF、抗FAP抗體、抗TGF-β抗體;TGF-β陷阱、誘餌或其他抑制分子;抗BMP抗體;BMP陷阱、誘餌或其他抑制分子。
用於 有效載荷表現之信號傳導。於本發明之各種實施態樣中,該有效載荷係以受經活化之轉錄途徑控制的DNA構建體形式表現在經修飾之B細胞中。於某些實施態樣中,該有效載荷之表現受活化之T細胞核因子(“NFAT”)途徑控制。該NFAT途徑為在免疫反應過程中活化之轉錄因子途徑且被NFκB活化。於各種實施態樣中,該經修飾之B細胞同時表現有效載荷和CAR-B二者。於各種實施態樣中,當該經修飾之B細胞同時表現有效載荷和CAR-B二者時,該CAR-B可進一步編碼誘導NFκB途徑活化之信號傳導分子。該等分子包括,但不限於:CD79a(免疫球蛋白α)、CD79b(免疫球蛋白β)、CD40、CD19、CD137、Fcγr2a和MyD88。
於各種實施態樣中,本發明關於表現至少一種有效載荷之經分離的B細胞。於各種實施態樣中,本發明關於表現多於一種之有效載荷的經分離之B細胞。於各種實施態樣中,本發明關於表現1、2、3、4、5、6、7、8、9、10、11或12種不同之有效載荷的經分離之B細胞。
用於 歸巢之 B 細胞修飾。於本發明之各種實施態樣中,該等經工程處理之B細胞可使用歸巢結構域修飾(例如,如圖2中所示),從而使該等B細胞可歸巢至所欲之部位/標靶並在與該標靶交互作用時活化。此外,表現在B細胞膜上之識別標靶組織上之尋址素(addressin)和配體的B細胞歸巢受體、改變B細胞之運輸至特定部位的化合物或其衍生物以及該等B細胞之抑制性分子發炎和自體免疫活性可在B細胞歸巢和特化之免疫反應的發展中發揮作用。
表現所欲之整合素之經修飾的 B 細胞。由淋巴細胞表現之主要歸巢受體為整合素,其為以α和β鏈之異二聚體結構為特徵的一大類分子。一般而言,整合素之特異性α和β鏈的配對決定該歸巢受體之類型。例如α4鏈與β7鏈之配對決定該主要整合素分子(α4β7)的特徵,該主要整合素分子負責淋巴細胞與表現在派爾斑(Peyer's patch)(PP)中之高內皮小靜脈(HEV)和胃腸道(GI)道固有層(lamina propria)內皮小靜脈(LPV)上之黏膜尋址素細胞黏附分子1(MAdCAM-1)結合。同樣地,α4鏈與β1鏈之配對決定皮膚之歸巢受體(α4β1)的特徵。
於本發明之各種實施態樣中,可預先選擇具有介導較佳定位之特定性狀之B細胞來進行修飾。例如,可富集表現CXCR3之記憶B細胞,然後經工程處理。CXCR3細胞可被吸引至表現在發炎部位之配體。因此,經修飾之B細胞可被優先定位在該等部位。
於本發明之各種實施態樣中,提供表現整合素之α4鏈與β7鏈之經修飾的B細胞。理想的是,表現α4β7整合素將促進該經修飾之B細胞歸巢至結腸。於各種實施態樣中,提供表現整合素之α4鏈和β1鏈之經修飾的B細胞。理想的是,表現α4β1整合素將促進該經修飾之B細胞歸巢至皮膚。於各種實施態樣中,提供表現整合素之α和β鏈的合需配對之經修飾的B細胞,從而使所表現之α整合素促進該經修飾之B細胞歸巢至合需之所欲部位/標靶。因此,於各種實施態樣中,考慮用於在B細胞中表現之整合素之α和β鏈的任何合需組合,從而使表現該特定整合素之經修飾的B細胞靶向合需之所欲部位/標靶。
表現所欲之歸巢受體的經修飾之 B 細胞。B細胞具有歸巢至發炎組織之能力,而改變其歸巢受體表現可補充其天然歸巢傾向。B細胞定位亦由表現在特定位置或組織之發炎部位的引誘分子(例如,諸如配體和趨化因子之標靶)驅動。該等分子亦可包括抗體,諸如將細胞靶向外周淋巴結尋址素(PNAd)之MECA79抗體。Bahmani
et al., J Clin Invest. 2018;128(11):4770-4786;Azzi et al., Cell Rep. 2016;15(6):1202-13。因此,可對B細胞進行工程處理以表現有助於B細胞歸巢至所欲之部位/標靶及該等B細胞與合需標靶之交互作用的某些抗體、蛋白質和受體。在某些情況下,該等受體之表現將B細胞重定向至所欲之組織。
於本發明之各種實施態樣中,提供能夠表現歸巢抗體、蛋白質或受體之經修飾的B細胞,該歸巢抗體、蛋白質或受體之表現能夠將該經修飾之B細胞導向所欲之特定部位/標靶。表3中列出使用特定之歸巢受體/配體對之T細胞歸巢至特定歸巢組織(靶組織)的實例。該相同之特定歸巢受體/配體對亦能促進B細胞歸巢至特定之歸巢組織(標靶組織)。因此,於本發明之各種實施態樣中,使用表3中列出之對應的歸巢受體/配體對促進該等經修飾之B細胞歸巢至示例性歸巢組織(靶組織)。
於本發明之各種實施態樣中,提供表現一或多種抗體、蛋白質或受體的經修飾之B細胞,該一或多種抗體、蛋白質或受體使用如表3中列出之特定歸巢受體/配體對來促進該經修飾之B細胞歸巢至示例性標靶/歸巢組織。於本發明之各種實施態樣中,提供表現一或多種歸巢受體之經修飾的B細胞,該歸巢受體利用如表3和/或4中所列出之配體或趨化因子促進該經修飾之B細胞歸巢至該示例性標靶/歸巢組織。如本文所使用之術語“
B 細胞歸巢”係指將本申請案之B細胞定位、靶向、運輸、指導或重定向至其中需要將該治療性有效載荷遞送至所欲之部位/標靶,例如歸巢或標靶組織、特定位置或組織中之發炎部位、或腫瘤或腫瘤微環境。如在B細胞歸巢之背景下所使用的術語“
抗體”、“
蛋白質”或“
受體”係指作為治療劑之胺基酸序列、編碼肽或蛋白質之核酸序列或RNA分子,當其表現在本發明之經修飾的B細胞中時,其將B細胞導向所欲之部位/標靶。
於某些實施態樣中,該歸巢抗體、蛋白質或受體分子係用於將表現該等分子之經修飾的B細胞歸巢/靶向至所欲的部位/標靶。於某些實施態樣中,該歸巢抗體、蛋白質或受體分子係用於將表現該等分子之經修飾的B細胞歸巢/靶向在特定位置或組織中之發炎部位。於某些實施態樣中,該歸巢抗體、蛋白質或受體係用於將該B細胞靶向腫瘤或腫瘤微環境。於某些實施態樣中,將B細胞靶向特定位置是合需的,從而使本發明之經工程處理或經修飾的B細胞可將治療有效載荷遞送至所欲之合需位置,例如歸巢或靶組織、特定位置或組織中之發炎部位、或腫瘤或腫瘤微環境。因此,於某些實施態樣中,該等B細胞歸巢至所欲之部位/標靶,例如腫瘤或腫瘤微環境,並將能夠,例如增加所欲部位/標靶之交叉呈遞樹突狀細胞(DC)之數量的有效載荷遞送至所欲部位/目標(例如在腫瘤中)是合需的。
於各種實施態樣中,該歸巢抗體、蛋白質或受體係以DNA構建體之形式表現在經修飾或經工程處理的B細胞中。於各種實施態樣中,該歸巢抗體、蛋白質或受體係以在組成型活化之轉錄途徑之控制下的DNA構建體形式表現在經修飾的B細胞中。於各種實施態樣中,該涉及B細胞歸巢/靶向之歸巢抗體、蛋白質或受體並非天然表現在B細胞中或以高於B細胞中之天然表現水準的水準表現。使用根據本發明之特定歸巢受體/配體對使該等經修飾之B細胞歸巢至特定之歸巢/靶組織的實例列於表4中。應理解的是,雖然該示例性歸巢組織、歸巢受體和配體對列於表4中,但本發明之經修飾之B細胞可經工程處理以表現任何歸巢抗體、蛋白質、或受體(例如表5中所列之任何歸巢受體),從而使該經修飾之B細胞可被引導至所欲之特定部位/標靶。
本發明之用於特定歸巢受體/配體對之歸巢(靶)組織類型的非排他性實例包括:皮膚、腸道(腸、結腸、腸系膜淋巴結(mLN)、派爾斑(PP)、小腸)、肝臟、肺、骨髓、心臟、外周淋巴結(LN)、CNS、胸腺和骨髓。
可與本發明之特定或對應之引誘劑/配體/趨化因子配對之歸巢受體的非排他性實例包括:CLA(PSGL-1糖型)、CLA(PSGL-1糖型)、CCR10、CCR3、CCR4、CCR5、CCR6、CCR9、CD43E、CD44、c-Met、CXCR3、CXCR4、LFA-1、LFA-1(αLβ2)、選擇素配體、VLA-4、VLA-4(α4β1)和α4β7。
可與本發明之特定或對應的歸巢受體配對之配體/趨化因子的非排他性實例包括:CXCL16、CCL17、CCL17(22)、CCL20(MIP-3α)、CCL21、CCL25、CCL27、CCL28、CCL4、CCL5、CD62E、CD62P、CXCL10、CXCL12、CXCL13、CXCL16、CXCL9/CXCL10、CXCR3、E/P-選擇素、E-選擇素、GPR15L、HGF、透明質酸鹽、ICAM-1、用於CCR1、2、5之配體、MAdCAM、MAdCAM-1、PNAd、VAP-1、VCAM和VCAM-1。
於本發明之某些實施態樣中,提供經修飾之B細胞,該經修飾之B細胞表現或具有增加之示例性B細胞歸巢受體(例如,如表3中所列者)表現,從而使該經修飾之B細胞靶向所欲之對應歸巢組織,該對應之歸巢組織表現對應之配體/趨化因子(例如,如表3和/或4中所列者)。於本發明之某些實施態樣中,提供共同表現具有特異性α和β鏈配對之整合素和特異性B細胞歸巢受體(例如,如表3和/或4中所列者)的B細胞,該整合素和/或歸巢受體之表現促進或加速該經修飾之B細胞歸巢/靶向所欲之部位/標靶。於一些實施態樣中,提供共同表現α4β7整合素和CCR9之經修飾的B細胞。理想的是,α4β7和CCR9之共同表現將促進本發明之經修飾的B細胞之小腸歸巢。於一些實施態樣中,提供共同表現α4β1整合素和CCR4之經修飾的B細胞。理想的是,α4β1和CCR4之共同表現將促進本發明之經修飾的B細胞歸巢至小腸。
表現免疫抑制分子之經修飾的 B 細胞。B細胞為許多自體免疫性疾病的關鍵因素。然而,B細胞可治療性地用來拮抗自體免疫。具體而言,B細胞可經工程處理以表現至少一或多種免疫抑制分子,該免疫抑制分子可能會降低B細胞之自體免疫活性,從而減少自體免疫性疾病。免疫抑制分子為本技藝所周知。該等抑制分子可包括,但不限於IL-10、TGF-β、PD-L1、PD-L2、LAG-3和TIM-3。於本發明之某些實施態樣中,提供經工程處理之經修飾之B細胞以表現至少一或多種選自下列者之抑制性分子:IL-10、TGF-β、PD-L1、PD-L2、LAG-3和TIM-3,或彼等之任何組合,從而使該部位之發炎和定位於該部位之B細胞的自體免疫活性降低,從而導致正向治療反應。
