TWI510622B - 用於治療及/或預防自體免疫疾病及用於調節性t細胞形成之藥劑 - Google Patents
用於治療及/或預防自體免疫疾病及用於調節性t細胞形成之藥劑 Download PDFInfo
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Description
本發明是有關於一種用於治療及/或預防自體免疫疾病的藥劑、一種在生物體內用於調節性T細胞(regulatory T cells,TReg
)形成的藥劑以及根據本發明之藥劑被使用於其中的各種方法。
自體免疫疾病的特徵在於對抗內生組織(endogenous tissue)的免疫系統過度反應。免疫系統錯誤地將內生組織辨識成要對抗的外來體。這造成嚴重的發炎反應,其導致受到它們所影響的器官損傷。
一個區別內生以及外生結構之間的重要角色是由T淋巴球或T細胞所扮演,它們在胸腺中被“培訓”成只會靠接(dock)到內生細胞表面分子(所謂MHC分子)上,並且因而對內生結構具有耐受性。這些過程被稱為“品系刪除(clonal deletion)”以及“品系選擇(clonal selection)”。在胸線中的初始篩選期間,只有那些能夠辨識內生細胞膜上的MHC分子的T細胞能夠存活下來,然而結合並不足以能夠引起T細胞的活化。根本無法結合至或辨識內生MHC分子的T細胞被淘汰。品系刪除也會發生在胸腺中,那些能夠以它們會被活化的方式來“準確地(unerringly)”辨識並且強力地結合內生MHC分子而在最後造成內生細胞摧毀的T細胞會被淘汰。這個過程是免疫系統所採取的那些手段之一,好能夠保護“自身”並且對抗“外生”。
在自體免疫疾病中,一群T細胞表現異常。除了仍然能夠防禦外來分子以及生物,它們現在也攻擊內生結構。器官或組織被理解為外生的。可能有各種的結果:若活的結構受到影響,自體免疫疾病將採一致命路線(fatal course)。免疫系統指揮它的防禦對抗這些結構,細胞性還有體液性防禦反應被設定為啟動,且自體抗體形成,結果在時間過程中受到影響的器官停止運行。最為常見地,免疫系統被削弱並且身體變得易蒙受所有種類的疾病。在某些情況下,外生的辨識也被破壞,而且結果退化性癌細胞的擴張無法被有效地防止,並且那些受影響者更易蒙受傳染病。在疾病的過程中,免疫系統的細胞摧毀內生結構,而身體的修復機制盡可能地再生受到損傷的器官部分。通常,在沒有治療的情況下,這個防禦系統的錯誤攻擊會持續一生或直到標的結構完全摧毀。
儘管有深入的研究,自體免疫疾病的確切病因仍是未知。公認的假說以假設自體免疫疾病是透過遺傳素因(genetic predisposition)為基礎,例如因為存在某種MHC分子類型,與外在影響一起。若這樣的遺傳決定因子是存在於受影響者的身體內,並且另外有不利的環境因素(諸如嚴重的壓力、感染、懷孕等)發生,這可能會導致自體免疫疾病的開始。
免疫系統是由各種能夠對抗侵入身體之傳染媒介物(infectious agents)的細胞所組成。免疫反應的機制包括活化特化的細胞(specialized cells)並且獲得效應子功能(effector functions),諸如某些T細胞的細胞毒殺作用,它們表現所謂CD8穿膜醣蛋白並且因而被形容為CD8+
T細胞。
調節性T細胞(TReg
),先前亦被形容為抑制T細胞(suppressor T cells),是一種特化的T細胞次群。它們具有抑制免疫系統活化並且藉此調控免疫系統的自我耐受性(self-tolerance)的功能。因此,在健康的生物體內,它們防止自體免疫疾病的開始。各種不同的TReg
族群已被描述,包括那些表現蛋白質CD4、CD25以及Foxp3者並且因而被形容為CD4+
CD25+
Foxp3+
T細胞。此外,TReg
已被形容為表現CD4以及Foxp3但不表現CD25,所謂CD4+
CD25-
Foxp3+
T細胞。再者,已知TReg
表現CD8並且因而是CD4陰性的,例如CD3+
CD4-
CD25+
Foxp3+
以及CD3+
CD4-
CD25-
Foxp3+
T細胞,它們被描述為在抑制自體免疫性上扮演一個重要的角色;參見Singh et al.(2007),CD8+
T cell-mediated suppression of autoimmunity in a murine lupus model of peptide-induced immune tolerance depends on Foxp3 expression,The Journal of Immunology 178,p.7649-7657,以及Tennakoon et al.(2006),Therapeutic induction of regulatory,cytotoxic CD8+
T cells in multiple sclerosis,The Journal of Immunology 176,p.7119-7129。
Lan et al.(2005),Regulatory T cells:development,function and role in autoimmunity,Autoimmun.Rev.4(6),p.351 to 363描述一個鼠類模型,其中CD4+
CD25+
調節性T細胞的耗竭會導致自體免疫疾病的自發性發生。
Chatila T.A.(2005),Role of regulatory T cells in human diseases,116(5),p.949 to 959報導CD4+
CD25+
調節性T細胞由於在編碼蛋白質Foxp3的基因突變所致的一個先天性缺陷會促使自體免疫疾病的發生。
在期刊“Nature Immunology”中有一篇涉及調節性T細胞的回顧,它是在2005年3月被發表的。
