TWI747178B - 單鏈trail-受體激動劑蛋白質 - Google Patents
單鏈trail-受體激動劑蛋白質 Download PDFInfo
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- TWI747178B TWI747178B TW109106778A TW109106778A TWI747178B TW I747178 B TWI747178 B TW I747178B TW 109106778 A TW109106778 A TW 109106778A TW 109106778 A TW109106778 A TW 109106778A TW I747178 B TWI747178 B TW I747178B
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Abstract
本文提供特異性TRAIL受體激動劑蛋白質、編碼該蛋白質之核酸、及治療患有與TRAIL相關之疾病或病症之個體之方法。本文所提供的TRAIL受體激動劑蛋白質包含三個可溶性TRAIL域及Fc片段。TRAIL受體激動劑蛋白質實質上無聚集性且適用於治療、診斷及/或研究應用。
Description
本發明提供包含三個可溶性TRAIL域及Fc片段之特異性TRAIL受體激動劑蛋白質、編碼TRAIL受體激動劑蛋白質之核酸分子、及其用途。TRAIL受體激動劑蛋白質實質上無聚集性且適用於治療、診斷及/或研究應用。
已知TNF超家族(TNF superfamily,TNFSF)細胞激素之三聚作用係為受體有效結合及活化所需。然而,TNF超家族細胞激素之三聚錯合物難以從重組單體單元製得。
WO 01/49866及WO 02/09055揭示包含TNF細胞激素及多聚化組分(特別是來自C1q蛋白質家族之蛋白質或膠原凝集素)之重組型融合蛋白。然而,此等融合蛋白之一個缺點是三聚化域通常具有大的分子量且/或三聚化相當無效率。
Schneider等人(J Exp Med 187 (1989), 1205-1213)描述TNF細胞激素之三聚物藉由N-端定位穩定模體(stabilization motif)得以穩定。在CD95L中,據推測受體結合域三聚物之穩定化係由位於細胞質膜附近的N-端胺基酸域所引起。
Shiraishi等人(Biochem Biophys Res Commun 322 (2004), 197-202)描述CD95L之受體結合域可藉由定位在N-端的人工α-螺旋形捲曲螺旋(白胺酸拉鏈)模體得以穩定。然而,發現可能極難預測多肽鏈彼此之定向,例如平行或反向平行定向。另外,難以測定捲曲螺旋拉鏈模體中七肽重複區之最佳數量。此外,捲曲螺旋結構具有在改變pH及/或離子強度後形成大分子聚集物之傾向。
WO 01/25277係關於結合至細胞受體之細胞外配體結合域之單鏈寡聚多肽,其中該多肽包含至少一者可結合至細胞受體之配體結合域及至少一者無法有效地結合至細胞受體之配體結合域之至少三個受體結合位點,藉此該等單鏈寡聚多肽可結合至受體,但無法活化受體。例如,單體係衍生自TNF家族,特定言之衍生自TNF-α之細胞激素配體。
WO 2005/103077揭示包含至少三個TNF家族配體成員之單體及至少兩個使TNF配體家族成員之單體彼此連接之肽連接子之單鏈融合多肽。然而,新近的實驗已證實此等單鏈融合多肽顯示非所欲之聚集。
WO 2010/010051揭示包含三個可溶性TNF家族細胞激素域及至少兩個肽連接子之單鏈融合多肽。所述融合多肽實質上無聚集性。
除此之外,先前的著作(包括Papadopoulos等人(Cancer Chemother Pharmacol, 2015, DOI 10.1007/s00280-015-2712-0)之著作)已證實TRAIL受體超蔟集會導致毒性。
相應地,在相關技藝中需要新穎TRAIL受體激動劑展現高生物活性、高穩定性、低毒性,且容許有效地製造重組體。
本發明提供展現低蛋白質分解降解、長半衰期、及活體內低TRAIL受體超簇集(及伴隨之毒性)之特異性TRAIL受體激動劑蛋白質。
本發明之TRAIL受體激動劑蛋白質一般包含:(i)第一可溶性TRAIL細胞激素域;(ii)第一肽連接子;(iii)第二可溶性TRAIL域;(iv)第二肽連接子;(v)第三可溶性TRAIL域;及(vi)抗體Fc片段。
在一個態樣中,本發明提供一種單鏈融合多肽,其包含:(i)第一可溶性TRAIL域、(ii)第一肽連接子、(iii)第二可溶性TRAIL域、(iv)第二肽連接子、(v)第三可溶性TRAIL域、及(vi)抗體Fc片段。在一個實施例中,抗體Fc片段(vi)以N端位於第一TRAIL域(i)且/或以C-端位於第三TRAIL域(v)。在另一實施例中,抗體Fc片段以C-端位於第三TRAIL域(v)。在一個實施例中,該多肽實質上無聚集性。在另一個實施例中,該第二及/或第三可溶性TRAIL域係視需要包含胺基酸序列突變之N-端縮短的域。
在一個實施例中,可溶性TRAIL域中之至少一者、特定言之可溶性TRAIL域(iii)及(v)中之至少一者係具有始於人類TRAIL之胺基酸Gln120及Val122之間之N-端序列之可溶性TRAIL域且其中Arg121可由中性胺基酸例如Ser或Gly置換。在另一實施例中,可溶性TRAIL域中之至少一者、特定言之可溶性TRAIL域(iii)及(v)中之至少一者係具有選自(a)Arg121–Val122–Ala123及(b)(Gly/Ser)121–Val122–Ala123之N-端序列之可溶性TRAIL域。在一個實施例中,可溶性TRAIL域以人類TRAIL之胺基酸Gly281結束且/或視需要包含位置R130、G160、H168、R170、H177、Y189、R191、Q193、E195、N199、K201、Y213、T214、S215、H264、I266、D267或D269或兩個或更多個該等位置處之突變。在一個實施例中,可溶性TRAIL域(i)係由如SEQ ID NO:1之人類TRAIL之胺基酸Gln120–Gly281組成及可溶性TRAIL域(iii)及(v)係由如SEQ ID NO:1之人類TRAIL之胺基酸Arg121–Gly281組成。
在一個實施例中,該第一及第二肽連接子(ii)及(iv)獨立地具有3至8個胺基酸之長度,尤其是3個、4個、5個、6個、7個、或8個胺基酸之長度,且較佳係視需要包含可經醣基化之天冬醯胺酸殘基之甘胺酸/絲胺酸連接子。在一個實施例中,該第一及第二肽連接子(ii)及(iv)係由如SEQ ID NO:2之胺基酸序列組成。在另一實施例中,多肽另外包含例如具有SEQ ID NO:12之N-端信號肽域,其可包含蛋白酶裂解位點,且/或其另外包含可包含且/或鏈接至識別/純化域例如如SEQ ID NO:13之Strep標籤之C-端元素。
在一個實施例中,抗體Fc片段(vi)經較佳為具有SEQ ID NO:11之鉸合連接子融合至可溶性TRAIL域(i)及/或(v)。在另一實施例中,抗體Fc片段(vi)係由以SEQ ID NO:10或17中所顯示之胺基酸序列組成。在一個實施例中,多肽包含具有SEQ ID NO:14、15或18之胺基酸序列。
在另一態樣中,本發明提供一種包含具有如SEQ ID NO:19、20或21所示胺基酸序列之多肽之TRAIL受體激動劑蛋白質。
在另一態樣中,本發明提供一種包含具有如SEQ ID NO:26、27、28、29、或30所示胺基酸序列之多肽之TRAIL受體激動劑蛋白質。
在另一態樣中,本發明提供一種包含兩個具有如SEQ ID NO:19所示胺基酸序列之多肽之TRAIL受體激動劑蛋白質。在一個實施例中,此兩個多肽係經三個形成於各多肽之半胱胺酸殘基513、519、及522之間之鏈間雙硫鍵共價連接。
在一個實施例中,在多肽之位置168及337之處之天冬醯胺酸殘基中之一或多者係經N-醣基化。在另一實施例中,該一或多個多肽之位置168及337之處之兩個天冬醯胺酸殘基係經N-醣基化。
在另一實施例中,該一或多個多肽進一步經轉譯後修飾。在另一實施例中,該轉譯後修飾包括N-端麩醯胺酸經過修飾為焦麩胺酸鹽。
在另一態樣中,本發明提供一種包含本文所揭示之TRAIL受體激動劑蛋白質及一或多種醫藥上可接受之載劑、稀釋劑、賦形劑、及/或佐劑之醫藥組合物。
在另一態樣中,本發明提供一種編碼TRAIL受體激動劑蛋白質之核酸分子。在另一實施例中,本發明提供一種包含核酸分子之表現載體。在另一實施例中,本發明提供一種包含核酸分子之細胞。在另一實施例中,該細胞係真核細胞。在另一實施例中,該細胞係哺乳動物細胞。在另一實施例中,該細胞係中國倉鼠卵巢(CHO)細胞。在其他實施例中,該細胞係選自由CHO-DBX11、CHO-DG44、CHO-S、及CHO-K1細胞組成之群。在其他實施例中,該細胞係選自由Vero、BHK、海拉(HeLa)、COS、MDCK、HEK-293、NIH-3T3、W138、BT483、Hs578T、HTB2、BT20、T47D、NS0、CRL7030、HsS78Bst、PER.C6、SP2/0-Agl4、及融合瘤細胞組成之群。
在另一態樣中,本發明提供一種治療患有與TRAIL相關之疾病或病症之個體之方法,該方法包括投與該個體有效量之TRAIL受體激動劑蛋白質。在一個實施例中,TRAIL受體激動劑蛋白質係單獨地投與。在另一實施例中,TRAIL受體激動劑蛋白質係在投與第二藥劑之前、同時、或之後投與。在另一實施例中,該疾病或病症係選自由以下組成之群:腫瘤、傳染性疾病、發炎性疾病、代謝疾病、自體免疫疾病、退化性疾病、與細胞凋亡相關之疾病、及移植排斥。在一個實施例中,該等腫瘤係實體腫瘤。在一個實施例中,該等腫瘤係由由肉瘤、食道癌、及胃癌組成之癌症之群引起。在另一實施例中,該等腫瘤係由尤因氏肉瘤(Ewing's sarcoma)或纖維肉瘤。在另一實施例中,該等腫瘤係由由非小細胞肺癌(NSCLC)、胰臟癌、結腸直腸癌、乳癌、卵巢癌、頭部及頸部癌症、及小細胞肺癌(SCLC)組成之癌症之群引起。在另一實施例中,該等腫瘤係淋巴腫瘤。在一個實施例中,該等腫瘤係血液性腫瘤。在另一實施例中,該等腫瘤係由非霍奇金氏淋巴瘤(non-Hodgkin's lymphoma)、白血病、急性淋巴母細胞性白血病(ALL)、急性骨髓性白血病(AML)、B細胞淋巴瘤、勃氏淋巴瘤(Burkitt's lymphoma)、慢性骨髓細胞性白血病(CML)、慢性淋巴球性白血病(CLL)、或髮樣細胞白血病引起。在另一實施例中,該等自體免疫疾病係類風濕疾病、關節疾病、或類風濕與關節疾病。在另一實施例中,該疾病或病症係類風濕性關節炎。在另一實施例中,該退化性疾病係神經退化性疾病。在另一實施例中,該神經退化性疾病係多發性硬化症。
在一個實施例中,該第二藥劑係化學治療劑、放射治療劑、或生物藥劑。在一個實施例中,該第二藥劑係選自由杜維利西(Duvelisib)、依布魯替尼(Ibrutinib)、納威塔勒(Navitoclax)、及維那塔勒(Venetoclax)組成之群。在另一實施例中,該第二藥劑係細胞凋亡劑。在一個實施例中,細胞凋亡第二藥劑係選自由硼替佐米(Bortezomib)、阿札胞苷(Azacitidine)、達沙替尼(Dasatinib)、及吉非替尼(Gefitinib)組成之群。在一特定實施例中,本文所揭示之醫藥組合物係經靜脈內或皮下投與來投與患者。在其他實施例中,所揭示之醫藥組合物係經口服、非經腸式、肌肉內、關節內、支氣管內、腹內、囊內、軟骨內、腔內、體腔內、小腦內、腦室内、結腸內、子宮頸管內、胃內、肝內、心肌內、骨內、骨盆內、心包內、腹膜內、肋膜內、前列腺內、肺內、直腸內、腎內、視網膜內、脊柱內、滑膜內、胸內、子宮內、膀胱內、血管推注(bolus)、陰道、直腸、頰內、舌下、鼻內、或經皮投與來投與患者。