改變 B 細胞運輸之化合物。於本發明之某些實施態樣中,提供使用至少一或多種化合物或其衍生物處理之經修飾的B細胞,該化合物或其衍生物藉由誘導特異性B細胞整合素和/或歸巢受體之表現來改變B細胞的運輸。改變B細胞之運輸的化合物或其衍生物為本技藝所周知。於某些實施態樣中,提供使用全反維他命A酸(ATRA)或其衍生物處理之經修飾的B細胞,該等經修飾之B細胞由於α4β7整合素和CCR9歸巢受體之表現增加而促進B細胞歸巢至腸(小腸)受體。如本文所使用者,術語“化合物”係指以合需方式改變B細胞運輸之化學品、藥物、治療劑或其衍生物。
於本發明之各種實施態樣中,經工程處理以共同表現特定整合素(例如,具有特定α和β鏈配對)和所欲之特定B細胞歸巢受體之經修飾的B細胞係使用至少一或多種化合物或其衍生物處理,該化合物或其衍生物改變該經修飾之B細胞的運輸並由於該特定整合素和/或歸巢受體之表現增加而促進該細胞歸巢至所欲之部位/標靶。於各種實施態樣中,經修飾以共同表現具有特定之α和β鏈配對之整合素和特定之B細胞歸巢受體的B細胞進一步表現至少一或多種免疫抑制分子,從而使該等經修飾之B細胞之靶向特定發炎部位的自體免疫活性降低,而導致自體免疫性疾病減少。於一些實施態樣中,該經工程處理以表現一或多種免疫抑制分子(例如IL-10、TGF-β、PD-L1、PD-L2、LAG-3和TIM-3或彼等之組合)的經修飾之B細胞係使用ATRA或其衍生物處理一段具體指定的期間,從而誘導α4β7整合素和CCR9歸巢受體表現以促進B細胞歸巢至所欲之特定部位/標靶(例如腸道),但該部位之發炎和定位於該部位之B細胞的自體免疫活性降低,導致正向之治療反應。於一實施態樣中,使用ATRA或其衍生物處理經工程處理以表現一或多種免疫抑制分子(例如IL-10、TGF-β或彼等之組合)的經修飾之B細胞一段具體指定的期間,從而誘導α4β7整合素和CCR9歸巢受體表現以促進B細胞歸巢至所欲之特定部位/標靶(例如腸道),但該部位之發炎和定位於該部位之B細胞的自體免疫活性降低,導致正向之治療反應。
應理解的是,本發明之任何經修飾以共同表現特定之B細胞整合素和歸巢受體(其將B細胞靶向所欲之特定歸巢/標靶組織)的B細胞可進一步經工程處理以表現一或多種免疫抑制分子,以減少發炎和定位於該部位之B細胞的自體免疫活性,和/或使用化合物處理以藉由誘導該特定之B細胞整合素和/或歸巢受體之表現來改變該等經修飾之B細胞的歸巢/靶向。
使 用 TLR 激動劑和 TLR 活化 B 細胞。B細胞具有天然能力來攝取和呈遞可被其特定B細胞受體(BCR)識別之抗原。由Toll樣受體(TLR)活化之B細胞會產生在免疫反應中保護身體之有效的效應B細胞。B細胞中之TLR的表現或TLR之表現增加可提供機制來增強B細胞調節適應性免疫反應的先天信號。
使 用 TLR 激動劑活化 B 細胞。於本發明之各種實施態樣中提供B細胞,其中該等B細胞係在玻管內或生物體外使用至少一種TLR激動劑處理。於各種實施態樣中,該TLR可為TLR1、TLR2、TLR3、TLR4、TLR5、TLR6、TLR7、TLR8、TLR9、TLR10、TLR11、TLR12和/或TLR13。於各種實施態樣中,該TLR激動劑優先與一或多種選自由下列所組成之群組的TLR結合:TLR1、TLR2、TLR3、TLR4、TLR5、TLR6、TLR7、TLR8、TLR9、TLR10、TLR11、TLR12和TLR13。TLR激動劑為本技藝眾所周知且可包括,但不限於富含CpG之寡核苷酸和雙股RNA模擬物,聚肌苷酸:聚胞苷酸(poly-I:C)。於各種實施態樣中,該TLR激動劑可為CpG寡核苷酸。
於各種實施態樣中,可使用一種TLR激動劑處理各B細胞。於各種實施態樣中,可使用多於一種TLR激動劑處理各B細胞。例如,可使用1、2、3、4、5、6、7、8、9、10、11或12種不同之TLR激動劑處理各B細胞。或者,可將異質之B細胞群投予患者,各B細胞使用獨特之TLR激動劑或TLR激動劑之組合處理。於一些實施態樣中,在將B細胞投予有其需要之個體或患者的同時或之前使用一或多種TLR激動劑處理該用於治療劑之B細胞。於某些實施態樣中,使用一或多種TLR激動劑之處理能夠產生更有效之效應B細胞以在免疫反應中保護身體。於某些實施態樣中,使用一或多種TLR激動劑之處理能夠增強用於免疫反應之B細胞。於一些實施態樣中,使用至少一或多種TLR激動劑處理本發明之B細胞可誘導一或多種TLR之表現或活化。
活化 具 TLR 表現之 B 細胞。於本發明之各種實施態樣中,提供能夠表現組成型活性TLR之經修飾的B細胞。於各種實施態樣中,該TLR係以在組成上活化之轉錄途徑控制下的DNA構建體形式表現在經修飾或經工程處理之B細胞中。於各種實施態樣中,該TLR並非天然表現在B細胞中或係以較B細胞中之天然表現水準來得高的水準表現。於各種實施態樣中,該TLR可為TLR1、TLR2、TLR3、TLR4、TLR5、TLR6、TLR7、TLR8、TLR9、TLR10、TLR11、TLR12和/或TLR13。
於各種實施態樣中,各B細胞可表現多於一種之組成型活性TLR。例如,各B細胞可表現1、2、3、4、5、6、7、8、9、10、11、12或13種不同之組成型活性TLR。或者,可將異質之B細胞群投予患者,各B細胞能夠表現和/或分泌組成上活性之獨特的TLR或TLR之組合。於各種實施態樣中,透過異質之B細胞群可將1、2、3、4、5、6、7、8、9、10、11、12或13種不同之組成上活性TLR投予個體或患者。
於本發明之某些實施態樣中,該B細胞為表現至少一種組成型活性TLR之經修飾的B細胞。於某些實施態樣中,使用一或多種TLR激動劑處理該表現至少一種組成型活性TLR之經修飾的B細胞。於某些實施態樣中,該組成型活性TLR之表現能夠產生更有效之效應B細胞以在免疫反應中保護身體。於某些實施態樣中,該組成型活性TLR之表現能夠增強用於免疫反應之B細胞。於某些實施態樣中,該經修飾之B細胞表現組成型活性之TLR和本申請案之任何CAR-B。於各種實施態樣中,在將該經修飾之B細胞投予有其需要之個體或患者的同時或之前進一步使用一或多種TLR激動劑處理該表現組成型活性之TLR和/或CAR-B的經修飾之B細胞。於某些實施態樣中,可對B細胞進行工程處理以在無CAR-B存在的情況下表現有效載荷和修飾物(諸如TLR)以用於瘤內投予。
同時在第 I 類和第 II 類 HLA 分子中呈遞抗原之經修飾的 B 細胞。除了其在抗體產製中之功能外,B細胞亦表現高水準之第II類人白血球抗原(HLA)分子,並可將抗原呈遞給CD4+T細胞。Hong
et al., 2018, Immunity 49,695-708。於本發明之各種實施態樣中,提供能夠同時將所欲之特定抗原和/或抗原衍生之表位(諸如腫瘤抗原或傳染病抗原)呈遞在第I類和第II類HLA分子中的經修飾之B細胞。腫瘤抗原和傳染病抗原為本技藝所周知且描述於前述部分中。於某些實施態樣中,將所關注之特定抗原,例如腫瘤抗原或傳染病抗原與溶酶體蛋白之靶向信號融合(其將該抗原靶向溶酶體並同時且有效地將該抗原呈遞在第I類和第II類HLA分子中)。於一些實施態樣中,該靶向信號為溶酶體相關膜蛋白-1(LAMP1)之靶向信號。於一些實施態樣中,該靶向信號能夠進入內體再循環隔室。Clec9A之c端序列為靶向部分。如本文所使用者,與靶向信號融合之特定腫瘤抗原或傳染病抗原係指作為治療劑之胺基酸序列、編碼肽或蛋白質之核酸序列或RNA分子(例如mRNA分子)。於一實施態樣中,與靶向信號融合之特定腫瘤抗原或傳染病抗原係指作為治療劑之mRNA分子。於某些實施態樣中,理想的是,與靶向信號(諸如LAMP1或Clec9A之靶向信號)融合之特定腫瘤抗原和/或傳染病抗原被靶向溶酶體或內體並同時且有效地將該抗原呈遞在第I類和第II類HLA分子中。於某些實施態樣中,理想的是,在成熟之前或之後使用編碼所欲之特定腫瘤抗原和/或傳染病抗原之mRNA將B細胞(例如人B細胞)進行電穿孔,該mRNA係與靶向信號(諸如LAMP1或Clec9A之靶向信號)融合,該靶向信號能夠同時且有效地將該特定抗原和/或抗原衍生之表位呈遞在第I類和第II類HLA分子中。於各種實施態樣中,該所關注之特定腫瘤抗原和/或傳染病抗原並非天然由B細胞呈遞,並非天然由B細胞同時呈遞在第I類和第II類HLA分子中,或並非天然由B細胞以高效率呈遞在第I類和第II類HLA分子中。可預期的是,將該等經電穿孔之B細胞引入個體(例如人類宿主)中將藉由同時且有效地將該所欲之特定抗原和/或抗原衍生之表位呈遞在第I類和第II類HLA分子中來促進抗原特異性免疫反應之發展或增強抗原特異性免疫反應。
於各種實施態樣中,本發明關於作為B細胞電穿孔中之治療劑的的核酸序列(例如mRNA序列),該核酸序列編碼至少一種與靶向信號(諸如LAMP1之靶向信號)融合之所欲的特定抗原(例如腫瘤抗原或傳染病抗原),該等B細胞可用於同時且有效地將該特定抗原和/或抗原衍生之表位呈遞在第I類和第II類HLA分子中。於各種實施態樣中,本發明關於編碼多於一種(例如1、2、3、4、5或更多種)所欲的特定腫瘤抗原和/或傳染病抗原的核酸序列(例如mRNA序列),該特定抗原與靶向信號融合。於各種實施態樣中,本發明關於不同核酸序列之匯集庫(例如不同mRNA序列之匯集庫),以作為如上述之B細胞電穿孔中的治療劑,其中各匯集庫編碼至少一種所欲之特定抗原(例如腫瘤抗原或傳染病抗原),該所欲之特定抗原與不同於該mRNA序列之其他匯集庫的靶向信號融合。因此,於一些實施態樣中,可將同質之B細胞群投予個體,其中各B細胞係使用編碼至少一種與靶向信號融合之所欲之特定抗原的mRNA進行電穿孔。於一些實施態樣中,可將同質之B細胞群投予個體,其中各B細胞係使用編碼多於一種所欲之特定抗原的mRNA進行電穿孔,該所欲之特定抗原係與靶向信號融合。於一些實施態樣中,可將異質之B細胞群投予個體,其中各B細胞係使用mRNA之組合進行電穿孔,該mRNA各自編碼至少一種與不同之靶向信號融合之所欲的特定抗原。