自體免疫疾病是依據受到影響的器官來作治療。因此,病因治療(causal therapy)的基本原則是透過免疫抑制劑(immunosuppressants)(例如可體松(cortisone))的投藥來抑制免疫系統的活性。這些物質的特徵在於多重性全身性副作用以及交互作用,因為它們被嘗試著發展出能夠專一性地影響涉及該疾病事件的機制的新藥物。這個的實例是那他珠單抗(natalizumab)以及因福利美(infliximab)。那他珠單抗是一種單株抗體以及IgG4的選擇性抑制劑,IgG4是一種位在白血球表面的黏附因子。那他珠單抗會抑制白血球移往發炎位置並且被用作為治療斑塊進行性多發性硬化症(plaque progressive multiple sclerosis)的特定侵犯型(aggressive forms)。因福利美是一種對抗在自體免疫發炎反應中扮演一個關鍵性角色的腫瘤壞死因子α(tumor necrosis factor α,TNFα)的嵌合單株抗體。因福利美被用在類風濕性關節炎(rheumatoid arthritis)、克隆氏病(Crohn’s disease)、Bechterew病(Bechterew disease)以及牛皮癬(psoriasis)。
在Ehrenstein et al.(2004),Compromised function of regulatory T cells in rheumatoid arthritis and reversal by anti-TNFα therapy,J.Exp.Med.,Vol.200,No.3,p.227-285中報導作為一被指引對抗TNFα的單株抗體的因福利美可以改善類風濕性關節炎的治療。
一個類似的提議是由Nadkarni et al.(2007),Anti-TNFα therapy induces a distinct regulatory T cell population in patients with rheumatoid arthritis via TGF-β,JEM Vol.204,p.33-39所作出的。
Bresson et al.(2006)提議藉由一種抗-CD3ε專一性抗體以及一種原胰島素肽的組合投藥來治療第I型糖尿病。
Vandenbark et al.(2008),Therapeutic vaccination with a trivalent T-cell receptor(TCR)peptide vaccine restores deficient FoxP3 expression and TCR recognition in subjects with multiple sclerosis,Immunology Vol.123,p.66-78描述在患者接種特定TCR肽之後增進對於多發性硬化症的自體反應(autoreactive response)的控制。
雖然這些較新的物質能夠非常專一性地作用,嚴重的副作用仍可能會發生,例如進行性多處腦白質病(progressive multifocal leukoencephalopathy)的侵襲。為此,就在它於美國首次註冊之後的3個月,那他珠單抗從市場上被再次撤回。這些新的活性成分的成本是非常高的。現今,3000 mg的那他珠單抗要價超過2,000.00歐元。200 mg的因福利美要價大約1,700.00歐元。
基於這個背景,本發明之目的在於提供一種用於治療及/或預防自體免疫疾病的藥學組成物,由於習知技藝的缺點藉其能夠儘可能地被避免。特別地,一種特徵在於令人滿意的耐受性以及低毒性的藥學組成物可以被提供。
本發明之又一目的在於提供一種在生物體內用於調節性T細胞(TReg
)形成的藥劑。
這些問題是透過提供人類介白素2的突變蛋白(mutein of human interleukin 2,hIL-2 mutein)或其節段(section)或片段(fragment)而獲得解決,人類介白素2的一突變蛋白或其節段或片段是依據hIL-2野生型來編號並且在位置20、88或126的至少一者處具有一胺基酸取代。
發明人已驚訝地發現到,此一hIL-2突變蛋白或其一片段具有高的治療潛力,它能夠被應用於治療和預防自體免疫疾病。因此例如它們能夠在不同實驗製備物(experimental preparations)中證實:hIL-2突變蛋白會在一生物體內選擇性地誘導調節性T細胞(諸如CD4+
CD25+
Foxp3+
以及CD4+
CD25-
Foxp3+
)形成。
出乎意料地,依據本發明之hIL-2突變蛋白對於調節性T細胞上展現出要比hIL-2野生型還要明顯更高的活性。這在高濃度下尤為明顯。
有關依據本發明之hIL-2突變蛋白,它被揭示於WO 99/60128,它結合至三鏈IL-2受體(IL-2Rαβγ)要比結合至雙鏈IL-2受體(IL-2Rβγ)還要強。如同發明人目前首次顯示的,相較於hIL-2野生型,依據本發明之hIL-2突變蛋白誘導,亦令人驚訝地強化那些缺少IL-2受體(CD25)之α次單位的調節性T細胞(CD4+
CD25-
Foxp3+
)形成。這個次群另外促進免疫系統活化的抑制並且藉此調節免疫系統的自體耐受性。因此,依據本發明之hIL-2突變蛋白要比hIL-2野生型展現出更高的潛力作為治療自體免疫疾病的活性成分。
發明人亦能夠證實:hIL-2突變蛋白會誘導CD8陽性調節性T細胞(諸如CD3+
CD4-
CD25+
Foxp3+
以及CD3+
CD4-
CD25-
Foxp3+
)形成(數據未顯示),其在抑制自體免疫疾病上展現一決定性的角色。
此外,依據本發明之hIL-2突變蛋白相較於hIL-2野生型更具有的優點是當對抗自然殺手細胞(natural killer cells,NK cells)時,它會選擇性地活化T細胞並且因而展現一被降低的毒性型態以及一被增加的治療指數(therapeutic index)。因此,依據本發明之hIL-2突變蛋白要比hIL-2野生型是更具有耐受性的;參見WO 99/60128。
再者,依據細胞毒性CD3+
CD8+
CD45RO+
T細胞,首次出乎意料地顯示依據本發明之hIL-2突變蛋白相對於hIL-2野生型在CD8-陽性細胞毒性T細胞的增生上不具有或僅具有少許的效果,該等CD8-陽性細胞毒性T細胞被形容為“單純的、中央記憶、早期分化的”並且“晚期發育的”CD8 T細胞。這是有利的,因為CD8+
-細胞毒性T細胞在自體免疫疾病中被維持著負責持續性、慢性發炎過程;參見Liu et al.(2007),Multiple Sclerosis,13