在一個實施例中,TRAIL受體激動劑蛋白質係以單一推注劑投與。在另一實施例中,TRAIL受體激動劑蛋白質可在若干分次劑量範圍投與。TRAIL受體激動劑蛋白質可以約0.1至100 mg/kg投與。在一個實施例中,TRAIL受體激動劑蛋白質可以選自由:約0.1至0.5、0.1至1、0.1至10、0.1至20、0.1至50、0.1至75、1至10、1至15、1至7.5、1.25至15、1.25至7.5、2.5至7.5、2.5至15、5至15、5至7.5、1至20、1至50、7至75、1至100、5至10、5至15、5至20、5至25、5至50、5至75、10至20、10至50、10至75、及10至100 mg/kg組成之群的劑量投與。在其他實施例中,TRAIL受體激動劑蛋白質係以約0.1至100 mg/ml的量存於醫藥組合物中。在一個實施例中,TRAIL受體激動劑蛋白質係以選自由:約0.1至0.5、0.1至1、0.1至10、0.1至20、0.1至50、0.1至75、1至10、1至20、1至50、1至75、1至100、5至10、5至15、5至20、5至25、5至50、5至75、10至20、10至50、10至75、或10至100 mg/ml組成之群的量存於醫藥組合物中。在其他實施例中,將治療有效量之TRAIL受體激動劑蛋白質投與個體。在另一實施例中,將預防有效量之TRAIL受體激動劑蛋白質投與個體。
相關申請案
本申請案主張2014年4月23日申請之美國臨時專利申請案第61/983,152號之優先權,該案之全文以引用的方式併入本文中。
根據本發明,已發現使單鏈TRAIL受體結合域融合至Fc域形成提供高生物活性並結合良好穩定性之六價TRAIL受體激動劑。因此,提供單鏈融合多肽包含至少三個由兩個肽連接子連接之可溶性TRAIL域及在N端及/或在C端之抗體Fc片段。
較佳地,單鏈融合多肽無聚集性。術語「無聚集性」係指製劑之單體含量≥50%,較佳≥70%且更佳≥90%。單體含量對聚集物含量之比率可藉由利用粒徑篩析層析法(SEC)檢測聚集物之形成量來測定。關於穩定性之聚集可藉由SEC在指定時段例如從數天至幾天、幾週及幾個月後於不同儲藏條件例如在4℃或25℃下來測定。就融合蛋白而言,為了歸類為是實質上無聚集性,較佳係如上在4℃、或25℃儲藏幾天例如10天之時段之後,更佳係在幾週例如2、3或4週之後,及最佳係在幾個月例如2或3個月之後來界定單體含量。
單鏈融合多肽可包含額外的可位於其N-及/或C-端之域。額外融合域之實例為(例如)可包含蛋白酶裂解位點之N-端信號肽域或可包含且/或鏈接至識別/純化域之C-端元素。根據一較佳實施例,融合多肽包含在其C端之經連接子融合之Strep標籤。一包括短絲胺酸連接子之例示性Strep標籤以SEQ ID NO:13顯示。
本發明之TRAIL受體激動劑蛋白質包含三個衍生自TRAIL之可溶性域。較佳地,其等可溶性域係衍生自哺乳動物,特別是人類TRAIL,包括對偶基因變異體及/或其衍生物。該等可溶性域包含TRAIL之細胞外部分,包括不含膜所在之域之受體結合域。像TNF超家族之其他蛋白質,TRAIL經15至30個胺基酸之N端部分(所謂的莖部區域)固定至該膜。莖部區域有助於三聚合及提供離細胞膜特定距離。然而,莖部區域並非是受體結合域(RBD)之一部分。
重要的是,RBD之特徵係其N端及C端胺基酸之特定定位。該等胺基酸緊密相鄰且位於三聚物之軸的中心。RBD之第一N端胺基酸與RBD之C端胺基酸形成反平行β-股(圖2及3)。
因此,RBD之反平行β-股與細胞膜形成介面,其經莖部區域之胺基酸連接至細胞膜並固定於細胞膜內。極佳地,TRAIL受體激動劑蛋白質之可溶性TRAIL域包含缺乏任何來自莖部區域之胺基酸之TRAIL之受體結合域(圖4及5)。否則,將需要使可溶性域中之一者之C端與下一個可溶性域之N端連接之長連接子以補償下一個可溶性域之N端莖部區域(圖6),此可能會導致不穩定性且/或形成聚集物。
此等可溶性域之另一優點在於任何抗藥物抗體均無法接近RBD之N端及C端胺基酸。較佳地,單鏈融合多肽可形成各別TRAIL受體之包含至少一個功能性結合位點之有序三聚結構。
TRAIL受體激動劑蛋白質包含三個功能性TRAIL受體結合位點,即,可與TRAIL受體形成複合物之胺基酸序列。因此,可溶性域可結合至對應之TRAIL受體。在一個實施例中,可溶性域中之至少一者能受體活化,藉此可影響細胞凋亡及/或增生活性。在另一實施例中,選擇可溶性域中之一或多者無法受體活化。
可溶性TRAIL域可衍生自如以SEQ ID NO:1顯示之人類TRAIL。較佳地,可溶性TRAIL域係衍生自特定言之始於胺基酸120至122之人類TRAIL且尤其包含具有SEQ ID NO:1之胺基酸120至281、121至281或122-281。視情況,具有SEQ ID NO:1之胺基酸Arg121可經不帶電荷的胺基酸例如Ser或Gly置換。
表1:人類TRAIL蛋白質之序列
如所示,可溶性TRAIL域可包含如以SEQ ID NO:1指示之野生型序列。然而,應注意,可在此等可溶性域中之一或多者中引入突變,例如,改變(例如,增加或減低)可溶性域之結合性質之突變。在一個實施例中,可選擇無法結合至對應細胞激素受體之可溶性域。
在本發明之另一較佳實施例中,可溶性TRAIL域(i)包含TRAIL之突變體或其之結合及/或活化TRAIL-受體1(TRAILR1)及/或TRAIL‑受體2(TRAILR2)之受體結合域。突變體之結合及/或活性可(例如)藉由如van der Sloot等人(PNAS, 2006, 103:8634-8639)、Kelley等人(J. Biol. Chem., 2005, 280:2205-2215)、或MacFarlane等人(Cancer Res., 2005, 65:11265-11270)中所述之分析來測定。
突變體可藉由任何技術來產生且為熟練技術者已知,例如,述於van der Sloot等人(PNAS, 2006, 103:8634-8639)、Kelley等人(J. Biol. Chem., 2005, 280:2205-2215)、或MacFarlane等人(Cancer Res., 2005, 65:11265-11270)中之技術且可包含任何類型之結構突變,例如,胺基酸之代換、缺失、複製及/或插入。一較佳實施例係代換之產生。代換可影響TRAIL之至少一個胺基酸或其之如本文所述之受體結合域。在一較佳實施例中,代換可影響TRAIL例如人類TRAIL(例如,SEQ ID NO:1)之胺基酸中之至少一者。就此而言,較佳之代換係影響具有SEQ ID NO:1之人類TRAIL之以下胺基酸中之至少一者:R130、G160、Y189、R191、Q193、E195、N199、K201、Y213、T214、S215、H264、1266、D267、D269。具有SEQ ID NO:1之人類TRAIL之較佳胺基酸代換係以下代換中之至少一者:R130E、G160M、Y189A、Y189Q、R191K、Q193S、Q193R、E195R、N199V、N199R、K201R、Y213W、T214R、S215D、H264R、I266L、D267Q、D269H、D269R、或D269K。
胺基酸代換可影響TRAIL例如人類TRAIL至TRAILR1或TRAILR2任一者或於TRAILR1或TRAILR2任一者上之結合及/或活性。或者,胺基酸代換可影響TRAIL例如人類TRAIL至TRAILR1及TRAILR2二者或於TRAILR1及TRAILR2二者上之結合及/或活性。TRAILR1及/或TRAILR2之結合及/或活性可能受到正面影響,亦即,受體之更強力、更具選擇性或更具特異性地結合且/或具更多活化作用。或者,TRAILR1及/或TRAILR2之結合及/或活性可能受到負面影響,亦即,受體之較弱、較低選擇性或較低特異性地結合且/或較低或無活化作用。
具有影響TRAILR1及TRAILR2二者之結合及/或活化之本發明之胺基酸代換之TRAIL突變體之實例可參見例如MacFarlane等人(請參閱上述)之表1且可包括具有以下具有SEQ ID NO:1 Y213W及S215D之兩種胺基酸代換或具有以下單一胺基酸代換:Y189A之人類TRAIL突變體。
具有影響TRAILR1之結合及/或活化之本發明之胺基酸代換之TRAIL突變體之實例可參見例如MacFarlane等人(請參閱上述)之表1且可包括具有以下SEQ ID NO:1 N199V、K201R、Y213W及S215D之四種胺基酸代換或具有以下五種胺基酸代換:Q193S、N199V、K201R、Y213W及S215D之人類TRAIL突變體,或可參見Kelley等人(請參閱上述)之表2且可包括具有以下六種胺基酸代換:Y213W、S215D、Y189A、Q193S、N199V、及K201R、或具有Y213W、S215D、Y189A、Q193S、N199R、及K201R之人類TRAIL突變體。
具有影響TRAILR2之結合及/或活化之本發明之胺基酸代換之TRAIL突變體之實例可參見例如MacFarlane等人(請參閱上述)之表1或Kelley等人(請參閱上述)之表2且可包括具有以下六種SEQ ID NO:1:Y189Q、R191 K、Q193R、H264R、I266L、及D267Q之胺基酸代換之人類TRAIL突變體,或可參見van der Sloot等人(請參閱上述)之表2且可包括具有以下單一胺基酸代換:D269H、或具有以下兩種胺基酸代換:D269H及E195R或D269H及T214R之人類TRAIL突變體。
因此,一個較佳實施例係一種如本文所述之TRAIL受體激動劑蛋白質,其中可溶性域中之至少一者包含TRAIL或其之結合且/或活化TRAILR1及/或TRAILR2之受體結合域之突變體。
顯示減少的TRAIL引起受體聚集之TRAIL突變體之其他實例物係H168(S、T、Q)、R170(E、S、T、Q)及H177(S、T)。
包含TRAIL或如本文所述受體結合域之突變體之TRAIL受體激動劑蛋白質之一個較佳實施例係TRAIL受體激動劑蛋白質,其中組分(i)包含至少一處尤其如下文指定的胺基酸代換。
此胺基酸代換會影響人類TRAIL(SEQ ID NO:1)之至少一個以下胺基酸位置:R130、G160、H168、R170、H177、Y189、R191、Q193、E195、N199、K201、Y213、T214、S215、H264、1266、D267、D269。
此胺基酸代換係至少一種以下代換:R13OE、G16OM、H168(S、T、Q)、R170(E、S、T、Q)、H177(SJ)1 Y189A、Y189Q、R191K、Q193S、Q193R、E195R、N199V、N199R、K201R、Y213W、T214R、S215D、H264R、I266L、D267Q、D269H、D269R、或D269K。
一較佳TRAIL-R2選擇性域包含胺基酸代換Y189Q、R191K、Q193R、H264R、I266L及D267Q。
一較佳TRAIL-R1選擇性域包含胺基酸代換Y189A、Q193S、N199V、K201R、Y213W及S215D。
本發明之單鏈融合分子包含三個可溶性TRAIL域,亦即,組分(i)、(iii)及(v)。假若第二及/或第三可溶性TRAIL域係視需要包含胺基酸序列突變之N端變短的域,則得以增強單鏈TRAIL融合多肽抗聚集之穩定性。因此,較佳地,第二及第三可溶性TRAIL域二者均係視需要在N端區域中,較佳在可溶性TRAIL域之N端之前五個胺基酸中包含胺基酸序列突變之N端變短的域。此等突變可包含改由中性胺基酸(特別是絲胺酸或甘胺酸)代換帶電之例如酸性或鹼性胺基酸。
與其相反,第一可溶性TRAIL域之選擇不那麼關鍵。此處,可使用具有全長N端序列之可溶性域。然而,應注意第一可溶性TRAIL域亦可具有N端變短且視需要突變的序列。
在本發明之另一較佳實施例中,可溶性TRAIL域(i)、(iii)及(v)係可溶性人類TRAIL域。第一可溶性TRAIL域(i)可選自天然、變短及/或突變序列。因此,第一可溶性TRAIL域(i)具有可始於人類TRAIL之胺基酸Glu116及Val122之間之N端序列,且其中Arg121可改由中性胺基酸例如Ser或Gly置換。第二及第三可溶性TRAIL域(iii)及(v)具有較佳始於人類TRAIL之胺基酸Gln120及Val122之間之N端變短的序列且其中Arg121可改由另一胺基酸例如Ser或Gly置換。
較佳地,可溶性TRAIL域(iii)及(v)之N端序列係選自:
