TWI721352B - 含有gm3神經節苷酯作為免疫調節劑之奈米粒子 - Google Patents
含有gm3神經節苷酯作為免疫調節劑之奈米粒子 Download PDFInfo
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Abstract
本發明描述醫藥組成物,該醫藥組成物之活性成分包括腦膜炎奈瑟氏球菌之膜囊泡與GM3神經節苷脂之共軛物,該腦膜炎奈瑟氏球菌之膜囊泡與GM3神經節苷脂係以過量蛋白質之共軛比共軛,該醫藥組成物具有與奈米粒子系統相關之大小、表面電荷和形態之特定特徵,該等特徵使該醫藥組成物擁有作為免疫調節劑之有益性質,因為該醫藥組成物促使對腫瘤患者之T淋巴細胞的反應和存活有影響之髓源抑制細胞合宜且顯著減少。本發明進一步揭示所揭露之醫藥組成物於治療癌症(尤其是其中該髓源抑制細胞(MDSC)數量高之癌症)的用途及使用該組成物以治療癌症患者之方法和選擇將接受該治療之癌症患者之方法。
Description
本發明關於免疫奈米技術和免疫腫瘤學之領域,尤其是關於用於治療患有癌症和/或慢性感染之個體的免疫調節劑。本發明特別描述特定干擾這些個體中之髓源抑制細胞(MDSC)並恢復T細胞反應之特化的奈米微粒免疫調節劑。
最近,使用能夠誘導長期客觀反應之免疫檢查點抑制性抗體(Ab)已獲得對患者之生存造成顯著影響的重要臨床結果。這些調節患者之免疫系統並恢復患者摧毀腫瘤細胞之能力的治療已導致特別注重設計新的免疫調節劑之癌症免疫療法復活。
然而,該抗腫瘤免疫反應還有其他抑制因子路徑,這些其他抑制因子路徑為研發新免疫調節劑之重要靶的(Malmberg K.J. et al (2004) Cancer Immunol Immunother 53 (10): 879-92)。髓源抑制細胞(MDSC)構成主要細胞群其中一者,該細胞群被腫瘤動員且具有抑制該免疫反應之能力(Mantovani A. et al. (2010) Curr Opin Immunol 22 (2): 231-7;Condamine T. et al (2011) Trends Immunol 32 (1): 19-25)。特別是,如Shipp等人在評論性文章中所提出者,循環MDSC之頻率為具有來自各種不同部位之腫瘤的患者預後較差的因素之一。此外,這些細胞群之高循環數量與常規療法(諸如化學療法、放射療法,甚至是抗檢查點Ab)之效益較低有關(Shipp C. et al. (2016) Cell Mol Life Sci 73(21): 4043-61)。如一般共識,已有描述之人體中的MDSC群體有三種:早期MDSC(eMDSC),其定義為LIN-
CD11b+
CD33+
HLA-DR-
;單核細胞MDSC (mMDSC),其定義為CD14+
HLA-DR低 /-
/-及粒子性MDSC (gMDSC),其定義為CD11b+
CD33+
CD14-
CD15+
(CD66b+
)表型(Bronte V. et al (2016) Nat Commun 7: 12150)。所有三種群體均被視為腫瘤特異性免疫反應之抑制劑(Shipp C. et al (2016) Cell Mol Life, Sci 73 (21): 4043-61)。
目前研發之用於抵消由MDSC引起之免疫抑制作用的研究策略聚焦在三種方法:(1)減少其數量,(2)影響其功能和(3)影響其分化。在這些方向中,藉由幾種評估之藥物已獲得令人鼓舞之結果的報告(Najjar Y. G. et al (2013) Frontiers in Oncology 3 (49): 1-9)。