,p.149,以及Haegele et al.(2007),Neuroimmunol,183
,p.168)。因此,相較於hIL-2野生型,依據本發明之hIL-2突變蛋白預防這個由CD8+
T細胞所致的發炎反應進一步增強,其代表一個進一步的耐受性優點。
有如發明人所能夠顯示的,依據本發明之hIL-2突變蛋白亦刺激免疫細胞的抗原-專一性活性。這有個優點:藉由hIL-2突變蛋白,疾病-專一性免疫細胞選擇性地被刺激並且藉此免疫治療的全身性效果受到限制。因此,其他因為hIL-2突變蛋白的投藥所致使的疾病誘發也會被預防。
此外,依據第I型糖尿病的鼠類模型,發明人能夠顯示出自體免疫疾病的侵襲可以透過使用依據本發明之hIL-2突變蛋白來治療而被預防。
因此為本發明基礎的問題被完全地解決。
依據本發明,人類介白素2的“野生型”(hIL-2野生型)被理解為是表示一種具有133個胺基酸之胺基酸序列的多肽或蛋白質,其存在於天然人類IL-2中(不具有再一個20個N-端胺基酸所構成之訊號肽)。hIL-2野生型可以天然地也可以重組地被表現。hIL-2野生型的胺基酸序列被描述於Fujita et al.(1983),PNAS USA 80,p.7437-7441,具有或不具有一個額外的N-端甲硫胺酸,當該等蛋白質被表現於E.coli中作為一個細胞內部分時,它是必需存在的。hIL-2野生型的胺基酸序列是以序列辨識編號:1被揭示於隨附的序列表中。編碼hIL-2的cDNA的核苷酸序列是以序列辨識編號:2被揭示於隨附的序列表中。
依據本發明,人類介白素2的“突變蛋白(mutein)”(hIL-2 mutein)被理解為是表示一種多肽或蛋白質,其相較於hIL-2野生型,特定的取代已產生。鑑定取代已產生的位置處是以在hIL-2野生型中的胺基酸位置為基礎,其可以舉序列辨識編號:1作為例子。因此,一個丙胺酸(alanine,A)是位在位置1,一個脯胺酸(proline,P)在位置2,一個蘇胺酸(threonine,T)在位置133等。在位置20的天冬胺酸殘基(aspartic acid residue,D)(“D20”)可以例如被一個異白胺酸殘基(I)或一個組胺酸(H)所取代,以使得分別被形容為hIL-2-D20I以及hIL-2-D20H的IL-2突變蛋白形成。
無疑地,依據本發明之hIL-2突變蛋白可以在數個所述位置20、88或126處被取代,以使得特別適於治療自體免疫疾病或用於誘導調節性T細胞的組合突變體形成。
依據本發明,hIL-2突變蛋白亦包括一經修飾的多肽,例如一經醣化的hIL-2突變蛋白。經醣化的hIL-2突變蛋白是例如被揭示在美國專利申請案09/310,026以及10/051,657中,它們被併入此處以作為參考資料。
依據本發明,hIL-2突變蛋白的“節段(section)”或“片段(fragment)”被理解為是表示一多肽,其相較於hIL-2突變蛋白有一或多個胺基酸在N-及/或C-端漏失,然而這仍然展現出要依據本發明而被使用之hIL-2突變蛋白的充分生物活性以供治療及/或預防自體免疫疾病。若該節段或片段展現出hIL-2突變蛋白的至少50%活性以供誘導調節性T細胞,較佳地至少60%、更佳地至少70%、更佳地至少80%、更佳地至少90%以及最佳地至少95%,這個活性被視為是足夠的。hIL-2突變蛋白的活性可易於藉由習於該技藝者所熟知的方法來測定。此一方法是例如被揭示在WO 99/60128,實施例3至5中。作為參考資料,這份公開文件被併入本揭示內容中。
依據本發明,較佳的是在所述位置處的取代並非保守性取代,藉此一個胺基酸可以被替換成另一個具有類似生化特性者。
在這個方面,較佳的是在位置20處的取代不是天冬胺酸(aspartic acid,D)替換成麩胺酸(glutamic acid,E)。較佳地在位置88處的取代不是天門冬醯胺酸(asparagine,N)替換成一丙胺酸(alanine,A)、脯胺酸(praline,P)、甘胺酸(glycine,G)、麩醯胺酸(glutamine,Q)、絲胺酸(serine,S)或蘇胺酸(threonine,T)。再者,在位置126處的取代較佳地不是麩醯胺酸(Q)替換成一丙胺酸(A)、脯胺酸(P)、甘胺酸(G)、天門冬醯胺酸(N)、絲胺酸(S)或蘇胺酸(T)。這些取代將不會或僅些微地改變hIL-2野生型的生物活性。
另外,較佳的是沒有會引入供分子間交聯或不正確雙硫橋鍵聯的位址的取代在所述位置產生影響。因此,依據本發明之hIL-2突變蛋白在位置20處的取代較佳地不是天冬胺酸(D)替換成精胺酸(R)、天門冬醯胺酸(N)、天冬胺酸(D)、半胱胺酸(cysteine,C)、麩胺酸(E)、甘胺酸(G)、白胺酸(leucine,L)、離胺酸(lysine,K)、苯丙胺酸(phenylalanine,F)、脯胺酸(P)、蘇胺酸(T)或色胺酸(tryptophan,W)。在位置88處的取代較佳的不是天門冬醯胺酸(N)替換成天冬胺酸(D)、半胱胺酸(C)、麩醯胺酸(Q)、色胺酸(W)或脯胺酸(P)。在位置126處的取代較佳地不是麩醯胺酸(Q)替換成丙胺酸(A)、組胺酸(H)、色胺酸(W)、半胱胺酸(C)、麩醯胺酸(Q)、麩胺酸(E)或離胺酸(K)。
依據本發明之hIL-2突變蛋白可以藉由任何在該習知技藝中為已知的適當方法來製備。此等方法包含建構一編碼依據本發明之IL突變蛋白並且例如包括核苷酸序列序列辨識編號:2的DNA序列以及在一適當的宿主中表現這個序列。這個方法造成依據本發明之突變蛋白是呈重組型形式。然而,依據本發明之突變蛋白也可以藉由化學合成或化學合成與重組型DNA技術的組合來被製備。製備依據本發明之突變蛋白被詳細描述於WO 99/60128,具體例1以及2中,其被併入本揭示文件以作為參考資料。
對於習於該技藝者而言,一個依據本發明之尤佳的hIL-2突變蛋白是以BAY50-4798為名而為可取得的,其中在位置88處的天門冬醯胺酸(N)替換成一精胺酸(R)(hIL-2-N88R);參見Shanafelt et al.(2002),A T-cell-selective interleukin 2 mutein exhibits potent antitumor activity and is well tolerated in vivo,Nat.Biotechnol.Vol.18,p.1197-1202。hIL-2-N88R的胺基酸序列以序列辨識編號:3被揭示於隨附的序列表中。