(a)Arg121-Val122-Ala123及
(b)(Gly/Ser)121。
可溶性TRAIL域較佳以人類TRAIL之胺基酸Gly281結束。在某些實施例中,TRAIL域可包含如上所述之內部突變。
TRAIL受體激動劑蛋白質之組分(ii)及(iv)係分別位於組分(i)及(iii)或(iii)及(v)之間之肽連接子元素。可撓性連接子元素具有3至8個胺基酸之長度,特定言之3個、4個、5個、6個、7個、或8個胺基酸之長度。連接子元素較佳係甘胺酸/絲胺酸連接子,即,肽連接子實質上係由胺基酸甘胺酸及絲胺酸組成。在可溶性細胞激素域以S或G(C端)封端之情況中,例如人類TRAIL,連接子在S或G後開始。在可溶性細胞激素域始於S或G(N端)之情況中,連接子在此S或G前結束。
應注意連接子(ii)及連接子(iv)無需具有相同長度。為了減少可能的免疫原性,可較佳使用較短的連接子。此外,證實較短的連接子獲得形成聚集物之傾向降低之單鏈分子。然而,實質上比本文所揭示者長之連接子會展現不利的聚集性質。
若須要,則連接子可包含可形成醣基化位點Asn-Xaa-Ser之天冬醯胺酸殘基。在某些實施例中,連接子例如連接子(ii)或連接子(iv)中之一者包含醣基化位點。在其他實施例中,兩個連接子(iv)包含醣基化位點。為了增加sc TRAIL蛋白質之溶解度且/或為了降低可能的免疫原性,可能較佳的是,連接子(ii)或連接子(iv)或二者包含醣基化位點。
較佳之連接子序列係選自GSGSGSGS(SEQ ID NO:3)、GSGSGNGS(SEQ ID NO:2)、GGSGSGSG(SEQ ID NO:4)、GGSGSG(SEQ ID NO:5)、GGSG(SEQ ID NO:6)、GGSGNGSG(SEQ ID NO:7)、GGNGSGSG(SEQ ID NO:8)、GGNGSG(SEQ ID NO:9)、及GSGS(SEQ ID NO:23)。
根據一最佳實施例,連接子序列各自係如SEQ ID NO:2之GSGSGNGS。連接子序列實例顯示於表2中。
表2:連接子序列實例
TRAIL受體激動劑蛋白質另外包含可位於第一TRAIL域(i)之N端及/或第三TRAIL域(v)之C端之抗體Fc片段域。較佳地,抗體Fc片段域包含如以SEQ ID NO:10顯示之胺基酸序列或由其組成。或者,Fc片段域包含如以SEQ ID NO:17顯示之胺基酸序列或由其組成。Fc片段域實例顯示於表3中。
表3:Fc片段域實例
醣基化位點(glycosite)之總數及碳水化合物在三維中之個別位置會影響TRAIL受體激動劑蛋白質之活體內穩定性。另外,碳水化合物識別係基於末端醣之局部密度、碳水化合物樹狀結構之支化度及碳水化合物物質之相對位置。
必需耗乏CH2域碳水化合物以避免基於Fc受體的活體內交聯及可能之基於TRAIL受體超簇集的毒性。另外,部分劣化的碳水化合物透過凝集素驅動機制縮短TRAIL受體激動劑蛋白質之活體內半衰期。藉由減少分子上醣基化位點的總數,所得化合物較不為此等機制所及,從而延長半衰期。因此,在一個實施例中,藉由耗乏CH2醣基化位點來減少本發明之TRAIL受體激動劑蛋白質上醣基化位點的總數,形成包含N297S等效突變(根據EU編號系統)而建立無糖基-CH2域(aglycosl-CH2 domain)之TRAIL受體激動劑蛋白質。
存於內表面區域上之CH2-醣基化位點通常在鉸合鏈間雙硫鍵減少及共價鏈間連接被破壞之「敞開Fc構形轉變」期間遮蔽來自蛋白酶之子域。此可實現CH2解離及使得內表面區域暴露於蛋白酶。包含N297S等效突變(根據EU編號系統)而建立無糖基-CH2之TRAIL受體激動劑蛋白質因此極有可能蛋白質分解穩定較低而致使等效結構經野生型CH2醣基化。此將影響化合物在USP/DSP/儲藏期間的穩定性,其中宿主細胞蛋白酶存在且長時間內有到達該結構。因此,在某些實施例中,TRAIL受體激動劑缺乏CH2醣基化位點,但在各多肽鏈之連接子序列(例如,如SEQ ID NO:2之GSGSGNGS)中包含醣基化位點。在某些例示性實施例中,TRAIL受體激動劑之每條多肽鏈包含兩個醣基化位點,總計四個醣基化位點。
根據本發明之一較佳實施例,抗體Fc片段域係經鉸合‑連接子元素融合。該鉸合-連接子元素具有10至30個胺基酸之長度,特定言之15至25個胺基酸例如22個胺基酸之長度。該鉸合-連接子元素較佳包含免疫球蛋白之鉸合區序列,文中稱作「Ig鉸合區」。術語「Ig鉸合區」意指包含與天然生成之Ig鉸合區序列之包括雙硫鍵連接免疫球蛋白之兩條重鏈之半胱胺酸殘基之部分具有序列相同性或相似性之胺基酸序列之任何多肽。
鉸合區之衍生物及類似物可藉由突變來獲得。本文中引起的衍生物或類似物係包含與野生型(或天然生成之蛋白質)之全長序列具有序列相同性或相似性之胺基酸序列但其具有一或多處可歸因於缺失、插入及/或代換之胺基酸序列差異之多肽。然而,根據本發明,術語「鉸合-連接子」不限於彼等包含Ig鉸合區或其衍生物之連接子,但任何連接子係長到足使域經鉸合‑連接子元素連接以實現生物活性構形。
個別TRAIL受體激動劑蛋白質中之具有敞開Fc構形之分子的數量係取決於存於鉸合區中之鏈間雙硫鍵的數量。因此,在一個實施例中,將第三半胱胺酸引入至本發明之TRAIL受體激動劑蛋白質之鉸合區中以改良耗乏CH2-醣基化位點之效應。
另外,本發明之TRAIL受體激動劑蛋白質另外包含上方鉸合離胺酸突變為甘胺酸以減少在此位點之蛋白質分解處理。
一尤佳的鉸合-連接子元素包括如以SEQ ID NO:11顯示之胺基酸序列或由其組成(表4)。
TRAIL受體激動劑蛋白質可另外包含N端信號肽域,此容許在適宜之宿主細胞中進行處理,例如,細胞外分泌。較佳地,N端信號肽域包含蛋白酶裂解位點,例如信號肽酶裂解位點且因而可在表現之後或期間移除以獲得成熟蛋白質。一尤佳的N端信號肽域包含如以SEQ ID NO:12顯示之胺基酸序列(表4)。
另外,TRAIL受體激動劑蛋白質可另外包含具有例如1至50個,較佳10至30個胺基酸之長度之可包括或連接至識別/純化域例如FLAG域、Strep‑標籤或Strep標籤Il域及/或聚-His域之C端元素。根據一尤佳的實施例,融合多肽包含經如以SEQ ID NO:13顯示之短絲胺酸連接子融合至C-端之Strep標籤(表4)。
一例示性鉸合-連接子元素、N端信號肽域、及短絲胺酸連接子顯示於表4中。
表4:例示性域及連接子
根據本發明之一尤佳實施例,融合多肽包含三個經具有SEQ ID NO:2之肽連接子元素融合之可溶性TRAIL域。第一可溶性TRAIL域(i)係由如SEQ ID NO:1之人類TRAIL之胺基酸120至281組成及可溶性TRAIL域(iii)及(v)係由如SEQ ID NO:1之人類TRAIL之胺基酸121至281組成。另外,融合多肽包含在C端經如SEQ ID NO:11之鉸合-連接子融合至可溶性TRAIL域(v)之如SEQ ID NO:10的抗體Fc片段域。本發明者驚人地發現此特定融合多肽提供改良之生物活性且特別地穩定。本發明之TRAIL受體激動劑蛋白質之一例示性實施例之胺基酸序列係以SEQ ID NO:19描述。
另外,融合多肽可包含例如如SEQ ID NO:12之N端信號肽域。本發明之TRAIL受體激動劑蛋白質之一特定實例係以SEQ ID NO:14顯示。
根據另一較佳實施例,融合多肽可另外包含經如以SEQ ID NO:13顯示之短絲胺酸連接子融合至本發明之多肽之C端Strep標籤。根據本發明之此態樣,Fc片段較佳係由以SEQ ID NO:10或17顯示之胺基酸序列組成。另外,Fc片段可由較短Fc片段,例如包括具有SEQ ID NO:10之胺基酸1至217組成。包含C端Strep標籤之融合多肽之尤佳實例係以SEQ ID NO:15及18顯示。
如以SEQ ID NO:14、15及18顯示之例示性TRAIL受體激動劑蛋白質各自包含N端信號肽域。信號肽域包含胺基酸1至20。在各情況中,成熟蛋白質係以胺基酸21開始。本發明之成熟例示性TRAIL受體激動劑蛋白質係以SEQ ID NO:19、20、21、26、27、28、29、及30描述。上文所述之例示性TRAIL受體激動劑蛋白質顯示於表5中。
如以SEQ ID NO:19所示TRAIL受體激動劑具有總數減少之醣基化位點(提供去醣基化CH2域之CH2區中之N297S突變)、鉸合區中增加數量之鏈間雙硫鍵、及上方鉸合離胺酸突變為甘胺酸。此等變動減少可能降解及TRAIL受體超簇集(及伴隨之毒性)同時延長分子半衰期。在一些實施例中,N端麩醯胺酸經改質為焦麩胺酸鹽(Liu等人2011, J. Biol. Chem. 286:11211-11217)。
表5:例示性TRAIL受體激動劑蛋白質
本發明之另一態樣係關於編碼如本文所述之TRAIL受體激動劑蛋白質之核酸分子。核酸分子可係DNA分子(例如,雙股或單股DNA分子)或RNA分子。核酸分子可編碼TRAIL受體激動劑蛋白質或其前驅物,例如,TRAIL受體激動劑蛋白質之可包含信號序列或用於分泌或純化較佳位於TRAIL受體激動劑蛋白質之N端及/或C端之其他異種胺基酸部分之原-或前原形式。異種胺基酸部分可透過蛋白酶裂解位點(例如因子X3)、凝血酶或IgA蛋白酶裂解位點連接至第一及/或第二域。本發明之核酸序列之一特定實例以SEQ ID NO:16顯示於表6中。此核酸分子係編碼具有SEQ ID NO:14之融合多肽。
表6:例示性TRAIL受體激動劑蛋白質之核酸序列
核酸分子可以操作方式連接至表現控制序列,例如容許核酸分子在所需宿主細胞中表現之表現控制序列。核酸分子可位於載體,例如,質體、噬菌體、病毒載體、染色體整合載體等上。例如Sambrook等人(1989) Molecular Cloning,實驗室手冊,冷泉港出版社(Cold Spring Harbor Press)、及Ausubel等人(1989), Current Protocols in Molecular Biology, John Wiley & Sons或其更新近的版本已描述適宜表現控制序列及載體之實例。
各種表現載體/宿主細胞系統可用於表現編碼本發明之TRAIL受體激動劑蛋白質之核酸序列。適宜之宿主細胞包括(但不限於)原核細胞,諸如細菌(例如大腸桿菌)、真核宿主細胞(諸如酵母細胞)、昆蟲細胞、植物細胞或動物細胞(較佳哺乳動物細胞且更佳人類細胞)。另外,本發明係關於經如上所述之核酸分子轉形或轉染之非人類生物。此等轉基因生物可由已知的包括同源重組之基因轉移方法來產生。
本發明之另一態樣係關於一種包含均如本文所述之作為活性劑的至少一種TRAIL受體激動劑蛋白質、為其編碼之各別核酸、或經轉形或轉染之細胞之醫藥或診斷組合物。
本文所用之術語「與TRAIL相關之疾病或病症」係可藉由添加TRAIL受體激動劑改善之任何疾病或病症。均如本文所述之至少一種TRAIL受體激動劑蛋白質、為其編碼之各別核酸、或經轉形或轉染之細胞可用於例如預防及/或治療由TRAIL之功能障礙引起之疾病、與TRAIL之功能障礙相關及/或伴隨其之疾病,特別是增生疾病,諸如腫瘤,例如實體或淋巴腫瘤;傳染性疾病;發炎性疾病;代謝疾病;自體免疫疾病,例如類風濕疾病及/或關節疾病;退化性疾病,例如神經退化性疾病,諸如多發性硬化症;與細胞凋亡相關之疾病或移植排斥。
本文所用之術語「TRAIL之功能障礙」應理解為偏離TRAIL之正常功能或表現之TRAIL之任何功能或表現,例如,TRAIL基因或蛋白質之過度表現,TRAIL基因或蛋白質之表現比TRAIL之正常生理表現程度減少或消除,TRAIL之活性增加,TRAIL之活性降低或消除,TRAIL與任何結合對象,例如受體,特定言之TRAIL受體或另一細胞激素分子之結合增強,與任何結合對象,例如受體、特定言之TRAIL受體或另一細胞激素分子之結合比TRAIL之正常生理活性或結合減少或消除。