於一些實施態樣中,用於電穿孔之上述B細胞可為本申請案之任何經修飾的B細胞。於一些實施態樣中,該經修飾之B細胞包含用於B細胞之嵌合抗原受體(CAR-B)。於各種實施態樣中,該經修飾之B細胞可表現CAR-B並同時且有效地在將所欲之特定抗原和/或抗原衍生之表位呈遞在第I類和第II類HLA分子中。
於各種實施態樣中,本發明關於將經分離之B細胞投予有其需要之患者的方法。於各種實施態樣中,可將B細胞群投予該患者。於各種實施態樣中,各B細胞可表現多於一種之有效載荷肽或蛋白質。例如,各B細胞可表現1、2、3、4、5、6、7、8、9、10、11或12種不同之有效載荷。或者,可將異質之B細胞群投予患者,各B細胞能夠表現和/或分泌獨特之有效載荷或有效載荷之組合。於各種實施態樣中,可透過異質之B細胞群將1、2、3、4、5、6、7、8、9、10、11或12種不同的有效載荷投予該患者。
V. 治療方法
於本發明之各種態樣中,該等經擴增之B細胞群將以治療劑形式遞送至有其需要之患者。於各種實施態樣中,該經擴增之B細胞群將能夠治療或預防各種疾病或病症,包括癌症。
於一些實施態樣中,本發明關於在個體中創建由B細胞介導之免疫反應,其包含將有效量之本申請案之經擴增和/或經工程處理的B細胞投予該個體。於一些實施態樣中,該由B細胞介導之免疫反應係針對一或多個靶細胞。於一些實施態樣中,該經工程處理之免疫細胞包含用於B細胞之嵌合抗原受體(B-CAR)。於一些實施態樣中,該靶細胞為腫瘤細胞。於一些態樣中,本發明包含治療或預防惡性腫瘤之方法,該方法包含將有效量之至少一種本文描述的經分離之抗原結合分子投予有其需要之個體。於一些態樣中,本發明包含治療或預防惡性腫瘤之方法,該方法包含將有效量之至少一種免疫細胞投予有其需要之個體,其中該免疫細胞包含至少一種嵌合抗原受體。
於一些態樣中,本發明包含醫藥組成物,該醫藥組成物包含經擴增之經工程處理的B細胞群,該經工程處理的B細胞群包含至少一種如本及描述之抗原結合分子和醫藥上可接受之賦形劑。於一些實施態樣中,該醫藥組成物進一步包含另外之活性劑。
於一些實施態樣中,該個體被診斷為患有侷限於肝臟之轉移性疾病。於其他實施態樣中,該轉移性疾病為癌症。再於其他實施態樣中,該癌症係從乳房、結腸、直腸、食道、肺、胰臟和/或胃中之原發性腫瘤轉移。再於其他實施態樣中,該個體被診斷為具有不可切除之轉移性肝腫瘤。於其他實施態樣中,該個體被診斷為具有來自原發性結腸直腸癌之不可切除的轉移性肝腫瘤。於一些實施態樣中,該個體被診斷為患有肝細胞癌。
應理解的是,該等經修飾之B細胞的目標劑量範圍可在1x10
6至2x10
10個細胞/kg,較佳為2x10
6個細胞/kg,更佳地。應理解的是,高於和低於該範圍之劑量對於某些個體而言可能是合適的,且可由醫療保健提供者依需要決定適當之劑量水準。此外,可根據本發明提供多個細胞劑量。
亦提供用於縮小個體之腫瘤大小的方法,其包含將本發明之經修飾的B細胞投予該個體,其中該細胞包含CAR-B受體、有效載荷或CAR-B和有效載荷二者,該CAR-B受體包含與腫瘤上之抗原結合的抗原結合結構域。於一些實施態樣中,該個體具有實體瘤或血液惡性腫瘤,諸如淋巴瘤或白血病。於一些實施態樣中,該經修飾之B細胞係被遞送至腫瘤床。於一些實施態樣中,該癌症係存在於個體之骨髓中。
亦提供用於將B細胞歸巢至個體中之所欲部位/標靶的方法,其包含將本發明之經修飾的B細胞投予該個體,其中該細胞包含被吸引至所欲之部位/標靶處的受體、趨化因子或引誘劑之整合素、歸巢抗體、蛋白質或配體。於一些實施態樣中,該所欲之部位/標靶為,例如其中需要遞送治療性有效載荷之歸巢或標靶組織、在特定位置或組織中之發炎部位、或腫瘤或腫瘤微環境。
亦提供用於減少個體中所欲部位/標靶處之發炎和B細胞之自體免疫活性的方法其包含將本發明之經修飾的B細胞投予該個體,其中該細胞包含免疫抑制分子。於一些實施態樣中,該所欲部位/標靶為,例如其中需要遞送治療性有效載荷之歸巢或標靶組織、特定位置或組織中之發炎部位、或腫瘤或腫瘤微環境。
於一些實施態樣中,該經擴增之經工程處理的B細胞群為自體B細胞。於一些實施態樣中,該等經修飾之B細胞為同種異體B細胞。於一些實施態樣中,該等經修飾之B細胞為異源B細胞。於一些實施態樣中,本申請案之經修飾之B細胞在體內被轉染或轉導。於其他實施態樣中,該經工程處理之細胞係在生物體外經轉染或轉導。
如本文所使用之術語“
個體”或“
患者”係指個人。於一些態樣中,該個體可為哺乳動物,諸如人。於一些態樣中,個體可為非人類靈長類動物。非人類靈長類動物包括,舉一些例子而言:狨猿(marmoset)、猴子、黑猩猩、大猩猩、紅毛猩猩(orangutan)和長臂猿。術語“個體”亦包括馴養動物,諸如貓、狗,等、家畜(例如美洲駝(llama)、馬、牛)、野生動物(例如鹿、麋鹿、駝鹿,等)、實驗室動物(例如小鼠、兔子、大鼠、沙鼠、天竺鼠,等)和鳥類(例如雞、火雞、鴨,等)。較佳地,該個體為人類個體。更佳地,該個體為人類患者。
於某些實施態樣中,包含本文揭示之表現CAR的免疫效應細胞之組成物可與任何數量之化療劑聯合投予。化療劑之實例包括烷化劑,諸如噻替派(thiotepa)和環磷醯胺(CYTOXAN™);烷基磺酸鹽,諸如白消安(busulfan)、異丙硫丹(improsulfan)和哌泊硫丹(piposulfan);氮丙啶(aziridine)類藥物,諸如苯多巴(benzodopa)、卡波醌(carboquone)、美妥多巴(meturedopa)和烏多巴(uredopa);乙烯亞胺和甲基三聚氰胺(methylamelamine),包括阿曲他明(altretamine)、三乙烯三聚氰胺(triethylenemelamine)、三乙烯磷醯胺(trietylenephosphoramide)、三乙烯硫代磷醯胺(triethylenethiophosphaoramide)和三羥甲基三聚氰胺(trimethylolomelamine);氮芥,諸如苯丁酸氮芥(chlorambucil)、氯萘氮芥(chlornaphazine)、氯磷醯胺(cholophosphamide)、雌莫司汀(estramustine)、異環磷醯胺(ifosfamide)、甲氯乙胺(mechlorethamine)、鹽酸氧甲氯乙胺、美法崙(melphalan)、諾維貝辛(novembichin)、芬乃斯特(phenesterine)、潑尼莫司汀(prednimustine)、曲磷醯胺(trofosfamide)、尿嘧啶芥;亞硝基脲類,諸如卡莫司汀(carmustine)、氯脲佐菌素(chlorozotocin)、氟替莫司汀(fotemustine)、洛莫司汀(lomustine)、尼莫司汀(nimustine)、雷莫司汀(ranimustine);抗生素,諸如阿克拉黴素(aclacinomysin)、放線菌素(actinomycin)、紅黴素(authramycin)、氮絲胺酸(azaserine)、博來黴素(bleomycin)、放線菌素(cactinomycin)、加利車黴素(calicheamicin)、卡比星(carabicin)、胭脂紅黴素(carminomycin)、嗜癌素(carzinophilin)、色黴素(chromomycins)、放線菌素(dactinomycin)、柔紅黴素(daunorubicin)、去托比星(detorubicin)、6-重氮-5-氧代-L-正白胺酸、多柔比星(doxorubicin)、表柔比星(epirubicin)、埃柔比星(esorubicin)、伊達比星(idarubicin)、馬賽黴素(marcellomycin)、絲裂黴素(mitomycins)、黴酚酸(mycophenolic acid)、諾加拉黴素(nogalamycin)、橄欖黴素(olivomycins)、培洛黴素(peplomycin)、潑非黴素(potfiromycin)、嘌呤黴素(puromycin)、三鐵阿黴素(pque-lamycin)、羅多比星(rodorubicin)、鏈黑黴素(streptonigrin)、鏈脲佐菌素(streptozocin)、結核菌素(tubercidin)、烏苯美司(ubenimex)、淨司他汀(zinostatin)、佐柔比星(zorubicin);抗代謝物,諸如胺甲喋呤(methotrexate)和5-氟尿嘧啶(5-FU);葉酸類似物,諸如地喋呤(denopterin)、胺甲喋呤、喋喋呤(pteropterin)、三胺甲喋呤(trimetrexate);嘌呤類似物,諸如氟達拉濱(fludarabine)、6-巰基嘌呤(6-mercaptopurine)、硫胺嘌呤(thiamiprine)、硫鳥嘌呤(thioguanine);嘧啶類似物,諸如安西他濱(ancitabine)、阿扎胞苷(azacitidine)、6-氮雜尿苷(6-azauridine)、卡莫氟(carmofur)、阿糖胞苷(cytarabine)、雙脫氧尿苷(dideoxyuridine)、多西氟尿苷(doxifluridine)、依西他濱(enocitabine)、氟尿苷(floxuridine)、5-FU;雄激素,諸如鈣固酮(calusterone)、丙酸屈他雄酮(dromostanolone propionate)、環硫雄醇(epitiostanol)、美雄烷(mepitiostane)、睾酮內酯(testolactone);抗腎上腺素,諸如胺基麩胺醯胺(aminoglutethimide)、米托坦(mitotane)、曲洛司坦(trilostane);葉酸補充劑,諸如亞葉酸(frolinic acid);乙醯丙酮(aceglatone);醛磷醯胺糖苷(aldophosphamide