發明人的發現是特別出乎意料的,因為在習知技藝中並沒有暗示IL-2突變蛋白的此活性被發現到。
因此在有關於hIL-2-N88R的WO 99/60128中,揭露它可以選擇性地活化對抗自然殺手細胞並且能夠在肺臟中降低轉移形成。
在WO 02/00243,一個有關於突變蛋白hIL-2-N88R的穩定、含有組胺酸、無白蛋白的組成被描述。
在US 2002/0164300中,突變蛋白hIL-2-N88R的一個經醣化變異體被描述。
使用依據本發明之hIL-2突變蛋白用於標靶治療及/或預防自體免疫疾病或在一生物體內選擇性地活化調節性T細胞在習知技藝中均未被描述過並且亦不是顯而易見的。
即便是人類野生型IL-2,沒有對應的發現。
Van der Vliet et al.(2007),Effects of the administration of high-dose interleukin-2 on immunoregulatory cell subsets in patients with advanced melanoma and renal cell cancer,Clin.Cancer Res.Vol.13,p.2100-2108報導在高劑量的IL-2的投藥之後,它用於治療腫瘤的效用被降低。
Ahmadzadeh and Rosenberg(2006),IL-2 administration increases CD4+
CD25hi
Foxp3+
regulatory T cells in cancer patients,Blood,Vol.107,p.2409-2414提議藉由消除腫瘤患者的調節性T細胞來增進人類野生型IL-2在患者中的治療效力。然而,這個方法證明是不可行的;參見Powell et al.(2007),Inability to mediate prolonged reduction of regulatory T cells after transfer of autologous CD25-depleted PBMC and interleukin-2 after lymphodepleting chemotherapy,J.Immunother.Vol.30,p.438-447。
Antony and Restifo(2005),CD4+
CD25+
T regulatory cells,immunotherapy of cancer,and interleukin-2,J.Immunother.Vol.28,p.120-128卻有點懷疑地看待IL-2作為一免疫-治療藥劑並且甚至報導IL-2的投藥可能會誘發自體免疫性。
Knoechel et al.(2005),Sequential development of interleukin 2-dependent effector and regulatory T cells in response to endogenous systemic antigen,JEM Vol.202,p.1375-1386傾向相同的觀點並且甚至暗示IL-2拮抗作用(亦即,抑制IL-2機制)來治療自體免疫疾病的早期。
因此在習知技藝中並沒有線索使得依據本發明的解決方案是顯而易見的。
因而發明人亦已發現hIL-2突變蛋白的治療效果可以視適應症(indication)以及所使用的濃度而有所不同。高濃度的hIL-2對於治療自體免疫疾病可能是有利的,但是在治療腫瘤疾病中卻是相反的。
在依據本發明的使用中,較佳的是在位置88處的天門冬醯胺酸透過取代被替換成一精胺酸(hIL-2-N88R),或一甘胺酸(hIL-2-N88G),或一異白胺酸(hIL-2-N88I),及/或在位置20處的天冬胺酸透過取代被替換成一組胺酸(hIL-2-D20H),或一異白胺酸(hIL-2-D20I)、或一酪胺酸(hIL-2-D20Y),或在位置126處的麩醯胺酸透過取代被替換成一白胺酸(hIL-2-Q126L)。
這個方法的優點在於依據本發明之一hIL-2突變蛋白被使用,該突變蛋白因為它特別選擇性地活化T細胞對抗自然殺手細胞並且因而展現出一高的治療潛力以及低毒性而為突出的。依據本發明之較佳hIL-2突變蛋白的這些特性被描述於WO 99/60128中,其被併入本揭示內容中以作為參考資料。
依據本發明,較佳的是hIL-2突變蛋白或其片段在除了位置20、88或126以外的任何位置處具有至少又一個胺基酸取代,以使得被進一步取代的hIL-2突變蛋白或其被進一步取代的節段或片段具有一胺基酸序列與hIL-2突變蛋白或其節段或片段(除了在位置20、88或126的至少一者處以外,其相較於hIL-2野生型並沒有進一步的取代)有至少80%,較佳地85%,更佳地90%,更佳地95%,最佳地99%是相同的。
這個方法的優點在於:替代性的一級結構被提供,在某些例子中要比除了在位置20、88或126的至少一者以外是對應於hIL-2野生型的hIL-2突變蛋白還要容易合成。為了要獲得一具有hIL-2突變蛋白或其節段的生物活性的多肽,並且因此用於治療及/或預防自體免疫疾病的藥物,提供一與依據本發明之hIL-2突變蛋白或其節段的胺基酸序列是100%相同的胺基酸序列並不是必需的。當然,若存在足夠高的同一性是充分的,若有需要的話,中等程度的活性喪失是可接受的,但較佳地至少50%、60%、70%、80%、90%、95%和99%的活性被保留。所述同一性是以具有≧10個胺基酸的依據本發明之hIL-2突變蛋白的一節段為基礎。同源性程度可以藉由習於該技藝者所熟知的方法而被容易地決定,例如一BLAST分析,或使用DNAStar Inc.的Lasergene程式的MegAlign模組。
依據本發明,更佳的是在除了位置20、88或126以外的任一位置處的進一步胺基酸取代是一保守性胺基酸取代。
