TW201838654A - IgG刺激之周圍神經再髓鞘形成 - Google Patents
IgG刺激之周圍神經再髓鞘形成 Download PDFInfo
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- TW201838654A TW201838654A TW107124197A TW107124197A TW201838654A TW 201838654 A TW201838654 A TW 201838654A TW 107124197 A TW107124197 A TW 107124197A TW 107124197 A TW107124197 A TW 107124197A TW 201838654 A TW201838654 A TW 201838654A
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- neuropathy
- ivig
- igg
- myelin
- nerve
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Abstract
本發明係基於多株IgG能夠促進許旺細胞(Schwann cell)成熟、分化及髓磷脂產生的發現。提供經由投予多株IgG來治療哺乳動物之非特發性脫髓鞘周圍神經病變的方法,其中該神經病變並非免疫介導型或感染介導型。可用本發明治療之脫髓鞘周圍神經病變之類型包括周圍神經創傷及毒素誘發型周圍神經病變。或者,可將多株IgG之組成物直接施用於周圍神經細胞以誘發成熟、分化成髓鞘形成狀態及髓磷脂表現或促進細胞存活。
Description
本發明係關於經由投予多株IgG來治療哺乳動物之非特發性脫髓鞘周圍神經病變的方法,其中該神經病變並非免疫介導型或感染介導型。
周圍神經病變為使周圍神經系統(PNS),即在中樞神經系統(CNS)(亦即腦及脊髓)與身體之所有其他部分之間傳輸信號的神經節與神經元之網狀結構遭受損傷之病症表現。PNS之神經元依靠許旺細胞(Schwann cell)進行例如髓鞘形成、加速神經傳導、神經發育及再生、營養支持、產生神經細胞外基質及調節神經肌肉突觸活動。此等許旺細胞藉由在運動神經元及感覺神經元之軸突周圍包裹蛋白質及富含脂質之髓鞘來提供電絕緣。考慮到髓磷脂的關鍵作用,周圍軸突之脫髓鞘為急性及慢性周圍神經病變(諸如格巴二氏症候群(Guillain-Barré syndrome,GBS)、慢性脫髓鞘多發性神經病變(CIDP)及多源性運動神經病變(multifocal motor neuropathy,MMN)以及由毒素、藥物或全身性疾病(例如糖尿病)誘發之其他周圍神經神經病變變)之標誌並不令人驚訝。
周圍神經病變會扭曲信號傳輸,造成隨神經病變之由來及受影響神經之類型或數目而變化的症狀。舉例而言,症狀會視病症是否影響自受影響區域至CNS傳輸感覺信息之感覺神經纖維或自CNS至肌肉傳輸脈衝且協調運動活動之運動神經纖維或兩者而定。周圍神經病變可分類為單神經病變,涉及損傷一根神經,或多神經病變,涉及損傷多根神經;急性神經病變,其中症狀出 現突然,進展迅速且消退緩慢,或慢性神經病變,其中症狀開始輕微且進展緩慢。迄今已鑑定超過100種不同類型之周圍神經病變。周圍神經病變之臨床診斷可基於個體臨床病史、身體檢查、使用肌電描記術(EMG)及神經傳導研究(NCS)、自主測試及神經活組織檢查等來進行。
周圍神經病變之當前治療係針對潛在病狀,其中可能且通常與症狀治療結合使用,該等症狀治療諸如有消炎劑、疼痛管理、機械輔助及/或外科介入等。身體亦具有其回應於PNS損傷或損害而自身再生的能力。在PNS損傷後,出現遠端神經斷端之華勒氏變性(Wallerian degeneration),繼之以由許旺細胞降解髓磷脂、吞噬胞外髓磷脂及募集巨噬細胞來進一步清除髓磷脂。許旺細胞可因其去分化、增殖、促進軸突再生及再分化且產生髓磷脂的能力而進一步適應於病理情況。參見Bhatheja等人(2006)Int.J.Biochem.Cell Biol.38(12):1995-9。在修復過程中,許旺細胞藉由迅速增殖且向軸突提供往前生長的路徑來刺激、引導軸突再生且靶向神經移植,形成軸突之再生管,稱為邦氏帶(Bunger's band)。參見Burstyn-Cohen等人(1998)J.Neurosci 18(21):8875-8885。雖然一般可觀察到PNS中之功能性神經再生(與不具有髓磷脂清除及軸突再生之再生機制的CNS相反),但其通常受限或長期受損。因此需要新穎的PNS之修復促進方法。
關於CNS之新近研究已得出IgM對於寡樹突神經膠質細胞(oligodendrocyte),即中樞神經系統之髓鞘形成膠質細胞有直接影響的證據。舉例而言,發現使寡樹突神經膠質細胞反應性IgMκ抗體靶向寡樹突神經膠質細胞會促進CNS再髓鞘形成(Asakura等人,1998)。其他研究顯示使用經彙集之人類IgM分子處理髓鞘脫失病之非免疫性毒素誘發模型引起CNS中寡樹突神經膠質細胞分化顯著增加(Bieber等人,2000;Bieber等人,2002;Warrington等人,2007)。在CNS中之寡樹突神經膠質細胞、其前體細胞及髓磷脂上發現IgM之Fc 受體提供有關可能的配位體-受體相互作用之更多線索(Nakahara等人,2003)。
由此等寡樹突神經膠質細胞-IgM研究獲得之知識儘管對CNS修復有意義,但未能利用PNS(其不含有寡樹突神經膠質細胞)之再生能力。在更多相關研究中,發現投予人類IVIG可減少模擬PNS特異性脫髓鞘格巴二氏症候群(GBS)之EAN(自體免疫神經炎)大鼠模型之疾病持續時間(Lin等人,2007)。假定效應可歸因於IVIG的免疫調節作用及可能的消炎及輔助的旁觀者軸突損失減小之能力。在體液免疫系統之獨立研究中,B細胞基因敲除的JHD小鼠展現PNS損傷後巨噬細胞流入、髓磷脂清除及軸突再生有顯著延遲。經由天然WT小鼠之抗體或抗PNS髓磷脂抗體的被動轉移來恢復快速的髓磷脂碎屑清除,藉此確認內源性抗體促進巨噬細胞進入及吞噬活性之作用(Vargas等人,2010)。投予靜脈內免疫球蛋白(IVIG)之臨床試驗已現示對於GBS、慢性脫髓鞘多發性神經病變(CIDP)及多源性運動神經病變(MMN)有正面影響,並假定此等自體免疫或免疫介導型神經病變中之每一者的治療係經由IVIG的免疫調節作用實現。
迄今未知多株IgG對許旺細胞之作用(若存在時)。因此,仍存在關於許旺細胞之再生功能如何可用於脫髓鞘周圍神經病變之治療性目的之問題。本發明有關外源多株IgG誘發許旺細胞成熟、分化及髓磷脂產生之能力的發現為對提供治療所有脫髓鞘周圍神經病變之新穎方法之機制的重要說明。
在本發明之一個態樣中,提供治療哺乳動物之脫髓鞘周圍神經病變之方法,其中該神經病變並非免疫介導型或感染介導型,該等方法係藉由向診斷出患有該神經病變之哺乳動物投予治療有效量之多株IgG來達成。在本發明之一些具體實例中,所治療之脫髓鞘周圍神經病變並非格巴二氏症候群、慢性脫髓鞘多發性神經病變或多源性運動神經病變。在本發明之其他具體實例中,脫髓鞘周圍神經病變為非特發性神經病變。可用本發明治療之脫髓鞘周圍神經 病變可選自創傷誘發型神經病變、毒素誘發型神經病變、遺傳性神經病變及由代謝疾病誘發之神經病變(例如糖尿病性神經病變)。
在本發明之另一態樣中,提供藉由向患有周圍神經創傷之哺乳動物投予治療有效量之多株IgG來治療周圍神經創傷之方法。
在本發明之另一態樣中,提供治療毒素誘發型周圍神經病變之方法,其中該神經病變並非感染介導型,該等方法係藉由向診斷出患有該神經病變之哺乳動物投予治療有效量之多株IgG來達成。
為了治療本文所述之脫髓鞘周圍神經病變,可局部或全身投予本發明之多株IgG。可經肌肉內或皮內局部投予多株IgG。可經鼻內、皮下、經口、動脈內或靜脈內全身性投予多株IgG。在本發明之一些具體實例中,將消炎劑與多株IgG一起共投予哺乳動物。消炎劑可選自促腎上腺皮質激素、皮質類固醇、干擾素、乙酸格拉替雷(glatiramer acetate)或非類固醇消炎藥。
可每週、每兩週或每月以每公斤患者體重約0.05至5g、或每公斤患者體重約0.5至2g之劑量投予本發明之多株IgG。
在本發明之另一態樣中,提供促進許旺細胞對周圍神經細胞產生之髓鞘形成作用之方法,其係藉由使該許旺細胞與足以促進該許旺細胞對該周圍神經細胞產生之髓鞘形成作用之量的多株IgG接觸來達成。
在本發明之另一態樣中,提供促進未成熟許旺細胞分化成髓鞘形成狀態之方法,其係藉由使該許旺細胞與足以誘發許旺細胞分化之量的多株IgG接觸來達成。
在另一態樣中,提供促進許旺細胞產生髓磷脂之方法,包含使該許旺細胞與足以正調控MBP基因之量的多株IgG接觸。
在本發明之另一態樣中,提供培養包含軸突之哺乳動物神經組織之方法,其係如下進行:使培養物中之組織與有效量之許旺細胞及有效量之多 株IgG接觸,藉此許旺細胞與多株IgG接觸誘發MBP基因正調控。
在本發明之另一態樣中,提供藉由以下步驟治療哺乳動物之周圍神經損傷之方法:將神經細胞移植至該周圍神經損傷之部位;及使該等神經細胞與包含許旺細胞及多株IgG之組成物接觸。
在本文所述之方法中,多株IgG可經由一或多種投藥途徑,諸如經肌肉內、皮內、皮下、經頰、經口、經鼻內、或動脈內或靜脈內給予需要該療法之個體。該個體可為人類或家養動物。在一些具體實例中,該多株IgG來源於經彙集之人類血清。
在一些具體實例中,多株IgG與消炎劑一起共投予需要該療法之哺乳動物。消炎劑可選自促腎上腺皮質激素、皮質類固醇、干擾素、乙酸格拉替雷或非類固醇消炎藥。
在本發明之另一態樣中,提供用於治療非特發性脫髓鞘周圍神經病變之醫藥組成物,包含醫藥學上可接受之載劑及有效量之多株IgG。
藉由參考附圖中所說明之本發明之某些例示性具體實例來對本發明作出更具體的描述。此等圖式構成說明書的一部分。然而,應注意附圖說明本發明之例示性具體實例且因此不應視為限制在其範疇內。
圖1展示暴露於未透析(圖1A)及經透析(圖1B)IVIG/緩衝劑調配物之未成熟許旺細胞在2天後藉由BrdU併入分析所量測之相對增殖速率。此等相對增殖速率係基於對在細胞增殖期間併入細胞DNA中之5-溴-2'-脫氧尿苷(BrdU)呈陽性之細胞的數目而得出。
圖2展示暴露於未透析(圖2A)及經透析(圖2B)IVIG/緩衝劑調配物之未成熟許旺細胞在2天後使用Ki-67分析所量測之相對增殖速率。此等相對增殖速率係基於對在細胞增殖期間Ki-67表現呈陽性之細胞的數目而得出。
圖3展示暴露於經透析IVIG/緩衝劑調配物之未成熟許旺細胞在第1天及第3天時間點之P0(圖3A)及MBP(圖3B)基因表現程度。
圖4展示暴露於經透析IVIG/緩衝劑調配物之p57kip2抑制型許旺細胞在第7天時間點(9天抑制)之P0(圖4A)及MBP(圖4B)基因表現程度。
圖5展示與對照組經轉染許旺細胞(無p57kip2抑制)相比,p57kip2抑制型許旺細胞中CD64 Fc受體之表現程度。任一組許旺細胞均未暴露於IVIG/緩衝劑調配物。
圖6展示在用20mg經透析IVIG/緩衝劑調配物刺激後,p57kip2抑制型許旺細胞(圖6B)及對照組經轉染細胞(圖6A)之螢光影像。細胞過程之位置及長度由疊加於螢光影像上之箭頭指示。
圖7展示在用經透析IVIG/緩衝劑調配物刺激3天後(5天抑制)p57kip2抑制型許旺細胞及對照組經轉染細胞之細胞突起生長長度之圖形(圖7A)以及用20mg IVIG刺激之p57kip2抑制型許旺細胞(圖7B)、用緩衝劑刺激之p57kip2抑制型許旺細胞(圖7C)、用20mg IVIG處理之對照組經轉染細胞(圖7D)及用緩衝劑處理之對照組經轉染細胞(圖7E)各自之螢光影像。
圖8展示在用經透析IVIG/緩衝劑調配物刺激7天後(9天抑制)p57kip2抑制型許旺細胞及對照組經轉染細胞之細胞突起生長長度之圖形(圖8A)以及用20mg IVIG刺激之p57kip2抑制型許旺細胞(圖8B)、用緩衝劑刺激之p57kip2抑制型許旺細胞(圖8C)、用20mg IVIG處理之對照組經轉染細胞(圖8D)及用緩衝劑處理之對照組經轉染細胞(圖8E)各自之螢光影像。
圖9為建立PNS神經元(大鼠背根神經節)及髓鞘形成許旺細胞之共培養物之方法的流程圖。
多株IgG促進許旺細胞穩態、成熟、分化及髓磷脂產生之能力的 發現可應用於藉由促進天然許旺細胞之再生能力來治療不同來源之脫髓鞘周圍神經病變,例如毒素誘發型神經病變、糖尿病性神經病變、創傷誘發型神經病變。涵蓋投予多株IgG作為脫髓鞘周圍神經病變現有治療方案或症狀治療之輔助或替代。此外,本發明可在實驗室設置中用於實現周圍神經再髓鞘形成。基於本文所述之發現,多株IgG可應用於神經移植、細胞培養、例如誘發許旺細胞分化、決定前驅細胞命運、髓磷脂基因調節或蛋白質表現且作為治療前或術後護理方案用於危及或涉及周圍神經之手術技術。
I. 定義
術語「非特發性(non-idiopathic)」係指潛在病因已知的病症。