在各種不同實施例中,提供一種診斷及/或治療罹患可藉由靶向TRAIL受體來診斷及/或治療之疾病之人類個體之方法,該方法包括對人類個體投與本文所揭示之TRAIL受體激動劑蛋白質,以對人類個體中一或多個標靶之活性產生激動效應,減輕一或多種症狀,且/或達成治療。本文所提供之TRAIL受體激動劑蛋白質可用於診斷及/或治療罹患原發性及轉移性癌症之人類,該等原發性及轉移性癌症包括乳癌、結腸癌、直腸癌、肺癌(例如,小細胞肺癌「SCLC」及非小細胞肺癌「NSCLC」)、口咽癌、下咽癌、食道癌、胃癌、胰臟癌、肝癌、膽囊癌及膽管癌、小腸癌、尿道癌(包括腎癌、膀胱癌及尿路上皮癌)、女性生殖道癌(包括子宮頸癌、子宮癌、及卵巢癌及絨毛膜癌及妊娠滋養層細胞疾病)、男性生殖道癌(包括前列腺癌、儲精囊癌、睪丸癌及生殖細胞腫瘤)、內分泌腺癌(包括甲狀腺癌、腎上腺癌、及腦下垂體腺癌)、及皮膚癌、及血管瘤、黑色素瘤、肉瘤(包括彼等自骨骼及軟組織引起者及卡波西氏肉瘤(Kaposi's sarcoma))、腦、神經、眼、及腦膜之腫瘤(包括星狀細胞瘤、神經膠瘤、神經膠母細胞瘤、視網膜母細胞瘤、神經瘤、神經母細胞瘤、神經鞘瘤(Schwannomas)、及腦膜瘤)、由造血惡性疾病引起之腫瘤、急性白血病、急性淋巴母細胞性白血病(ALL)、急性骨髓性白血病(AML)、B細胞淋巴瘤、勃氏(Burkitt’s)淋巴瘤、慢性骨髓細胞性白血病(CML)、慢性淋巴球性白血病(CLL)、髮樣細胞白血病、霍奇金氏及非霍奇金氏淋巴瘤、DLBCL、濾泡性淋巴瘤、造血性惡性疾病、卡波西氏肉瘤、惡性淋巴瘤、惡性組織細胞增生、惡性黑色素瘤、多發性骨髓瘤、腫瘤伴生症候群/惡性高血鈣症、或實體腫瘤。
提供一種包含本文所揭示之TRAIL受體激動劑蛋白質及醫藥上可接受之載劑之醫藥組合物。在一些實施例中,醫藥組合物包含至少一種額外的用於治療疾病之治療藥劑。例如,該額外藥劑可係治療藥劑、化學治療劑;造影劑、細胞毒性劑、血管生成抑制劑、激酶抑制劑(包括(但不限於)KDR及TIE-2抑制劑)、共刺激分子調節劑或免疫查核點抑制劑(包括(但不限於)抗-B7.1、抗-B7.2、抗-B7.3、抗-B7.4、抗-CD28、抗-B7RP1、CTLA4-Ig、抗-CTLA-4、抗-PD-1、抗-PD-L1、抗-PD-L2、抗-ICOS、抗-LAG-3、抗-Tim3、抗-VISTA、抗-HVEM、抗-BTLA、LIGHT融合蛋白、抗-CD137、抗-CD137L、抗-OX40、抗-OX40L、抗-CD70、抗-CD27、抗-GAL9、抗-A2AR、抗-KIR、抗-IDO-1、抗-CD20)、樹突細胞/抗原呈現細胞調節劑(包括(但不限於)抗-CD40抗體、抗-CD40 L、抗-DC-SIGN、抗-Dectin-1、抗-CD301、抗-CD303、抗-CD123、抗-CD207、抗-DNGR1、抗-CD205、抗-DCIR、抗-CD206、抗-ILT7)、用於Toll樣受體之調節劑(包括(但不限於)抗-TLR-1、抗-TLR-2、抗-TLR-3、抗-TLR-4、抗-TLR-4、抗-TLR-5、抗-TLR-6、抗-TLR-7、抗-TLR-8、抗-TLR-9)、黏著分子阻斷劑(包括(但不限於)抗-LFA-1抗體、抗-E/L選擇素抗體、小分子抑制劑)、抗-細胞激素抗體或其功能性片段(包括(但不限於)抗-IL-18、抗-TNF、或抗-IL-6/細胞激素受體抗體)、雙特異性再導向T細胞或NK細胞細胞毒性(包括(但不限於)BiTE®)、基於嵌合T細胞受體(CAR-T)的療法、基於T細胞受體(TCR)的療法、治療性癌症疫苗、滅殺除癌(methotrexate)、環孢素、雷帕黴素(rapamycin)、FK506、可檢測標記或報導子、TNF拮抗劑、抗風濕藥、肌肉鬆弛劑、麻醉藥(narcotic)、非類固醇消炎藥劑(NSAID)、鎮痛藥、麻醉劑(anesthetic)、鎮靜劑、局部麻醉劑、神經肌肉阻斷劑、抗微生物劑、抗乾癬劑、皮質類固醇、同化性類固醇、紅血球生成素、免疫劑、免疫球蛋白、免疫抑制劑、生長激素、激素替代藥、放射性藥物、抗抑鬱藥、抗精神病藥、興奮劑、氣喘藥物、β激動劑、吸入性類固醇、腎上腺素或類似物、細胞激素、或細胞激素拮抗劑。
在一實施例中,本文所述之一種治療癌症或預防或抑制自腫瘤轉移之方法,該一或多種TRAIL受體激動劑蛋白質可單獨地或以與一或多種額外藥劑,例如化學治療劑、放射治療劑、或生物藥劑組合方式使用。在一些實施例中,該藥劑可包括以下物質:13-順-視黃酸;2-CdA;2-氯去氧腺苷;5-阿札胞苷(5-Azacitidine);5-氟尿嘧啶;5-FU;6-巰基嘌呤;6-MP;6-TG;6-硫代鳥嘌呤;阿巴生(Abraxane);異維A酸(Accutane®);放線菌素-D;阿德力霉素(Adriamycin®);阿朱希爾(Adrucil®);阿非尼特(Afinitor®);安閣靈(Agrylin®);阿拉寇(Ala-Cort®);阿地白介素(Aldesleukin);阿來組單抗(Alemtuzumab);ALIMTA;阿曲諾英(Alitretinoin);阿卡本-AQ(Alkaban-AQ®);威克瘤(Alkeran®);全反式視黃酸;α干擾素;六甲蜜胺(Altretamine);胺甲碟呤;阿米福汀(Amifostine);胺麩精(Aminoglutethimide);安那克來得(Anagrelide);尼魯米特(Anandron®);阿那曲唑(Anastrozole);胞嘧啶阿拉伯糖苷(Arabinosylcytosine);Ara-C阿法達貝伯汀(Ara-C Aranesp®);雷狄亞(Aredia®);安美達(Arimidex®);諾曼癌素(Aromasin®);奈拉濱(Arranon®);三氧化二砷;亞舍拉(Arzerra™);天冬醯胺酶;ATRA;癌思停(Avastin®);阿札胞苷;BCG;BCNU;苯達莫司汀(Bendamustine);貝伐單抗(Bevacizumab);貝沙羅汀(Bexarotene);BEXXAR®;比卡魯胺(Bicalutamide);BiCNU;博萊黴素(Blenoxane®);撲類惡(Bleomycin);硼替佐米;白消安(Busulfan);補束剋(Busulfex®);C225;若克瘤(Calcium Leucovorin);卡帕什(Campath®);開普拓(Camptosar®);喜樹鹼(Camptothecin)-11;卡培他濱(Capecitabine)Carac™;卡鉑(Carboplatin);卡莫司汀(Carmustine);卡莫司汀藥片(Carmustine Wafer);可蘇多(Casodex®);CC-5013;CCI-779;CCNU;CDDP;CeeNU;柔紅黴素(Cerubidine®);西妥昔單抗(Cetuximab);苯丁酸氮芥(Chlorambucil);順鉑;嗜橙菌因數(Citrovorum Factor);克拉屈濱(Cladribine);皮質酮(Cortisone);可美淨(Cosmegen®);CPT-11;環磷醯胺(Cyclophosphamide);塞特准(Cytadren®);賽德拉濱(Cytarabine);賽德拉濱脂質體;賽德薩-U(Cytosar-U®);治多善(Cytoxan®);達卡巴仁(Dacarbazine);達珂(Dacogen);放線菌素D(Dactinomycin);達依泊汀α(Darbepoetin Alfa);達沙替尼;道諾黴素(Daunomycin);柔紅黴素(Daunorubicin);柔紅黴素鹽酸鹽(Daunorubicin Hydrochloride);柔紅黴素脂質體;枸櫞酸柔紅黴素脂質體(DaunoXome®);地卡特龍(Decadron);地西他濱(Decitabine);強的松龍(Delta-Cortef®);德耳塔松(Deltasone®);地尼白介素(Denileukin);白喉毒素(Diftitox);DepoCyt™;地塞米松(Dexamethasone);醋酸地塞米松;地塞米松磷酸鈉;特康舒(Dexasone);右雷佐生(Dexrazoxane);DHAD;DIC;地德克斯(Diodex);多烯紫衫醇;多辛(Doxil®);多柔比星(Doxorubicin);多柔比星脂質體;Droxia™;DTIC;DTIC-Dome®;Duralone®;杜維利西(Duvelisib);Efudex®;Eligard™;Ellence™;Eloxatin™;Elspar®;Emcyt®;表柔比星(Epirubicin);促紅細胞生成素α(Epoetin Alfa);爾必得舒(Erbitux);厄洛替尼(Erlotinib);歐文氏L-天冬醯胺酸酶(Erwinia L-asparaginase);雌氮芥(Estramustine);Ethyol Etopophos®;依託泊苷(Etoposide);磷酸依託泊苷(Etoposide Phosphate);Eulexin®;依維莫司(Everolimus);Evista®;依西美坦(Exemestane);Fareston®;Faslodex®;Femara®;非格司亭(Filgrastim);氟尿苷(Floxuridine);Fludara®;氟達拉濱(Fludarabine);Fluoroplex®;氟尿嘧啶(Fluorouracil);氟尿嘧啶(霜劑);氟甲睪酮(Fluoxymesterone);氟他胺(Flutamide);醛葉酸;FUDR®;氟維司群(Fulvestrant);吉非替尼;吉西他濱(Gemcitabine);吉妥珠單抗奧唑米星(Gemtuzumab ozogamicin);健擇(Gemzar);Gleevec™;Gliadel®藥片;GM-CSF;戈舍瑞林(Goserelin);粒細胞群落刺激因子(G-CSF);粒細胞巨噬細胞群落刺激因子(G-MCSF);Halotestin®;Herceptin®;糖皮質激素(Hexadrol);愛治(Hexalen®);六甲蜜胺;HMM;癌康定(Hycamtin®);Hydrea®;醋酸氫皮質酮(Hydrocort Acetate®);氫皮質酮(Hydrocortisone);氫皮質酮磷酸鈉(Hydrocortisone Sodium Phosphate);氫皮質酮琥珀酸鈉;氫皮質酮磷酸鹽;羥基脲;依布魯替尼(Ibrutinib);替伊莫單抗(Ibritumomab);替伊莫單抗(Ibritumomab Tiuxetan);Idamycin®;Idarubicin Ifex®;干擾素-α;干擾素-α-2b(PEG共軛物);異環磷醯胺(Ifosfamide);介白素-11(IL-11);介白素-2(IL-2);甲磺酸伊馬替尼(Imatinib mesylate);咪唑羧醯胺;Intron A®;伊匹單抗(ipilimumab)、艾瑞莎(Iressa®);伊立替康(Irinotecan);異視黃酸(Isotretinoin);易莎平(Ixabepilone);Ixempra™;KADCYCLA®;Kidrolase (t)、Lanacort®;拉帕替尼(Lapatinib);L-天冬醯胺酸酶;LCR;來那度胺(Lenalidomide);來曲唑(Letrozole);若克瘤(Leucovorin);瘤克寧(Leukeran);Leukine™;亮丙瑞林(Leuprolide);長春新鹼(Leurocristine);祿斯得停(Leustatin™);利瑞魯單抗(Lirilumab);微脂體Ara-C(Liposomal Ara-C);Liquid Pred®;羅氮芥(Lomustine);L-PAM;L-沙可來星(L-Sarcolysin);Lupron®;Lupron Depot®;Matulane®;目滴舒(Maxidex);氮芥(Mechlorethamine);氮芥鹽酸鹽(Mechlorethamine Hydrochloride);Medralone®;Medrol®;Megace®;甲地羥孕酮(Megestrol);醋酸甲地羥孕酮;MEK抑制劑;美法侖(Melphalan);巰基嘌呤(Mercaptopurine);美司那(Mesna);Mesnex™;滅殺除癌(Methotrexate);滅殺除癌鈉;甲潑尼龍(Methylprednisolone);Meticorten®;絲裂黴素;絲裂黴素-C;Mitoxantrone