這個方法的優點在於提供更多依據本發明之hIL-2突變蛋白的變異體,它們展現出夠高的活性以供治療及/或預防自體免疫疾病或用於在一生物體內誘導調節性T細胞。對於一習於該技藝者而言,已知保守性取代對突變蛋白的二級或三級結構不具有或僅具有最低的影響。此等保守性取代包括那些由Dayhoff描述於”The Atlas of Protein Sequence and Structure.Vol.5”,Natl.Biomedical Research 者。舉例而言,屬於下列群組中之一者的胺基酸可以被替換成另一者,亦即構成一個保守性替換:
-丙胺酸(A)、脯胺酸(P)、甘胺酸(G)、天門冬醯胺酸(N)、絲胺酸(S)、蘇胺酸(T);
-半胱胺酸(C)、絲胺酸(S)、酪胺酸(Y)、蘇胺酸(T);
-纈胺酸(V)、異白胺酸(I)、白胺酸(L)、甲硫胺酸(M)、丙胺酸(A)、苯丙胺酸(F);
-離胺酸(K)、精胺酸(R)、組胺酸(H);
-苯丙胺酸(F)、酪胺酸(Y)、色胺酸(W)、組胺酸(H);以及
-天冬胺酸(D)、麩胺酸(E)。
用於在一生物體內誘導調節性T細胞形成之依據本發明的藥劑較佳地是一藥學組成物,其含有一藥學上可接受的載體(carrier)。
這個方法的優點在於該藥劑呈一能夠直接投藥給該生物(較佳地給一人)的形式而被提供。
藥學上可接受的載體被廣泛描述於該習知技藝中;參見Row et al.(2006),Handbook of Pharmaceutical Excipients,5th
Edition,Pharmaceutical Press and American Pharmacists’ Association;Bauer et al.(1999),Lehrbuch der pharmazeutischen Technologie,Wissenschaftliche Verlagsgesellschaft mbH Stuttgart。一個尤佳的配方是被揭示於WO 02/00243中者,其為本揭示內容的一部分而作為參考資料。這個配方是無白蛋白的並且hIL-2突變蛋白或其節段的穩定是使用組胺酸而被達到的。較佳地完成的藥物具有呈下列濃度的下列組分:hIL-2突變蛋白或其一節段=0.1-5 mg/ml;組胺酸=0.08-1.6 wt.%;NaCl=0-0.9 wt.%;醣=1-10 wt.%;甘胺酸=0-0.3 wt.%,以及具有一大約為5至6.5的pH值。
依據一特定具體例,該藥學組成物亦含有一免疫抑制劑。
由於依據本發明之hIL-2突變蛋白的特殊效力,該藥學組成物可以被用作為用於治療及/或預防自體免疫疾病的一單製劑(monopreparation)。此一單製劑含有依據本發明之hIL-2突變蛋白作為唯一的活性成分。在本文中,藥學上可接受的載體、溶劑(緩衝液、水等等)、添加劑等不是活性成分。
這個方法的優點在於依據本發明之藥物的治療指數是藉由包含一標準的免疫抑制劑而被進一步增高。
較佳地該免疫抑制劑是選自於由下列所構成的群組:糖皮質素(glucocorticoid),包括脫氫皮醇(decortin)、潑尼松龍(prednisol);硫唑嘌呤(azathioprine);環孢靈A(cyclosporin A);霉酚酸脂(mycophenolate mofetil);他克莫司(tacrolimus);抗-T淋巴球球蛋白、抗-CD3抗體,包括莫羅莫那(muromonab);抗-CD25抗體,包括巴利昔單抗(basiliximab)以及達利珠單抗(daclizumab);抗-TNF-α抗體,包括因福利美(infliximab)以及阿達木單抗(adalimumab);硫唑嘌呤;甲胺蝶呤(methotrexate);環孢靈(cyclosporin);西羅莫司(sirolimus);依維莫司(everolimus);芬戈莫德(fingolimod);CellCept;麥考酚酸(myfortic)以及環磷醯胺(cyclophosphamide)。
這個方法的優點在於使用一在自體免疫疾病上具有明確治療活性並且在習知技藝中是可充分取得的免疫抑制劑。
再者,較佳的是該自體免疫疾病是選自於由下列所構成的群組:第I型糖尿病、類風濕性關節炎、多發性硬化症、慢性胃炎、克隆氏病、巴塞多氏病(Basedow disease)、Bechterew病、牛皮癬、重症肌無力(myasthenia gravis)、自體免疫肝炎、APECED、Chrug-Strauss症候群(Chrug-Strauss syndrome)、潰瘍性大腸炎(ulcerative colitis)、腎小球性腎炎(glomerulonephritis)、格林-巴厘症候群(Guillain-Barrsyndrome)、橋本甲狀腺炎(Hashimoto thyroiditis)、硬化性苔藓(lichen sclerosus)、全身性紅斑性狼瘡(systemic lupus erythematodes)、PANDAS、風濕性熱(rheumatic fever)、類肉瘤病(sarcoidosis)、修格蘭氏症(Sjrgren syndrome)、僵硬人症候群(Stiff-Man syndrome)、硬皮症(scleroderma)、華格納氏肉芽病(Wegener’s granulomatosis)、白斑病(vitiligo)、自體免疫腸病(autoimmune enteropathy)、Goodpasture症候群(Goodpasture syndrome)、皮肌炎(dermatomyositis)、多發性肌炎(polymyositis)、自體免疫過敏(autoimmune allergy)、氣喘(asthma)以及在器官移植之後的自體免疫反應。
這個方法的優點是提供一種可以被用於治療及/或預防最為重要的自體免疫疾病的藥物。
本發明的又一主旨是有關於一種用於治療及/或預防自體免疫疾病的藥學組成物,其含有依據本發明之hIL-2突變蛋白或其片段。
所述有關使用依據本發明的特性以及優點與定義同樣適用於依據本發明的藥學組成物。
本發明的又一主旨是有關於一種用於在一生物體內的形成調節性T細胞(TReg
)的藥劑,其含有依據本發明之hIL-2突變蛋白或其片段。
所述有關使用依據本發明的特性以及優點與定義同樣適用於依據本發明的藥劑。
本發明的更多主旨是用於在生物體內治療及/或預防自體免疫疾病以及用於在生物體內形成調節性T細胞(TReg