在靶向該MDSC之治療策略甲與本發明特別有關者為基於奈米微粒系統之策略。已知,奈米粒子提供廣泛之應用且根據尺寸和表面特徵,它們在體內會有不同的行為表現。例如,尺寸決定該排水部位,而表面特徵影響黏附和捕獲機制(Wilkerson A. et al (2017) Current Topics in Medicinal Chemistry 17: 1843-57)。從這個意義來說,如Serda R所報告者,直徑介於500至2000 nm之粒子系統優先在注射部位被捕獲並移至淋巴結(LN),而直徑介於20至200 nm之粒子被動地排至淋巴結,這些粒子在該淋巴結處與駐在該處之細胞交互作用(Serda R.E. (2013) Int J of Nanomed 8:1683-1696)。
迄今為止,已說明之對MDSC具有效果的基於奈米粒子之策略僅有六種,其中包括:裝載吉西他濱(gemcitabine)之奈米粒子、裝載趨化因子CCL21之奈米粒子、裝載CpG之奈米粒子、裝載全反式視黃酸之脂質體和以葡聚醣進行工程處理之奈米粒子(Wilkerson A. et al (2017) Current Topics in Medicinal Chemistry 17:1843-57)。這五種策略分享三種基本特徵:該奈米粒子之尺寸係介於30至250nm、其用途侷限在鼠科動物模型且其構成之粒子本身對MDSC無作用,而是作為生物製劑之載體系統。
基於對MDSC具有作用之奈米微粒系統的第六種策略係使用含有GM3神經節苷脂之非常小的蛋白脂質體(VSSP)。這些製劑可被視為最接近本發明之技術方案。最初,Molina等人在美國專利案第8,591,917 B2號中描述使用皮下(SC)投予之VSSP來刺激受試者之免疫反應的方法。此外,Fernández等人和Oliver等人之研究證明在健康、荷瘤小鼠或具有化療引起之白細胞減少的小鼠中,投予VSSP會在脾臟中誘導具有類似於MDSC之表型,但抑制能力顯著降低之細胞顯著增加(Fernández A. et al. (2011) J Immunol 186: 264-74;Oliver L. et al (2012) Vaccine 30: 2963-72)。其他研究亦描述在荷瘤小鼠中使用VSSP防止由該腫瘤誘導之MDSC交叉呈遞抗原並誘導它們分化成抗原呈遞細胞(Fernández A. et al (2014) J ImmunoTherapy of Cancer 2:5)。Rodríguez等人在美國專利案第6,149,921號中描述獲得這些VSSP之方法,該方法強調在洗滌劑之存在下將腦膜炎奈瑟氏球菌蛋白之共軛物與過量神經節苷脂GM3混合,然後再藉由透析方法除去該洗滌劑。此外,Estevez等人描述在透析後進行超速離心法以丟棄具有較大之質量和尺寸之共軛物(Estevez F. et al (2000) Vaccine 18: 190-7)。
本發明中描述之免疫調節製劑的新穎活性成分亦包括腦膜炎奈瑟氏球菌膜囊泡和GM3神經節苷脂之共軛物。此製劑具有從不曾描述於任何技術方案或先前之科學出版物中的與奈米粒子系統相關之特定大小、表面電荷和方法學特徵。與先前Fernández A.等人和Oliver L.等人所描述者相比較,就其對MDSC之效果而言,這些特徵提供本新發明有益且令人驚奇之性質。與先前技藝所教示者相反,用於治療患有腫瘤之患者的本發明(較佳為經由SC投予)可誘導gMDSC和mMDSC合適且顯著減少,並對經治療之患者的T淋巴細胞反應和存活造成影響。因此,本發明之新穎性包含提供新的免疫調節劑,該免疫調節劑具有減少腫瘤患者之MDSC數量的效果。