glycoside);胺基乙醯丙酸(aminolevulinic acid);吖啶(amsacrine);苯丁酸(bestrabucil);比生群(bisantrene);依達曲沙(edatraxate);去氧麻黃鹼(defofamine);去甲高辛(demecolcine);二嗪酮(diaziquone);二甲雙胍(elformithine);醋酸艾立替銨(elliptinium acetate);胃泌素(etoglucid);硝酸鎵;羥基脲;香菇多醣(lentinan);氯尼達胺(lonidamine);米托胍(mitoguazone);米托蒽醌(mitoxantrone);莫匹達莫(mopidamol);硝化鈉(nitracrine);噴司他汀(pentostatin);蛋胺氮芥(phenamet);吡柔比星(pirarubicin);鬼臼酸(podophyllinic acid);2-乙基醯肼(2-ethylhydrazide);丙卡巴肼(procarbazine);PSK®;雷佐生(razoxane);西佐非蘭(sizofiran);螺鍺(spirogermanium);肌鬆酸(tenuazonic acid);三嗪酮(triaziquone);2,2',2"-三氯三乙胺;聚胺酯(urethan);長春地辛(vindesine);達卡巴嗪(dacarbazine);甘露莫司汀(mannomustine);米托溴醇(mitobronitol);米託內酯(mitolactol);双溴丙基呱嗪(pipobroman);加西托星(gacytosine);阿拉伯糖苷(“Ara-C”);環磷醯胺;噻替哌(thiotepa);紫杉醇類(taxoid),例如太平洋紫杉醇(TAXOL®),Bristol-Myers Squibb)和多西紫杉醇(doxetaxel)(TAXOTERE®,Rhone-Poulenc Rorer);苯丁酸氮芥(chlorambucil);吉西他濱(gemcitabine);6-硫鳥嘌呤;巰基嘌呤;甲胺喋呤;鉑類似物,諸如順鉑和卡鉑;長春鹼;鉑;依托泊苷(etoposide)(VP-16);異環磷醯胺(ifosfamide);絲裂黴素C(mitomycin C);米托蒽醌(mitoxantrone);長春新鹼(vincristine);長春瑞濱(vinorelbine);溫諾平(navelbine);諾萬龍(novantrone);替尼泊苷(teniposide);道諾黴素(daunomycin);胺基喋呤(aminopterin);希羅達(xeloda);伊班膦酸鹽(ibandronate);CPT-11;拓撲異構酶抑制劑RFS2000;二氟甲基鳥胺酸(DMFO);視黃酸衍生物,諸如TARGRETIN
TM(貝沙羅汀(bexarotene))、PANRETIN
TM(阿利維A酸(alitretinoin));ONTAK
TM(地尼介白素(denileukin diftitox));埃斯派拉黴素(esperamicin);卡培他濱(capecitabine);以及上述任一者之醫藥上可接受之鹽、酸或衍生物。該定義亦包括用於調節或抑制激素對腫瘤之作用的抗激素劑,諸如抗雌激素,包括,例如他莫昔芬(tamoxifen)、雷洛昔芬(raloxifene)、抑制4(5)-咪唑之芳香酶、4-羥基他莫昔芬、曲昔芬(trioxifene)、柯昔芬(keoxifene)、LY117018、奧那司酮(onapristone)和托瑞米芬(toremifene)(Fareston);及抗雄激素,諸如氟他胺(flutamide)、尼魯米特(nilutamide)、比卡魯胺(bicalutamide)、亮丙瑞林(leuprolide)和戈舍瑞林(goserelin);以及上述任一者之醫藥上可接受之鹽、酸或衍生物。當適當時,亦投予化療劑之組合,包括,但不限於CHOP,即,環磷醯胺(CYTOXAN®)、多柔比星(羥基多柔比星)、氟達拉濱、長春新鹼(ONCOVIN®)和潑尼松。
各種不同之其他治療劑可與本文描述之組成物聯合使用。例如,可能有用之其他治療劑包括PD-1(或PD-L1)抑制劑,諸如納武單抗(nivolumab)(OPDIVO®)、派姆單抗(pembrolizumab)(KEYTRUDA®)、派姆單抗、匹迪珠單抗(pidilizumab)和阿特珠單抗(atezolizumab) (TECENTRIQ
®)。
適合與本發明組合使用之其他治療劑包括,但不限於依魯替尼(ibrutinib)(IMBRUVICA®)、奧法木單抗(ofatumumab)(ARZERRA®)、利妥昔單抗(rituximab) (RITUXAN®)、貝伐單抗(bevacizumab)(AVASTIN®)、曲妥珠單抗(trastuzumab)(HERCEPTIN®)、賀癌寧(trastuzumab emtansine)(KADCYLA®)、伊馬替尼(imatinib) (GLEEVEC®)、西妥昔單抗(cetuximab) (ERBITUX®)、帕利珠單抗(panitumumab)(VECTIBIX®),卡妥索單抗(catumaxomab)、替伊莫單抗(ibritumomab)、奧法木單抗(ofatumumab)、托西莫單抗(tositumomab)、布妥昔單抗(brentuximab)、阿崙單抗(alemtuzumab)、吉妥珠單抗(gemtuzumab)、厄洛替尼(erlotinib)、吉非替尼(gefitinib)、凡迪他尼(vandetanib)、阿法替尼(afatinib)、拉帕替尼(lapatinib)、奈拉替尼(neratinib)、阿西替尼(axitinib)、馬賽替尼(masitinib)、帕唑帕尼(pazopanib)、舒尼替尼(sunitinib)、索拉非尼(sorafenib)、托塞拉尼(toceranib)、來司他替尼(lestaurtinib)、阿西替尼(axitinib)、西地拉尼(cediranib)、樂伐替尼(lenvatinib)、尼達尼布(nintedanib)、帕唑帕尼(pazopanib)、瑞戈非尼(regorafenib)、塞馬尼布(semaxanib)、索拉非尼(sorafenib)、舒尼替尼(sunitinib)、替沃扎尼(tivozanib)、托塞拉尼(toceranib)、凡德他尼(vandetanib)、恩曲替尼(entrectinib)、卡博替尼(cabozantinib)、伊馬替尼(imatinib)、達沙替尼(dasatinib)、尼洛替尼(nilotinib)、普納替尼(ponatinib)、雷多替尼(radotinib)、博舒替尼(bosutinib)、來司他替尼(lestaurtinib)、魯索替尼(ruxolitinib)、帕克替尼(pacritinib)、考比替尼(cobimetinib)、司美替尼(selumetinib)、曲美替尼(trametinib)、比尼米替尼(binimetinib)、艾樂替尼(alectinib)、色瑞替尼(ceritinib)、克唑替尼(crizotinib)、阿柏西普(aflibercept)、阿迪波肽(adipotide)、地尼介白素、mTOR抑制劑,諸如依維莫司(Everolimus)和坦西羅莫司(Temsirolimus)、刺猬抑制劑,諸如索尼德吉(sonidegib)和維莫德吉(vismodegib)、CDK抑制劑,諸如CDK抑制劑(帕波西利伯(palbociclib))。
於另外之實施態樣中,該包含含有CAR免疫劑的組成物可與抗炎劑一起投予。抗炎劑或藥物包括,但不限於類固醇和糖皮質激素(包括倍他米松(betamethasone)、布地奈德(budesonide)、地塞米松(dexamethasone)、醋酸氫化可的松(hydrocortisone acetate)、氫化可的松、氫化可的松、甲基強的松龍(methylprednisolone)、強的松龍、強的松(prednisone)、曲安西龍(triamcinolone))、非類固醇抗炎藥(NSAIDS),包括阿斯匹靈、布洛芬、萘普生(naproxen)、甲胺喋呤、柳氮磺胺吡啶(sulfasalazine)、來氟米特(leflunomide)、抗TNF藥物、環磷醯胺和黴酚酸酯。示例性NSAID包括布洛芬、萘普生、萘普生鈉、Cox-2抑制劑和唾液酸。示例性鎮痛劑包括對乙醯胺基酚(acetaminophen)、羥考酮、鹽酸丙泊昔芬(proporxyphene hydrochloride)之曲馬多(tramadol)。示例性糖皮質激素包括可的松、地塞米松、氫化可的松、甲基強的松龍、強的松龍或強的松。示例性生物反應調節劑包括針對細胞表面標記(例如CD4、CD5,等)之分子、細胞因子抑制劑,諸如TNF拮抗劑(例如依那西普(etanercept)(ENBREL®)、阿達木單抗(adalimumab) (HUMIRA®)和英夫利昔單抗(infliximab)(REMICADE®))、趨化因子抑制劑和黏附分子抑制劑。生物反應調節劑包括單株抗體以及重組形式之分子。示例性DMARD包括硫唑嘌呤(azathioprine)、環磷醯胺、環孢素、甲胺喋呤、青黴胺、來氟米特、柳氮磺胺吡啶(sulfasalazine)、羥氯喹、Gold(口服(金諾芬(auranofin))和肌肉注射)及米諾環素(minocycline)。
於某些實施態樣中,本文描述之組成物係與細胞因子聯合投予。如本文所使用之“