如本文中所用,術語「周圍神經病變(peripheral neuropathy)」係指影響周圍神經系統(不包括腦及脊髓之神經節及神經)的病症。「周圍神經病變」可表現為運動、感覺、感覺運動或自主神經功能障礙之一或組合。由周圍神經病變展現之多種形態可歸結於許多不同原因。舉例而言,周圍神經病變可能由遺傳獲得、可能由全身疾病引起、或可能由毒性劑誘發。實例包括(但不限於)糖尿病性周圍神經病變、遠端感覺運動神經病變或自主神經病變,諸如胃腸道蠕動減少或膀胱弛緩。與全身疾病相關之周圍神經病變之實例包括脊髓灰質炎後症候群或AIDS相關神經病變;遺傳性周圍神經病變之實例包括恰克-馬利-杜斯氏病(Charcot-Marie-Tooth disease)、無β脂蛋白血症(Abetalipoproteinemia)、丹吉爾病(Tangier disease)、異染性腦白質營養不良(Metachromatic leukodystrophy)、法布里氏病(Fabry's disease)及德熱里納-索塔斯病(Dejerine-Sottas syndrome);且由毒性劑所引起之周圍神經病變之實例包括因用化學治療劑(諸如長春新鹼(vincristine)、順鉑(cisplatin)、甲胺喋呤(methotrexate)或3'-疊氮基-3'-脫氧胸苷)治療所引起之彼等周圍神經病變。
一種周圍神經病變為「脫髓鞘周圍神經病變(demyelinating peripheral neuropathy)」。如本文中所用,「脫髓鞘周圍神經病變」描述與破壞或自神經移除髓磷脂(即圍繞神經纖維且使其絕緣之富含脂質之鞘)相關的廣義類周圍神經病變。脫髓鞘周圍神經病變之非限制性實例包括糖尿病性周圍神經病變、遠端感覺運動神經病變或自主神經病變,諸如胃腸道蠕動減少或膀胱弛緩。脫髓鞘周圍神經病變之其他實例及描述可見於實施方式之第II部分。
如本文中所用,「免疫介導型(immune-mediated)」病症係指由身體免疫系統之異常活性引起之病狀。「免疫介導型」病症之子集包括(但不限於)免疫系統攻擊身體之自體免疫疾病、免疫複合物病、涉及移植後排斥之病症、發炎性疾病及過敏症。
「感染介導型(infection-mediated)」周圍神經病變係指由於病毒、細菌或真菌感染而持續的周圍神經系統功能障礙。
「創傷誘發型周圍神經病變(trauma-induced peripheral neuropathy)」或「創傷性周圍神經病變(traumatic peripheral neuropathy)」係指由身體休克、損傷或「物理創傷」所引起之周圍神經系統功能障礙。物理創傷(例如由於搏鬥、交通事故、跌倒及運動相關活動)可導致神經部分或完全斷裂、擠壓、壓迫或牽張,有時太強烈使得神經部分或完全自神經節或脊髓處分開且引起脫髓鞘。創傷誘發型周邊神經病變亦可由於例如電擊、低溫等而持續。
「毒素(toxin)」或「化學品誘發(chemical induced)」周圍神經病變係指由毒素(例如化學藥劑)所引起之周圍神經系統功能障礙。引起周圍神經病變之毒素一般可分成三組:藥品及藥物;工業化學品;及環境毒素。可導致周圍神經病變之毒素的非限制性實例描述於下文實施方式之第II部分。
如本文中所用,「消炎劑(anti-inflammatory agent)」包括減少受感染血管及/或相鄰組織之炎症的任何藥劑。消炎劑之非限制性實例為類固醇(例如糖皮質激素及皮質類固醇)、免疫選擇性消炎衍生物(ImSAID)、冷卻劑、草 本補充劑(例如鉤果草、牛膝草、薑、薑黃、山金車及柳樹皮(含有柳酸)及具有消炎作用之食物(例如石榴、綠茶、蔬菜、含有ω-3脂肪酸之食物)、堅果、種子及特級初榨橄欖油)。特定言之,前列腺素2(PGE2)為促炎性化合物且PGE1及PGE3為消炎化合物。因此,減少PGE2或增加PGE1及PGE3之藥劑亦可充當消炎劑。消炎劑之其他非限制性實例可見於下文第VI部分「組合療法」。
如本文中所用,「未成熟許旺細胞(immature Schwann cell)」係指許旺細胞系之特定階段。順著許旺細胞系之第一步驟給出許旺細胞前驅體,即變得與許多軸突相關且表現神經生長因子受體(NGF-R)、生長相關蛋白質43(GAP-32)及神經細胞黏著分子N-CAM及L1之增殖細胞。後續「定型(committed)」許旺細胞稱為未成熟許旺細胞;其變得與逐步減少之軸突相關且除先前提示之標記之外表現S-100蛋白質(由此階段向前,所有許旺細胞表現S-100)。定型許旺細胞發育成非髓鞘形成許旺細胞,其仍與若干軸突相關且除先前標記之外表現半乳糖腦苷脂(GalC),或發育成髓鞘形成許旺細胞。髓鞘形成許旺細胞進展至藉由短暫表現抑制型cAMP誘導性Pou域轉錄因子(SCIP)表徵之增殖「髓鞘形成前」階段,隨後「髓鞘形成後」GalC陽性階段,在進展中變得與單一軸突相關。最終分化為成熟髓鞘形成許旺細胞涉及下調NGF-R、GAP-43、N-CAM及L1表現,同時正調控GalC及髓磷脂蛋白質表現且活體內合成且加工髓磷脂。
如本文中所用,術語「IgG」係指IgG免疫球蛋白之組成物。IgG類免疫球蛋白如名稱所暗示,以存在γ(gamma)重鏈表徵。例示性完整IgG免疫球蛋白結構包含四聚體。每一四聚體由兩對相同多肽鏈組成,每對具有一個「輕」鏈(約25kDa)及一個「重」鏈(約50-70kDa)。各鏈N端界定主要負責抗原識別之約100至110個或110個以上胺基酸之可變區。術語可變輕鏈(VL)及可變重鏈(VH)分別指此等輕鏈及重鏈。
「免疫球蛋白(immunoglobulin)」或「抗體(antibody)」為與特定抗原免疫反應之多肽。如本文中所用,術語「免疫球蛋白」涵蓋各種同型之完整分子以及具有抗原結合能力之片段,例如Fab'、F(ab')2、Fab、Fv及rlgG。參見例如Pierce Catalog and Handbook,1994-1995(Pierce Chemical Co.,Rockford,111.);Kuby,J.,Immunology,第3版增刊,W.H.Freeman & Co.,New York(1998)。該術語亦涵蓋重組單鏈Fv片段(scFv)。該術語進一步涵蓋二價或雙特異性分子、雙功能抗體、三功能抗體及四功能抗體。二價分子及雙特異性分子描述於例如Kostelny等人(1992)J.Immunol.148:1547、Pack及Pluckthun(1992)Biochemistry 31:1579、Hollinger等人,1993,上述、Gruber等人(1994)J.Immunol.:5368、Zhu等人(1997)Protein Sci 6:781、Hu等人(1996)Cancer Res.56:3055、Adams等人(1993)Cancer Res.53:4026及McCartney等人(1995)Protein Eng.8:301中。
如本文中所用,術語「多株IgG(polyclonal IgG)」係指來源於多種B細胞且具有不同特異性及抗原決定基親和力之IgG免疫球蛋白的不均勻集合。製備多株抗體之方法為熟習此項技術者所已知(例如Harlow及Lane,1988,Antibodies:A Laboratory Manual.(Cold Spring Harbor Press))。本發明之多株IgG可自已對病原性病症預篩選之不同哺乳動物個體集中之血漿提取。在一些具體實例中,本發明之多株IgG代表超過100個個體、超過200個個體、超過300個個體、超過400個個體、超過500個個體、超過600個個體、超過700個個體、超過800個個體、超過900個個體、超過1000個個體、超過1100個個體、超過1200個個體、超過1300個個體、超過1400個個體、超過1500個個體、超過1600個個體、超過1700個個體、超過1800個個體、超過1900個個體、或超過2000個個體。
片語「特異性(或選擇性)結合(specifically(or selectively)binds)」於抗體或當提及蛋白質或肽時,「對」蛋白質或肽「具有特異性(或選擇性)免 疫反應性(specifically(or selectively)immunoreactive with)」係指在蛋白質及其他生物素之異質群體中確定蛋白質存在之結合反應。因此,在指定免疫檢定條件下,規定抗體結合於至少兩倍背景且更典型超過10至100倍背景之特定蛋白質序列。特異性結合於蛋白質之配位體(例如抗體)一般具有至少103M-1或104M-1、有時105M-1或106M-1、在其他情況中106M-1或107M-1、較佳108M-1至109M-1、且更佳約1010M-1至1011M-1或1011M-1以上之締合常數。多種免疫檢定格式可用於選擇對特定蛋白質具有特異性免疫反應性之抗體。舉例而言,固相ELISA免疫檢定常規用於選擇對蛋白質具有特異性免疫反應性之單株抗體。關於可用於測定特異性免疫反應性之免疫檢定格式及條件的描述,參見例如Harlow及Lane(1988)Antibodies,A Laboratory Manual,Cold Spring Harbor Publications,New York。
術語「多肽(polypeptide)」、「肽(peptide)」及「蛋白質(protein)」在本文中可互換使用以指代胺基酸殘基之聚合物。該等術語適用於一或多個胺基酸殘基為相應天然存在之胺基酸之人造化學模擬物的胺基酸聚合物,以及天然存在之胺基酸聚合物及非天然存在之胺基酸聚合物。
術語「胺基酸(amino acid)」係指天然存在之胺基酸及合成胺基酸,以及功能與天然存在之胺基酸類似的胺基酸類似物及胺基酸模擬物。天然存在之胺基酸為由遺傳密碼編碼之胺基酸,以及後來經修飾之胺基酸,例如羥基脯胺酸、γ-羧基麩胺酸及O-磷絲胺酸。胺基酸類似物係指與天然存在之胺基酸具有相同基本化學結構(亦即碳鍵結於氫、羧基、胺基及R基團)之化合物,例如高絲胺酸、正白胺酸、甲硫胺酸亞碸、甲硫胺酸甲基鋶。該等類似物具有經修飾之R基團(例如正白胺酸)或經修飾之肽主結構,但保留與天然存在之胺基酸相同之基本化學結構。胺基酸模擬物係指結構與胺基酸之一般化學結構不同之化合物,但其功能與天然存在之胺基酸類似。
胺基酸在本文中可藉由其通常已知的三字母符號或藉由IUPAC-IUB生物化學命名委員會建議之單字母符號來提及。核苷酸同樣可用其通常已接受之單字母碼提及。
如本文中所用,「髓磷脂鹼性蛋白(Myelin basic protein)」(MBP)係指基因以及由此編碼之蛋白質,該蛋白質為髓磷脂之主要蛋白質組分,包含髓鞘總蛋白質含量之約30%。已展示MBP為MS中之主要目標自體抗原,且對MBP具有反應性之T細胞在其發病機制中起關鍵作用(參見例如Schwartz,R S,「Autoimmunity and Autoimmune Diseases」in Paul,Fundamental Immunology,第3版Raven Press,New York,1993,第1033 1097頁;Brown及McFariin 1981.Lab Invest 45,第278 284頁;Lehmann等人1992.Nature 358,第155 157頁;Martin等人1992.Ann Rev Immunol 10,第153 187頁;Sprent 1994.Cell 76,第315 322頁;Su及Sriram.1991.J of Neuroimmunol 34,第181 190頁;及Weimbs及Stoffel.1992.Biochemistry 31,第12289 12296頁)。
術語「軸突(axon)」係指負責體內信號傳導之神經細胞的細長纖維。
在本文中可互換使用之術語「個體(individual)」、「個體(subject)」及「患者(patient)」係指哺乳動物,包括(但不限於)鼠類、類人猿、人類、哺乳動物農畜、哺乳動物運動型動物及哺乳動物寵物。在較佳具體實例中,該個體可為人類。
術語「劑量(dose)」及「劑量(dosage)」在本文中可互換使用。劑量係指在每次投藥時給予個體之活性成分之量。劑量將視許多因素而變化,包括投藥頻率;個體之體型及耐受性;病狀嚴重程度;副作用之危險性;及投藥途徑。熟習此項技術者應認識到劑量可視上述因素或基於治療性進展而修改。術語「劑型(dosage form)」係指藥物之具體樣式且視投藥途徑而定。舉例 而言,劑型可呈液體形式,例如注射用生理食鹽水溶液。
「治療有效(therapeutically effective)」量或劑量或「充足/有效(sufficient/effective)」量或劑量為投予產生效應之劑量。精確劑量將視治療目的而定,且可由熟習此項技術者使用已知技術確定。(參見例如Lieberman,Pharmaceutical Dosage Forms(第1-3卷,1992);Lloyd,The Art,Science and Technology of Pharmaceutical Compounding(1999);Pickar,Dosage Calculations(1999);及Remington:The Science and Practice of Pharmacy,第20版,2003,Gennaro,編,Lippincott,Williams & Wilkins)。
術語「治療(treatment)」或「療法(therapy)」一般意謂獲得所需生理效應。就完全或部分預防疾病或其病狀或症狀而言,效應可為預防性的,及/或就部分或完全治癒損傷、疾病或病狀及/或改善可歸因於損傷、疾病或病狀之不利效應且包括延滯疾病或病狀之發展或造成疾病或病狀退化而言,效應可為治療性的。治療亦可包括減輕損傷效應之預防性用途,且應存在。舉例而言,在一個態樣中,本發明包括在涉及周圍神經系統之手術之前預先投藥以減輕損害。治療亦可指任何發病延遲、症狀改善、患者存活率改良、存活時間或存活率增加等。治療效應可與未接收治療之個體或個體庫相比。