發明之簡短描述
本發明之一實施態樣為用於免疫調節癌症患者之免疫反應的醫藥組成物,該醫藥組成物包含藉由腦膜炎奈瑟氏球菌之外膜蛋白複合物(OMPC)與GM3神經節苷脂疏水性共軛所形成的奈米粒子,其中該蛋白質-神經節苷脂之共軛比例係介於1.5:1至10:1。
特別地,該組成物之特徵在於尺寸之單峰分佈係介於15至25 nm粒度,多分散性指數為0.230,負Z電位之標稱值係介於25至45mV。
於一特定之實施態樣中,本發明關於本發明之醫藥組成物於治療癌症之用途,特別是作為癌症患者之MDSC的免疫調節劑,增加該等細胞之存在。
於另一實施態樣中,本發明關於治療有此需要之個體的方法,該方法包含每週一次經由皮下、皮內、肌肉內、腫瘤內途徑或經由直接施用於黏膜來投予本發明中描述之醫藥組成物至少共四個劑量,然後每二週或每月投予維持劑量達至少六個月。
於一特定之實施態樣中,本發明之目標為選擇癌症患者作為接受治療之候選者的方法,該治療係以所描述之醫藥組成物進行,該選擇方法涉及:
- 從該患者提取者血液和/或腫瘤組織之樣本;和
- 測定該血液和/或腫瘤組織之樣本中MDSC的數量。
其血液中具有高頻率或高絕對數量之MDSC的患者或其腫瘤組織中之MDSC浸潤度測試呈陽性的患者將被認為是該等治療之候選者。發明之詳細描述 免疫調節組成物
本發明提供免疫調節系統,該免疫調節系統顯著減少其循環中或腫瘤中具有大量MDSC之癌症患者體內的循環MDSC。如在MDSC之情況中,免疫調節系統可被定義為能夠排除或調節免疫反應之任何抑制性介導因子的系統。
本發明申請專利之免疫調節性標的係由奈米粒子組成,該奈米粒子係從與神經節苷脂GM3共軛之革蘭氏陰性菌腦膜炎奈瑟氏球菌的外膜獲得。本發明創立首先將腦膜炎奈瑟氏球菌之OMPC分散在攪拌反應器中之Tris-HCl緩衝溶液中1至36小時,該Tris-HCl緩衝溶液含有脫氧膽酸鈉(10至40 mM)和十二烷基硫酸鈉(1至10 mM)之混合物。
接著,添加GM3神經節苷脂,該GM3神經節苷脂之質量較所添加之OMPC的質量少0.6至10倍,從而使該蛋白質:神經節苷脂比為1.5:1至10:1並延長攪動。透過使用具有10kDa至100kDa之濾膜的切向過濾系統及1.15至1.75巴之跨膜壓力來形成奈米粒子,如此可完全除去該洗滌劑。將經超濾之殘餘溶液在100000g
下超速離心並濃縮,以將其濃度調節成所需劑量0.1至2 mg/ml之OMPC,並藉由通過無菌0.2μm孔徑膠囊過濾來滅菌。
藉由有利於蛋白質之量的蛋白質質量和神經節苷脂的共軛比及在受控制之條件下進行之切向超濾可取得稱為VSSP-iMod之具有確定特徵的製劑。該粒子之形態、大小和表面電荷密度之分析顯示出該粒子呈異質性、奈米微粒製劑,大小為15至25 nm且具有標稱值介於25至45 mV之負Z電位。鑑定和 / 或選擇接受 VSSP-iMod 治療之患者的方法
為了選擇欲投予VSSP-iMod之患者,測定可抑制該對腫瘤之T特異性反應的gMDSC和mMDSC數量。由於腫瘤存在而增加之MDSC可藉由評估這些細胞在循環或腫瘤微環境中之不同亞群來確定。此外,MDSC增加的出現意味著某些血漿蛋白和循環DNA增加。用於評估之樣本來源包括外周血和腫瘤樣本(包括,但不限於腫瘤活檢組織、循環血漿蛋白、腹水和循環DNA)。