M-Prednisol®;MTC;MTX;Mustargen®;莫司汀(Mustine);Mutamycin®;邁樂寧(Myleran®);Mylocel™;滅髓瘤(Mylotarg®);納威塔勒(Navitoclax);溫諾平(Navelbine®);耐拉濱(Nelarabine);Neosar®;Neulasta™;Neumega®;Neupogen®;蕾莎瓦(Nexavar®);Nilandron®;尼勒替尼(Nilotinib);尼魯米特(Nilutamide);Nipent®;氮芥Novaldex®;尼沃單抗(Nivolumab);Novantrone®;恩沛板(Nplate);奧曲肽(Octreotide);醋酸奧曲肽;奧法妥米單抗(Ofatumumab);Oncospar®;Oncovin®;Ontak®;Onxal™;奧普瑞白介素(Oprelvekin);Orapred®;Orasone®;奧沙利鉑(Oxaliplatin);紫杉醇(Paclitaxel);紫杉醇蛋白質結合物(Paclitaxel Protein-bound);帕米膦酸鹽(Pamidronate);盤尼圖單抗(Panitumumab);Panretin®;佳鉑帝(Paraplatin®);帕唑帕尼(Pazopanib);Pediapred®;PEG干擾素;培加帕酶(Pegaspargase);培非格司亭(Pegfilgrastim);PEG-INTRON™;PEG-L-天冬醯胺酸酶;培美曲(PEMETREXED);派姆單抗(Pembrolizumab);噴司他丁(Pentostatin);皮妥珠單抗(Pertuzumab);苯丙胺酸氮芥;匹地利珠單抗(Pidilizumab);Platinol®;Platinol-AQ®;潑尼松龍(Prednisolone);潑尼松(Prednisone);Prelone®;丙卡巴肼(Procarbazine);PROCRIT®;普留淨(Proleukin®);具有卡莫司汀(Carmustine)植入劑之Prolifeprospan 20;Purinethol®;BRAF抑制劑;雷洛昔芬(Raloxifene);瑞復美(Revlimid®);Rheumatrex®;Rituxan®;利妥昔單抗(Rituximab);羅飛龍-A(Roferon-A®);羅米司亭(Romiplostim);Rubex®;紅比黴素鹽酸鹽(Rubidomycin hydrochloride);善得定(Sandostatin®);善得定長效型(Sandostatin LAR®);沙格司亭(Sargramostim);舒汝固體膚(Solu-Cortef®);舒汝美卓佑(Solu-Medrol®);索拉菲尼(Sorafenib);SPRYCEL™;STI-571;癌瑞格(STIVAGRA™);鏈脲黴素(Streptozocin);SU11248;蘇尼替尼(Sunitinib);紓癌特(Sutent®);它莫西芬(Tamoxifen);得舒緩(Tarceva®);Targretin®;泰息安(Tasigna®);汰癌勝(Taxol®);剋癌易(Taxotere®);Temodar®;替莫唑胺(Temozolomide);替西羅莫司(Temsirolimus);替尼泊苷(Teniposide);TESPA;沙利竇邁(Thalidomide);Thalomid®;TheraCys®;硫代鳥嘌呤;硫代鳥嘌呤藥片® (Thioguanine Tabloid®);硫代磷醯胺;Thioplex®;噻替哌(Thiotepa);TICE®;Toposar®;拓撲替康(Topotecan);托瑞米芬(Toremifene);特癌適(Torisel®);托西莫單抗(Tositumomab);曲妥珠單抗(Trastuzumab);Treanda®;曲莫林單抗(Tremelimumab);維生素A酸(Tretinoin);Trexall™;Trisenox®;TSPA;TYKERB®;尤瑞單抗(Urelumab);VCR;維必施(Vectibix™);Velban®;萬科(Velcade®);維那塔勒(Venetoclax);滅必治(VePesid®);凡善能(Vesanoid®);Viadur™;Vidaza®;長春鹼(Vinblastine);硫酸長春鹼;Vincasar Pfs®;長春新鹼(Vincristine);長春瑞濱(Vinorelbine);酒石酸長春瑞濱;VLB;VM-26;伏立諾他(Vorinostat);福退癌(Votrient);VP-16;威孟(Vumon®);截瘤達(Xeloda®);Zanosar®;Zevalin™;Zinecard®;諾雷德(Zoladex®);唑來磷酸(Zoledronic acid);容立莎(Zolinza);或Zometa®、及/或此處未明確列舉之標靶類似路徑之任何其他藥劑。
當使用兩種或更多種物質或有效組分作為組合治療療程之一部分時,其等可在基本上相同時間或不同時間(例如基本上同時、連續、或根據一替代療程)經相同投藥途徑或經不同投藥途徑投與。當該等物質或有效組分意欲同時地經相同投藥途徑投與時,熟練者將明瞭其等可作為不同醫藥調配物或組合物或組合醫藥調配物或組合物之部分投與。
此外,當兩種或更多種活性物質或有效組分意欲用作組合治療療程之一部分時,該等物質或有效組分中之各者可在化合物或有效組分獨立地使用時以相同量且依照如使用的相同療程投與,且此組合使用可或可不導致協同效應。然而,當此兩種或更多種活性物質或有效組分之組合使用導致協同效應時,亦可減少一種、多於一種、或所有意欲投與之該等物質或有效組分的量,同時仍舊達成所需治療作用。此可(例如)用於避免、限制或減少在一或多種該等物質或有效組分以其常用量使用時與其等之用途相關之任何非所欲副作用,同時仍舊達成所需醫藥或治療效應。
臨床醫師將明瞭根據本發明使用的治療療程之有效性可以本身已知之用於所涉及之疾病或病症之任何方式來測定且/或遵循。臨床醫師亦可在適宜情況下且基於個案基礎上改變或修改特定治療療程,來達成所需治療效應,以避免、限制或減少非所欲副作用,且/或在一方面達成所需治療效應及另一方面避免、限制或減少非所欲副作用之間達成平衡。
一般而言,將遵循該治療療程直到達成所需治療效應且/或長達維持所需治療效應般長的時間。同樣的,此可由臨床醫師來判定。
在各種不同實施例中,本文提供單獨的或以與預防藥劑、治療藥劑、及/或醫藥上可接受之載劑組合之包含一或多種TRAIL受體激動劑蛋白質之醫藥組合物。在各種不同實施例中,本文所揭示之醫藥組合物之用途之非限制性實例包括診斷、偵測、且/或監測疾病,預防、治療、管理、且/或改善疾病或其一或多種症狀,及/或用於研究。熟習此項技藝者已知單獨或與預防藥劑、治療藥劑、及/或醫藥上可接受之載劑組合之醫藥組合物之調配物(美國專利公開案第20090311253 A1號)。
在各種不同實施例中,醫藥組合物可包含一或多種胺基酸、一或多種多醣及/或聚山梨醇酯,及TRAIL受體激動劑蛋白質,其係以介於約0.1與100 mg/ml之間(包含端值)(例如,0.1至10、1至10、0.1至50、1至50、1至100、10至100、25至100、25至50、或50至100 mg/ml)之濃度存在,其中該調配物處在介於約5.0與7.0(包含端值)之間之pH(例如,約5.0至6.0、5.5至6.0、5.0至6.5、5.5至6.5、或6.0至7.0之pH)。在一個實施例中,調配物中之至少一種胺基酸係組胺酸並以約10至20 mM、10至15 mM、15至20 mM、或約15 mM之濃度存在。在一個實施例中,調配物中之至少一種多醣係蔗糖並以約0至8.0%重量/體積(w/v)之濃度存在。在一個實施例中,調配物中之聚山梨醇酯係聚山梨醇酯80並以約0至0.06% w/v之濃度存在。在一個實施例中,調配物中之至少一種胺基酸係精胺酸並以約0至1.5% w/v(例如,0.5至1.5、1.0至1.5、或0.5至1.0 w/v)之濃度存在。在一個實施例中,TRAIL受體激動劑蛋白質係以約0.1至100 mg/ml(例如,約1至100 mg/ml、或約1至15 mg/ml、或約1至7.5 mg/ml、或約2.5至7.5 mg/ml、或約5至7.5 mg/ml、或約25至100 mg/ml、或約20至60 mg/ml、或約25至50 mg/ml、或約25 mg/ml、或約50 mg/ml、或約0.1至60 mg/ml、或約0.1至25 mg/ml、或約1.0至60 mg/ml、或約0.5至60 mg/ml、或約0.1至2.0 mg/ml、或約0.5至2.0 mg/ml、或約1至5 mg/ml、或約1至7.5 mg/ml、或約1至15 mg/ml、或約0.5 mg/ml、或約1.0 mg/m)之濃度存於調配物中。
如本文所用,詞語「有效量」意指TRAIL激動劑蛋白質之使得一或多個與TRAIL之功能障礙或與TRAIL相關之疾病或病症相關之參數可偵測改善(例如,自基線改善至少約5%、10%、15%、20%、25%、30%、35%、40%、45%、50%、55%、60%、65%、70%、75%、或更大)之量。
在各種不同實施例中,醫藥調配物係水性調配物、凍乾調配物、或凍乾且復水調配物。在一實施例中,水合溶液係右旋糖及/或鹽水(例如,濃度為約5% w/v之右旋糖及/或濃度為約0.9% w/v之鹽水)。在一實施例中,醫藥調配物包含約15 mM組胺酸、約0.03%(w/v)聚山梨醇酯80、約4%(w/v)蔗糖、及約0.1至25 mg/ml之TRAIL受體激動劑蛋白質、或約1至15 mg/ml之TRAIL受體激動劑蛋白質,且處在約6之pH。在一實施例中,該調配物進一步包含至少一種額外藥劑。
在各種不同實施例中,使用包含約25 mg/ml TRAIL受體激動劑蛋白質、約15 mM組胺酸、0.03%聚山梨醇酯80(重量/體積,w/v)、4.0%蔗糖(w/v)、且pH為約6.0之調配物。在一些實施例中,該調配物不包含精胺酸。在一些實施例中,該調配物與包含其他組分或濃度之其他調配物相比展現出人意料地改良之冷凍-解凍穩定性、液體調配物穩定性、及/或凍乾調配物穩定性。
投與本文所提供治療藥劑之方法包括(但不限於)口服、非經腸投與(例如,皮內、肌肉內、腹膜內、靜脈內及皮下)、硬膜外投與、腫瘤內投與、黏膜投與(例如,鼻內及口腔途徑)及肺部投與(例如,利用吸入器或噴霧器投與之霧化化合物)。用於特定投藥途徑之醫藥組合物之調配物、及各種投藥方法所需要的材料及技術係可取得的且為熟習此項技藝者已知(美國專利公開案第20090311253 A1號)。
在各種不同實施例中,可調整給藥方案以提供最佳所需反應(例如,治療或預防反應)。例如,可投與單一推注劑,可隨時間投與若干分次劑量或可如治療情況之緊急狀態所指示按比例減少或增加劑量。在一些實施例中,基於容易投藥及劑量均勻而將非經腸式組合物調配呈單元劑型。術語「單元劑型」係指適用作待治療的哺乳動物個體之單一劑型的物理上獨立單元;各單元包含經計算以產生出所需治療效應的預定量的活性化合物及所需醫藥載劑。
本文所提供之TRAIL受體激動劑蛋白質之治療或預防有效量之一例示性、非限制性範圍係約0.1至100 mg/kg(例如,約0.1至0.5、0.1至1、0.1至10、0.1至20、0.1至50、0.1至75、1至10、1至15、1至7.5、1.25至15、1.25至7.5、2.5至7.5、2.5至15、5至15、5至7.5、1至20、1至50、7至75、1至100、5至10、5至15、5至20、5至25、5至50、5至75、10至20、10至50、10至75、或10至100 mg/kg、或在其之間之任何濃度)。在一些實施例中,TRAIL受體激動劑蛋白質係以治療有效濃度,例如,約0.1至100 mg/ml(例如,約0.1至0.5、0.1至1、0.1至10、0.1至20、0.1至50、0.1至75、1至10、1至20、1至50、1至75、1至100、5至10、5至15、5至20、5至25、5至50、5至75、10至20、10至50、10至75、或10至100 mg/ml、或在其之間之任何濃度)之濃度存於醫藥組合物中。應注意劑量值可根據意欲緩解之病症之類型及/或嚴重度改變。應進一步明瞭就任何特定個體而言,可隨時間根據個體需要及/或投與或監控組合物之投與的人之專業人員判斷調整特定給藥方案,及本文所述之劑量範圍僅係例示性而非意欲限制限制所主張組合物之範疇或實施。實例 1. 製造 TRAIL 受體激動劑蛋白質 (sc TRAIL wt) 1.1 多肽結構