「對照(control)」在本文中使用,係指與實驗組比較之參考,一般為已知參考。熟習此項技術者應理解對照在指定情況中有價值,且能夠基於與對照值之比較分析資料。對照亦對測定資料之顯著性有價值。舉例而言,若指定參數之值在對照中變化很大,則測試樣品中之變化將不視為顯著。
在較詳細描述本發明之前,應瞭解本發明不限於所述特定具體實例,本身當然可變化。亦應瞭解,本文中所用之術語係僅用於描述特定具體實例之目的且不意欲具限制性,因為本發明之範疇將僅受隨附申請專利範圍限制。
在提供值範圍的情況下,應瞭解,除非上下文另外明確規定,否 則該範圍及任何其他規定範圍之上下限之間的每一居中值或該規定範圍內之居中值(至下限單位之十分之一)涵蓋在本發明內。此等較小範圍之上下限可獨立地包括於較小範圍內且亦涵蓋在本發明內,隸屬於規定範圍中任何特定排除之界限。在規定範圍包括一個或兩個界限的情況下,排除彼等包括界限之一者或兩者的範圍亦包括在本發明內。
除非另作定義,否則本文中所用之所有技術及科學術語具有與一般熟習本發明所屬技術者通常所理解之含義相同的含義。雖然與本文所述之彼等方法及材料類似或等效的任何方法及材料亦可用於本發明之實踐或測試,但目前描述代表性說明方法及材料。
本說明書中所引用之所有公開案及專利以引用的方式併入本文中,如特定且單獨指出以引用的方式併入之每一單個公開案或專利,及以引用的方式併入本文中以揭示及描述與所引用之公開案有關的方法及/或材料。任何公開案之引用是由於其揭示內容在申請日期之前且不應視為許可本發明無權先於該藉助於先前發明之公開案。另外,所提供之公佈日期可不同於可能需要獨立確認之實際公佈日期。
應注意,除非上下文另外明確規定,否則如本文及隨附申請專利範圍中所用,單數形成「一」及「該」包括複數個指示物。另外注意,申請專利範圍可經起草以排除任何可選要素。因此,此陳述由於使用與申請專利範圍要素列舉相連之諸如「單獨」、「僅」及其類似物之排他術語或使用「負面」限制而意欲充當前置基礎。
如熟習此項技術者在閱讀本發明後應明瞭,在不悖離本發明之範疇或精神的情況下,本文中所述及所說明之個別具體實例之每一者具有可易於與任何其他若干具體實例之特徵分離或組合之離散組分及特徵。任何所列舉之方法可按照所列舉事件之排序或邏輯上可能的任何其他順序來進行。
II. 脫髓鞘周圍神經病變
本發明基於多株IgG可經由刺激許旺細胞成熟、分化及髓磷脂產生而駕馭許旺細胞再生能力之發現。本發明以此方式靶向脫髓鞘周圍神經病變之統一機制,以便提供用於該等病症之廣譜治療。舉例而言,本發明靶向由物理創傷、毒性劑及糖尿病所引起之脫髓鞘周圍神經病變。
可由本文所述之多株IgG組成物治療之脫髓鞘病症包括例如遺傳獲得之周圍神經病變、由全身疾病導致的周圍神經病變、或由毒素或創傷誘發之周圍神經病變。
遺傳性脫髓鞘神經病變(亦稱為遺傳性神經病變)為最常見的遺傳性神經病變之一。遺傳性脫髓鞘神經病變分成四個主要子類:1)運動及感覺神經病變、2)感覺神經病變、3)運動神經病變及4)感覺及自主神經病變。特定言之,脫髓鞘遺傳性神經病變經常為明顯減少神經傳導及減小神經傳導速度且周圍神經慢性分段脫髓鞘之進行性神經病變。Gabreels-Festen等人,「Hereditary demyelinating motor and sensory neuropathy,」Brain Pathol.3(2):135-146(1993)。普通類遺傳性脫髓鞘神經病變之實例包括(但不限於)糖尿病性周圍神經病變、遠端感覺運動神經病變或自主神經病變,諸如胃腸道蠕動減少或膀胱弛緩。遺傳性周圍神經病變之實例包括恰克-馬利-杜斯氏病、無β脂蛋白血症、丹吉爾病、異染性腦白質營養不良、法布里氏病及德熱里納-索塔斯病。
全身性脫髓鞘周圍神經病變起源於全身性疾病之副作用。與全身疾病相關之周圍神經病變之非限制性實例包括脊髓灰質炎後症候群及AIDS相關神經病變。此外,以下非限制性全身性疾病可具有周圍神經病變症狀:癌症、營養不良、酒精中毒、糖尿病、AIDS、萊姆病(Lyme disease)、類風濕性關節炎、慢性腎衰竭、自體免疫病症、甲狀腺低能症及病毒感染(例如肝炎)。
毒素誘發型脫髓鞘周圍神經病變藉由暴露於神經毒劑(諸如醫藥劑、生物製劑及化學品暴露)而引起。引起周圍神經病變之毒素的實例包括(但不限於)化學治療劑(例如長春新鹼、太平洋紫杉醇、順鉑、甲胺喋呤、或3'-疊氮基-3'-脫氧胸苷)、鉛、汞、鉈、有機溶劑、殺有害生物劑、二硫化碳、砷、丙烯醯胺、白喉毒素、酒精、抗HIV藥物(例如去羥肌苷(didanosine)及紮西他濱(zalcitabine))、抗結核病藥物(例如異煙肼(isoniazid)及乙胺丁醇(ethamubtol))、抗微生物藥品(例如胺苯碸(dapsone)、甲硝達唑(metronidazole)、氯喹(chloroquine)及氯黴素(chloamphenicol))、精神藥物(例如鋰)、放射線及以下藥物,諸如胺碘酮(amiodarone)、金硫葡糖(aurothioglucose)、苯妥英(phenytoin)、沙力度胺(thalidomide)、秋水仙鹼(colchicine)、西咪替丁(cimetidine)、雙硫侖(disulfiram)、聯胺肼(hydralazine)及高含量維生素B6。可能引起周圍神經病變之其他毒性劑列於下文。
如上所述之創傷誘發型脫髓鞘周圍神經病變由身體休克、損傷或物理創傷引起。
因此,周圍神經病變之病因範圍廣泛,例如自糖尿病性併發症;創傷;毒素,包括(但不限於)藥品及藥物、工業化學品及環境毒素;自體免疫反應;營養缺乏;至血管及代謝障礙。舉例而言,脫髓鞘周圍神經病變可作為骨硬化性骨髓瘤、單株蛋白質相關周圍神經病變、遺傳性運動及感覺周圍神經病變類型1及3及遺傳性壓力敏感性麻痹之結果而出現。
類似地,脫髓鞘周圍神經病變之症狀亦例如隨著患病神經之類型而變化。舉例而言,患有脫髓鞘病症之人類患者可具有以下一或多個脫髓鞘病症之症狀,諸如(但不限於)視力損害、麻木、四肢疲軟、震顫或痙攣、怕熱、言語障礙、失禁、眩暈或本體感覺(例如平衡、協調、肢體位置覺)損害。具有脫髓鞘病症家族史(例如脫髓鞘病症遺傳傾向性)或顯示出上述脫髓鞘病症 之輕度或很少發生症狀之人類(例如人類患者)出於方法之目的,可視為處於患上脫髓鞘病症之風險中。
特定言之,由脫髓鞘周圍神經病變所引起之感覺神經損害可引起一系列更複雜的症狀,因為感覺神經具有一系列更廣泛、更高度專門化之功能。封閉於髓磷脂(成螺旋形包裹且隔離許多神經之富含脂質之膜皺襞)中之較大感覺纖維探測震動、輕觸及位置感知。對大感覺纖維之損害使感覺震動及接觸的能力衰減,導致普通麻感(尤其手及腳)。許多患者不能僅藉由接觸識別小物件之形狀或辨別不同形狀。此對感覺纖維之損害可造成反射喪失(運動神經損害亦可)。位置覺喪失常常使個體不能協調如行走或扣鈕扣之複雜動作,或在個體閉眼時保持平衡。神經痛難以控制且可能嚴重地影響良好情緒及總體生活品質。
無髓鞘之較小感覺纖維傳輸疼痛及溫度感覺。對此等纖維之損害可干擾感覺疼痛或溫度變化之能力。個體可能無法感知其已割傷或創傷開始感染。其他個體可能無法偵測到逼近心臟病發作或其他急性病狀之警告的疼痛。(痛覺喪失對於患有糖尿病之個體為尤其嚴重的問題,在此群體中造成高下肢截肢率。)皮膚之疼痛感受器亦可變得過於敏感,以使得按理無痛的刺激感受到劇痛(異常疼痛)。
自主神經損害之症狀多種多樣且視患病器官或腺體而定。自主神經功能障礙可危及生命且可能在呼吸受損或心臟開始不規則搏動的情況下需要緊急醫療護理。自主神經損害之常見症狀包括不能正常出汗,其可能導致怕熱;膀胱控制損失,其可能引起感染或失禁;及不能控制肌肉擴張或收縮血管以保持安全血壓水準。當個體突然自坐姿行動至立姿時,控制過高血壓之喪失可引起眩暈、頭昏眼花或甚至暈厥(稱為姿勢性低血壓或起立性低血壓之病狀)。
胃腸症狀經常伴隨自主神經病變。控制腸道肌肉收縮之神經常常 功能障礙,導致腹瀉、便秘或失禁。若某些自主神經患病,則個體亦可遭受難以進食或吞咽。
本發明之多株IgG組成物亦可用以治療作為糖尿病(亦即I型、II型)之併發症發展之脫髓鞘周圍神經病變。周圍神經病變為糖尿病主要併發症之一。由局部缺血所引起之神經傳導速度減小及傳導失敗之抗性增加為糖尿病患者及該疾病之動物模型中偵測到最早變化。超微結構研究已顯示軸突及許旺細胞(SC)兩者中之變化(例如軸突口徑減小及分段脫髓鞘)以及微血管系統中之變化,所有該等變化似乎獨立發展。一些研究推斷出人類糖尿病性神經病變中所觀測到的周圍神經之進行性纖維損失可至少部分歸因於神經變性延遲及神經再生受損。代謝及微血管異常以及神經營養因子缺乏已視為造成糖尿病性神經病變之發病機制。糖尿病之血管變化主要由局部缺血及神經內膜缺氧組成。此等血管異常之潛在機制包括神經滋養血管交感神經末端之病變性變化,伴以隨之發生的神經血流之神經控制障礙及神經中前列環素及氧化氮產生減少。
糖尿病性神經病變之兩種不同臨床表現為由罹患疼痛對稱性多發性神經病變之患者及患有無感覺無痛足之患者代表的彼等臨床表現。無痛性神經病變為普遍病症且根據若干研究,可能反映神經變性之程度。另一方面,疼痛症候群與較少形態異常相關。雖然亦已提出疼痛症候群與變性相反可能反映神經再生,但若干記錄表明神經再生在糖尿病方面為有害的。糖尿病性齧齒動物之周圍感覺神經中若干功能指標之分析亦表明抑制而非增強功能。舉例而言,實驗性糖尿病誘發若干傷害感受性反應,包括早期熱痛覺過敏,其隨時間推移變成痛覺減退;機械痛覺過敏;熱及觸覺異常疼痛;C纖維活動增加及類鴉片敏感性降低。在此情形中,機械痛覺過敏可在C纖維之持續閾上機械刺激後由放電(firing)增加導致。
雖然使用抗氧化劑、血管舒張劑及神經營養因子之療法可逆轉糖尿病性神經之一些功能及代謝異常,但其僅部分改善異常痛覺,表明其他路徑在起作用。本發明能夠促進許旺細胞的癒合能力以便治療糖尿病性神經病變。
本發明之多株IgG組成物亦可用以治療由創傷引起之脫髓鞘周圍神經病變。「創傷誘發型」神經病變係指外部物理傷害對神經系統之損害。損傷或意外創傷(例如由於戰爭、交通事故、跌倒及運動相關活動)可導致神經部分或完全斷裂、擠壓、壓迫或牽張,有時太強烈使得神經部分或完全自脊髓處分開且引起脫髓鞘。較少突發性創傷亦可引起嚴重的神經損傷。
本發明之多株IgG組成物亦可用以治療由毒性劑引起之周圍神經病變。引起周圍神經病變之毒素一般可分成三組:藥品及藥物;工業化學品;及環境毒素。如本文中所用,術語「毒性劑(toxic agent)」定義為經由化學作用損害周圍神經系統一或多個組分之常規功能的任何物質。該定義包括空氣傳播的藥劑、作為食物或藥品之污染物攝食的藥劑、或作為治療性方案之一部分有意服用的藥劑。
可能引起周圍神經病變之毒性劑清單包括(但不限於):3'-疊氮基-3'-脫氧胸苷、乙醯唑胺、丙烯醯胺、阿黴素(adriamycin)、酒精、烯丙基氯、阿米三嗪(almitrine)、阿米曲替林(amitriptyline)、胺碘酮、兩性黴素(amphotericin)、砷、金硫葡糖、胺基甲酸酯、二硫化碳、一氧化碳、卡鉑、氯黴素、氯喹、消膽胺(cholestyramine)、西咪替丁(cimetidine)、順鉑(cisplatin)、順鉑(cis-platinum)、氯碘羥喹(clioquinol)、考來替泊(colestipol)、秋水仙鹼(colchicine)、黏菌素(colistin)、環絲胺酸、阿糖胞苷、胺苯碸、二氯苯氧基乙酸、去羥肌苷;雙脫氧胞苷、雙脫氧肌苷、雙脫氧胸苷、二甲胺基丙腈、雙硫侖、多西他賽(docetaxel)、小紅莓(doxorubicin)、乙胺丁醇、乙硫異煙胺、環氧乙烷、FK506(他克莫司,tacrolimus)、格魯米特(glutethimide)、金、六 碳(hexacarbons)、己烷、激素避孕藥、六羥甲基三聚氰胺、聯胺肼、羥氯喹(hydroxychloroquine)、丙咪嗪(imipramine)、吲哚美辛(indomethacin)、無機鉛、無機汞、異煙肼、鋰、甲基汞、二甲雙胍(metformin)、甲胺喋呤、甲基溴、甲基肼、甲硝達唑、米索硝唑、甲基正丁基甲酮、硝化呋喃妥因(nitrofurantoin)、氮芥(nitrogen mustard)、氧化亞氮、有機磷酸酯、歐斯旁特(ospolot)、太平洋紫杉醇、青黴素(penicillin)、哌克昔林(perhexiline)、順丁烯二酸哌克昔林(perhexiline maleate)、苯妥英(phenytoin)、鉑、聚氯化聯苯、撲米酮(primidone)、普魯卡因胺(procainamide)、丙卡巴肼(procarbazine)、吡哆醇(pyridoxine)、辛伐他汀(simvastatin)、氰酸鈉、鏈黴素(streptomycin)、磺醯胺、蘇拉明(suramin)、他莫昔芬(tamoxifen)、沙力度胺(thalidomide)、鉈、甲苯、胺苯喋啶(triamterene)、三甲基錫、磷酸三鄰甲酚酯、L-色胺酸、滅鼠優(vacor)、長春花生物鹼、長春新鹼、長春地辛、大劑量維生素A、大劑量維生素D、紮西他濱(zalcitamine)、齊美定(zimeldine);工業藥劑,尤其溶劑;重金屬;及嗅膠或其他毒性化合物。