)的方法,其各自包含下列步驟:(a)提供人類介白素-2的突變蛋白(hIL-2 mutein)或其片段,(b)將該hIL-2突變蛋白或其節段投與一生物,以及(c)若需要時重複步驟(a)與(b),其中hIL-2突變蛋白或其節段是依據本發明之hIL-2突變蛋白或其節段。
該生物較佳地是一哺乳動物,更佳地是一人類生物。所述有關使用依據本發明的特性以及優點與定義同樣適用於依據本發明的前述方法用於在生物體內治療及/或預防自體免疫疾病並且用於在生物體內形成調節性T細胞(TReg
)。
本發明的又一主旨是有關於一種用於活體外形成調節性T細胞(TReg
)的方法,其包含下列步驟:(a)提供人類介白素-2的突變蛋白或其片段,(b)令該hIL-2突變蛋白或其片段與周邊單核血球細胞(peripheral mononuclear blood cells,PBMCs)接觸,以及(c)若需要時重複步驟(a)與(b),其中hIL-2突變蛋白或其片段是依據本發明之hIL-2突變蛋白或其片段。
該hIL-2突變蛋白或其片段與PBMCs的接觸可以在任何用於培養PBMCs的適當培養基中被實現。
所述有關使用依據本發明的特性以及優點與定義同樣適用於依據本發明的前述方法用於在活體外形成調節性T細胞(TReg
)。
本發明的又一主旨是有關於一種用於在生物體內治療及/或預防自體免疫疾病的方法,其包含下列步驟:(a)提供人類介白素-2的突變蛋白(hIL-2突變蛋白)或其片段,(b)令該hIL-2突變蛋白或其片段與衍生自第一生物的周邊單核血球細胞(PBMCs)接觸,(c)培育該hIL-2突變蛋白或其片段與PBMCs,以獲得一含有調節性T細胞(TReg
)的細胞群,以及(d)將該細胞群引入至第二生物,其中該hIL-2突變蛋白或其片段是依據本發明之hIL-2突變蛋白或其片段。
該第一生物以及該第二生物較佳地具有相同的血型,尤佳地是該第一以及第二生物是同一生物或個體。
優點在於引入或再灌注(reinfusion)該細胞群不會有對抗該等細胞的非所欲免疫反應發生並且該方法因而在副作用上是特別地低。
所述有關使用依據本發明的特性以及優點與定義同樣適用於依據本發明的前述方法用於生物體內治療及/或預防自體免疫疾病。
在不偏離本發明之範疇的情況下,上述特色以及那些在下面要被說明者顯然不僅適用於所述特定組合中,也適用於在其他的組合中或單獨。
來自於健康個體,黑色素瘤患者或MS患者的周邊單核血球(PBMCs)是藉由淋巴球分離培養基(Histopaque,Sigma Aldrich)的方法而從血液中被分離出。為此,2管來自於相同個體或患者的血液(7或10 ml)被轉移到一個無菌50 ml試管並且以RPMI 1640(InVitrogen,# 14190-69)補到30 ml。接著,30 ml的經稀釋血液被疊加至15 ml的密度梯度溶液(密度=1.077;Histopaque,Sigma Aldrich,# 10771)上。
在沒有煞車的情況下,於20℃下以400 g離心歷時40分鐘之後,2個“白血球環”被收穫以及被轉移到一無菌50 ml試管中並且以磷酸鹽緩衝鹽水(PBS;InVitrogen # 14190-169)洗滌2次。在有紅血球汙染的情況下,RBC(“紅血球”)溶解被執行;2 ml的RBC溶解溶液被添加至細胞丸(cell pellet)並且培育是在室溫下以溫和混合的方式被執行歷時2分鐘,接而為使用大量完全培養基(RPMI 1640加上10%胎牛血清)的洗滌步驟。
活的白血球數目是藉由使用錐蟲藍(InVitrogen # 15250-061)的排除染色(exclusion staining)以及一血球計(haemocytometer)(FisherBioblock A2759B)而被決定。
在計數之後,細胞在PBS中洗滌2次並且以一為1 x 106
細胞/ml的濃度被再懸浮於PBS中。CFSE(InVitrogen # C1157)以一為0.5 μM的最終濃度被加入。在黑暗中於37℃下培育10分鐘之後,經CFSE標記的細胞以新鮮的完全培養基於4℃下洗滌3次並且以一為1 x 106
細胞/ml的濃度再懸浮於完全培養基中以供平板塗佈(plating out)。
PBMCs維持未受刺激的或以加上或未加上一群合成肽的hIL-2野生型(普留淨(proleukin))或hIL-2-N88R(BAY 50-4798;Lot #PR312C008)予以刺激,合成肽是衍生自黑色素瘤-專一性蛋白質gp100、TRP-2、MART-1以及酪胺酸酶或衍生自對多發性硬化症(MG)具有專一性的蛋白質MOG,各個肽是以一為2.5 μM(黑色素瘤肽)或30 μg/ml(MS肽)的最終濃度被添加。
刺激劑以及肽是依據下列23種條件而被加入:
接著細胞在一具有5% CO2
含量的氣氛下被培養於37℃下歷時6天。
針對細胞表面分子使用經螢光標記的抗體來染色細胞使得研究一特定淋巴球次群(記憶以及活化標記,參見表2)的增生是可行的。使用螢光染料(PE:藻紅素,ECD:PE-德州紅,APC:別藻藍蛋白,PC7:PE-Cy7)-標記之抗體的免疫染色在與刺激劑培養6天之前以及之後被執行。
在第六天,前兩種染色(1以及liso)是使用非-CFSE(CFSE:羧基螢光素乙醯乙酸琥珀醯亞胺酯)-標記的細胞被執行;其他的染色是在經CFSE-標記的細胞上被執行。
CD25-PE、Foxp3-APC以及大鼠IgG2a-APC是來自於ebiosciences;CD25-APC、CD45RA-APC以及CD45RO-APC是購自於BD Biosciences。其他所有抗體是來自於Beckman-Coulter,法國。
12週大的NOD(“非-糖尿病”)小鼠每日被處理以hIL-2突變蛋白以及hIL-2野生型。陰性對照動物被類似地處理以生理鹽溶液(鹽水)。處理組是由3-5隻動物所組成。在第0至15天,數量為5K或25-單位的hIL-2突變蛋白或hIL-2野生型被投藥給小鼠。從第17天起,在使用5K單位的處理組中,數量被增加至100K-單位(=6.112 μg)。以25K-單位處理的動物維持不變。最後一次給藥是在第31天被執行。在一個相同的實驗中,處理是以一為25K-單位的固定劑量從第0至31天被執行。糖尿病是藉由監測尿液中的葡萄糖水準而被偵測。血液樣品在第17天以及第30天從小鼠取得。樣品在使用抗-CD4、抗-CD25以及抗-FoxP3染色的FACS中被分析並且FoxP3+