細胞因子”係指由一細胞群釋出之蛋白質,其作為細胞間介質來作用於另一細胞上。細胞因子之實例為淋巴因子、單核因子和傳統多肽激素。包括在細胞因子中的有生長激素,諸如人生長激素、N-甲硫胺醯人生長激素和牛生長激素;副甲狀腺激素;甲狀腺素(thyroxine);胰島素;胰島素前體;鬆弛素;鬆弛素前體;糖蛋白激素,諸如卵泡刺激激素(FSH)、甲狀腺刺激激素(TSH)和黃體激素(luteinizing hormone)(LH);肝生長因子(HGF);纖維母細胞生長因子(FGF);催乳素(prolactin);胎盤催乳素;輸卵管抑制物質;小鼠促性腺激素(gonadotropin)相關肽;抑制素;活化素;血管內皮生長因子;整合素;血小板生成素(TPO);神經生長因子(NGF),諸如NGF-β;血小板生長因子;轉形生長因子(TGF),諸如TGF-α和TGF-β;胰島素樣生長因子-I和-II;紅血球生成素(erythropoietin)(EPO);骨誘導因子;干擾素,諸如干擾素-α、β和γ;株落刺激因子(CSF),諸如巨噬細胞-CSF(M-CSF);粒細胞-巨噬細胞-CSF(GM-CSF);和粒細胞-CSF(G-CSF);介白素(IL),諸如IL-1、IL-1α、IL-2、IL-3、IL-4、IL-5、IL-6、IL-7、IL-8、IL-9、IL-10、IL-11、IL-12;IL-15、腫瘤壞死因子,諸如TNF-α或TNF-β;和其他多肽因子,包括LIF和套組配體(KL)。如本文所使用者,術語細胞因子包括來自天然來源或來自重組細胞培養物之蛋白質,以及天然序列細胞因子之生物活性等同物。
實施例
雖然為了清楚理解已藉由說明和實例來對前述發明進行一些詳細的描述,但本技藝之一般技術人士鑑於本發明之教示內容將能輕易明白可在不背離所附之申請專利範圍之精神或範圍的情況下對本發明做某些改變和修飾。下列實施例僅用於說明,而非用於限制。本技藝之技術熟習人士將能輕易識別可改變或修飾之各種非關鍵參數,以產生實質上相似之結果。
實施例 1 :純化和富集人 B 細胞
根據下列方案從PBMC中收集和富集人B細胞。依下述從膚色血球層製備PBMC。使用PBS將每一供體(約25 ml)之體積增加至120 ml。接著,將30 ml疊層在四個50 ml試管中的15ml Ficoll上。然後在450 g下旋轉20分鐘。然後移除並丟棄上層。再分離出緊接於第一層下方的PBMC界面(中性粒細胞為最密集的,且朝該層底部增加數量)。從各供體的4個試管之每一者採取界面並轉移至二個50 ml錐形管中。使用PBS將每一管之體積加至50 ml。然後將該二個管的每一者在500g下旋轉5分鐘。
藉由吸出沉澱小丸將RBC溶解並將二個沉澱小丸組合在總體積10 ml之ACK溶解緩衝液中。然後將該溶液保持在室溫下5分鐘。接著,加入40ml PBS,混合該溶液,然後在500 g下離心5分鐘。再使用PBS使該混合物之體積達到40 ml,以計算PBMC之產量。每一B細胞富集製品係使用1.5億個PBMC。
根據人類B細胞純化產品ID17954 EASYSEP®(Stem Cell Technologies)的說明進行B細胞富集。將溶液離心並將1.5億個PBMC重新懸浮於3 ml之EASYSEP®分離緩衝液中。將沉澱小丸重新懸浮於在15 ml試管中之3 ml EASYSEP®緩衝液中。加入150μl之混合物增強劑。加入150 μl之分離混合物,將該試管混合並在室溫下培育5分鐘。將Rapid spheres震盪混合30秒,然後將150μl加入試管中,再混合之,然後移至磁體。3分鐘後,將其倒入新管中並重複磁體步驟。
實施例 2 :使用 HELA-CD40L 飼養細胞或 MEGA-CD40L 擴增 B 細胞
由於B細胞在人外周血中之頻率較低,很難獲得足夠數量之B細胞來用於臨床細胞療法目的。因此,B細胞擴增為製造臨床級B細胞的重要步驟。人類B細胞生長需要CD40L。已確立的是,若將B細胞生長在表現CD40L之單層HEL細胞上,則B細胞可存活並擴增。然而,有必要建立不依賴飼養細胞之B細胞生長方法。在致力於確定是否存在用於此目的之市售工具或試劑時,測試Enzo MEGA-CD40L以與在HELA-CD40L飼養細胞上之生長情況相比較。
在
HeLa-CD40L 飼養細胞上之生長培養基條件。藉由放射線照射在24孔盤上之每盤5x10
6個CD40L HeLa細胞來製備飼養細胞盤。該基礎培養基係由RPMI-1640+10% FCS;Penn/鏈球菌(100 u/ml,100 μg/ml);亞硒酸鈉(100 nM);和IL-4(2 ng/ml)(R & D 204-IL)所組成。在接種B細胞之前,令飼養細胞生長至少24小時。
使用 MEGA-CD40L 之生長培養基條件。該培養基條件與上述相同,除了沒有飼養細胞外。而是,將B細胞接種在由RPMI-1640 + 10% FCS;Penn/鏈球菌(100 u/ml,100μg/ml);亞硒酸鈉(100 nM);IL-4(2 ng/ml)(R&D 204-IL);和MEGA-CD40L(100 ng/ml)所組成之培養基中。
B細胞在HeLa-CD40L和MEGA-CD40L條件下之生長速率描述於圖1中。該研究表明人類B細胞可在具有HELA-CD40L飼養細胞之培養基中生長和擴增,但在MEGA-CD40L之存在下不能擴增。
第0天,該純化之B細胞以約10,000個細胞/ml之相等密度開始並在HELA-CD40L飼養細胞上生長。第4天,將培養物分成二組,一組繼續在具有HELA-CD40L飼養細胞之相同培養基中生長,而另一組則在補充有MEGA-CD40L(0.1μg/mL),但缺乏HELA飼養細胞之培養基中生長。第8天,在MEGA-CD40L條件下的生長培養基中加入另外之100 ng/mL MEGA-CD40L。圖1中之箭頭表明MEGA-CD40L處理發生的時間。
數據顯示,當在HELA-CD40L飼養細胞上生長時,到第11天時B細胞顯著增殖,但若在具有MEGA-CD40L之條件下生長,則在第11天未觀察到顯著生長。
實施例 3 :無飼養細胞之 B 細胞擴增
於本實例中,在無表現HELA-CD40L之飼養細胞存在的情況下擴增B細胞。將B細胞接種在包含下列者之擴增培養基中:IL-4(5μg;5000 IU/μg溶解在100μL H
2O中以達到2.5 x 10
5IU/ml);CD40L(SEQ ID NO:140,500μg重新懸浮於500μL);CD40L交聯抗體(SEQ ID NOS:143和144);人AB血清(IC092938249 VWR);以及10μL青黴素鏈黴素。將B細胞以(i) 100,000至150,000/ml;或(ii) 1,000,000/mL之密度接種並擴增至少15天,每7天重新餵入新鮮培養基。
維持在100,000至150,000個細胞/mL之密度的細胞能夠在二週內擴增200倍以上;而維持在1,000,000個細胞/mL之密度的細胞則顯示出細胞生長顯著減少。參見圖2。
實施例 4 :經擴增之 B 細胞的工程處理
然後使用如本文描述之B細胞擴增培養基將包含該Ad5腺病毒之B細胞在體外培養10天。然後按照下列方案使用腺病毒轉導該經擴增之B細胞。
使B細胞生長10天並取得約1400萬個細胞之產量。測試數種編碼人BCR之腺病毒F35病毒構建體。一種實例如下。使用編碼GPC3特異性BCR之腺病毒。亦使用腺病毒空載體對照組。亦使用無病毒之模擬對照組。
在下列條件下,將20μl之10
9/ml病毒顆粒加入50萬個B細胞中:
將B細胞接種在24孔盤中之含有下列者的200μl OPTIMEM®中:0.2% BSA和CD40L+Xlinker (Miltenyi產品#130-098-775,濃度與上文概述之擴增培養基中者相同)、IL-4(如擴增培養基中者)和0.5μg/ml聚凝胺(polybrene)。加入病毒後,將盤在1100 g下離心1小時,然後轉移到培養箱中2.5小時,並給予2 mL之新鮮擴增培養基。3天後,使用GPC3-BV對細胞染色以檢測表現該BCR之B細胞。結果示於圖2A至2C中,並顯示出至少67%之該細胞在轉導後72小時表現該GPC3 BCR。
實施例 5 :在人類 B 細胞中表現 Ad5RGD-GFP
令來自PBMC之B細胞在培養物中生長10天。使用編碼GFP之Ad5-RGD構建體轉導B細胞,並置於具有0.2% BSA、CD40L+Xlinker、5%人AB血清和IL-4之OPTIMEM®中。然後加入病毒並在1100 g下離心1小時,再在37°C下培育3小時。然後將培養基轉換成正常之人類B細胞生長培養基直到進行分析。
為了解決病毒對細胞存活力的影響,在第6、8和10天藉由VICELL®和FACS測試總細胞計數和GFP陽性計數分率。結果示於圖4中。Ad5-RGD修飾之GFP轉導導致B細胞中之高效率GFP表現。約60%之總B細胞保持表現至少10天。經轉導之B細胞在轉導後繼續增殖至少1週。
實施例 6 :使用腺病毒轉導之人 B 細胞中的鼠 BCR 構建體或 IL-10 之表現
令來自PBMC之B細胞在培養物中生長10天。然後使用編碼鼠IL-10或數種鼠BCR形式之Ad5-RGD構建體轉導B細胞。(在等待人類形式時使用鼠)。然後將B細胞培養在包含具有0.2% BSA、CD40L+Xlinker、5%人AB血清和IL-4之OPTIMEM®的條件下。加入病毒並在1100 g下離心1小時,再在37°C下培育3小時,然後將培養基轉換成正常人B細胞生長培養基直到進行分析。將病毒以二種比例進行測試(20μl:50萬個B細胞和2μl:50萬個B細胞)。
在轉導後第4天,96小時進行表現測試。將IL-10上清液儲存在-80°C。藉由與人GPC3-BV結合來檢測GPC3構建體。藉由與FITC strep標籤結合來檢測肌聚醣構建體。結果示於圖5至圖9中。
實施例 7 :藉由腺病毒遞送後監測體內歸巢和人 BCR 在人 B 細胞中之表現
令來自PBMC之B細胞在培養物中生長10天。然後使用編碼螢光素酶+/-GPC3-BCR之Ad5f35構建體轉導B細胞。將PWF-524/PWWF-684(Luc + GPC3 CAR)和PWF-684(Luc)轉導後在Wennhold培養基中培養一整夜,以便有時間表現BCR和Luc。之後,將約90萬個細胞經由靜脈內(IV)遞送入患有HEPG2腫瘤之小鼠體內。藉由生物發光監測Luc。