本發明之多株IgG組成物亦可用以治療由癌症療法之化學毒性劑投予所導致的脫髓鞘周圍神經病變。已知引起周圍神經病變之化學毒性劑為長春新鹼、長春鹼、順鉑、太平洋紫杉醇、丙卡巴肼、雙脫氧肌苷、阿糖胞苷、α-干擾素及5-氟尿嘧啶(參見Macdonald,Neurologic Clinics 9:955-967(1991))。
III. 脫髓鞘周圍神經病變之診斷及監測
脫髓鞘周圍神經病變之診斷可由醫師或臨床醫師使用一或多種此項技術中已知的方法來進行。在典型情況下,神經學測試為需要的且涉及獲取患者病史(包括患者的症狀、工作環境、社交習慣、暴露於任何毒素、酒精中毒歷史、HIV或其他傳染性疾病之危險性及神經病變家族史),執行可確定神經性病症之病因的測試及進行測試以測定神經損傷之程度、部位及類型。
一般身體檢查及相關測試可顯示引起神經損傷之全身疾病的存在。血液試驗可偵測糖尿病、維生素缺乏、肝臟或腎臟功能障礙、其他代謝障礙及異常免疫系統活動之跡象。腦及脊髓周圍之腦脊髓液的檢驗可顯示與神經病變相關的異常抗體。更多專業測試可顯示其他血液或心血管疾病、結締組織病症或惡性腫瘤。肌力測試以及痙攣或束化之證據表明運動纖維涉入。患者探測震動、輕觸、身體姿勢、溫度及疼痛之能力的評估顯示感覺神經損害且可表明小或大感覺神經纖維是否患病。
基於神經學檢驗、身體檢驗、患者病史及任何先前篩檢或測試之結果,可安排其他測試以幫助確定神經病變之性質及程度。輔助診斷周圍神經病變之例示性技術包括:電腦斷層攝影掃描、磁共振成像、肌電描記術、神經傳導速度、神經活組織檢查或皮膚活組織檢查。適用於診斷周圍神經病變之設備包括(但不限於)美國專利第7,854,703號。
電腦斷層攝影或CT掃描為用於產生器官、骨骼及組織之快速清晰二維影像之非侵入性無痛方法。X射線以各種角度穿過身體且由電腦化掃描儀偵測。資料經處理且以身體或器官內部結構之橫剖面影像或「切片」形式呈現。神經學CT掃描可偵測骨骼及血管不規則性、某些腦腫瘤及囊腫、椎間盤突出、腦炎、脊椎狹窄(脊椎管變窄)及其他病症。
磁共振成像(MRI)可檢查肌肉品質及尺寸、偵測肌肉組織之任何脂肪替代及確定神經纖維是否受持續壓迫損害。MRI儀器在身體周圍形成強磁場。無線電波接著穿過身體以觸發共振信號,可在體內以不同角度偵測共振信號。電腦將此共振處理成掃描區之三維圖像或二維「切片」。
肌電描記術(EMG)包含將細針插入肌肉以比較當肌肉靜止時及當肌肉收縮時提供之電活動之量。EMG測試可幫助區分肌肉病症及神經病變症。
神經傳導速度(NCV)測試可精確量測較大神經纖維之損害程度,顯示症狀是否由髓鞘或軸突之變性所引起。在此測試期間,探針電刺激神經纖維,神經纖維藉由產生其自身電脈衝而起反應。進一步沿著神經路徑安置之電極量測脈衝順著軸突傳輸之速度。緩慢傳輸速率及脈衝阻斷趨向於表明髓鞘受損,而脈衝強度減小為軸突變性之跡象。
神經活組織檢查包含移取及檢查神經組織之樣品(最常來自下肢)。雖然此測試可提供關於神經損傷程度之有價值資訊,但其為難以執行之侵入性程序且本身可引起神經病變變性副作用。
皮膚活組織檢查為醫生移取薄皮膚樣品且檢查神經纖維末端之測試。與NCV不同,其可顯示較小纖維中存在之損害;與習知神經活組織檢查相反,皮膚活組織檢查具較少侵入性、具有較少副作用且較易於執行。
監測個體脫髓鞘或再髓鞘形成之方法為此項技術中已知。如本文中所定義,監測個體(例如人類患者)之再髓鞘形成意謂評估個體之變化,例如指示再髓鞘形成之一或多個參數的改善,例如吾人可監測脫髓鞘病症之一或多個症狀的改善。該等症狀包括本文所述之脫髓鞘病症之任何症狀。再髓鞘形成亦可由以下方法來監測,包括直接測定個體之髓磷脂狀態,例如吾人可使用磁共振成像(MRI)量測白質或使用磁共振波譜(MRS)腦掃描量測髓磷脂纖維厚度。
在一些具體實例中,在投予(較佳第一次投予)多株IgG後,執行評估至少1小時、例如至少2、4、6、8、12、24或48小時、或至少1天、2天、3天、4天、5天、6天、7天、8天、9天、10天、11天、12天、13天、14天、15天、16天、17天、18天、19天、或20天或20天以上、或至少1週、2週、3週、4週、5週、6週、7週、8週、9週、10週、12週、13週、14週、15週、16週、17週、18週、19週、20週或20週以上、或其任何組合。可在一或多個以下時段評估個體: 在開始治療之前;在治療期間;或已投予治療之一或多個要素後。評估可包括評估進一步治療之需要,例如評估劑量、投藥頻率或治療持續時間是否應改變。其亦可包括評估增加或減少所選治療性模態之需要,例如加或減少本文所述之脫髓鞘病症之任何治療。舉例而言,必要時多株IgG可與一或多種其他治療劑一起繼續投予。在一個較佳具體實例中,若獲得評估之預選結果,則採用另一步驟,例如投予個體另一治療或執行另一評估或測試。再髓鞘形成之程度可用於確定患者護理,例如選擇或修改療程或判定第三方償還治療費。
在一些具體實例中,監測個體(例如人類患者)之再髓鞘形成亦可包括使用例如磁共振成像(MRI)掃描、正電子發射斷層攝影(PET)掃描、擴散加權成像(DW-I或DW-MRI)、擴散張量成像、脊髓攝影、磁化轉移監測發炎病灶(亦即硬化症)之尺寸或數目之減小。在一些具體實例中,監測個體之再髓鞘形成可包括偵測例如(i)異常蛋白,諸如髓磷脂微小片段;(ii)含量升高或特定類型之淋巴細胞;及/或(iii)異常含量之免疫球蛋白(IgG)分子。在其他具體實例中,監測個體之再髓鞘形成可包括評估個體神經心理學(例如,諸如記憶力、算術、注意力、判斷及推理之各種能力的狀態)之變化。在一些具體實例中,監測個體(例如人類患者)之再髓鞘形成可包含測試患者尿液之類髓磷脂鹼性蛋白物質(類MBP物質)之含量減少,該物質在疾病進展期間隨著軸突損害而升高。在一些具體實例中,當脫髓鞘病症影響個體的眼睛或視力時,監測個體之再髓鞘形成可包含測試例如色盲之改善。
本文提供評估個體之方法,以確定例如個體是否對脫髓鞘病症之治療,例如增加個體再髓鞘形成之療法,諸如投予多株IgG起反應或不起反應。該方法包括提供關於個體髓磷脂之含量或狀態的參考值(例如投予前之值)及視情況向個體投予增加再髓鞘形成之藥物(例如多株IgG)。在投予藥物之具體實例中,該方法亦包括提供關於個體髓磷脂含量或狀態的投予後之值(例如在 再髓鞘形成療法投予後髓磷脂之含量或狀態),且比較該投予後之值與該參考值,從而評估個體,例如確定個體是否對該療法起反應或不起反應。可例如藉由本文所述之任何評估方法測定投予後之值(亦即在再髓鞘形成療法後,與個體髓磷脂之狀態或含量對應之值)。亦可例如藉由本文所述之任何評估方法測定參考值(亦即在使用再髓鞘形成療法治療之前個體髓磷脂之狀態或含量)。
在一些具體實例中,確定個體起反應表明可/應/將/現向個體投予較短持續時間之治療(例如,比向對療法不起反應之個體所建議之治療短,或比目前使用的現有脫髓鞘病症療法之持續時間短),且視情況將適應症記入報告中。
在一些具體實例中,確定個體起反應表明向個體反向指示較短持續時間之治療(例如,比目前使用的現有脫髓鞘病症治療(例如本文所述之任何脫髓鞘病症治療)之持續時間短)且視情況將適應症記入報告中。
在一些具體實例中,比較投予後之值與參考值包括:在開始投予再髓鞘形成療法(例如多株IgG)後之第一時間點(例如,其中該第一時間點為6、7、8、9、10、11、12、13、14天或14天以上(例如3、4、5、6、8週或8週以上(例如3、4、6、12個月或12個月以上)))測定個體髓磷脂之投予後含量;在該第一時間點之前的第二時間點(例如,其中該第二時間點在開始投予再髓鞘形成療法(例如多株IgG)之前或在開始投予再髓鞘形成療法(例如多株IgG)約1、2、3、4或5天內)測定個體髓磷脂之狀態或含量之參考值;且比較個體髓磷脂之投予後含量與參考值,其中該投予後含量與參考值之間個體髓磷脂含量之增加(例如含量相差至多約60%、約50%、約40%、約30%、約20%、約10%、約5%、約2%或約1%)表明個體起反應。
在一些具體實例中,確定患者是否對療法起反應係藉由評估個體指示再髓鞘形成之一或多個參數的變化(例如改善)來進行,例如吾人可監測 脫髓鞘病症之一或多個症狀的改善。該等症狀包括本文所述之脫髓鞘病症之任何症狀。再髓鞘形成亦可由以下方法來監測,包括直接測定個體之髓磷脂狀態,例如吾人可使用磁共振成像(MRI)量測白質、使用磁共振波譜(MRS)腦掃描量測髓磷脂纖維厚度、或本文所述之任何其他直接量測。
在另一具體實例中,確定患者是否對療法起反應亦可藉由本文所述之任何其他評估或指標來評估,包括(但不限於)監測患者關於該患者中存在之發炎病灶(亦即硬化症)之尺寸或數目的減小;監測患者神經內膜流之例如(i)含量升高或特定類型之淋巴細胞及/或(ii)異常含量之免疫球蛋白(IgG)分子之存在或量的減少;監測患者之神經心理學(例如,諸如記憶力、算術、注意力、判斷及推理之各種能力的狀態)之陽性變化;及/或監測患者尿液之類髓磷脂鹼性蛋白物質(類MBP物質)之含量減少。
在一些具體實例中,在再髓鞘形成療法(例如,誘發個體再髓鞘形成之療法,例如,諸如多株IgG之療法)後脫髓鞘病症之一或多個症狀或其他上述指標改善至少5%(例如至少10%、至少15%、至少20%、至少25%、至少30%、至少35%、至少40%、至少50%、至少60%、至少70%)足以將患者歸類為對療法起反應者。
IV. 多株IGG之製備
本發明之免疫球蛋白製劑可由任何合適起始物質製備。舉例而言,免疫球蛋白製劑可由供體血清或單株或重組免疫球蛋白製備。在典型實例中,採集健康供體之血液。一般,採集與免疫球蛋白製劑將投予之個體相同物種之動物的血液(典型地稱為「同源」免疫球蛋白)。免疫球蛋白自血液中分離且藉由諸如以下之一或多種合適程序純化,例如科恩分部分離法(Cohn fractionation)、超速離心、電泳製備、離子交換層析、親和性層析、免疫親和層析、聚乙二醇分餾法、酒精分餾法、奈米過濾、超濾/透濾或其類似程序。(參見 例如Cohn等人,J.Am.Chem.Soc.68:459-75(1946);Oncley等人,J.Am.Chem.Soc.71:541-50(1949);Barundern等人,Vox Sang.7:157-74(1962);Koblet等人,Vox Sang.13:93-102(1967);Teschner等人Vox Sang(92):42-55(2007);Hoppe等人Munch Med Wochenschr(34):1749-1752(1967);Falksveden(瑞典專利第348942號);Tanaka等人,Braz J Med Biol Res(33)37-30(2000);Lebing等人,Vox Sang(84):193-201(2003);美國專利第5,122,373號及第5,177,194號;PCT/US2010/036470;及PCT/US2011/038247;其揭示內容係以引入的方式併入本文中。)
為使來源於血漿之產品中存在的各種病毒污染物失活,可對澄清的PptG濾液進行溶劑清潔劑(S/D)處理。來源於血漿之部分的清潔劑處理方法為此項技術中所熟知(回顧參見Pelletier JP等人,Best Pract Res Clin Haematol.2006;19(1):205-42)。任何標準S/D處理一般可與本文中所提供之方法結合使用。
為進一步純化及濃縮IgG,可使用陽離子交換及/或陰離子交換層析。使用離子交換層析純化及濃縮IgG之方法為此項技術中所熟知。舉例而言,美國專利第5,886,154號描述一種方法,其中在低pH值(在約3.8與4.5之間)下萃取部分II+III沈澱,隨後使用辛酸沈澱IgG,且最後實施兩個陰離子交換層析步驟。美國專利第6,069,236號描述完全不依靠酒精沈澱在層析IgG純化流程。PCT公開案第WO 2005/073252號描述一種IgG純化方法,包含萃取部分II+III沈澱、辛酸處理、PEG處理及單個陰離子交換層析步驟。美國專利第7,186,410號描述一種IgG純化方法,包含萃取部分I+II+III或部分II沈澱,隨後在鹼性pH值下執行單個陰離子交換步驟。美國專利第7,553,938號描述一種方法,包含萃取部分I+II+III或部分II+III沈澱、辛酸鹽處理及一或兩個陰離子交換層析步驟。美國專利第6,093,324號描述一種純化方法,包含使用在約6.0至約6.6之pH值下操作的大孔隙陰離子交換樹脂。美國專利第6,835,379號描述一種在不存在酒精分餾法的情況 下依靠陽離子交換層析之純化方法。上述公開案之揭示內容出於所有目的係以全文引用的方式併入本文中。
為減少本文中所提供之IgG組成物的病毒負荷,可使用合適奈米過濾裝置奈米過濾該組成物。在某些具體實例中,奈米過濾裝置具有約15nm至約200nm之平均孔徑。適用於此用途之奈米過濾器之實例包括(但不限於)DVD、DV 50、DV 20(Pall)、Viresolve NFP、Viresolve NFR(Millipore)、Planova 15N、20N、35N及75N(Planova)。在一特定具體實例中,奈米過濾器可具有約15nm至約72nm、或約19nm至約35nm、或約15nm、19nm、35nm或72nm之平均孔徑。在一個較佳具體實例中,奈米過濾器具有約35nm之平均孔徑,諸如Asahi PLANOVA 35N過濾器或其等效物。在一特定具體實例中,使用具有30nm至40nm、較佳35±2nm之孔徑的奈米過濾器奈米過濾自陰離子交換步驟中回收之IgG組成物。在另一較佳具體實例中,奈米過濾器具有約19或20nm之平均孔徑,諸如Asahi PLANOVA 20N過濾器(19±2nm)或其等效物。在一特定具體實例中,使用具有15nm至25nm、較佳19±2nm之孔徑的奈米過濾器奈米過濾自陰離子交換步驟中回收之IgG組成物。