這些細胞之增加可藉由使用流式細胞術、免疫組織化學(IHC)、ELISA、免疫螢光或聚合酶鏈反應之診斷或預後分析測定。另一方面,由於其階段或腫瘤部位而使MDSC數量未增加之患者為其MDSC數量較正常健康供體高,但未達到在具有相同病理之患者中所觀察到之相當數量者。
患者血液樣本中之MDSC數量係藉由流式細胞術測定,其中該二種群體均係在FSC中 / 高
/SSC低 / 高
區內分析。特別是,在gMDSC群體方面,選擇CD11b和CD33雙陽性群體並在此群體中,選擇CD66b陽性和CD14陰性之亞群。在mMDSC方面,選擇HLA-DR表現陰性或低且CD14陽性之群體。基於這些結果並相關於對年齡和性別匹配之健康供體所進行之相同測定,根據MDSC之頻率或絕對數量,MDSC之數量可依下述分類:
- 陰性:百分比數值和/或數目在藉由正常值之平均值(M)+/-標準偏差(置信度95%)決定之範圍內。
- 低:相對於M,百分比數值和/或數目為2M≤MDSC< 3M。
- 高:百分比數值和/或數目之數值為3M≤MDSC。
血液中具有高頻率或絕對數量之MDSC的患者將接受VSSP-iMod治療。
為了測定腫瘤組織樣本中之MDSC的量,可使用IHC技術測量CD33+細胞。為達此目的,必須測定組織中之CD33+細胞的百分比並依下述方式表示:
- 陰性:陽性細胞少於10%
- 陽性/低滲透MDSC:陽性細胞介於10-19%
- 陽性/高滲透MDSC:陽性細胞超過20%
根據其組織學類型和階段,腫瘤被認為可召募MDSC,其先決條件為該腫瘤被CD33 +細胞浸潤之程度為陽性的。治療應用和治療方法
本發明提供專門降低MDSC(gMDSC和mMDSC二種表型)之免疫調節組成物,該免疫調節組成物建立免疫腫瘤學特別重要之解決方法,其中已知MDSC構成該抗腫瘤反應之必要抑制節點。
某些腫瘤之進展伴隨著召募MDSC至腫瘤部位,該專門化機制被描述為抑制T淋巴細胞和NK淋巴細胞之抗腫瘤免疫反應。本發明提出在那些其循環系統和/或腫瘤中具有增加之gMDSC和/或mMDSC的患者中,這些細胞之數目可藉由使用VSSP-iMod治療而顯著減少。該細胞數目之減少將允許這些患者之天然抗腫瘤免疫反應或藉由某些療法所誘導之抗腫瘤免疫反應不會被MDSC抑制,此點將轉化成為該經治療之患者的存活。
本發明之VSSP-iMod免疫調節劑可經由:SC、皮內、肌肉內、腫瘤內途徑或藉由直接施用在黏膜上引入患者中。
可使用本發明之VSSP-iMod免疫調節劑治療之癌症類型為那些據報導會召募MDSC作為抗腫瘤免疫反應之免疫抑制機制者。更特別地,這些癌症之實例包括黑色素瘤、前列腺癌、頭頸癌、卵巢癌、膀胱癌、肝細胞癌、非小細胞肺癌、慢性淋巴細胞白血病、食道鱗狀細胞癌、何杰金氏淋巴瘤、腎癌和乳癌。
欲在人體中使用之VSSP-iMod免疫調節劑的劑量範圍係介於100μg至2 mg,較佳為200μg至1200μg(根據OMPC含量)。
該免疫調節劑係每週一次投予個體,至少共四個劑量,從而達成快速降低MDSC且隨後每二週或每月投予維持劑量達至少六個月。該治療可長期投予,只要患者需要該治療。
本發明藉由下列實施例和附圖進一步詳細說明。然而,這些實施例不應被解釋為限制本發明之範圍。這些實施例中包含允許驗證該VSSP-iMod之特定物理化學特徵及其有效減少經治療之患者中之MDSC數量的實驗細節。此外,該實施例顯示關於MDSC數量減少對T淋巴細胞反應及對經治療之患者的存活率之影響。
實施例
1.