數據顯示於圖10中,其顯示在帶有HEPG2腫瘤之SHORN小鼠中,GPC3 CAR(524)富集之歸巢至TDLN之人類B細胞為100倍。具體地說,SHORN小鼠缺乏T、B和NK細胞,這使得人類B細胞不會被排斥。值得注意的是,在TDLN之富集程度相對於肺為100倍。在肺中觀察到高出2至5倍之信號,這可能是由於HEPG2轉移。圖10表明經工程處理之GPC3 CARS可協助指導B細胞歸巢至發炎的淋巴器官。
[圖1]顯示人B細胞可在含有HELA-CD40飼養細胞之培養基中生長和擴增,但在MEGA-CD40L(Enzo Life Sciences)之存在下不能擴增。在第0天以約10,000個細胞/ml之相同密度的經純化之B細胞開始,並在HELA-CD40L飼養細胞上生長。在第4天,將培養物分成二組,一組繼續在含有HELA-CD40L飼養細胞之相同培養基中生長,而另一組在補充有MEGA-CD40L(0.1μg/ml),但缺乏HELA飼養細胞之培養基中生長。第8天,在MEGA-CD40L之條件下的生長培養基中添加額外之100ng/ml MEGA-CD40L。箭頭表示發生MEGA-CD40L處理之時間。該數據顯示當生長在HELA-CD40L飼養細胞上時B細胞在第11天有顯著增殖,但若生長在MEGA-CD40L上則第11天未觀察到顯著的生長。
[圖2]顯示人細胞在包含CD40L和CD40L交聯劑的培養基中生長和擴增僅經過二週後可具有至少約3×10
7個細胞,即使是在不存有HELA-CD40L飼養細胞的情況下。在整個研究過程中維持二種密度(150K和1MM)。較低密度之培養物亦能夠保持較高之生長速率並產生較大之相對總質量。即使是僅在二週內,細胞亦能夠擴增至少200倍。
[圖3]表明該經擴增之經工程處理的B細胞可維持轉基因表現。圖3A表明在腺病毒載體轉染後72小時,67%之該經擴增之經工程處理的B細胞表現出GPC B細胞受體表現。圖3B顯示使用空載體(不表現GPC3之載體)轉染之細胞中表現GPC-BCR之細胞的百分比。圖3C顯示完全未使用任何載體轉導之細胞。
[圖4]顯示B細胞在Ad5RGD-GFP轉導後之擴增和生長速率。Ad5RGD-GFP導致B細胞中高效率之GFP表現。表現可在約60%之總B細胞中維持至少8至10天。GFP+B細胞在轉導後持續增殖超過一週。
[圖5]顯示使用鼠GPC3構建體經由RGD(601)轉導之人B細胞成功擴增。圖5A描繪經轉導之抗GPC3 scFV嵌合受體的結構,該抗GPC3 scFV嵌合受體包含抗GPC3 scFv、CD8鉸鏈結構域、CD28跨膜結構域和CD79a信號傳導結構域。圖5B表明表現該經轉導之GPC3嵌合受體的B細胞之相對百分比。
[圖6]顯示使用鼠GPC3構建體經由RGD(602)轉導之人B細胞成功擴增。圖6A描繪經轉導之抗GPC3 scFV嵌合受體的結構,其包含抗GPC3 scFv、CD8鉸鏈結構域、CD28跨膜結構域和CD79b信號傳導結構域。圖6B表明表現該經轉導之抗GPC3嵌合受體的相對百分比。
[圖7]顯示使用RGD功能化之非病毒基因遞送載體轉導之人B細胞的擴增,該載體表現靶向GPC3之嵌合受體。圖7A描繪該包含抗GPC3 scFv、CD8鉸鏈結構域、CD28跨膜結構域和CD79b或CD79a信號傳導結構域之嵌合受體的結構。圖7B表明表現該經轉導之GPC3嵌合受體的B細胞之相對百分比。
[圖8]顯示使用鼠GPC3構建體經由RGD(463)轉導之人B細胞的成功擴增。圖8A描繪該經轉導之抗GPC3 scFV嵌合受體的結構,該抗GPC3 scFV嵌合受體包含抗GPC3 scFv、CD8鉸鏈結構域、CD28跨膜結構域和CD79b信號傳導結構域。圖8B表明表現該經轉導之GPC3嵌合受體的B細胞之相對百分比。
[圖9]顯示使用RGD功能化之非病毒基因遞送載體轉導之人B細胞的擴增,該載體表現靶向肌聚醣(sarcoglycan)(394)之嵌合受體。圖9A描繪該包含抗肌聚醣scFv、鼠G2a Fc結構域、跨膜結構域和胞質尾之嵌合受體的結構。圖9B表明B細胞轉導和擴增後顯示出表現嵌合受體之細胞的百分比。
[圖10]顯示經工程處理和擴增之人B細胞在攜帶HPEG2腫瘤之小鼠體內歸巢至腫瘤引流淋巴結(“TDLN”)。
<![CDATA[<110> 美商步行魚醫療公司 (Walking Fish Therapeutics)]]> <![CDATA[<120> 用於細胞療法的B細胞擴增之方法]]> <![CDATA[<130> 109036-0061]]> <![CDATA[<140> TW 111114678]]> <![CDATA[<141> 2022-04-18]]> <![CDATA[<150> US 63/176,463]]> <![CDATA[<151> 2021-04-19]]> <![CDATA[<160> 7 ]]> <![CDATA[<170> PatentIn 3.5版]]> <![CDATA[<210> 1]]> <![CDATA[<211> 149]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<22]]>3> 合成的]]> <br/> <br/><![CDATA[<400> 1]]> <br/> <br/><![CDATA[Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val Ile Ser 1 5 10 15 Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu Lys Gly 20 25 30 Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly Lys Gln 35 40 45 Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln Val Thr 50 55 60 Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile Ala Ser 65 70 75 80 Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu Arg Ala 85 90 95 Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser Ile His 100 105 110 Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe Val Asn 115 120 125 Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr Ser Phe 130 135 140 Gly Leu Leu Lys Leu 145 <![CDATA[<210> 2]]> <![CDATA[<211> 30]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的]]> <![CDATA[<400> 2]]> Ala Cys Gly Cys Ala Ala Ala Pro Asp Ile Lys Asp Leu Leu Ser Arg 1 5 10 15 Leu Glu Glu Leu Glu Gly Leu Val Ser Ser Leu Arg Glu Gln 20 25 30 <![CDATA[<210> 3]]> <![CDATA[<211> 219]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的]]> <![CDATA[<400> 3]]> Val Gly Asp Gly Ser Ser His His His His His His Ser Ser Gly Gly 1 5 10 15 Gly Arg Gly Ser His His His His His His Gly Gly Ala Cys Gly Cys 20 25 30 Ala Ala Ala Pro Asp Ile Lys Asp Leu Leu Ser Arg Leu Glu Glu Leu 35 40 45 Glu Gly Leu Val Ser Ser Leu Arg Glu Gln Gly Gly Gly Ser Gly Gly 50 55 60 Gly Ser Gly Gly Gly Ser Met Gln Lys Gly Asp Gln Asn Pro Gln Ile 65 70 75 80 Ala Ala His Val Ile Ser Glu Ala Ser Ser Lys Thr Thr Ser Val Leu 85 90 95 Gln Trp Ala Glu Lys Gly Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr 100 105 110 Leu Glu Asn Gly Lys Gln Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr 115 120 125 Ile Tyr Ala Gln Val Thr Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln 130 135 140 Ala Pro Phe Ile Ala Ser Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu 145 150 155 160 Arg Ile Leu Leu Arg Ala Ala Asn Thr His