在某些具體實例中,由含有γ球蛋白之產物製備免疫球蛋白,該等含有γ球蛋白之產物藉由熟習此項技術者所熟知之酒精分餾法及/或離子交換及親和性層析法來產生。常用經純化之科恩部分II(Cohn Fraction II)。起始科恩部分II糊劑典型地為約95%之IgG且包含四種IgG亞型。不同亞型以與獲得其之經集中之人類血漿中所發現之大致相同比率存在於部分II中。部分II在調配之前進一步純化為可投予的產物。舉例而言,部分II糊劑可溶解於冷的經純化含水酒精溶液中且經由沈澱及過濾移除雜質。在最終過濾後,可透析或透濾(例如使用具有小於或等於100,000道爾頓之標稱分子量限制的超濾膜)免疫球蛋白懸浮液以移除酒精。可濃縮或稀釋溶液以獲得所需蛋白質濃度且可藉由熟習此項技術 者所熟知的技術進一步純化溶液。
可使用製備步驟增濃免疫球蛋白之特定同型或亞型。舉例而言,蛋白質A、蛋白質G或蛋白質H瓊脂糖層析可用於增濃IgG或特定IgG亞型之免疫球蛋白混合物。(一般參見Harlow及Lane,Using Antibodies,Cold Spring Harbor Laboratory Press(1999);Harlow及Lane,Antibodies,A Laboratory Manual,Cold Spring Harbor Laboratory Press(1988);美國專利第5,180,810號。)
亦可使用市售來源之多株免疫球蛋白。該等來源包括(但不限於):Kiovig® 10% IVIG(Baxter Healthcare);Gammagard Liquid® 10% IVIG(Baxter Healthcare);Gammagard S/D®(Baxter Healthcare);Gammagard S/D®,含小於1mg/mL IgA之5%溶液(Baxter Healthcare);Gamunex®-C,10%(Grifols USA);Flebogamma®,5%及10% DIF(Grifols USA);Privigen® 10%溶液(CSL Behring);Carimune ® NF或Sandoglobulin®(CSL Behring);及Hizentra® 20%液體(CSL Behring);Octagam®,5%及10% IVIG(Octapharma AG);Gammanorm® 16.5% SCIG(Octapharma AG)。用於本發明方法之免疫球蛋白製劑的市售來源並非關鍵。
替代性方法為使用具有抗原結合能力之抗體片段,例如Fab'、F(ab')2、Fab、Fv及rlgG。參見例如Pierce Catalog and Handbook,1994-1995(Pierce Chemical Co.,Rockford,111.);Kuby,J.,Immunology,第3版增刊,W.H.Freeman & Co.,New York(1998)。本發明之多株IgG組成物可包括一種免疫球蛋白同型(亦即IgG)之片段,或可含有不同同型免疫球蛋白片段(例如IgA、IgD、IgE、IgG及/或IgM)之混合物。Fc製劑亦可主要含有(至少60%、至少75%、至少90%、至少95%或至少99%)IgG免疫球蛋白同型之片段且可含有少量其他亞型。舉例而言,Fc製劑可含有至少約75%、至少約90%、至少約95%或至少約99%之IgG片段。此外,多株IgG製劑可包含單個IgG亞型或兩種或兩種以上IgG亞型之混合 物。合適IgG亞型包括IgG1、IgG2、IgG3及IgG4。在一特定具體實例中,多株IgG製劑包含IgG1片段。
免疫球蛋白可在製備期間之任何合適時間裂解以產生Fab、F(ab')及/或F(ab')2片段(若適用)。適用於裂解之酶為例如番木瓜蛋白酶、胃蛋白酶或纖維蛋白溶酶。(參見例如Harlow及Lane,Using Antibodies,Cold Spring Harbor Laboratory Press(1999);Plan及Makula,Vox Sanguinis 28:157-75(1975)。)裂解後,Fc部分可藉由例如親和性層析、離子交換層析、凝膠過濾或其類似方法而與Fab、F(ab')及/或F(ab')2片段分離。在特定實例中,使用番木瓜蛋白酶消化免疫球蛋白以使Fc片段與Fab片段分離。接著對消化混合物進行陽離子交換層析以使Fc片段與Fab片段分離。
免疫球蛋白片段亦可由表現單株抗體之融合瘤或其他培養系統製備。(參見例如Kohler及Milstein,Nature 256:495-97(1975);Hagiwara及Yuasa,Hum.Antibodies Hybridomas 4:15-19(1993);Kozbor等人,Immunology Today 4:72(1983);Cole等人,in Monoclonal Antibodies and Cancer Therapy,Alan R.Liss,Inc.,第77-96頁(1985)。)人類單株抗體可例如自人類融合瘤(參見例如Cote等人,Proc.Natl.Acad.Sci.USA 80:2026-30(1983))或藉由使用EBV病毒活體外轉型人類B細胞(參見例如Cole等人,前述)來獲得。可純化由融合瘤產生之單株抗體,且如本文所述或如熟習此項技術者所已知,使Fc片段與Fab、F(ab')及/或F(ab')2片段分離。
IgG片段亦可諸如由真核細胞培養系統重組產生。舉例而言,單鏈Fv片段(scFv)可由轉染以含有編碼Fv片段之DNA序列之載體的中國倉鼠卵巢(CHO)細胞重組產生。創建該等重組哺乳動物細胞之方法描述於例如Sambrook及Russell,Molecular Cloning,A Laboratory Manual,第3版(Cold Spring Harbor Laboratory Press(New York)2001)及Ausubel等人,Short Protocols in Molecular Biology,第4版(John Wiley & Sons,Inc.(New York)1999)中且為熟習此項技術者所已知。重組免疫球蛋白片段亦可在其他哺乳動物細胞系中產生,諸如幼倉鼠腎(BHK)細胞。培養重組細胞以產生重組蛋白質之方法亦為此項技術中已知。
多種其他表現系統可用以表現重組免疫球蛋白IgG片段。此等表現系統包括(但不限於)已用編碼所需IgG片段之表現卡匣轉染或轉型之昆蟲細胞系統及微生物(諸如酵母或細菌)。在某些具體實例中,微生物視情況可經工程改造以再現哺乳動物或人類IgG片段之糖基化型態。
在某些具體實例中,為使免疫球蛋白製劑安全用於本發明之方法,可使用其他製備步驟。該等步驟可包括例如使用溶劑/清潔劑處理、巴氏滅菌及滅菌。為確保多株IgG製劑之安全性,可使用額外製備步驟。該等製備步驟可包括例如酵素水解、經由還原及烷基化、磺化之化學修飾、使用B-丙內酯處理、在低pH值下處理或其類似步驟。合適方法之描述亦可見於例如美國專利第4,608,254號;第4,687,664號;第4,640,834號;第4,814,277號;第5,864,016號;第5,639,730號及第5,770,199號;Romer等人,Vox Sang.42:62-73(1982);Romer等人,Vox Sang.42:74-80(1990);及Rutter,J.Neurosurg.Psychiat.57(增刊):2-5(1994)(其揭示內容係以引入的方式併入本文中)。
V. 醫藥組成物及劑量
投予多株IgG(如本文中所述,為脫髓鞘周圍神經病變之有效治療性方案)之個體較佳為人類,但可為任何哺乳動物。因此,如一般熟習此項技術者可易於瞭解,本發明之方法及醫藥組成物尤其適於投予任何哺乳動物,且包括(但不限於)家畜,諸如貓科或犬科個體;農畜,諸如(但不限於)牛類、馬類、山羊、綿羊及豬個體;野生動物(無論在野外或在動物園中);研究動物,諸如亦即用於獸醫學醫藥用途之小鼠、大鼠、兔、山羊、綿羊、豬、犬、 貓等。
預期本發明之包含多株IgG之醫藥組成物可藉由此項技術中已知的多種方法投予。投藥途徑及/或模式視所需結果而變化,但典型地應為靜脈內、肌肉內、鼻內、腹膜內、動脈內或皮下。醫藥組成物可包括適用於靜脈內、肌肉內、皮下、非經腸、脊椎或表皮投藥(例如藉由注射或輸注)之可接受之載劑。
本發明之多株IgG適用於局部或全身投予以實現預防性及/或治療性治療。例示性投藥模式包括(但不限於)經皮、皮下、動脈內、靜脈內、鼻內、肌肉內、經直腸、頰內及經口投予。視投藥方法而定,醫藥組成物可以多種單位劑型投予。舉例而言,單位劑型包括散劑、錠劑、丸劑、膠囊、栓劑、安瓿及口含錠。僅需制定活性成分有效量,亦即使得合適有效劑量應與單個或多個單位劑量所用之劑型相符。當然,精確個體劑量以及日劑量應在醫師或獸醫指導下根據標準醫藥原則來確定。當口服時,本發明之藥物多株IgG免疫球蛋白組成物較佳避免被消化。其典型地藉由使抗體與組成物複合以使抗體耐酸性及酵素水解或藉由將抗體封裝於適當抗性載體(諸如泡囊,詳言之脂質體)中來實現(參見Langer,Science 249:1527-1533(1990);Treat等人,in Liposomes in the Therapy of Infectious Disease and Cancer,Lopez-Berestein及Fidler(編),Liss,New York,第353-365頁(1989);Lopez-Berestein,同上,第317-327頁;一般參見同上)。防止蛋白質被消化之方式為此項技術中所熟知。
本發明之醫藥組成物尤其適用於非經腸投藥,諸如靜脈內投藥或投藥至體腔或器官內腔中。投藥組成物一般包含多株IgG與醫藥學上可接受之載劑(較佳水性載劑)之組成物。可使用多種水性載劑,例如緩衝生理食鹽水及其類似物。
可用於適合形成錠劑、糖衣藥丸、膠囊及丸劑之含有活性化合物 之醫藥組成物(例如顆粒)的稀釋劑包括以下:(a)填充劑及增量劑,例如澱粉、糖、甘露醇及矽酸;(b)黏合劑,例如羧甲基纖維素及其他纖維素衍生物、海藻酸鹽、明膠及聚乙烯吡咯啶酮;(c)保濕劑,例如甘油;(d)崩解劑,例如瓊脂、碳酸鈣及碳酸氫鈉;(e)延緩溶解劑,例如石蠟;(f)再吸收促進劑,例如第四銨化合物;(g)表面活性劑,例如鯨蠟醇、單硬脂酸甘油酯;(g)吸附載劑,例如高嶺土及膨潤土;(i)潤滑劑,例如滑石、鈣及硬脂酸鎂及固體聚乙二醇。欲用於適合形成栓劑之醫藥組成物的稀釋劑可例如為常用水溶性稀釋劑,諸如聚乙二醇及脂肪(例如椰子油及高碳酯[例如C14醇酯及C16脂肪酸酯])或此等稀釋劑之混合物。
本發明之醫藥組成物無菌且一般不含不符合要求的物質。關於非經腸投藥,溶液及懸浮液應無菌,例如安瓿中所含之水或花生油且適當時血液等滲。此等組成物可藉由習知的熟知滅菌技術來滅菌。組成物可視需要含有醫藥學上可接受之輔助物質以接近於生理條件,諸如pH調節劑及緩衝劑、毒性調節劑及其類似物,例如乙酸鈉、氯化鈉、氯化鉀、氯化鈣、乳酸鈉及其類似物。此等調配物中多株IgG之濃度可大範圍變化,且將主要基於流體容量、黏度、患者體重及其類似物,根據所選具體投藥模式及患者需要來選擇。
可例如藉由使用包衣(諸如卵磷脂)、藉由在分散液情況下維持所需粒徑及藉由使用界面活性劑來保持組成物之適當流動性。在一些情況下,較佳於組成物中包括等滲劑,例如糖(諸如蔗糖)、多元醇(諸如甘露糖醇或山梨糖醇)及氯化鈉。亦可使用穩定劑,諸如煙醯胺、L-脯胺酸、L-甘胺酸或L-異白胺酸。可藉由使延遲吸收之藥劑(例如單硬脂酸鋁或明膠)包括於組成物中而促使長期吸收可注射性組成物。
醫藥組成物(其為懸浮液)可含有常用稀釋劑,諸如液體稀釋劑,例如水、乙醇、丙二醇、表面活性劑(例如乙氧化異十八醇、聚環氧乙烷山梨 糖醇及脫水山梨糖醇酯)、微晶纖維素、偏氫氧化鋁、膨潤土、瓊脂及黃蓍膠或其混合物。
醫藥組成物亦可含有著色劑及防腐劑,以及香料及調味添加劑(例如薄荷油及按樹油)及甜味劑(例如糖精及阿斯巴甜糖)。
以總組成物之重量計,醫藥組成物一般含有0.5至90%之活性成分。
除單株抗體之外,醫藥組成物及藥物亦可含有其他醫藥學活性化合物,例如類固醇、消炎劑或其類似物。
本發明藥物中之任何稀釋劑可為上文關於醫藥組成物所提及之任何彼等稀釋劑。該等藥物可包括分子量小於200之溶劑作為唯一稀釋劑。
本發明之醫藥組成物可根據此項技術中所熟知且常規實踐之方法製備。參見例如Remington:The Science and Practice of Pharmacy,Mack Publishing Co.,第20版.,2000;及Sustained and Controlled Release Drug Delivery Systems,J.R.Robinson,編,Marcel Dekker,Inc.,New York,1978。醫藥組成物較佳在GMP條件下製造。典型地,本發明之醫藥組成物中使用治療有效劑量或有功效劑量之免疫球蛋白製劑。醫藥組成物可藉由熟習此項技術者已知的習知方法調配成劑型。調整給藥方案以提供最佳所需反應(例如治療反應)。舉例而言,可投予單次大丸劑,可隨時間推移投予若干分次劑量或劑量可如治療情況之迫切要求所指示按比例減少或增加。將非經腸組成物調配成單位劑型以便於投藥及劑量之均一性可為有利的。如本文中所用之單位劑型係指物理上適合作為單次劑量用於所治療個體的離散單位;各單位含有預定數量之計劃與所需醫藥載劑相關聯用以產生所需治療作用的活性化合物。
