TW202313106A - 治療性組成物於治療患有上皮起源之腫瘤的病患之用途 - Google Patents
治療性組成物於治療患有上皮起源之腫瘤的病患之用途 Download PDFInfo
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Abstract
本發明屬於生物技術和醫學之分支。本發明描述包含阻斷表皮生長因子之化合物及阻斷PD-1/PD-1配體傳訊路徑之抗體的治療性組成物於治療上皮起源之腫瘤(特別是表現天然形式之人類KRAS蛋白質之腫瘤)的用途。在經由該治療性組成物治療之患有表現天然KRAS之上皮起源的癌症之病患中可觀察到其存活率增加。
Description
本發明屬於生物技術和醫學之分支。特別是,本發明描述藉由同時阻斷表皮生長因子及PD-1/PD-1配體傳訊路徑來治療患有上皮起源的腫瘤之病患的治療性組成物之用途。
稱為“檢查點”之分子(其中PD1受體及其PDL1配體脫穎而出)負調節由免疫系統產生之抗腫瘤反應。阻斷這些檢查點處之抑制訊號傳輸的單株抗體(mAb) (抗CPI)可誘導更有效之抗腫瘤反應。截至2020年12月,已有七種抗CPI mAb被核准用於治療多種“免疫敏感性”惡性腫瘤,諸如黑色素瘤、肺癌、鱗狀細胞頭頸瘤、肝癌、尿道上皮癌(urothelial cancer)、胃癌、乳癌和結直腸腫瘤(Ravindranathan D et al.(2021)Biology, 10: 325)。
最成功之抗CPI mAb為針對PDL1之PD1特異性(抗PD1)納武利尤單抗(Nivolumab)和派姆利珠單抗(Pembrolizumab),以及阿替利珠單抗(Atezolizumab)和德瓦魯單抗(Durvalumab)。這些療法已被證明對那些表現PDL1分子並具有高突變頻率的腫瘤更有效,且若該抑制訊號被阻斷,則免疫細胞之浸潤可能能夠攻擊腫瘤(Gibney GT y cols.(2016)Lancet Oncol. 17(12): e542-e551)。亦已研發針對PD1/PDL1之低分子量抑制劑,該低分子量抑制劑在阻斷該傳訊路徑方面取得令人鼓舞之結果,且未顯示出與免疫系統相關之不良作用(Liu Ch y cols.(2021)Cancer Cell Int. 21:e1-e17)。
表皮生長因子受體(EGFR)為酪胺酸激酶受體和已知之致癌基因(Yarden Y.(2001)European Journal of Cancer. 37: S3-S8),其可被七種天然配體活化。根據與EGFR結合之配體,有幾項研究已報告EGFR傳訊級聯反應的不同活化作用。諸如EGF之配體誘導有利於腫瘤增殖之傳訊,而低親和力配體,諸如雙調蛋白(ampfiregulin)則促進分化(Freed DM y cols.(2017)Cell 171: 1-13)。與直接受體阻斷相反,配體依賴性傳訊級聯反應之差別活化在針對這些分子的靶向療法(例如經由抗EGFR mAb或TKI傳訊級聯反應之抑制劑)中可能至關重要。該等差異可能影響治療之耐受性/安全性,以及在不同治療背景下之較大或較少的臨床療效。從這個意義上說,靶向EGFR配體之治療方式係使用疫苗組成物誘導針對配體之特異性抗體(Ab),從而阻斷該配體與EGFR之交互作用。該治療策略之實例為CIMAvax-EGF疫苗,其產生針對人表皮生長因子(EGF)之特異性mAb,使腫瘤失去該重要的配體。在使用CIMAvax-EGF免疫化之非小細胞肺癌(NSCLC)的病患中進行之大量臨床試驗表明該疫苗為安全且具有免疫原性。從臨床反應之觀點來看,投予疫苗已顯著增加病患之存活率(Rodriguez PC y cols.(2016)Clin Cancer Res. 22(15):3782-90)。
參與EGFR傳訊的最重要分子之一為GTPase KRAS。該分子亦活化參與腫瘤發生的多個傳訊級聯反應。全部人類腫瘤中約30%在編碼KRAS之基因中具有突變,其誘導某些EGF-R級聯反應之組成性活化,而與傳統的膜受體活化無關(Fernández-Medarde, A y cols.(2011)Genes and Cancer. 2:344-358)。