細胞在CD4+
T細胞中的百分率與CD25表現在CD4+
FoxP3+
細胞上的平均螢光強度(mean fluorescence intensity,MFI)因而被決定。
作為一用於測試依據本發明之突變蛋白效果的適當活體外系統,周邊單核血球(PBMCs)被使用。PBMCs是由T細胞(~75% CD4-與CD8-陽性)和B與NK細胞(~25%陽性)所組成並且因而構成一頗能代表免疫系統的細胞群。
來自於6位健康個體的PBMCs(106
細胞/ml)以濃度介於10-11
以及10-6
M的野生型IL-2(普留淨)或IL-2-N88R[BAY 50-4798,Lot #PR312C008(“BAY#C008”)],或者在陽性對照中以濃度為5 μg/ml的非專一性分裂素植物血球凝集素(non-specific mitogen phytohaemaglutinin(“PHA”))予以刺激或僅有培養基(“Med”)。在第0天以及刺激之後的第6天,CD3+
淋巴球中的調節性CD4+
CD25+
Foxp3+
T細胞含量被決定。結果被顯示在第1圖以及下面的表3中。
從這個實驗,在以濃度為10-7
M以及10-6
M的hIL-2-N88R之後造成調節性T細胞的次群CD4+
CD25+
Foxp3+
的一個顯著誘導。於此這個誘導是明顯大於藉由hIL-2野生型刺激PBMCs。
在一第二製備物中,以hIL-2-N88R刺激之後,在調節性T細胞的次群CD4+
CD25-
Foxp3+
上的增加相較於hIL-2野生型被研究。結果被顯示在第2圖以及下面的表4。
此處亦可見,以hIL-2-N88R刺激會在調節性T細胞的次群CD4+
CD25-
Foxp3+
上造成一個顯著增加,其於濃度為10-6
M時是明顯高於以hIL-2野生型刺激。
接下來研究依據本發明的hIL-2突變蛋白N88R是否也會刺激免疫細胞的抗原-專一性活性。為此,在有或沒有一與黑色素瘤-相關聯的肽池(peptide pool)的存在下,來自於3名黑色素瘤患者的PBMCs(106
細胞/ml)是以濃度介於10-11
以及10-6
M的hIL-2-N88R(BAY 50-4798,Lot #PR312C008)或hIL-2野生型(普留淨),5 μg/ml PHA予以刺激或僅有培養基。繼而,調節性T細胞的次群CD4+
CD25+
Foxp3+
以及CD4+
CD25-
Foxp3+
分別被決定。結果被顯示在第3圖與表5以及第4圖與表6。
於此發現hIL-2-N88R的投藥也會在黑色素瘤患者體內造成一個在調節性T細胞上的顯著增加。在濃度為10-7
M以及10-6
M下的次群CD4+
CD25+
Foxp3+
,以及在濃度為10-6
M下的次群CD4+
CD25-
Foxp3+
中,要比以對應濃度的野生型-IL-2(普留淨)刺激還要明顯地高。
接下來是研究依據本發明之hIL-2突變蛋白N88R是否也會刺激免疫細胞的抗原-專一性活性。為此,在有或沒有一與多發性硬化症-相關聯的肽的存在下,來自於2名多發性硬化症患者的PBMCs(106
細胞/ml)是以濃度介於10-11
以及10-6
M的hIL-2-N88R(BAY 50-4798,Lot #PR312C008)或hIL-2野生型(普留淨),5 μg/ml PHA予以刺激或僅有培養基。接著,調節性T細胞的次群CD4+
CD25+
Foxp3+
以及CD4+
CD25-
Foxp3+
分別被決定。結果被顯示在第5圖與表7以及第6圖與表8。
發現到hIL-8-N88R的投藥也會在多發性硬化症患者體內造成一個在T細胞上的顯著增加。在濃度為10-8
M以及10-7
M下的次群CD4+
CD25+
Foxp3+
,以及在濃度為10-6
M下的次群CD4+
CD25-
Foxp3+
中,要比以對應濃度的hIL-2野生型(普留淨)刺激還要明顯地高。
另外,細胞毒性CD8+
中央記憶T細胞的刺激被研究。為此,來自健康個體或多發性硬化症患者的PBMCs是如同在2.3中所述般被處理。CFSElow/CD3+
CD8+
CD45RO+
T細胞的百分率被分析。結果被顯示於第7圖與表9以及第8圖與表10中。
相對於hIL-2野生型,hIL-2-N88R在多發性硬化症患者還有在健康個體中僅會在中央記憶CD8+
T細胞造成些許增生,並且這在每一個濃度被發現到。
與hIL-2野生型相較之下,以hIL-2-N88R處理的NOD小鼠在CD4+細胞的FoxP3+細胞中造成一個較高百分率的增加(第9(A)圖)。此外,這些CD4+FoxP3+陽性細胞展現出較高的CD25表現(第9(B)圖)。第10圖顯示,與hIL-2野生型相較之下,在小鼠第I型糖尿病模型中,hIL-2-N88R處理於所有的處理組中皆能預防小鼠發生糖尿病。
由發明人所執行的實驗清楚地顯示:因為依據本發明之hIL-2突變蛋白及其節段用於誘導調節性T細胞(TReg
)的潛力,它們是適用於治療及/或預防自體免疫疾病或用於在一生物體內誘導TReg
並且用於在活體外形成TReg
的物質。這是在活體外還有活體內被發明人所證實的。
在下面,本發明將根據實施例來被進一步地說明,該等實施例僅具有例示性質而非限制本發明的範疇。在這些中,參照隨附的圖式,其表示下列:
第1圖顯示於相同或較低劑量下,hIL-2-N88R與普留淨相較之下在健康的個體體內於調節性CD4+
CD25+
Foxp3+
T細胞上誘導一個較大的增加;
第2圖顯示於相同或較低劑量下,hIL-2-N88R與普留淨相較之下在健康的個體體內於調節性CD4+
CD25-
Foxp3+
T細胞上誘導一個較大的增加;
第3圖顯示於相同或較低劑量下,hIL-2-N88R與普留淨相較之下在黑色素瘤患者體內於調節性CD4+
CD25+
Foxp3+
T細胞上誘導一個較大的增加;
第4圖顯示於相同或較低劑量下,hIL-2-N88R與普留淨相較之下在黑色素瘤患者體內於調節性CD4+
CD25-
Foxp3+
T細胞上誘導一個較大的增加;
第5圖顯示於相同或較低劑量下,hIL-2-N88R與普留淨相較之下在多發性硬化症患者體內於調節性CD4+