Ser Ser Ala Lys Pro Cys 165 170 175 Gly Gln Gln Ser Ile His Leu Gly Gly Val Phe Glu Leu Gln Pro Gly 180 185 190 Ala Ser Val Phe Val Asn Val Thr Asp Pro Ser Gln Val Ser His Gly 195 200 205 Thr Gly Phe Thr Ser Phe Gly Leu Leu Lys Leu 210 215 <![CDATA[<210> 4]]> <![CDATA[<211> 220]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的]]> <![CDATA[<400> 4]]> Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ser Val Ser Ala Gly 1 5 10 15 Glu Lys Val Thr Met Asn Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser 20 25 30 Gly Asn Gln Arg Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Leu Leu Ile His Gly Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Asn 85 90 95 Asp His Arg Tyr Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu 100 105 110 Lys Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser 115 120 125 Glu Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn 130 135 140 Phe Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu 145 150 155 160 Arg Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp 165 170 175 Ser Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr 180 185 190 Glu Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr 195 200 205 Ser Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys 210 215 220 <![CDATA[<210> 5]]> <![CDATA[<211> 113]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的]]> <![CDATA[<400> 5]]> Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ser Val Ser Ala Gly 1 5 10 15 Glu Lys Val Thr Met Asn Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser 20 25 30 Gly Asn Gln Arg Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Leu Leu Ile His Gly Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Asn 85 90 95 Asp His Arg Tyr Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu 100 105 110 Lys <![CDATA[<210> 6]]> <![CDATA[<211> 453]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的]]> <![CDATA[<400> 6]]> Glu Val Gln Leu Gln Gln Phe Gly Ala Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Asn Met Asp Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile 35 40 45 Gly Asp Ile Asn Pro Asn Tyr Gly Ser Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Trp Thr Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser 100 105 110 Val Thr Val Ser Ser Ala Lys Thr Thr Pro Pro Ser Val Tyr Pro Leu 115 120 125 Ala Pro Gly Cys Gly Asp Thr Thr Gly Ser Ser Val Thr Leu Gly Cys 130 135 140 Leu Val Lys Gly Tyr Phe Pro Glu Ser Val Thr Val Thr Trp Asn Ser 145 150 155 160 Gly Ser Leu Ser Ser Ser Val His Thr Phe Pro Ala Leu Leu Gln Ser 165 170 175 Gly Leu Tyr Thr Met Ser Ser Ser Val Thr Val Pro Ser Ser Thr Trp 180 185 190 Pro Ser Gln Thr Val Thr Cys Ser Val Ala His Pro Ala Ser Ser Thr 195 200 205 Thr Val Asp Lys Lys Leu Glu Pro Ser Gly Pro Ile Ser Thr Ile Asn 210 215 220 Pro Cys Pro Pro Cys Lys Glu Cys His Lys Cys Pro Ala Pro Asn Leu 225 230 235 240 Glu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Asn Ile Lys Asp Val 245 250 255 Leu Met Ile Ser Leu Thr Pro Lys Val Thr Cys Val Val Val Asp Val 260 265 270 Ser Glu Asp Asp Pro Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val 275 280 285 Glu Val His Thr Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Asn Ser 290 295 300 Thr Ile Arg Val Val Ser Thr Leu Pro Ile Gln His Gln Asp Trp Met 305 310 315 320 Ser Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Lys Asp Leu Pro Ser 325 330 335 Pro Ile Glu Arg Thr Ile Ser Lys Ile Lys Gly Leu Val Arg Ala Pro 340 345 350 Gln Val Tyr Ile Leu Pro Pro Pro Ala Glu Gln Leu Ser Arg Lys Asp 355 360 365 Val Ser Leu Thr Cys Leu Val Val Gly Phe Asn Pro Gly Asp Ile Ser 370 375 380 Val Glu Trp Thr Ser Asn Gly His Thr Glu Glu Asn Tyr Lys Asp Thr 385 390 395 400 Ala Pro Val Leu Asp Ser Asp Gly Ser Tyr Phe Ile Tyr Ser Lys Leu 405 410 415 Asn Met Lys Thr Ser Lys Trp Glu Lys Thr Asp Ser Phe Ser Cys Asn 420 425 430 Val Arg His Glu Gly Leu Lys Asn Tyr Tyr Leu Lys Lys Thr Ile Ser 435 440 445 Arg Ser Pro Gly Lys 450 <![CDATA[<210> 7]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的]]> <![CDATA[<400> 7]]> Glu Val Gln Leu Gln Gln Phe Gly Ala Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Asn Met Asp Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile 35 40 45 Gly Asp Ile Asn Pro Asn Tyr Gly Ser Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Trp Thr Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser 100 105 110 Val Thr Val Ser Ser 115