A) 胺基酸Met1–Gly20
Ig-κ-信號肽,假設信號肽酶裂解位點係在胺基酸Gly 20後。
B) 胺基酸Gln21–Gly182
人類TRAIL配體之第一可溶性細胞激素域(TRAIL,具有SEQ ID NO:1之胺基酸120至281)。
C) 胺基酸Gly 183–Ser 190
具有SEQ ID NO:2之第一肽連接子元素。
D) 胺基酸Arg191–Gly351
人類TRAIL配體之第二可溶性細胞激素域(TRAIL,具有SEQ ID NO:1之胺基酸121至281)。
E) 胺基酸Gly352–Ser359。
具有SEQ ID NO:2之第二肽連接子元素。
F) 胺基酸Arg360–Gly520
人類TRAIL配體之第三可溶性細胞激素域(TRAIL,具有SEQ ID NO:1之胺基酸121至281)。
G) 胺基酸Gly521–Cys542
具有SEQ ID NO:11之鉸合-連接子元素。
H) 胺基酸Pro543–Lys760
具有SEQ ID NO:10之抗體Fc片段域。
上述TRAIL受體激動劑蛋白質以SEQ ID NO:14顯示。
指定的連接子可改由其他較佳連接子,例如,如以SEQ ID NO:3至9所顯示替代。
應注意該第一及第二肽連接子無需相同。
信號肽序列(A)可改由任何其他適宜之(例如)哺乳動物信號肽序列替代。1.2 編碼多肽之基因表現盒 (gene cassette)
合成基因可根據其用於在適宜之宿主細胞例如昆蟲細胞或哺乳動物細胞中表現之密碼子來最佳化。一較佳之核酸序列以SEQ ID NO:16顯示。2. 表現及純化 融合多肽之選殖、表現及純化
前述融合蛋白以重組方式在兩種不同真核宿主細胞中得以表現:
就前述TRAIL受體激動劑融合蛋白之初始分析而言,利用包含用於融合多肽及適宜篩選標記之表現盒,例如包含殺稻瘟菌素(blasticidine)、嘌呤黴素或潮黴素抗性基因之功能性表現盒之質體過渡性轉染生長於補充10% FBS、100個單位/ml青黴素及100[mu]g/ml鏈黴素之DMEM+GlutaMAX(GibCo)中之Hek293T細胞。在彼等複數個多肽鏈必需達成最終產物之情況中,轉染期間表現盒在一個質體上組合或定位於不同質體上。在轉染三天後收穫包含重組型融合多肽之細胞培養上清液及藉由以300×g離心來澄清接著透過0.22 μm無菌過濾器過濾。
就活體內使用之TRAIL受體激動劑融合蛋白之大規模表現而言,將編碼前述蛋白之合成DNA表現盒插入至包含適宜篩選標記之真核表現載體(例如,包含殺稻瘟菌素、嘌呤黴素或潮黴素抗性基因之功能性表現盒)及適於增加宿主細胞基因組中轉錄活性插入位點之數量之遺傳因子中。藉由電穿孔將經序列驗證之表現載體引入至適應懸浮液之中國倉鼠卵巢細胞(CHO-S,Invitrogen)中。在轉染後第三天施加適宜之選擇壓至經轉染之細胞。藉由隨後在選擇壓下培養來回收帶有載體衍生之抗性基因之存活細胞。於37℃及7% CO2氛圍下在迴旋式振盪培養器(100 rpm,50 mm振盪擺度)中所選細胞池於化學定義的培養基(PowerCHO2-CD,Lonza)中穩定生長後,藉由偵測前述蛋白質之ELISA分析法來分析個別上清液及於蛋白質產生出之前在振盪燒瓶中使具有最高特定生產率之細胞池擴增(迴旋式振盪器,100 rpm,振盪擺度50 mm)。
就實驗室規模蛋白質生產而言,在Wave生物反應器20/50 EHT (GE-Healthcare)中於37℃及7% CO2氛圍下在化學定義的培養基(PowerCHO2-CD,Lonza)中培養個別細胞池7至12天。基礎培養基係補充4 mM Glutamax之PowerCHO2-CD。Wave培養以0.3至0.4×10e6個細胞/ml之活細胞濃度及以下設定(就5或10公升袋而言)開始進行:振盪頻率18 rpm,振盪角7度,氣流0.2至0.3 L/min,7% CO2,36.5℃。在Wave操作中,利用PowerFeed A(Lonza)通常在第2天(20%進料)及第5天(30%進料)進料細胞培養兩次。在第二次進料之後,增加振盪頻率至22 rpm,及增加振盪角至8°。
通常在第7天至第12天當細胞存活率下降低於80%時收穫生物反應器。首先,使用手動深度過濾系統(Millipore Millistak Pod,MC0HC 0.054 m2
)來澄清培養上清液。就帶有Strep標籤之蛋白質而言,添加抗生物素蛋白(Avidin)至0.5 mg/L之最終濃度。最終,使用瓶頂過濾器(0.22 μm,PES,Corning)無菌過濾包含TRAIL受體激動劑融合蛋白之培養上清液及儲藏於2至8℃直到進一步進行處理。
就親和純化而言,將Streptactin Sepharose填充至一柱(凝膠床1 ml),以15 ml緩衝液W(100 mM Tris-HCl,150 mM NaCl,pH 8.0)或PBS pH 7.4達成平衡,及以4 ml/min流速將細胞培養上清液施用至該柱。於隨後,利用15 ml緩衝液W洗滌該柱及藉由添加7×1 ml緩衝液E(100 mM Tris HCl,150 mM NaCl,2.5 mM脫硫生物素(Desthiobiotin),pH 8.0)來逐步洗脫結合多肽。或者,包含2.5 mM脫硫生物素之PBS pH 7.4可用於此步驟。
作為基於Streptactin Sepharose的方法之替代,利用具有用作親和配體之經固定蛋白質-A及Akta層析系統(GE-Healthcare)之柱來進行親和純化。選擇對融合蛋白之FC域具有高親和力之固相材料:MABSelect SureTM
(GE Healthcare)。簡言之,將經澄清之細胞培養上清液負載於在洗滌緩衝液-1(20 mM Pi,95 mM NaCl,pH7.2)中達成平衡之HiTrap MabSelectSure柱(CV=5 ml),負載率不超過10 mg融合蛋白/1 ml柱床。利用10柱體積(10CV)之前述平衡緩衝液接著利用4柱體積(4CV)之洗滌緩衝液-2(20 mM Pi,95 mM NaCl,pH 8.0)洗滌該柱以使宿主細胞蛋白質及宿主細胞DNA耗乏。接著利用洗脫緩衝液(20 mM Pi,95 mM NaCl,pH 3.5)洗脫該柱及分多達10個部分收集洗脫物,各部分具有相等於柱床體積(5 ml)之體積。利用等體積之前述洗滌緩衝液-2來中和各部分。將線速度設為150 cm/h且在前述親和層析方法期間維持恆定。
定量洗脫物部分之蛋白質的量及藉由超過濾濃縮最大量部分且進一步藉由粒徑篩析層析(SEC)純化。
在Superdex 200 10/300 GL或HiLoad 26/60柱上使用Akta層析系統(GE-Healthcare)來進行SEC。該等柱係以磷酸鹽緩衝鹽水達成平衡及將經濃縮之親和純化多肽負載至SEC柱上,樣品體積不超過柱體積之2%(v/v)。就Superdex200 10/300 GL柱(GE Healthcare)而言,應用0.5 ml/分鐘之流速。就HiLoad 26/60 Superdex200柱而言,應用2.5 ml/分鐘之流速。藉由280 nm下之吸光度來監測多肽之洗脫曲線。
為了測定經純化融合多肽在天然條件下之表觀分子量,使Superdex 200柱負載已知分子量之標準蛋白質。基於標準蛋白質之洗脫體積繪製校準曲線及測定經純化融合多肽之表觀分子量。通常從Supoerdex200柱洗脫出之包含TRAIL受體激動劑融合蛋白質之FC域具有就同型二聚物而言約160至180 kDa之表觀分子量。3. 細胞凋亡檢測
利用Jurkat A3永久T細胞株之細胞檢測用於測定TRAIL受體激動劑融合蛋白之細胞凋亡引起之活性。Jurkat細胞生長於具有補充10% FBS、100單位/ml青黴素及100 μg/ml鏈黴素之RPMI 1640培養基+GlutaMAX(GibCo)之燒瓶中。在檢測之前,在96孔微量滴定盤中每孔接種100,000個細胞。於37℃下培養3小時之前將不同濃度之融合肽添加至該等孔。藉由添加溶胞緩衝液(250 mM HEPES、50 mM MgCl2、10 mM EGTA、5% Triton-X-100、100 mM DTT、10 mM AEBSF,pH 7.5)來溶解該等細胞及將該等盤放置於冰上維持30分鐘至2小時。細胞凋亡隨著凋亡蛋白酶(caspase)例如凋亡蛋白酶-3之活性之增加而增加。因此,特異性凋亡蛋白酶基材Ac-DEVD-AFC(Biomol)之裂解用於測定細胞凋亡之程度。事實上,凋亡蛋白酶活性與以碘化丙啶及Hoechst-33342染色該等細胞後形態上測定之凋亡細胞之百分比相關。為了凋亡蛋白酶活性檢測,將20 μl細胞溶解產物傳送至黑色96-孔微量滴定盤。在添加包含50 mM HEPES、1%蔗糖、0.1% CHAPS、50 μM Ac-DEVD-AFC、及25 mM DTT之80 μl緩衝液(pH 7.5)後,將盤傳送至Tecan Infinite 500微量滴定盤讀取器及監測螢光強度之增加(激發波長400 nm,發射波長505 nm)。3.1 細胞死亡檢測
為了測定HT1080纖維肉瘤細胞中之細胞死亡,將15,000個細胞接種於含補充10% FBS(Biochrom)之RPM1 1640培養基+GlutaMAX(GibCo)之96-孔盤中過夜。該等細胞與最終濃度為2.5 g/ml之環己醯亞胺(Sigma)共同培養。藉由以緩衝液KV(0.5%結晶紫、20%甲醇)染色來量化細胞死亡。在染色後,利用水洗滌該等孔繼而進行空氣乾燥。利用甲醇洗脫染料及利用ELISA讀取器測量595 nm下之光密度。4. 穩定性 / 聚集測試 4.1 聚集分析之原理 ( 可溶性蛋白質之定義 )
藉由如實例2中所述之分析型SEC來測定單體(定義的TRAIL受體結合模組之三聚物組合體)及聚集物之含量。針對此特定目的,分析係在包含生理pH之生理鹽濃度之緩衝液(例如0.9% NaCl,pH 7.4; PBS pH 7.4)中進行。一典型聚集分析係在Superdex200柱(GE Healthcare)上進行。此柱分離在介於10與800 kDa之間之範圍之蛋白質。
為了測定經純化融合多肽於天然條件下之表觀分子量,使Superdex 200柱負載已知分子量之標準蛋白質。基於標準蛋白質之洗脫體積繪製校準曲線及基於洗脫體積計算經純化融合多肽之表觀分子量。
可溶性非聚集化蛋白質例如三聚TRAIL之SEC分析通常顯示在定義洗脫體積下獨特的單蛋白質峰。此洗脫體積對應於特定蛋白質之表觀天然分子量且近似與基於一級胺基酸序列基礎上計算得之理論分子量一致。
假若蛋白質聚集發生,則SEC分析顯示具有較小滯留體積之額外蛋白質峰。就TRAIL而言,可溶性蛋白質之聚集以特徵性方式發生。蛋白質傾向於形成「三聚物」之寡聚物,從而形成9聚物(3×3)及27聚物(3×9)。此等寡聚物充作聚集種子及高含量之寡聚物潛在性地導致蛋白質聚集。大分子量之寡聚物及聚集物在Superdex200柱之空隙體積中洗脫出及無法藉由SEC相對於其天然分子量來分析。
因誘發(完全)聚集之故,TRAIL-SF融合蛋白之經純化製劑應較佳僅包含定義之三聚體蛋白質及僅極少量之寡聚蛋白質。基於SEC分析基礎上藉由分別計算定義的三聚物及寡聚物/聚集物部分之OD280圖之峰面積來測定特定TRAIL-SF蛋白質製劑之聚集/寡聚之程度。基於總峰面積,可如下計算得定義的三聚物蛋白質之百分比:( 三聚物含量 %=[ 三聚物峰面積 ]/[ 總峰面積 ]×100)
用於本文中之可溶性蛋白質之定義描述在生理pH下生理鹽濃度之包含在0.2至10.0 mg/ml之典型蛋白質濃度範圍內定義的可溶性蛋白質(TRAIL域之三聚物組合體)含量>90%之緩衝液中之經純化TRAIL蛋白質之蛋白質製劑。5. 半衰期之測定
分子A至D各自由經鏈間雙硫鍵共價連接之兩個多肽構成。測試醣基化位點及鉸合半胱胺酸(在蛋白質之間產生鏈間雙硫鍵)之數量以測定此等特徵之改變對此等化合物之半衰期所產生的效應。