對於特定患者,可改變實際劑量含量以便獲得有效實現所需治療反應且對該患者無毒性的活性成分之量。醫師可在低於實現所需治療效應所需 的含量下開始醫藥組成物給藥,且逐漸增加劑量直至實現所需效應。一般,有效劑量視許多不同因素而變化,包括所治療之特定疾病或病狀、其嚴重程度、患者之生理狀態、所投予之其他藥物及治療是否為預防性或治療性。
多株IgG組成物可在多個時機投予。單劑量之間的時間間隔可為每日、每週、每兩週、每3週、每4週、每月或每年。時間間隔亦可按量測患者治療性進展所指示而為不定期的。劑量及頻率可視抗體在患者中之半衰期而改變。
或者,多株IgG可在控制釋放系統中傳遞。舉例而言,多株免疫球蛋白可使用靜脈內輸注、可植入式滲透泵、經皮貼片、脂質體或其他投藥模式來投予。在一個具體實例中,可使用泵(參見Langer,前述;Sefton,CRC Crit.Ref.Biomed.Eng.14:201(1987);Buchwald等人,Surgery 88:507(1980);Saudek等人,N.Engl.J.Med.321:574(1989))。在另一具體實例中,可使用聚合材料(參見Medical Applications of Controlled Release,Langer及Wise(編),CRC Pres.,Boca Raton,Fla.(1974);Controlled Drug Bioavailability,Drug Product Design and Performance,Smolen及Ball(編),Wiley,New York(1984);Ranger及Peppas,J.Macromol.Sci.Rev.Macromol.Chem.23:61(1983);亦參見Levy等人,Science 228:190(1985);During等人,Ann.Neurol.25:351(1989);Howard等人,J.Neurosurg.71:105(1989))。在另一具體實例中,控制釋放系統可安置在治療目標(亦即周圍神經系統損傷部位)附近,因此僅需要系統劑量之一部分(參見例如Goodson,in Medical Applications of Controlled Release,前述,第2卷,第115-138頁(1984))。其他控制釋放系統論述於Langer之評述(Science 249:1527-1533(1990))中。
就多株IgG免疫球蛋白製劑而言,常用靜脈內免疫球蛋白(IVIG)。IVIG調配物經設計藉由注射投予。由於多株IgG製劑已達到格外高的 免疫球蛋白濃度(例如,在一些具體實例中10% w/v,在其他具體實例中15% w/v,在其他具體實例中20% w/v及在其他具體實例中至多25% w/v),其顯著減少治療有效劑量之體積,故本發明之組成物尤其有利於皮下及/或肌肉內投予患者以及靜脈內投予。
術語「有效量」係指在個體中引起所治療醫學病狀之改善或補救(例如用於治療周圍神經創傷,用於治療毒素誘發型周圍神經病變等)的多株IgG製劑之量。欲投予個體之有效量可由醫師在考慮到年齡、體重、疾病嚴重程度、投藥途徑(例如靜脈內對皮下)及療法反應之個體差異的情況下來確定。
給藥時程可視循環半衰期及所用調配物而變化。以與劑量調配物相容的方式投予治療有效量之組成物。欲投予之所需活性成分之精確量視執業醫師之診斷而定且限於每一個體。
合適劑量之多株IgG可每週、每兩週、每3週、每4週或每月投予患者,其中該劑量範圍介於每公斤患者體重約0.050至5g、每公斤患者體重約0.095至4.7g、每公斤患者體重約0.140至4.4g、每公斤患者體重約0.185至4.1g、每公斤患者體重約0.230至3.8g、每公斤患者體重約0.275至3.5g、每公斤患者體重約0.320至3.2g、每公斤患者體重約0.365至2.9g、每公斤患者體重約0.410至2.6g、每公斤患者體重約0.455至2.3g、每公斤患者體重約0.500至2.0g。
在替代性具體實例中,本發明之多株IgG組成物以如下劑量每週、每兩週、每3週、每4週或每月投予個體:每公斤患者體重約0.05至4.9g、每公斤患者體重約0.05至4.8g、每公斤患者體重約0.05至4.7g、每公斤患者體重約0.05至4.6g、每公斤患者體重約0.05至4.5g、每公斤患者體重約0.05至4.4g、每公斤患者體重約0.05至4.3g、每公斤患者體重約0.05至4.2g、每公斤患者體重約0.05至4.1g、每公斤患者體重約0.05至4.0g、每公斤患者體重約0.05至3.9g、每公斤患者體重約0.05至3.8g、每公斤患者體重約0.05至3.7g、每公斤患者體重約 0.05至3.6g、每公斤患者體重約0.05至3.5g、每公斤患者體重約0.05至3.4g、每公斤患者體重約0.05至3.3g、每公斤患者體重約0.05至3.2g、每公斤患者體重約0.05至3.1g、每公斤患者體重約0.05至3.0g、每公斤患者體重約0.05至2.9g、每公斤患者體重約0.05至2.8g、每公斤患者體重約0.05至2.7g、每公斤患者體重約0.05至2.6g、每公斤患者體重約0.05至2.5g、每公斤患者體重約0.05至2.4g、每公斤患者體重約0.05至2.3g、每公斤患者體重約0.05至2.2g、每公斤患者體重約0.05至2.1g、每公斤患者體重約0.05至2.0g、每公斤患者體重約0.05至1.9g、每公斤患者體重約0.05至1.8g、每公斤患者體重約0.05至1.7g、每公斤患者體重約0.05至1.6g、每公斤患者體重約0.05至1.5g、每公斤患者體重約0.05至1.4g、每公斤患者體重約0.05至1.3g、每公斤患者體重約0.05至1.2g、每公斤患者體重約0.05至1.1g、每公斤患者體重約0.05至1.0g。通曉由IgG製劑治療之疾病的臨床醫師可根據此項技術中已知的準則確定用於患者之適當劑量。
在其他具體實例中,每次可投予個體每公斤患者體重約0.2g至約4g之範圍的IVIG產物,且投予頻率可介於一週兩次、一週一次、一月兩次、一月一次或隔月一次。一種例示性IVIG劑量範圍介於每公斤患者體重約0.1公克至約1公克、或約0.2公克至約0.8公克之間,典型地以一月兩次或一月一次之頻率投予。舉例而言,根據一月兩次時程,IVIG以每公斤患者體重0.2、0.4、0.6或0.8g之劑量投予一些患者。在其他情況下,根據一月一次時程,IVIG以每公斤患者體重0.2、0.4、0.6或0.8g之劑量投予。
脫髓鞘周圍神經病變之IVIG治療的持續時間可變化:其可為3或6個月短或可為18個月、2年、5年或10年長。在一些情況下,IVIG治療可能持續患者餘生。可在整個投藥過程期間在某一時段後評估IVIG治療之有效性,例如對於18個月治療計劃,可每3個月或每6個月評估一次。在其他情況下,對於較長治療過程,可每9個月或每12個月評估一次有效性。可相應調節任何後續投藥 之投藥時程(劑量及頻率)。
對於靜脈內投予,多株IgG以每小時0.5mL/kg(每分鐘0.8mg/kg)之例示性初步輸注速率投予30分鐘,然而,若耐受高達每小時5mL/kg(每分鐘8mg/kg),則例示性維持輸注速率將每30分鐘增加速率。輸注時間可視劑量、輸注速率及耐藥性而變化。
對於40公斤及40公斤以上患者體重之個體的皮下投予,例示性初步輸注速率為以20毫升/小時/部位輸注30毫升/部位,而例示性維持輸注速率為以20-30毫升/小時/部位輸注30毫升/部位。對於40公斤以下患者體重之個體的皮下投予,例示性初步輸注速率為以15毫升/小時/部位輸注20-30毫升/部位,而例示性維持輸注速率為以15-20毫升/小時/部位輸注20毫升/部位。輸注時間可視劑量、輸注速率及耐藥性而變化。
根據本發明,需要結束療程之時間可由醫師確定且可介於短至一天至超過一個月之範圍。在某些具體實例中,療程可為1至6個月。
製備可非經腸投予之組成物的方法應為熟習此項技術者所已知或顯而易見的且更詳細地描述於諸如Remington's Pharmaceutical Science,第15版,Mack Publishing Company,Easton,Pa.(1980)之出版物中。
VI. 組合療法
在一些具體實例中,多株IgG可與另一治療一起以組合療法形式投予個體,例如脫髓鞘病症(例如本文所述之任何脫髓鞘病症)之另一治療。舉例而言,組合療法可包括向個體(例如人類患者)投予一或多種對患有脫髓鞘病症或處於患上脫髓鞘病症危險中之個體提供治療效益之額外藥劑。在一些具體實例中,多株IgG與一或多種額外藥劑同時投予。在其他具體實例中,第一次投予多株IgG且第二次投予一或多種額外藥劑。在一些具體實例中,第一次投予一或多種額外藥劑且第二次投予多株IgG。多株IgG可置換或補充先前或當前 投予的療法。舉例而言,在用多株IgG治療後,可停止或減少一或多種額外藥劑之投予,例如以低含量投予。在其他具體實例中,保持先前療法之投予。在一些具體實例中,應保持先前療法直至多株IgG之含量達到足以提供治療效應之含量為止。兩種療法可組合投予。
在一些具體實例中,亦可向接受脫髓鞘病症第一療法之個體投予多株IgG,該第一療法為例如干擾素β 1a(Avonex)、干擾素β 1b(Rebif)、乙酸格拉替雷(Copaxone)、米托蒽醌(Novantrone)、硫唑嘌呤(Imuran)、環磷醯胺(Cytoxan或Neosar)、環孢素(Sandimmune)、甲胺喋呤、克拉屈濱(Leustatin)、甲基強的松(Depo-Medrol或Solu-Medrol)、強的松(Deltasone)、潑尼龍(Delta-Cortef)、地塞米松(Medrol或Decadron)、促腎上腺皮質激素(ACTH)或促皮質素(Acthar)。在一些具體實例中,當多株IgG投予人類時,中斷第一療法。在其他具體實例中,監測人類之第一預選結果,例如脫髓鞘病症之一或多種症狀(例如本文所述之脫髓鞘病症任何症狀)改善(諸如再髓鞘形成增加)。在一些具體實例中,當觀察到第一預選結果時,減少或中斷使用多株IgG治療。在一些具體實例中,在中斷使用多株IgG治療後接著監測人類之第二預選結果,例如脫髓鞘病症之症狀惡化。當觀察到第二預選結果時,恢復或增加向人類投予多株IgG,或恢復第一療法之投予,或投予人類多株IgG或增加量多株IgG與第一治療性方案兩者。
在一個具體實例中,接受脫髓鞘病症第一療法且接著用多株IgG治療之人類繼續接受相同或減少量之第一療法。在另一具體實例中,用第一療法治療與用多株IgG治療重疊一段時間,但隨後中斷用第一療法治療。
在本發明之一些具體實例中,治療有效量之多株IgG與消炎劑一起共投予有需要之患者。消炎劑為一類熟知的藉由作用於身體機制減少炎症之醫藥劑(Stedman's Medical Dictionary 26 e.,Williams and Wilkins,(1995); Physicians Desk Reference第51版,Medical Economics,(1997))。
與本發明之方法一起使用的消炎劑包括非類固醇消炎劑(NSAID)。NSAID典型地抑制身體合成前列腺素的能力。前列腺素為類激素化學品家族,其中一些回應於細胞損傷而產生。批准用於人類投藥之特定NSAID包括萘普生鈉(naproxen sodium)、雙氯芬酸(diclofenac)、舒林酸(sulindac)、噁丙嗪(oxaprozin)、二氟尼柳(diflunisal)、阿司匹林(aspirin)、吡羅昔康(piroxicam)、吲哚美辛(indomethocin)、依託度酸(etodolac)、布洛芬(ibuprofen)、非諾洛芬(fenoprofen)、酮洛芬(ketoprofen)、甲芬那酸(mefenamic acid)、萘丁美酮(nabumetone)、托美丁鈉(tolmetin sodium)及酮咯酸胺丁三醇(ketorolac tromethamine)。
與本發明之方法一起使用的其他消炎劑包括水楊酸鹽,諸如例如水楊酸、乙醯水楊酸、水楊酸膽鹼、水楊酸鎂、水楊酸鈉、奧色拉秦(olsalazine)及水楊醯水楊酸。
與本發明之方法一起使用的其他消炎劑包括環加氧酶(COX)抑制劑。COX催化花生四烯酸轉化為前列腺素H2(PGH2);COX抑制劑抑制此反應。COX亦稱為前列腺素H合成酶或PGH合成酶。已在若干物種中分離出兩種Cox基因,即Cox-1及Cox-2。COX-2在大多數組織中受到緊密調控且一般僅在異常條件(諸如炎症、風濕性關節炎及骨關節炎、腎病及骨質疏鬆症)誘發。咸信組成性表現COX-1以便維持血小板及腎臟功能及內穩態。適用於本發明方法之典型COX抑制劑包括依託度酸、西樂葆(celebrex)、美洛昔康(meloxicam)、吡羅昔康(piroxicam)、尼美舒利(nimesulide)、萘丁美酮(nabumetone)及羅非昔布(rofecoxib)。