CD25+
Foxp3+
T細胞上誘導一個較大的增加;
第6圖顯示於相同或較低劑量下,hIL-2-N88R與普留淨相較之下在多發性硬化症患者體內於調節性CD4+
CD25-
Foxp3+
T細胞上誘導一個較大的增加;
第7圖顯示於相同或較高劑量下,hIL-2-N88R與普留淨相較之下在多發性硬化症患者體內於細胞毒性CFSE-low/CD3+
CD8+
CD45RO+
T細胞上誘導一個較低的增加;
第8圖顯示於相同或較高劑量下,hIL-2-N88R與普留淨相較之下在健康的個體體內於細胞毒性CFSE-low/CD3+
CD8+
CD45RO+
T細胞上誘導一個較低的增加;
第9圖顯示與hIL-2野生型相較之下,hIL-2-N88R在小鼠第I型糖尿病模型中於CD4+
細胞的FoxP3+
上造成一個較高百分率的增加(A)。此外,這些CD4+
FoxP3+
細胞展現出CD25的較高表現(B)。
第10圖顯示相對於hIL-2野生型,hIL-2-N88R在小鼠第I型糖尿病模型中預防糖尿病的發生。
<110> AiCuris GmbH & Co.KG Wuppertal, Germany <120> 用於治療及/或預防自體免疫疾病以及調節性T細胞形成的藥劑 <130> 1043P108 <160> 3 <170> PatentIn Ver.2.0 <210> 1 <211> 133 <212> PRT <213> 智慧人 <400> 1<210> 2 <211> 465 <212> DNA <213> 智慧人 <400> 2<210> 3 <211> 133 <212> PRT <213> 人工的序列 <220> 突變體 <223> hIL-2-N88R <400> 3
Claims (12)
- 一種人類介白素-2的突變蛋白(hIL-2突變蛋白)或其片段供製備一用於治療及/或預防自體免疫疾病之藥劑的用途,其中該人類介白素-2的突變蛋白或其片段是對應於hIL-2野生型來編號並且在位置20、88或126的至少一者處具有一胺基酸取代,其特徵在於:在位置88處的一天門冬醯胺透過取代被替換成一精胺酸(hIL-2-N88R),或一甘胺酸(hIL-2-N88G),或一異白胺酸(hIL-2-N88I),及/或在位置20處的一天冬胺酸透過取代被替換成一組胺酸(hIL-2-D20H),或一異白胺酸(hIL-2-D20I)、或一酪胺酸(hIL-2-D20Y),及/或在位置126處的一麩醯胺酸透過取代被替換成一白胺酸(hIL-2-Q126L)。
- 如申請專利範圍第1項的用途,其中該藥劑另外含有一免疫抑制劑。
- 如申請專利範圍第2的用途,其中該免疫抑制劑是選自於由下列所構成的群組:糖皮質素,包括脫氫皮醇(decortin)、潑尼松龍;硫唑嘌呤;環孢靈A;霉酚酸脂;他克莫司;抗-T淋巴球球蛋白、抗-CD3抗體,包括莫羅莫那;抗-CD25抗體,包括巴利昔單抗以及達利珠單抗;抗-TNF-α抗體,包括因福利美以及阿達木單抗;硫唑嘌呤;甲胺蝶呤;環孢靈;西羅莫司;依維莫司;芬戈莫德;CellCept;麥考酚酸以及環磷醯胺。
- 如申請專利範圍第1至3項中任一項的用途,其中該自體免疫疾病是選自於由下列所構成的群組:第I型糖尿病、類風濕性關節炎、多發性硬化症、慢性胃炎、克隆氏病、巴塞多氏病、Bechterew病、牛皮癬、重症肌無力、自體免疫肝炎、APECED、Chrug-Strauss症候群、潰瘍性大腸炎、腎小球性腎炎、格林-巴厘症候群、橋本甲狀腺炎、硬化性苔藓、全身性紅斑性狼瘡、PANDAS、風濕性熱、類肉瘤病、修格蘭氏症、僵硬人症候群、硬皮症、華格納氏肉芽病、白斑病、自體免疫腸病、Goodpasture症候群、皮肌炎、多發性肌炎、自體免疫過敏、氣喘以及在器官移植之後的自體免疫反應。
- 如申請專利範圍第1至3項中任一項的用途,其中該藥劑含有一藥學上可接受的載體。
- 一種用於治療及/或預防自體免疫疾病的藥學組成物,其中該藥學組成物含有如申請專利範圍第1至5項中任一項之用途的hIL-2突變蛋白或其片段。
- 一種人類介白素-2的突變蛋白(hIL-2突變蛋白)或其片段供製備一用於在生物體內形成調節性T細胞(TReg )的藥劑的用途,該人類介白素-2的突變蛋白或其片段是對應於hIL-2野生型來編號並且在位置20、88或126的至少一者處具有一胺基酸取代,其特徵在於:在位置88處的一天門冬醯胺酸透過取代被替換成一精胺酸(hIL-2-N88R),或一甘胺酸(hIL-2-N88G),或一異白胺酸(hIL-2-N88I),及/或 在位置20處的一天冬胺酸透過取代被替換成一組胺酸(hIL-2-D20H),或一異白胺酸(hIL-2-D20I)、或一酪胺酸(hIL-2-D20Y),及/或在位置126處的一麩醯胺酸透過取代被替換成一白胺酸(hIL-2-Q126L)。
- 如申請專利範圍7項的用途,其中該藥劑是一藥學組成物並且含有一藥學上可接受的載體。
- 如申請專利範圍第8項的用途,其中該藥劑另外含有一免疫抑制劑。
- 如申請專利範圍第9項的用途,其中該免疫抑制劑是選自於由下列所構成的群組:糖皮質素,包括脫氫皮醇(decortin)、潑尼松龍;硫唑嘌呤;環孢靈A;霉酚酸脂;他克莫司;抗-T淋巴球球蛋白、抗-CD3抗體,包括莫羅莫那;抗-CD25抗體,包括巴利昔單抗以及達利珠單抗;抗-TNF-α抗體,包括因福利美以及阿達木單抗;硫唑嘌呤;甲胺蝶呤;環孢靈;西羅莫司;依維莫司;芬戈莫德;CellCept;麥考酚酸以及環磷醯胺。
- 一種用於在生物體內形成調節性T細胞(TREG )的藥學組成物,其特徵在於其含有如申請專利範圍第7至10項中任一項之用途的hIL-2突變蛋白或其片段。
- 一種用於活體外形成調節性T細胞(TReg )的方法,其包含下列步驟:(a)提供人類介白素-2的突變蛋白或其片段,(b)令該hIL-2突變蛋白或其片段與周邊單核血球細胞 (PBMCs)接觸,以及(c)若需要時重複步驟(a)與(b),其中該hIL-2突變蛋白或其片段是如申請專利範圍第7至10項中任一項之用途的hIL-2突變蛋白或其片段。
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