利用1.2 mg/kg bw及/或4 mg/kg bw之特定化合物以靜脈內單一推注劑處理雌NMRI小鼠。在施用前(投藥前)、及在測試項目投與後長達168小時收集全血。製備血清及將樣品儲藏在-80℃直到測定血清濃度。使用平均血清濃度及藥物動力學評估程序PK方法第2.0版基於非房室藥物動力學數據分析(Summit Research Services, Montrose, CO)來計算得藥物動力學參數。PK方法係一種從由在靜脈內或血管外投藥途徑後分析例如生物樣品所獲得之濃度-時間數據計算藥物動力學參數之自動化、基於Excel之應用。PK方法可無需假設任何特定房室化模型而計算得結果。
利用偵測表7中所顯示之獨立於為分子之一部分之Strep標籤之個別TRAIL受體激動劑之ELISA-分析來進行血清中測試條目之定量。一般佈局顯示於圖18中。結果概述於表7中。
分子A(由兩個具有SEQ ID NO:26之多肽構成)具有兩個鉸合半胱胺酸(形成兩個鏈間雙硫鍵)及在Fc區之位置297(根據歐洲指數(EU index))之處之N殘基,而導致野生型CH2醣基化。分子A亦具有在位置168及337之處之醣基化位點。分子B(由兩個具有SEQ ID NO:19之多肽構成)具有三個鉸合半胱胺酸(形成三個鏈間雙硫鍵)(在位置513、519、及522之處)及在Fc區之位置297(根據歐洲指數)之處之N297S突變,而導致CH2域之去醣基化。分子B亦具有在位置168及337之處之醣基化位點。分子C(由兩個具有SEQ ID NO:27之多肽構成)具有三個鉸合半胱胺酸(形成三個鏈間雙硫鍵)及在Fc區之位置297(根據歐洲指數)之處之N297S突變,而導致CH2域之去醣基化。另外,在位置168(連接子1)但非位置337(連接子2)之處具有醣基化位點。分子D(由兩個具有SEQ ID NO:28之多肽構成)具有三個鉸合半胱胺酸(形成三個鏈間雙硫鍵)及在Fc區之位置297(根據歐洲指數)之處之N297S突變,而導致CH2域之去醣基化。另外,分子D中位於連接子1及連接子2(分別地,位置168及337)二者上之醣基化位點已耗乏。
分子B(兩個連接子醣基化,CH2醣基化位點耗乏,及添加第三鉸合半胱胺酸)之活體內穩定性(如藉由化合物半衰期來判斷)與分子A相比增強。另外,化合物(分子D)所有醣基化位點耗乏導致活體內穩定性降低及轉染表現期間低的生產率。分子C(第一連接子醣基化,第二連接子去醣基化,不含CH2醣基化位點)與分子B及D相比證實中間物活體內穩定性(參見表7中之結果)。
表7:NMRI小鼠中化合物半衰期測試之結果
此等實驗結果證實將連接子醣基化(在連接子1及2二者中)與第三鏈間雙硫鍵(藉由添加鉸合半胱胺酸)及Fc區中之CH2域之去醣基化組合使得本發明分子之活體內穩定性變大。6. 活體外證實功效 6.1 具有 SEQ ID NO:19 之 TRAIL 受體激動劑蛋白質抑制人類血液病及實體腫瘤細胞之活體外存活
腫瘤細胞以10,000個細胞/孔接種於在96孔盤中之包含10% FBS之推薦的培養基中及於37℃在增濕之5% CO2
氛圍中利用由兩個具有如SEQ ID NO:19所示胺基酸序列之多肽構成之TRAIL受體激動劑蛋白質處理24小時。於隨後使用如由製造商說明書(Promega;威斯康辛州麥迪遜)所述之CellTiter-Glo®藥劑來評估細胞存活率。藉由非線性迴歸分析與未經處理之對照細胞標準化之濃度反應數據來測定IC50
值。Colo205、Jurkat及SKM-1細胞之證實對由兩個具有如SEQ ID NO:19所示胺基酸序列之多肽構成之TRAIL受體激動劑蛋白質之治療作出的反應是細胞存活率損失之所得濃度反應曲線之實例顯示於圖19中。表8顯示經由兩個具有如SEQ ID NO:19所示胺基酸序列之多肽構成之TRAIL受體激動劑蛋白質處理24小時之血液病(A;(n=40;非霍奇金淋巴瘤,NHL;急性骨髓性淋巴瘤,AML;急性淋巴母細胞性白血病,ALL)及實體腫瘤(B;(n=44;非小細胞肺癌,NSCLC;胰臟癌;結腸直腸癌,CRC;乳癌,BrCa;卵巢癌,纖維肉瘤;頭部及頸部癌症,H&N;小細胞肺癌,SCLC)細胞株之結果及藉由CellTiter-Glo®評估之存活率。提出所得的由兩個具有如SEQ ID NO:19所示胺基酸序列之多肽構成之TRAIL受體激動劑蛋白質介導對腫瘤細胞存活率之效應之IC50
。
6.2 具有 SEQ ID NO:19 之 TRAIL 受體激動劑蛋白質與抗腫瘤劑協同引起腫瘤細胞死亡
腫瘤細胞以10,000個細胞/孔接種於在96孔盤中之包含10% FBS之推薦的培養基中及於37℃在增濕之5% CO2
氛圍中以由兩個具有如SEQ ID NO:19所示胺基酸序列之多肽構成之TRAIL受體激動劑蛋白質及維那塔勒(venetoclax)(ABT-199)、納威塔勒(navitoclax)(ABT-263)或多烯紫衫醇(DTX)共同處理24 h。於隨後使用如製造商說明書所述之CellTiter-Glo®藥劑來評估細胞存活率。採用Bliss獨立模型(Wong等人,2012; Mol. Cancer Ther. 11:1026-1035;Bernebaum, 1981 Adv. Cancer Res. 35:269-335;Borisy等人,2003 Proc. Natl. Acad. Sci.USA 100:7977-7982)評估組合活性,負整數表示拮抗作用,零值表示添加劑活性,及正整數表示協同作用。在劑量矩陣中計算各組合之Bliss得分值及加總獲得「Bliss總和」值。協同腫瘤細胞死亡之一個實例係以由兩個具有如SEQ ID NO:19所示胺基酸序列之多肽構成之TRAIL受體激動劑蛋白質與維那塔勒(venetoclax)、納威塔勒(navitoclax)或DTX共同處理人類腫瘤細胞引起,相關之Bliss總和顯示於圖20(A至C)中。針對許多腫瘤細胞株中之此等組合所測定之Bliss總和述於表9中。
7. 具有 SEQ ID NO:19 之 TRAIL 受體激動劑蛋白質治療抑制活體內腫瘤生長
在植入SCID雌小鼠(Charles Rivers Laboratories;麻薩諸塞州威明頓)中之皮下Colo205(結腸直腸)、SKM-1(急性骨髓性白血病)、及H460LM(非小細胞肺部)異種移植腫瘤中評估由兩個具有如SEQ ID NO:19所示胺基酸序列之多肽構成之TRAIL受體激動劑蛋白質對腫瘤生長之效應。簡言之,在研究的第0天經皮下接種人類癌細胞至雌SCID小鼠之右後脅腹中。在大小匹配時開始投與具有SEQ ID NO:19之TRAIL受體激動劑蛋白質(如所示,給藥0.3、1、或3 mkd,IV,QDx5或IP、Q2Dx5)。在實驗期間測量腫瘤體積直到各組中之平均腫瘤體積達到就Colo205及SKM-1而言>2000 mm3
或就H460LM而言>2500 mm3
之端值。結果顯示於圖21至23中。由兩個具有如SEQ ID NO:19所示胺基酸序列之多肽構成之TRAIL受體激動劑蛋白質之投與引起Colo205、SKM-1、及H460LM異種移植腫瘤模型中腫瘤顯著之生長抑制。
亦在植入NSG雌小鼠(Champions Oncology;新澤西州哈肯薩克)中之CTG-0069(結腸直腸癌)、CTG-0167(NSCLC)、CTG-0293(胰臟癌)、CTG-0714(肉瘤)、CTG-0136(食道癌)、CTG-485(胃癌)、及CTG-0785(尤因氏肉瘤)之患者衍生之異種移植模型中評估由兩個具有如SEQ ID NO:19所示胺基酸序列之多肽構成之TRAIL受體激動劑蛋白質對腫瘤生長之效應。簡言之,在研究第0天經皮下將腫瘤片段繁殖至雌NSG小鼠之右後脅腹中。在大小匹配時開始投與由兩個具有如SEQ ID NO:19所示胺基酸序列之多肽構成之TRAIL受體激動劑蛋白質(3 mkd,經IP給藥,Q2Dx5)。在實驗期間測量腫瘤體積直到各組中之平均腫瘤體積達到>2000 mm3
之端值或60天。結果顯示於圖24(A至G)中。由兩個具有如SEQ ID NO:19所示胺基酸序列之多肽構成之TRAIL受體激動劑蛋白質之投與引起CTG-0069(結腸直腸癌)、CTG-0167(NSCLC)、CTG-0293(胰臟癌)、CTG-0714(肉瘤)、CTG-0136(食道癌)、CTG-485(胃癌)、及CTG-0785(尤因氏肉瘤)PDX模型中顯著之腫瘤生長抑制。
SEQ ID NO | 序列 |
1 |
SEQ ID NO | 序列 |
2 | GSGSGNGS |
3 | GSGSGSGS |
4 | GGSGSGSG |
5 | GGSGSG |
6 | GGSG |
7 | GGSGNGSG |
8 | GGNGSGSG |
9 | GGNGSG |
22 | GSGSGS |
23 | GSGS |
24 | GSG |
SEQ ID NO | 序列 |
10 | |
17 |
SEQ ID NO | 序列 |
11 | GPGSSSSSSSGSCDKTHTCPPC |
12 | METDTLLVFVLLVWVPAGNG |
13 | SSSSSSAWSHPQFEK |
25 | GPGSSSSSSGSCDKTHTCPPC |
SEQ ID NO | 序列 |
14 | |
15 | |
18 | |
19 | |
20 | |
21 | |
26 | |
27 | |
28 | |
29 | |
30 |
SEQ ID NO | 序列 |
16 |
分子 | 醣基化位點之數量 | 鉸合半胱胺酸之數量 | 末端半衰期4 mg/kg i.v.(小時) | 末端半衰期1.2 mg/kg i.v.(小時) |
A | 6 | 2 | 23.1 | 17.7 |
B | 4 | 3 | 33.94 | 28.28 |
C | 2 | 3 | 21.03 | - |
D | 0 | 3 | 8.81 | - |
表8 活體外具有SEQ ID NO:19之TRAIL受體激動劑蛋白質於人類腫瘤癌細胞株中之效價 | |||
腫瘤細胞株 | 腫瘤類型 | SEQ ID NO:19 IC50 (ng/ml) | |
A | |||
SU-DHL-8 | NHL | 1.36 | |
NUDHL-1 | NHL | 6.50 | |
OCI-Ly8 | NHL | 7.49 | |
ULA | NHL | 8.44 | |
OCI-Ly2 | NHL | 18.98 | |
OCI-LY19 | NHL | 26.34 | |
WSU-NHL | NHL | 31.60 | |
OCI-Ly7 | NHL | 63.76 | |
SU-DHL-5 | NHL | 82.07 | |
OCI-Ly18 | NHL | 196.20 | |
OCI-Ly1 | NHL | 416.95 | |
SU-DHL-16 | NHL | 545.55 | |
SU-DHL-2 | NHL | 1000.00 | |
WSU-DLCL2 | NHL | 1000.00 | |
Toledo | NHL | 1000.00 | |
OCI-LY3 | NHL | 1000.00 | |
RL | NHL | 1000.00 | |
SU-DHL-4 | NHL | 1000.00 | |
U2932 | NHL | 1000.00 | |
HT | NHL | 1000.00 | |
RC-K8 | NHL | 1000.00 | |
SKM-1 | AML | 0.95 | |
PL-21 | AML | 10.67 | |
EOL-1 | AML | 18.31 | |
HL-60 | AML | 76.62 | |
OCI-AML2 | AML | 124.32 | |
UKE-1 | AML | 205.35 | |
MV4-11 | AML | 312.55 | |
SET-2 | AML | 384.80 | |
MOLM-13 | AML | 722.10 | |
OCI-AML5 | AML | 1032.60 | |
Kasumi-1 | AML | 1000.00 | |
KG-1 | AML | 1000.00 | |