可併入聚合物基體以便在本發明方法中投予之較佳消炎劑包括:異尼辛(Isonixin)、哌胺托美丁(Amtolmetin Guacil)、丙谷美辛 (Proglumetacin)、吡酮洛芬(Piketoprofen)、二苯米唑(Difenamizole)、依匹唑(Epirizole)、阿紮丙宗(Apazone)、非普拉宗(Feprazone)、嗎拉宗(Morazone)、保泰松(Phenylbutazone)、哌布宗(Pipebuzone)、異丙安替比林(Propyphenazone)、雷米那酮(Ramifenazone)、噻唑布宗(thiazolinobutazone)、阿司匹林、貝諾酯(Benoiylate)、乙醯水楊酸鈣、依特柳酯(Etersalate)、水楊酸咪唑、乙醯水楊酸離胺酸、水楊嗎啉、水楊酸1-萘酯、乙醯水楊酸苯酯、安吡昔康(Ampiroxicam)、屈惡昔康(Droxicam)、S-腺苷甲硫胺酸、艾米西汀(amixetine)、苄達明(Benzydamine)、布可隆(Bucolome)、聯苯吡胺(Difenpiramide)、依莫法宗(Emorfazone)、瓜甘菊薁(Guaiazulene)、萘普酮(nabunetone)、尼美舒利、普羅喹宗(Proquazone)、過氧化物歧化酶及替尼達普(Tenidap)。
可附接於聚合物以便在本發明方法中投予之消炎劑包括:依託芬那酯(Etofenamate)、他尼氟酯(Talniflumate)、特羅芬那酯(Terofenamate)、阿西美辛(Acemetacin)、阿氯芬酸(Alclofenac)、丁苯羥酸(Bufexamac)、桂美辛(Cinmetacin)、氯吡酸(Clopirac)、聯苯乙酸(Felbinac)、苯環酸(Penclozic Acid)、芬替酸(Fentiazac)、異丁芬酸(Ibufenac)、吲哚美辛(Indomethacin)、三苯唑酸(Isofezolac)、伊索克酸(Isoxepac)、氯那唑酸(Lonazolac)、甲嗪酸(Metiazinic Acid)、莫苯唑酸(Mofezolac)、奧沙美辛(Oxametacine)、吡拉唑酸(Pirazolac)、舒林酸(Sulindac)、噻拉米特(Tiaramide)、托美丁(Tolmetin)、托普辛(Tropesin)、佐美酸(Zomepirac)、布馬地宗(Bumadizon)、布替布芬(Butibufen)、芬布芬(Fenbufen)、聯苯丁酸(Xenbucin)、環氯茚酸(Clidanac)、酮咯酸(Ketorolac)、替諾立定(Tinoridine)、苯惡洛芬(Benoxaprofen)、柏莫洛芬(Bermoprofen)、布氯酸(Bucloxic Acid)、非諾洛芬(Fenoprofen)、氟諾洛芬(Flunoxaprofen)、氟比洛芬(Flurbiprofen)、托布洛芬(Tbuprofen)、托布 洛康(Tbuproxam)、吲哚洛芬(Indoprofen)、酮洛芬(Ketoprofen)、洛索洛芬(Loxoprofen)、萘普生(Naproxen)、噁丙嗪(Oxaprozin)、吡洛芬(Pirprofen)、普拉洛芬(Pranoprofen)、普羅尼酸(Prodznic Acid)、舒洛芬(Suprofen)、噻洛芬酸(Tiaprofenic Acid)、紮托洛芬(Zaltoprofen)、苄哌立隆(Benzpiperylon)、莫非布宗(Mofebutazone)、羥布宗(Oxyphenbutazone)、琥布宗(Suxibuzone)、醋胺沙洛(Acetaminosalol)、帕沙米特(Parsalmide)、水楊酸苯酯、乙醯水楊醯胺、水楊基硫酸、伊索昔康(Isoxican)、氯諾昔康(Lomoxicam)、吡羅昔康(Piroxicam)、替諾昔康(Tenoxicam)、ε-乙醯胺基己酸(epsilon-acetamidocaproic Acid)、苄達酸(Bendazac)、α-沒藥醇(alpha-Bisabolol)、瑞尼托林(Paranyline)、哌立索唑(Perisoxal)及齊留通(Zileuton)。
可併入聚合物主鏈以便在本發明方法中投予之消炎劑包括:因法來酸(Enfenamic Acid)、醋氯芬酸(Aceclofenac)、葡美辛(Glucametacin)、阿明洛芬(Alminoprofen)、采普洛芬(Caiprofen)、新普洛芬(Xinoprofen)、水楊醯水楊酸、3-胺基-4-羥基丁酸、雙苯唑醇(Ditazol)、非普地醇(Fepradinol)及奧沙西羅(Oxaceprol)。
具有適合於併入如本文所述之式(I)聚合物主鏈中之鄰位官能基的消炎劑包括:氟芬那酸(Flufenamic Acid)、甲氯芬那酸(Meclofenamic Acid)、甲芬那酸(Mefenamic Acid)、尼氟酸(Niflumic Acid)、托芬那酸(Tolfenamic Acid)、胺芬酸(Amfenac)、溴芬酸(Bromfenac)、雙氯芬酸鈉(Diclofenac Sodium)、依託度酸、溴水楊醇(Bromosaligenin)、二氟尼柳(Diflunisal)、芬度柳(Fendosal)、格替酸(Getitisic Acid)、水楊酸乙二醇酯、水楊酸、美沙拉嗪(Mesalamine)、奧色拉秦(Olsalazine)、水楊醯胺O-乙酸、柳氮磺胺吡啶(sulfasalazine)。
對於本文中以商品名提及之任何消炎劑,應瞭解可使用該商品名 之產品或來自該產品之具有消炎活性之活性成分。另外,在本文中有關併入聚合物主鏈中所確定之較佳藥劑亦可較佳附接於聚合物或可併入聚合物基體中。可附接於聚合物之較佳藥劑亦可較佳併入聚合物基體中。
下文提供實施例以說明本發明。此等實施例並不意欲使本發明受任何特定應用或操作原理約束。
實施例1:有關IVIG對許旺細胞之影響的研究
使用以下三種模型研究來源於人類血清之多株免疫球蛋白對許旺細胞穩態、分化及成熟之直接影響,此係由各種分子及細胞變數所證明:1)初級大鼠許旺細胞培養模型;2)p57kip2抑制型許旺細胞模型;及3)PNS神經元與髓鞘形成許旺細胞之共培養物。
1.1. 大鼠許旺細胞模型1之製備:在此模型中,培養自新生大鼠坐骨神經分離之未處理初級許旺細胞(SC)。在此階段,SC未成熟且尚未開始分化過程。在培養中,SC未沿循其分化程式進展且保持增殖但未成熟,很可能是由於存在固有分化抑制劑(Heinen等人,2008a)。
1.2. p57kip2抑制型許旺細胞模型2之製備:本發明者已確定p57kip2基因為髓鞘形成膠質細胞分化、成熟及髓鞘形成之新穎固有抑制劑。已證明p57kip2基因之長期shRNA依賴性抑制會解除初級SC分化與軸突接觸間的聯繫。此係由退出細胞週期、SC形態改變以及誘發髓磷脂表現所顯示(Küry等人,2002;Heinen等人,2008a;Heinen等人,2008b)。在此第二模型中,p57kip2抑制型SC用於與對照組經轉染細胞(亦即非分化中的細胞)比較。此培養系統提供在不存在軸突的情況下以定量方式觀測到活體外SC分化及成熟的唯一機會。
1.3. PNS神經元與髓鞘形成許旺細胞之共培養物──模型3之製 備:在此模型中,產生髓鞘形成神經元/SC共培養物。培養製備物由含有PNS之未成熟感覺神經元及許旺細胞前驅體兩者的胚胎韋斯大鼠(Wistar rat)或C57/BL6小鼠背根神經節製成。此種共培養模擬活體內情況且提供研究最終包裹/髓鞘形成過程及此複雜相互作用是否會受免疫球蛋白投予影響之可能性。根據本發明者實驗室所用之既定方案或由Päiväläinen等人,(2008)公開之方案加上一些修改來使共培養條件及製備最佳化。使用經透析之IGIV/緩衝液製備物並行執行IVIG刺激以引發髓鞘形成過程。相對於無補給物之細胞培養基執行IGIV/緩衝液透析。在一種IGIV濃度(20mg/ml)下進行所有實驗。在繼添加經透析之IGIV/緩衝液之後3天及6天後,藉由分析髓鞘形成動力學(節間形成)來確定刺激之持續時間。
1.4. 細胞形態:在模型1(培養中之大鼠SC)及模型2(p57kip2抑制型SC)中,在藉由10mg/ml及20mg/ml IVIG刺激模型1至多9天(以便觀測劑量依賴性)且刺激(9天轉染)模型2至多7天的期間,研究其細胞形態。使用未透析及經透析之IGIV及緩衝液製備物進行實驗。相對於無補給物之細胞培養基執行IVIG及緩衝液透析。使用一種濃度之經透析之IGIV(20mg/ml)進行所有模型2實驗。在模型2中,亦在用經透析之IVIG刺激3及7天後藉由量測細胞突起長度來測定細胞生長及分化動力學。
1.5. 細胞死亡/增殖:在模型1中,在用未透析及經透析之IVIG/緩衝液製備物刺激2天後,研究細胞死亡/增殖情況。相對於無補給物之細胞培養基執行IVIG/緩衝液透析。在一種IVIG濃度(20mg/ml)下進行所有實驗。使用兩種用於量測細胞增殖之分析:針對Ki-67抗原之免疫細胞化學染色及針對BrdU之免疫細胞化學染色。Ki-67抗原為充當細胞增殖標記之核蛋白。BrdU(溴脫氧尿苷)為用於標記增殖細胞之胸苷的核苷酸類似物。使用針對卡斯蛋白酶-3之免疫細胞化學染色作為細胞凋亡標記。卡斯蛋白酶-3為凋亡細胞中活化的蛋白酶且 因此用作細胞死亡標記。在8小時及24小時之兩種不同BrdU脈衝持續時間後,固定細胞。
1.6. 基因表現:分析模型1(培養中之大鼠SC-部分1.1)及模型2(p57kip2抑制型SC-部分1.2)之基因表現,模型1暴露於使用未透析及經透析之IVIG/緩衝液製備物之刺激持續至多9天且模型2暴露於使用未透析及經透析之IVIG/緩衝液製備物之刺激持續至多7天(9天轉染)。針對未處理SC(模型1),使用經透析之SYNAGIS製備物作為IgG1對照物。相對於無補給物之細胞培養基執行IVIG/緩衝液/SYNAGIS透析。在一種IVIG濃度(20mg/ml)下進行所有實驗。使用即時RT-PCR量測髓磷脂基因(P0,MBP)及Fc受體(CD64、CD32及CD16)之轉錄。
實施例2:許旺細胞對使用IVIG之培育的反應
2.1. 形態:據觀測,IVIG處理會影響許旺細胞形態。在10mg/ml IVIG存在下及在較大程度下在20mg/ml IVIG存在下培養之SC似乎具有較大胞體及細胞核。目前不清楚此是否直接影響SC形狀及細胞骨架或黏著性,是否為不同細胞密度之結果,或是否反映可能連接至細胞表面上之IVIG結合位點的離散細胞表面變化。
使用模型2(p57kip2抑制)量測到在用IGIV刺激後細胞突起生長得到顯著加速。此效應僅在分化過程之最初階段即可觀察到,表明IVIG對許旺細胞之分化動力學的影響。解釋而言,細胞突起之生長為經發現視經抑制之p57kip2含量而定的成熟參數。另一方面,如藉由TRITC結合毒傘素染色所揭示,可在IVIG刺激後觀察到對肌動蛋白微絲總成及結構無影響。
2.2. 細胞死亡/增殖(模型1):如藉由使用增殖標記BrdU及Ki-67之分析所揭示,在用未透析之IVIG(20mg/ml)製備物刺激後,未處理SC之增殖速率顯著減小。參見圖1-2。對增殖速率的IVIG依賴性影響在IVIG透析的情況 下所有減弱,但此後保持統計學顯著性。基於卡斯蛋白酶-3之負染色,目前沒有在用IVIG處理後誘發細胞凋亡之證據。
2.3. 基因表現:使用未透析及經透析之IVIG/緩衝液製備物刺激未轉染之SC(模型1)使得在處理之前3天內(但不是在較長培育期後)P0基因有輕微正調控及MBP基因有大力正調控。使用未透析及經透析之IVIG/緩衝液製備物刺激p57kip2抑制型細胞(模型2)亦導致關於髓磷脂基因表現之類似結果。兩種髓磷脂基因之表現及正調控在經p57kip2抑制之細胞中比在對照組經轉染細胞中顯著要強。Fc受體基因調節之觀測結果顯示許旺細胞表現CD64及CD32且p57kip2之長期抑制導致此等基因顯著正調控。未成熟的SC中存在可偵測程度之CD64 Fc受體表現。在分化中的許旺細胞中(在固有抑制劑p57kip2抑制後),CD64含量隨IVIG刺激而顯著增加。
重要的是,單株IgG1對照物(Synagis、Avastin及Herceptin)顯示對髓磷脂基因表現無顯著影響。使用未透析及經透析之IVIG/緩衝液製備物刺激經p57kip2抑制之細胞(模型2)在類似程度上誘發髓磷脂基因表現。在IVIG刺激後再次強烈誘發MBP表現,而該處理適度誘發P0表現。注意到,髓磷脂基因誘發可在7天時間之刺激期間觀察到且因此不限於早期階段。此外,p57kip2基因之表現經發現編碼許旺細胞分化之固有抑制劑且在對照組經轉染(非分化中的)細胞中顯著減少。
所有已知Fcγ受體之基因調節的觀測結果顯示許旺細胞表現CD64 Fc受體。在分化中的許旺細胞(模型2)中,相較於對照組經轉染(非分化中的)細胞,CD64含量顯著增加。不能觀察到CD64受體表現回應於IVIG刺激之調節。值得注意的是,觀察所進行的所有基因表現實驗中對未透析之緩衝液對照組的效應。然而,此效應在透析後減弱。因此,僅使用經透析之IVIG製備物進行其他基因表現分析。
2.4. 研究結果之概述:在前18個月的研究中,發現初級SC在分化過程之早期階段隨著細胞形態改變伴隨細胞突起加速生長來對IVIG培育起反應。亦發現使用IVIG培育在不影響細胞存活的情況下減少許旺細胞增殖。此外,在使用IVIG刺激後,誘發未成熟的以及分化中的SC中兩種主要髓磷脂基因P0及MBP之表現。資料顯示初級大鼠許旺細胞表現CD64 Fc受體且在分化中的許旺細胞中(在固有抑制劑p57kip2抑制後),CD64含量隨著暴露於IVIG而顯著增加。證據亦提供在分化SC中Fc受體(詳言之CD64)正調控之有力指示。此外,顯示人類IVIG特異性結合於許旺細胞表面上。