該基因中之突變在某些該等腫瘤(諸如胰臟腺癌)中占主導地位,90%之腫瘤中顯示出突變。在其他腺癌(諸如結腸)中,40%之該等腺癌中存在該突變。在肺部之情況中,KRAS突變存在於全部非小細胞肺腫瘤的其中30%中,主要存在於腺癌組織中(Moore AR y cols.(2020)Nat Rev Drug Discov. 19(8): 533-552 )。
在諸如胰臟和結腸之腫瘤中,KRAS突變的出現有利於腫瘤生長和對療法的抗性(Haigis KM et al. (2008) Nat Genet. 40: 600-8;Bournet B et al. (2016) Clin Transl Gastroenterol. 7: e157)。然而,在其他腫瘤中,諸如肺腺癌,該基因中之突變的預後數值具有爭議之數據(Shepherd FA et al.(2013)J Clin. Oncol. 31(17):2173-81;Zer A et al. (2016)J Thoracic. Oncol. 11(13): 312-23)。在末期結腸腫瘤中,天然KRAS之存在為使用EGFR特異性mAb帕尼單抗(panitumumab)和西妥昔單抗(cetuximab)之治療的臨床利益預測指標。此外,將尼妥珠單抗(nimotuzumab) (另一種抗EGFR)與吉西他濱(gencitabine)組合使用可為其腫瘤中天然存在KRAS之末期胰臟癌病患提供臨床益處(Schultheis B et al. (2017) Ann. Oncol. 28: 2429-35)。然而,使用西妥昔單抗來治療NSCLC並未在其EGFR傳訊級聯反應中具有突變(包括,尤其是KRAS)之任何病患亞群中顯示出臨床優勢。另一方面,腫瘤中之KRAS是否突變本身並不影響或調節病患對於抗PD1/PDL1 mAb之臨床反應。在肺癌之抗PD1/PDL1 mAb的第III期臨床試驗中,在具有突變之KRAS腫瘤的病患中可觀察到顯著之臨床益處(Borghaei, H et al. (2015) N Engl J Med. 373 (17): 1627-1639;Socinski May cols. (2018) N Engl J Med. 378 (24): 2288-2301)。與此發現相一致,最近之臨床試驗表明在使用抗PD1/PDL1 mAb治療之病患中,其他突變與KRAS突變(共突變)之存在可能使反應更好或更差。特別是,在其中KRAS與TP53基因共同突變之肺腺癌中,其導致對CPI更敏感之免疫原性腫瘤。相較之下,STK11中之共突變產生不會發炎的腫瘤且對該類型之療法更具抵抗力(Dong ZY et al. (2017) Clin Cancer Res 23: 3012-3024;Skoulidis Fy cols. (2018) Cancer Discov; 8: 822-835)。
鑑於EGFR傳訊阻斷療法和CPI的成功,一些研究評估二種方法之聯合治療在不同治療領域中的益處,結果各不相同。幾位作者探討將抗PD1/PDL1 mAb與TKI療法相組合是否方便,該TKI療法阻斷肺癌病患中突變之EGFR變體的異常傳訊。這些研究表明該組合沒有利益且明增加毒性(Yang JC et al. (2019) J Thorac Oncol.; 14 (3): 553-9; Schoenfeld AJ et al. (2019) Ann Oncol. 30 (5): 839-44)。其他作者在肺癌病患中評估與奈昔妥珠單抗(Necitumumab) (另一種抗EGFRmAb)之組合。在該研究中,該毒性是可控的,但無臨床相關效果之證據(Besse B et al. (2020) Lung Cancer. 142: 63-69)。在這些試驗中,均未報告與KRAS分子狀態之關聯。
本發明首次報導在具有天然KRAS之病患中使用組合mAb和疫苗組成物之治療性組成物,該mAb阻斷PD1和PDL1之間的交互作用,而疫苗組成物誘導針對自體人EGF之Ab。所得之結果表明該療法耐受性良好且特別有益於患有呈遞天然KRAS之腫瘤的病患。此外,該療法有益於具有低PD-L1表現之腫瘤(其對抗PD1/和PDL1 mAb療法不太敏感)的病患。