OCI-AML3 | AML | 1000.00 | |
SHI-1 | AML | 1000.00 | |
SKNO-1 | AML | 1000.00 | |
TF-1 | AML | 1000.00 | |
THP-1 | AML | 1000.00 | |
HEL | AML | 1000.00 | |
Jurkat | ALL | 3.08 | |
B | |||
NCI-H847 | NSCLC | 14.53 | |
NCI-H647 | NSCLC | 24.75 | |
NCI-H2444 | NSCLC | 27.75 | |
NCI-H2170 | NSCLC | 30.16 | |
NCI-H460 | NSCLC | 36.85 | |
NCI-H838 | NSCLC | 44.48 | |
NCI-H1792 | NSCLC | 61.09 | |
NCI-H2347 | NSCLC | 81.06 | |
NCI-H1373 | NSCLC | 125.15 | |
NCI-H522 | NSCLC | 259.87 | |
NCI-H2110 | NSCLC | 314.20 | |
NCI-H596 | NSCLC | 397.80 | |
HCC4006 | NSCLC | 407.24 | |
NCI-H2122 | NSCLC | 480.55 | |
NCI-H1299 | NSCLC | 716.00 | |
NCI-H1975 | NSCLC | 741.50 | |
HCC827 | NSCLC | 2824.50 | |
NCI-H727 | NSCLC | 3178.00 | |
NCI-H1944 | NSCLC | 4068.75 | |
NCI-H1299 | NSCLC | 4214.87 | |
Calu-6 | NSCLC | 4757.00 | |
NCI-H1693 | NSCLC | 5000.00 | |
HCC2935 | NSCLC | 5000.00 | |
A549 | NSCLC | 5000.00 | |
NCI-H1395 | NSCLC | 5000.00 | |
NCI-H2172 | NSCLC | 5000.00 | |
Calu-1 | NSCLC | 5000.00 | |
NCI-H441 | NSCLC | 5000.00 | |
NCI-H23 | NSCLC | 5000.00 | |
NCI-H661 | NSCLC | 5000.00 | |
NCI-H1650-GFP | NSCLC | >3 | |
BxPC3 | 胰臟癌 | 16.00 | |
Capan-1 | 胰臟癌 | 393.00 | |
MIA PaCa-2 | 胰臟癌 | 158.00 | |
PANC-1 | 胰臟癌 | >1000 | |
SW48 | CRC | 6.10 | |
Colo205 | CRC | 1.30 | |
SW480 | CRC | 132.00 | |
HCT 116-GFP | CRC | 337.00 | |
HCC38 | BrCa | 3.00 | |
HCC1569 | BrCa | 219.00 | |
MCF7 | BrCa | >3000 | |
MDA-MB-231 | BRCa | 235.00 | |
HeyA8-GFP | 卵巢癌 | 141.00 | |
Fadu-GFP | H&N | >3 | |
HT-1080 | 纖維肉瘤 | 377.00 | |
NCI-H211 | SCLC | 72.58 |
表9 SEQ ID NO:19之TRAIL受體激動劑蛋白質在NSCLC細胞株(A)中與DTX及在NHL & AML細胞株(B)中與維那塔勒(venetoclax)或納威塔勒(navitoclax)之組合在活體外殺死細胞之Bliss協同評估。 | |||||
腫瘤細胞株 | Bliss 總和 (SEQ ID NO:19+DTX) | 腫瘤細胞株 | Bliss 總和 (SEQ ID NO:19+ venitoclax) | Bliss 總和 (SEQ ID NO:19+ 納威塔勒(navitoclax)) | |
LG0552 | 748.2 | WSU-DLCL2 | 1292 | 560 | |
NCI-H522 | 549.1 | SU-DHL-4 | 898 | 617 | |
NCI-H647 | 452 | OCI-AML3 | 831.9 | 456.4 | |
NCI-H727 | 429.4 | OCI-AML5 | 777.8 | 174.5 | |
NCI-H1373 | 387.1 | U2932 | 736.2 | 636.1 | |
NCI-H596 | 261 | PL-21 | 600.8 | 244.9 | |
HCC2935 | 224.2 | ULA | 343.8 | 79.4 | |
NCI-H2347 | 154 | OCI-Ly18 | 309.8 | 8.3 | |
NCI-H2444 | 135 | MV4;11 | 301.1 | 351 | |
A549 | 118.1 | RL | 286.1 | 446.7 | |
NCI-H23 | 70.6 | MOLM-13 | 270.6 | 264.8 | |
NCI-H847 | 64.2 | SKM-1 | 222.9 | 88.1 | |
HCC4006 | 15.75 | OCI-Ly1 | 218.8 | 69.1 | |
NCI-H2170 | -97.1 | SU-DHL-16 | 217.5 | 142.5 | |
LG0567 | -105.2 | OCI-AMl2 | 160.2 | 145.5 | |
HCC2935 | -183 | OCI-Ly8 | 154.9 | 177 | |
HCC827 | -292.8 | THP-1 | 152.7 | 43.1 | |
NCI-H661 | -344.5 | OCI-Ly3 | 146.5 | -242.2 | |
NCI-H441 | -362 | OCI-Ly2 | 145 | 127.2 | |
NCI-H1395 | -512 | OCI-Ly19 | 114.9 | 37.3 | |
NCI-H1944 | -565 | SKNO-1 | 104.7 | -138.9 | |
NCI-H1693 | -584 | UKE-1 | 80.5 | 28.9 | |
Calu-6 | -628.7 | WSU-NHK | 79.8 | 84 | |
LG0481 | -803 | EOL-1 | 69.7 | -6.3 | |
NCI-H2172 | -1404 | SU-DHL-2 | 53.5 | -31.8 | |
Toledo | 51.4 | -68.2 | |||
HEL | 21.5 | -92.4 | |||
NuDHL-1 | -28.4 | 18.7 | |||
TF-1 | -100.6 | -50.2 | |||
RC-K8 | -131 | -68 | |||
HT | -173 | 12.1 | |||
HL-60 | -176 | -112.7 | |||
SHI-1 | -208.4 | -122.6 | |||
SU-DHL-8 | -210.6 | -37 | |||
SU-DHL-5 | -233.8 | -280.6 | |||
SET-2 | -248.4 | 71.2 | |||
KG-1 | -260 | -20.3 | |||
Kasumi-1 | -356.4 | -241.2 |
圖1 包含三個TRAIL域之單鏈融合多肽之域結構。I、II、III。可溶性TRAIL域。
圖2 表示TRAIL之一般結構的示意圖。
■ ■ ■細胞膜,N-端位於細胞內,
1.受體結合域(RBD)之反平行β摺疊,
2.RBD與細胞膜之介面,
3.蛋白酶裂解位點。
圖3 表示天然TRAIL三聚物之結構的示意圖。圓柱形結構表示RBD。N-端以細胞膜連接RBD。
圖4 表示三個包含TRAIL之受體結合域之可溶性域之結構的示意圖。I、II、III。可溶性TRAIL域。
圖5 包含TRAIL之RBD之可溶性域之三聚作用,其特徵在於三個可溶性域之N-及C-端形成表面。
圖6 表示包含全部或部分莖部區域之單鏈TRAIL之結構的示意圖,說明需要更長的連接子來補償到下一個可溶性域之N-端的距離。
圖7 自本技藝已知的scFv-TRAIL融合蛋白。
圖8 自本技藝已知的Fc-TRAIL融合蛋白。
圖9A 包含一額外Fab抗體片段之單鏈融合多肽。
圖9B 包含一額外scFv抗體片段之單鏈融合多肽。
圖10 兩個在N端融合的scFc融合多肽經雙硫橋之二聚合。
圖11 兩個在C端融合的scFc融合多肽經雙硫橋之二聚合。
圖12 單鏈融合多肽經連接子之二聚合。
圖13 包含一額外進一步融合至第二融合多肽或scFv融合多肽之Fab抗體片段之單鏈融合多肽。
圖14 兩個scFab融合多肽經雙硫橋之二聚合。
圖15 進一步包含Fv及/或Fab抗體片段之在N端融合的scFc融合多肽。
圖16 進一步包含Fv及/或Fab抗體片段之在C端融合的scFc融合多肽。
圖17A 顯示為具有N端信號肽域之例示性TRAIL受體激動劑蛋白質係以SEQ ID NO:14描述。成熟蛋白質(其不包含N端信號肽域)以SEQ ID NO:19描述。
圖17B 表示例示性TRAIL受體激動劑蛋白質之整體結構及註解序列之示意圖。
圖18 用於定量包含FC域之TRAIL-受體激動劑之ELISA之檢測設置。
圖19 包含兩個具有如SEQ ID NO:19所示胺基酸序列之多肽之TRAIL受體激動劑蛋白質引起活體外人類腫瘤細胞株中之細胞死亡。以漸增濃度之TRAIL受體激動劑蛋白質處理SKM-1、Colo205或Jurkat細胞24小時及評估細胞存活率。
圖20(A至C) 包含兩個具有如SEQ ID NO:19所示胺基酸序列之多肽之TRAIL受體激動劑蛋白質與活體外抗腫瘤劑協同作用。SU-DHL-4細胞與漸增濃度之TRAIL受體激動劑蛋白質在存在或不存在指定濃度之維那塔勒(venetoclax)(圖20A)或納威塔勒(navitoclax)(圖20B)下培養24小時。或者,(圖20C)利用漸增濃度之TRAIL受體激動劑蛋白質在存在或不存在指定濃度之多烯紫杉醇(docetaxel)(DTX)下處理NCI-H596細胞72小時。評估細胞存活率及藉由Bliss總和來判定協同。
圖21 包含兩個具有如SEQ ID NO:19所示胺基酸序列之多肽之TRAIL受體激動劑蛋白質對Colo205結腸直腸癌異種移植模型中腫瘤生長之效應。
圖22 包含兩個具有如SEQ ID NO:19所示胺基酸序列之多肽之TRAIL受體激動劑蛋白質對SKM-1急性骨髓性白血病異種移植模型中腫瘤生長之效應。
圖23 包含兩個具有如SEQ ID NO:19所示胺基酸序列之多肽之TRAIL受體激動劑蛋白質對H460LM非小細胞肺部異種移植模型中腫瘤生長之效應。
圖24(A至G) 包含兩個具有如SEQ ID NO:19所示胺基酸序列之多肽之TRAIL受體激動劑蛋白質對PDX模型中腫瘤生長之效應。菱形,經TRAIL受體激動劑蛋白質處理;正方形,未經處理。顯示(A)CTG-0069、(B)CTG-0167、(C)CTG-0293、(D)CTG-0785、(E)CTG-0714、(F)CTG-0136、及(G)CTG-0485之腫瘤體積。
Claims (7)
- 一種核酸分子,其包含SEQ ID NO: 16。
- 一種核酸分子,其包含SEQ ID NO: 16之核苷酸79至2298。
- 一種表現載體,其包含如請求項1或2之核酸分子。
- 一種經分離之細胞,其包含如請求項3之表現載體。
- 如請求項4之細胞,其係真核細胞。
- 如請求項5之細胞,其中該細胞係哺乳動物細胞。
- 如請求項5之細胞,其中該細胞係中國倉鼠卵巢(CHO)細胞。
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