VSSP-iMod
具有
限
定之尺寸和表面電荷。
藉由光子相關光譜法測量構成VSSP-iMod之粒子的奈米尺寸和Z電位。以一式三份評估樣本,分別使用CONTIN和Smoluchowski算法取得尺寸和Z電位值。如第1圖所示,該VSSP-iMod顯示其體積分佈為介於15 nm至25nm之單峰分佈,多分散性指數(PDI)為0.230,這意味著呈現異質性粒子製劑。此外,該VSSP-iMod顯示負Z電位且如第2圖所示,其標稱值係介於25至45mV。實施例 2. VSSP-iMod 之奈米粒子形態。
VSSP-iMod之圖像係在原子力多模顯微鏡中並使用矽懸臂取得。將50μL樣本施於預先以50 mol/L之氯化鎳溶液官能化之雲母上。在施加至雲母之前,以Tris緩衝溶液(10 mmol/L pH 8.5)將VSSP-iMod進行1/10稀釋。第3圖之圖像顯示按照數十奈米順序之由球形奈米粒子結構所組成的異質性配製劑,其與藉由光子相關光譜法獲得之結果完全對應。實施例 3. VSSP 降低 mRCC 患者中之 MDSC 的頻率和抑制活性。
評估VSSP-iMod對mRCC患者之MDSC的影響。為達此目的,藉由SC途徑在15位被診斷為具有mRCC之患者的三角肌區域中投予400μg之VSSP-iMod。共投予四個VSSP-iMod劑量,每週投予一次,接著為每月投予一次維持劑量,直至完成6個月之治療。於該分析中,藉由流式細胞術評估gMDSC之頻率。為達此目的,共分析200,000個細胞並藉由測量全部PBMC之CD11b+
/CD66b+
/ CD14-
表型來測定gMDSC之百分比。評估年齡和性別相符之15名健康捐獻者之gMDSC的頻率以作為對照組。如第4a圖所示,在21天後或治療開始後三個劑量,VSSP-iMod降低患者體內之循環gMDSC的頻率。尖端技藝教示當患者呈現gMDSC低於某一地點之設立的患者之中位數時,該患者之存活率明顯高於那些其水準低於該數值者(Shipp C. et al (2016) Cell, Mol.Life, Sci. 73 (21): 4043-61)。gMDSC頻率高於和低於中位數之患者的百分比分析顯示於第4b圖中。使用VSSP-iMod治療後可觀察到僅約20%之經治療之患者的MDSC仍保持在高水準。此結果一直維持到第147天或第五個月後,這表明VSSP-iMod可在整個治療期間維持效果。
亦在增殖實驗中藉由流式細胞術評估VSSP-iMod對這些患者體內之MDSC的影響所導致之T淋巴細胞反應之結果。使用來自該患者之PBMC的共40×106
細胞作為起始物。使用與CD11b特異性Ab軛合之磁珠純化CD11b+細胞。以CFSE標記該CD11b-
陰性級分並將其單獨培養96小時或與CD11b+細胞以5:1之比例一起培養96小時。第5圖顯示對RCC患者投予VSSP-iMod後第0天和第21天T淋巴細胞之相對增殖百分比。如第5a圖中所示,TCD4+淋巴細胞在第21天增加增殖,此效果類似於在TCD8+淋巴細胞中所觀察到者(第5b圖),這意味VSSP-iMod能夠調節RCC患者中由MDSC介導之對T細胞增殖的抑制。
大多數登記試驗之患者在他們的治療結束後顯示出良好的生活品質,如該實驗計劃所設立的,該患者繼續每個月接受免疫接種。延長治療可將gMDSC維持在低於第0天之中位數且該試驗中之全部患者的存活中位數為37.5個月(表1)。此數值遠高於以干擾素治療(此為古巴目前的治療標準)之類似患者所報告之歷史中位數6.6個月。此外,國家綜合癌症網(NCCN)之mRCC臨床實踐指南根據斯隆-凱特琳紀念癌症中心(Memorial Sloan Kettering Cancer Center)(MSKCC)之模型將患者分類為有利、中等和不良預後。這些指南指出在被診斷為具有中等預後之患者的情況中,以針對血管內皮生長因子療法治療之mRCC患者的生存期中位數為27個月,而75%之被診斷為具有有利預後之患者的生存期中位數為24個月。在指南中陳述之數值與以VSSP-iMod治療所獲得之數值的相對比較指出VSSP-iMod對gMDSC之作用亦產生高於NCCN指南中規範之標準的存活期。在VSSP-iMod試驗中,具有有利預後之100%患者的存活時間為36個月,而那些具有中等預後者的生存期中位數為42個月。 實施例 4. VSSP 降低乳癌患者中單核細胞和粒細胞表型 之 MDSC 的頻率。
亦在乳癌患者中評估VSSP-iMod對MDSC之效果。為達此目的,設計0期機會窗口試驗,其中患者每週經由SC途徑在三角肌區域接受400μg之VSSP-iMod,共三週。該治療係在設定在診斷和由醫師指示之手術或化療標準治療開始之間的常規時間內投予。在該試驗中,藉由流式細胞術測定G-MDSC、mMDSC和CD8 T細胞之頻率。共分析200,000個細胞並使用表型CD11b+
/CD66b+
/CD14-
y、CD11b+
/CD14+
/HLA-DR低 /-
分別測定在全部PBMC內之gMDSC和mMDSC的百分比。如第6a圖中所示,治療21天後,VSSP-iMod降低循環gMDSC之頻率且在患者體內循環之mMDSC中可觀察到此相同行為(第6b圖)。此外,分析其gMDSC和mMDSC頻率高於和低於中位數之患者的百分比顯示出使用VSSP-iMod治療後,僅15%和0%經治療之患者分別保持高數量之gMDSC和mMDSC。該治療亦增加患者血液中之CD8 + T細胞的頻率(第7圖)。
第 1 圖 .