此等研究結果支持SC可能展現免疫能力之假設。增殖率減小且無細胞凋亡以及誘生髓磷脂基因之跡象,結合細胞突起加速生長,表明IVIG促進未成熟SC之分化過程。其為最初的活體外結果,證明許旺細胞不僅能回應於而且能特異性結合免疫球蛋白,且IVIG刺激可促進許旺細胞前驅體成熟。
實施例3:基因表現
為進一步檢驗對於分化(經p57kip2抑制之細胞,模型2)及非分化中的(對照組經抑制細胞,模型2)許旺細胞基因表現之IVIG依賴性影響,吾等自4個獨立實驗採集16個RNA樣品用於GeneChip陣列分析(由Miltenyi Biotec,Germany進行)。藉由測定MBP、P0、p57kip2及CD64基因之表現程度來進行樣品驗證。
進行統計及功能分析。經鑑定為在用IVIG處理後顯著正調控或下調之基因提供於表1及2中。未來目標在於進一步鑑定基因以及驗證所得結果。
為了在蛋白質層面上證實所觀察到的髓磷脂基因表現之誘發(詳言之P0及MBP),吾等對經p57kip2抑制之細胞與對照組經抑制細胞(模型2)在 用經透析之IVIG/緩衝液處理後進行西方墨點分析。吾等可證明在分化中的許旺細胞中,P0及在較小程度上MBP之蛋白質含量在IVIG處理後增加。
實施例4:免疫相關蛋白
證實IVIG直接結合於許旺細胞表面為重要的。應用抗人類Fab-特異性F(ab)'2及抗人類Fcγ-特異性F(ab)'2抗體,顯示IVIG中之人類免疫球蛋白特異性結合於許旺細胞表面。用IVIG刺激培養中之活許旺細胞,洗滌,固定且隨後單獨針對人類Fab片段、人類Fcγ片段染色或針對兩種抗原決定基進行組合式雙重染色。特異性表面結合可集中在細胞之核周區內。使用IVIG及IgG1對照物(Avastin及Herceptin)對未處理許旺細胞(模型1)以及使用IVIG對分化中的許旺細胞(模型2)進行此等結合研究。為解決CD64受體蛋白是否亦在許旺細胞表面上表現的問題,已開始有關兩種抗CD64抗體之染色實驗。
為確定CD64受體蛋白是否亦在許旺細胞表面上表現,進行有關兩種抗CD64抗體之染色實驗。一種抗CD64抗體似乎特異性結合於許旺細胞上之大鼠CD64受體且彌漫性受體染色分佈在非分化中的細胞之細胞表面上。比較而言,針對分化中的細胞之受體染色集中於核周區上的胞體。偵測到的CD64信號不與IVIG結合信號重合(免疫染色比較)。
實施例5:節間形成
為改良活體外髓鞘形成模型(模型3)之功效及再現性,執行且建立許多使用來源於C57/BL6小鼠胚胎之DRG培養物的實驗性改良步驟。為此,修改Päiväläinen等人(2008)之方案且該方案目前可用以研究IVIG應用對於軸突/許旺細胞相互作用之效應。使用經透析之IGIV/緩衝液製備物執行IVIG刺激(20mg/ml),伴隨著髓鞘形成過程之引發。
在確定最佳分析時間點在髓鞘形成引發後7天後,執行統計學顯著數目的IVIG刺激實驗(n=9)。為評估免疫球蛋白處理調節髓鞘產生(節間形 成)之能力,比較經IVIG處理之節間的數目(校正至共培養物中細胞核之全部數目)與對照共培養物中節間的數目。雖然可觀察到節間密度略微增加的趨勢,但在處理後未偵測到髓磷脂區段形成之統計學顯著差異。
實施例6:活體內神經修復範例
6.1. 概述
為將基於初級大鼠許旺細胞培養物之活體外研究結果轉變為活體內範例,在所謂「神經再生時段」期間在用IVIG或對照緩衝液治療之成年大鼠中誘發慢性周圍神經病變變。橫切坐骨神經且藉助於縫合神經再接合端,在三個月之時間防止神經再生。在此變性時段後,接合神經以允許進行再生且投予(腹膜內注射)IVIG或緩衝液。再使神經再生三個月直至殺死動物為止。
使用上述關於許旺細胞之手術方法以確定IVIG刺激是否可修復受損周圍神經之活性。在三個月再生(及IVIG/緩衝液處理)時段期間,對活大鼠進行許多功能測試。在殺死動物之後,解剖坐骨神經,固定且包埋用於目的在於描述許旺細胞/髓磷脂及軸突反應之形態學及免疫組織化學未來分析。自功能分析獲得初步結果。此等初步研究結果表明兩組(經IVIG處理之動物對比經緩衝液處理之動物)之間存在差異。特定言之,與經緩衝液處理之動物相比,經IVIG處理之動物呈現更長且更廣泛的足跡區域(足與地面之間的接觸區)。此等足跡區域亦在處理時段期間逐漸增加且此伴有著陸壓力(相當於腿用以行走之力或足施加於表面之壓力)增加。總之,此等第一初步資料表明經IVIG處理之動物經歷行走行為之加速校正及其腿使用強度增加。
6.2. 方法
研究對於許旺細胞存活率之IVIG依賴性效應。特定言之,使用先前建立的慢性周圍神經去神經模型(Fu及Gordon;J Neurosci 1995)研究活體內去神經之神經區段中之增殖以及再髓鞘形成及軸突再生。此活體內模型體現
與許多人類神經病變變中所觀察到神經病變狀類似的神經病變狀。此活體內模型亦提供在變性過程中僅集中在再生事件之優勢(亦即暫時排除免疫反應)。
為此,橫切24隻成年路易斯大鼠(Lewis rats)之坐骨神經且藉助於縫合神經再接合端防止神經再生。此計劃產生慢性傷害及去神經之神經區段。神經處理後三個月時間防止再生。在此期間,不對動物進行功能測試。
在三個月變性後,所有24隻大鼠受到延遲坐骨神經接合(相接)之影響,因為近端神經區段縫合至遠端神經區段,藉此允許進行神經再生。注意到在此慢性計劃中,總體再生能力與急性神經病變變相比顯著減小。在此前三個月時間,完成軸突及髓磷脂變性過程。
在第一組實驗(研究1)中,使用ELISA測試研究健康大鼠(未病變神經)中IVIG應用後抗藥品抗體(ADA)之產生及人類IgG血漿含量。接著監測病變且經處理之動物針對IVIG的ADA作為研究2中之輔助讀出數據(參見下文)。
在第二組實驗(研究2)中,用每公斤體重1g IVIG(高劑量處理)處理患有慢性周圍神經病變變之路易斯大鼠,接著神經接合(3個月再生期)。藉助於腹膜內注射施用IVIG,在第一個月每週一次且隨後在再生期之最後兩個月每兩週一次。患有神經病變變之對照大鼠接受IVIG調配緩衝液注射。經對照緩衝液處理之動物組及經IVIG處理之動物組各包含12隻成年雌性大鼠。在IVIG處理期間,自尾靜脈採集血液樣品以便監測ADA及測定人類IgG半衰期(參見研究1)。在處理之前每隔一週採集血漿樣品。
6.2. 結果
為在神經末端再結合後測試目標器官功能之恢復率,每週進行一組功能評估測試。在施加疼痛刺激(使用鉗子夾縮測試)後藉由測試腳趾之退縮反應4及5次評估感覺功能。使用腿伸展測試分析肌力及肌纖維之再生。在每 週基礎上進行此兩個功能測試以及監測動物體重(健康及幸福參數)。每週進一步監測動物之足跡及行走軌跡(亦即「貓步分析」)以評估坐骨神經之功能恢復。
在研究結束時,留下21隻動物:10隻動物接受緩衝液對照注射且11隻動物用IVIG處理。殺死所有大鼠且採集再生周圍神經區段以及對側健康對照神經進行進一步分析。為此,將動物分成三組:
組I由4隻經緩衝液處理之動物及4隻經IVIG處理之動物組成。處理此等動物之坐骨神經區段(健康且橫切)用於電子顯微鏡分析(EM)。除測定軸突密度(藉此量測再生效率)以外,其亦包括g比率計算(軸突直徑除以軸突及其髓鞘之直徑)以便測定再髓鞘形成效率。此分析目前在進行中。測定此等動物之功能評估資料(貓步資料、夾縮測試及腿伸展行為)且初步結果描述如下。
組II由3隻經緩衝液處理之動物及4隻經IVIG處理之動物組成。此等動物之坐骨神經區段(健康且橫切)應用於針對軸突、髓磷脂及神經膠質標記之免疫組織化學染色(IHC),以便測定細胞再分化及再生之程度。目前處理神經且此研究亦在進行中。測定此等動物之功能評估資料(貓步資料、夾縮測試及腿伸展行為)且初步結果描述如下。
組III由3隻經緩衝液處理之動物及3隻經IVIG處理之動物組成。此等動物之橫切坐骨神經區段因不發生相接而呈現無解剖學再生跡象。此等動物之功能評估資料將不包括於全面分析中。
貓步資料之初步評估表明兩組(經IVIG處理之動物對比經緩衝液處理之動物)之間存在差異。與經緩衝液處理之動物相比,經IVIG處理之動物呈現更長且更廣泛的足跡區域(足與地面之間的接觸區)。此等足跡區域亦在處理時段期間逐漸增加且此伴有著陸壓力(相當於腿用以行走之力或足施加於表面之壓力)增加。總之,此資料表明經IVIG處理之動物經歷行走行為之加速 校正及其腿使用強度增加。
實施例7:測定IVIG作用之潛在機制的補充研究
為更好理解IVIG作用之潛在機制及IVIG促進細胞成熟之機制,將對經刺激之許旺細胞進行詳細的分子/細胞研究。
如上所概述(參見5.1),對暴露於IVIG處理之非分化中的許旺細胞及分化中的許旺細胞進行GeneChip分析並分析研究。基於新發現的正調控及下調基因(表1及2),將使用定量即時RT-PCR對所選基因進行進一步驗證實驗。必要及適當時,將進行使用抗體之額外驗證(西方墨點、免疫染色以及ELISA)。尤其關注與免疫能力相關的基因。值得注意的是,此表現分析將不僅分析以便瞭解什麼細胞過程對IVIG最敏感,其很可能亦用來定義可用於監測及定量IVIG依賴性反應之額外標記基因。
在建立合適活體外髓鞘形成分析(模型3)後,將進行統計學顯著數目的IVIG刺激實驗。將評估活性時窗及免疫球蛋白處理可調節髓鞘產生(節間形成)之程度。
使用Cy3結合之抗人類Fab抗體可證明IVIG與許旺細胞之特異性結合。其仍展示此舉是否歸因於與CD64 Fc受體之相互作用或許旺細胞特異性抗原決定基是否由Fab介導型結合來識別。為此,許旺細胞(模型1)將與番木瓜蛋白酶消化之IVIG的Fc及F(ab)2部分接觸或將使用番木瓜蛋白酶當場消化許旺細胞上結合之IVIG。此外,FITC結合之抗人類Fc抗體以及Cy3結合之抗人類Fab抗體之應用預期產生番木瓜蛋白酶敏感性染色。兩種抗CD64抗體將應用於非分化中及分化中(模型2)的許旺細胞,以便測定CD64是否亦以許旺細胞表面上之受體蛋白形式表現。若IVIG結合實際上經由此Fc受體介導,則預期CD64信號與IVIG結合(免疫染色)重合。為此進一步檢查CD64蛋白質含量之增加是否可由於分化處理(西方墨點)而觀察到。
為提供Fc受體參與之功能證明,將在未處理許旺細胞(模型1)之IVIG刺激之前分別應用藥理學抑制劑,諸如3-(1-甲基-1H-吲哚-3-基-亞甲基)-2-側氧基-2,3-二氫-1H-吲哚-5-磺醯胺或受脾臟酪胺酸激酶(Syk)及磷脂醯肌醇-3-激酶(PI3K)干擾之Ly294002。其表明此等Fc依賴性信號傳導組分是否參與MBP誘發(或1中確定之適當標記基因)。此外,經消化之IVIG將用於刺激所培養的許旺細胞(模型1)以便揭示Fc或/及Fab部分是否引起IVIG特異性基因調節(MBP及基因表現分析中確定的其他標記基因)。最後,許旺細胞(模型1)中CD64表現之shRNA介導型抑制可用於證實IVIG結合為CD64依賴性以及造成MBP表現(或基因表現分析中確定的其他標記基因)之IVIG依賴性誘發。
標準許旺細胞培養(維持及分化)條件以高胎牛血清濃度(高達10%體積)為特徵。因此,可想到血清中存在之免疫球蛋白減弱IVIG依賴性許旺細胞反應。為了對此進行測試,將血清濃度減小至保證細胞存活及分化所需之下限,使用IVIG刺激許旺細胞且量測MBP表現程度(模型1及2)以及形態學參數(模型2)。
本發明者之最新研究揭示許旺細胞分化極其依賴組蛋白甲基轉移酶zeste增強子同源物2(EZH2;Heinen等人,修訂版)。在抑制EZH2活性後,所培養之許旺細胞顯示與神經病變變中所觀察到的去分化反應類似的去分化反應。作為未來研究之一部分,該等去分化許旺細胞將用IVIG刺激以測定許旺細胞標記及髓磷脂基因之表現。後者經展示下調至對照組之程度以下。將關注免疫球蛋白處理是否不僅能促進分化/成熟反應(如關於模型2所見;亦即在抑制基因p57kip2之抑制後)而且亦干擾去分化過程(諸如校正髓磷脂基因表現程度)。
儘管為了達成清楚瞭解之目的已經由圖示及舉例之方式相當詳細地描述了上述本發明,但一般熟習此項技術者根據本發明之教示顯而易見的是可在不悖離隨附申請專利範圍之精神或範疇之情況下對本發明作出某些變更 及修改。
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Claims (3)
- 一種治療脫髓鞘周圍神經病變之方法,其包含向診斷出患有該神經病變之哺乳動物投予治療有效量之多株IgG,其限制條件為該神經病變並非免疫介導型或感染介導型神經病變且排除格巴二氏症候群(Guillain-Barré syndrome)、慢性脫髓鞘多發性神經病變及多源性運動神經病變(multifocal motor neuropathy)。
- 一種多株IgG之用途,其係用於製造用以治療被診斷出患有脫髓鞘周圍神經病變的哺乳動物中之該神經病變的醫藥品,其限制條件為該神經病變並非免疫介導型或感染介導型神經病變且排除格巴二氏症候群、慢性脫髓鞘多發性神經病變及多源性運動神經病變。
- 一種如於說明書中所述之多株IgG的用途。
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WO2020146370A1 (en) * | 2019-01-07 | 2020-07-16 | Mallinckrodt Ard Ip Limited | Methods of promoting remyelination |
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