Claims (65)
- 一種治療有其需要之個體中之疾病或病症之方法,其包含 a. 從來源獲得B細胞群; b. 將該等B細胞培養在包含CD40L融合蛋白和CD40L交聯劑之培養基中; c. 將該等B細胞工程處理以表現有效載荷(payload)、嵌合受體、或二者;和 d. 將該等B細胞投予該個體。
- 如請求項1之方法,其中該來源為哺乳動物。
- 如請求項2之方法,其中該來源為包含外周單核血球之生物樣品。
- 如請求項1之方法,其中該CD40L融合蛋白包含與SEQ ID NO.3具有至少85%同一性之胺基酸序列。
- 如請求項1之方法,其中該CD40L融合蛋白包含與SEQ ID NO.3具有至少95%同一性之胺基酸序列。
- 如請求項1之方法,其中該CD40L融合蛋白包含SEQ ID NO.3之胺基酸序列。
- 如請求項1之方法,其中該CD40L交聯劑為抗體。
- 如請求項7之方法,其中該抗體包含輕鏈可變區和重鏈可變區,該輕鏈可變區包含與SEQ ID NO.5具有至少95%同一性之胺基酸序列且該重鏈可變區包含與SEQ ID NO.7具有至少95%同一性之胺基酸序列。
- 如請求項8之方法,其中該抗體包含輕鏈可變區和重鏈可變區,該輕鏈可變區包含SEQ ID NO.5之胺基酸序列且該重鏈可變區包含SEQ ID NO.7之胺基酸序列。
- 如請求項1之方法,其中該B細胞係將該等B細胞培養在具有CD40L融合蛋白和CD40L交聯劑之培養基中之前經工程處理。
- 如請求項1之方法,其中該B細胞係將該等B細胞培養在具有CD40L融合蛋白和CD40L交聯劑之培養基中之後經工程處理。
- 如請求項1之方法,其進一步包含在IL-4之存在下培養該等B細胞。
- 如請求項1之方法,其進一步包含在IL-21之存在下培養該等B細胞。
- 如請求項1之方法,其中該等經培養之B細胞表現下列標記中至少一者:CD62L、CCR7、CD80、CD86、CD54、ICAM、CD58、或CD27。
- 如請求項1之方法,其中該疾病或病症係選自由下列至少一者所組成之群組:癌症、心臟病、發炎性疾病、肌肉耗損疾病、或神經疾病。
- 如請求項15之方法,其中該癌症為下列至少一者:乳癌、結腸癌、直腸癌、食道癌、肺癌、胰臟癌、胃癌、肝癌、肝細胞癌、間質瘤,諸如GIST、膠質母細胞瘤和神經膠質瘤。
- 如請求項1之方法,其中至少約3x10 7個B細胞係經投予該個體。
- 如請求項1之方法,其中該B細胞群係培養至少14天。
- 一種治療有其需要之個體中之疾病或病症之方法,其包含 a. 從來源獲得B細胞群; b. 將該等B細胞培養在包含CD40L融合蛋白和CD40L交聯抗體之培養基中,其中該CD40L融合蛋白包含與SEQ ID NO.3之胺基酸序列具有至少95%同一性之胺基酸序列,而CD40L交聯抗體之輕鏈可變區與SEQ ID NO:5之胺基酸序列具有至少95%同一性,且其重鏈可變區與SEQ ID NO:7之胺基酸序列具有至少95%同一性;和 c. 將該等B細胞投予該個體。
- 如請求項19之方法,其中該來源為哺乳動物。
- 如請求項19之方法,其中該CD40L融合蛋白包含SEQ ID NO.3之胺基酸序列。
- 如請求項19之方法,其中該抗體包含輕鏈可變區和重鏈可變區,該輕鏈可變區包含SEQ ID NO. 5之胺基酸序列,且該重鏈可變區包含SEQ ID NO.7之胺基酸序列。
- 如請求項19之方法,其進一步包含將該等B細胞工程處理以表現有效載荷、嵌合受體、或二者。
- 如請求項19之方法,其中該B細胞係將該等B細胞培養在具有CD40L融合蛋白和CD40L交聯抗體之培養基中之前經工程處理。
- 如請求項19之方法,其中該B細胞係將該等B細胞培養在具有CD40L融合蛋白和CD40L交聯抗體之培養基中之後經工程處理。
- 如請求項19之方法,其進一步包含在IL-4之存在下培養該等B細胞。
- 如請求項19之方法,其進一步包含在IL-21之存在下培養該等B細胞。
- 如請求項19之方法,其中該等經培養之B細胞表現下列標記至少一者:CD62L、CCR7、CD80、CD86、CD54、ICAM、CD58、或CD27。
- 如請求項19之方法,其中該疾病或病症係選自由下列至少一者所組成之群組:癌症、心臟病、發炎性疾病、肌肉耗損疾病、或神經疾病。
- 如請求項29之方法,其中該癌症為下列至少一者:乳癌、結腸癌、直腸癌、食道癌、肺癌、胰臟癌、胃癌、肝癌、肝細胞癌、間質瘤,諸如GIST、膠質母細胞瘤和神經膠質瘤。
- 如請求項19之方法,其中至少約3x10 7個B細胞係經投予該個體。
- 如請求項19之方法,其中該B細胞群係培養至少14天。
- 一種用於製造經工程處理之B細胞之方法,該方法包含 a. 從來源獲得B細胞群; b. 將該等B細胞培養在包含CD40L融合蛋白和CD40L交聯劑之培養基中;和 c. 將該等B細胞工程處理以表現有效載荷、嵌合受體、或二者。
- 如請求項33之方法,其中該來源為哺乳動物。
- 如請求項33之方法,其中該來源為包含外周單核血球之生物樣品。
- 如請求項33之方法,其中該CD40L融合蛋白包含與SEQ ID NO.3具有至少85%同一性之胺基酸序列。
- 如請求項33之方法,其中該CD40L融合蛋白包含與SEQ ID NO.3具有至少95%同一性之胺基酸序列。
- 如請求項33之方法,其中該CD40L融合蛋白包含SEQ ID NO.3之胺基酸序列。
- 如請求項33之方法,其中該CD40L交聯劑為抗體。
- 如請求項39之方法,其中該抗體包含輕鏈可變區和重鏈可變區,該輕鏈可變區包含與SEQ ID NO.5具有至少95%同一性之胺基酸序列,且該重鏈可變區包含與SEQ ID NO. 7具有至少95%同一性之胺基酸序列。
- 如請求項40之方法,其中該抗體包含輕鏈可變區和重鏈可變區,該輕鏈可變區包含SEQ ID NO.5之胺基酸序列,且該重鏈可變區包含SEQ ID NO. 7之胺基酸序列。
- 如請求項33之方法,其中該B細胞係將該等B細胞培養在具有CD40L融合蛋白和CD40L交聯劑之培養基中之前經工程處理。
- 如請求項33之方法,其中該B細胞係將該等B細胞培養在具有CD40L融合蛋白和CD40L交聯劑之培養基中之後經工程處理。
- 如請求項33之方法,其進一步包含在IL-4之存在下培養該等B細胞。
- 如請求項33之方法,其進一步包含在IL-21之存在下培養該等B細胞。
- 如請求項33之方法,其中該等經培養之B細胞表現下列標記至少一者:CD62L、CCR7、CD80、CD86、CD54、ICAM、CD58、或CD27。
- 如請求項33之方法,其中獲得至少約3x10 7個B細胞。
- 如請求項33之方法,其中該B細胞群係培養至少14天。
- 一種用於製造經工程處理之B細胞之方法,該方法包含 a. 從來源獲得B細胞群;和 b. 將該等B細胞培養在包含CD40L融合蛋白和CD40L交聯抗體之培養基中,其中該CD40L包含與SEQ ID NO.3之胺基酸序列具有至少95%同一性的胺基酸序列,而該CD40L交聯抗體之輕鏈可變區與SEQ ID NO.5之胺基酸序列具有至少95%同一性,且CD40L交聯抗體之重鏈可變區與SEQ ID NO.7之胺基酸序列具有至少95%同一性。
- 如請求項49之方法,其中該來源為哺乳動物。
- 如請求項49之方法,其中該CD40L融合蛋白包含SEQ ID NO.3之胺基酸序列。
- 如請求項49之方法,其中該抗體包含輕鏈可變區和重鏈可變區,該輕鏈可變區包含SEQ ID NO.5之胺基酸序列,該重鏈可變區包含SEQ ID NO.7之胺基酸序列。
- 如請求項49之方法,其進一步包含將該等B細胞工程處理以表現有效載荷、嵌合受體、或二者。
- 如請求項49之方法,其中該B細胞係將該等B細胞培養在具有CD40L融合蛋白和CD40L交聯劑之培養基中之前經工程處理。
- 如請求項49之方法,其中該B細胞係將該等B細胞培養在具有CD40L融合蛋白和CD40L交聯劑之培養基中之後經工程處理。
- 如請求項49之方法,其進一步包含在IL-4之存在下培養該等B細胞。
- 如請求項49之方法,其進一步包含在IL-21之存在下培養該等B細胞。
- 如請求項49之方法,其中該等經培養之B細胞表現下列標記中至少一者:CD62L、CCR7、CD80、CD86、CD54、ICAM、CD58、或CD27。
- 如請求項49之方法,其中獲得至少約3x10 7個B細胞。
- 如請求項49之方法,其中該B細胞群係經培養至少14天。
- 一種B細胞擴增培養基,其包含 a. CD40L,其中該CD40L融合蛋白包含與SEQ ID NO.3之胺基酸序列具有至少95%同一性的胺基酸序列,和 b. CD40L交聯抗體,其輕鏈可變區與SEQ ID NO.5之胺基酸序列具有至少95%同一性且其重鏈可變區與SEQ ID NO:7之胺基酸序列具有至少95%同一性;及 c. 將該等B細胞投予該個體。
- 如請求項61之培養基,其中該CD40L融合蛋白包含SEQ ID NO.3之胺基酸序列。
- 如請求項61之培養基,其中該抗體包含輕鏈可變區和重鏈可變區,該輕鏈可變區包含SEQ ID NO.5之胺基酸序列,而該重鏈可變區包含SEQ ID NO.7之胺基酸序列。
- 如請求項61之培養基,其進一步包含IL-4。
- 如請求項61之培養基,其進一步包含IL-21。
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