藉由光子相關光譜法評估之VSSP-iMod粒子的直徑。
第 2 圖 .
藉由光子相關光譜法評估之VSSP-iMod粒子的Z電位。
第 3 圖 .
藉由原子力顯微鏡術獲得之VSSP-iMod粒子形之態圖像。
第 4 圖 .
藉由流式細胞術評估使用VSSP-iMod治療轉移性腎細胞癌(mRCC)患者時對a)
和b)
之影響:a)
gMDSC之頻率和b)
gMDSC之頻率高於和低於中位數之患者的百分比。
第 5 圖 .
藉由流式細胞術評估使用VSSP-iMod治療時對MDSC抑制a)
和b)
增殖之能力的影響:a)
TCD4+淋巴細胞和b)
TCD8+淋巴細胞。
第 6 圖 .
藉由流式細胞術評估使用VSSP-iMod治療乳癌患者時對a)和b)之影響:a) gMDSC頻率高於和低於中位數之患者的頻率和百分比,b) mMDSC頻率高於和低於中位數之患者的頻率和百分比。
第 7 圖 .
藉由流式細胞術測定使用VSSP-iMod治療時對乳癌患者之TCD8 +淋巴細胞的絕對數目之影響。
Claims (7)
- 一種用於免疫調節癌症患者之免疫反應之醫藥組成物,其包含藉由腦膜炎奈瑟氏球菌之外膜蛋白複合物(OMPC)與GM3神經節苷脂的疏水性共軛所形成之奈米粒子,其中該蛋白質-神經節苷脂共軛比係介於1.5:1至10:1,且其中該醫藥組成物具有介於15至25nm粒徑的體積之單峰分佈(monomodal distribution)、多分散性指數0.230及介於25至45mV的負Z電位之標稱值。
- 一種如申請專利範圍第1項之醫藥組成物於製備用於治療具有高數量之髓源抑制細胞(MDSC)的癌症之藥物之用途。
- 一種如申請專利範圍第1項之醫藥組成物於製備用於減少癌症患者的MDSC之數量的藥物之用途。
- 如申請專利範圍第2或3項之用途,其中該藥物係經由皮下(SC)、皮內、肌肉內或腫瘤內途徑投予或藉由直接施用在黏膜表面投予,投予頻率為每週投予一次,至少共四個劑量且隨後每二週或每個月投予維持劑量達至少六個月。
- 一種選擇癌症患者以作為接受以如申請專利範圍第1 項之醫藥組成物進行治療之候選者之方法,該方法涉及:- 從該患者提取血液和/或腫瘤組織之樣本;和- 測定該血液和/或腫瘤組織之樣本中MDSC的數量。
- 如申請專利範圍第5項之方法,其中該經選擇之患者為血液中具有高頻率之MDSC的患者。
- 如申請專利範圍第5項之方法,其中該經選擇之患者為MDSC之浸潤程度呈陽性之患者。
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