於一實施態樣中,本發明關於治療性組成物於治療上皮起源之腫瘤的用途。這些組成物之特徵在於使用誘導產生針對EGF之特異性抗體的疫苗組成物及阻斷PD1/PD1配體傳訊路徑之化合物。特別是,本發明描述上述治療性組成物在那些表現天然形式之KRAS蛋白(較佳為具有描述於SEQ ID NO:1和SEQ ID NO:2中所描示之序列者)的上皮起源之腫瘤中的用途。
特別是,誘導產生針對EGF之抗體的疫苗組成物包含作為活性成分之重組人EGF與載體蛋白的共軛物。該載體蛋白係選自包含下列者之群組:霍亂毒素B、破傷風類毒素、KLH及腦膜炎雙球菌(Neisseria meningitidis)p64k蛋白。
此外,該誘導產生針對EGF抗體之疫苗組成物具有選自包含下列者之群組的佐劑:不完全弗氏佐劑(Freund's adjuvant)、基於角鯊烯之佐劑、合成起源之佐劑、礦物起源之佐劑、植物起源之佐劑、動物起源之佐劑、顆粒化蛋白質和脂質體。
阻斷PD1/PD1配體傳訊路徑之化合物係選自包含下列者之群組:抗PD1 Ab(其中包含納武利尤單抗、派姆利珠單抗、MEDI0608和匹利珠單抗),及抗PDL1 Ab(其可為:阿替利珠單抗、德瓦魯單抗、阿維魯單抗(avelumab)和MDX-1105。
於本發明之一實施態樣中,藉由其腫瘤細胞之樣本中是否存有天然KRAS篩檢病患。選擇腫瘤細胞之樣本中存在天然KRAS之病患接受治療。接受治療之腫瘤類型為:非小細胞肺癌、鱗狀細胞頭頸癌、尿道上皮癌、結腸直腸癌、胃癌、食道癌、子宮頸癌、肝細胞癌、默克爾(Merkel)細胞癌、腎細胞癌、子宮內膜癌、乳癌和皮膚癌。
於另外之實施態樣中,本發明關於區分病患對使用本文所描述之治療性組成物之治療為反應者或非反應者之方法。該病患係藉由測定腫瘤細胞的樣本中是否存有天然KRAS區分,而其中檢測到存在天然KRAS的病患將被視為治療反應者。較佳地,其腫瘤樣本之PDL1水準低於1%之病患將被視為反應者。
發明詳細描述 KRAS
本發明之方法和用途被設想用於治療和/或區分其上皮腫瘤表現野生型蛋白質KRAS的病患。術語“野生型”KRAS係指天然產生之KRAS同種型(Uniprot登錄號P01116,2021年4月7日之246版)。設想野生型KRAS包含對應於SEQ ID NO:1或SEQ ID NO:2之序列。特別是,該野生型KRAS可由對應於SEQ ID NO:1或SEQ ID NO:2之序列組成。
術語“野生型KRAS”通常亦包含相對於SEQ ID NO:1(KRAS4A)或SEQ ID NO:2(KRAS4B)中所示之參考序列而言具有突變的KRAS多肽,且亦包含如下述之多肽:其具有與如本文描述之SEQ ID NO:1(KRAS4A,Uniprot登錄號P01116-1)或SEQ ID NO:2(KRAS4B,Uniprot登錄號P01116-2)中所示之胺基酸序列分享某種程度之同一性的胺基酸序列。更具體地,“野生型KRAS”包括與SEQ ID NO:1(KRAS4A)或SEQ ID NO:2(KRAS4B)具有至少80%、85%、90%、95%或100%同一性之KRAS多肽。特別是,KRAS同種型4A和4B包含在術語“野生型KRAS”中。較佳地,與SEQ ID NO:1或SEQ ID NO:2分別比較,“野生型KRAS”在其胺基酸序列中不包含突變。
治療性組成物
本發明關於用於治療癌症,特別是旨在阻斷該標靶EGF和傳訊路徑PD1/PD1配體的治療性組成物。本發明描述針對PD1或其配體PDL1之化合物與降低EGF濃度之藥劑的組合在患有上皮起源之腫瘤(尤其是那些通常對免疫治療有反應的腫瘤)之病患亞群中的有效用途。
在針對PD1或其配體之化合物中,本發明所使用者為抗PD1 MAb。該等化合物均為與細胞表面受體PD1特異結合並阻斷抑制途徑PD1/PDL1之化合物。這些抗PD1 MAb包括:美國專利案8,008,449中描述之納武利尤單抗,美國專利案8,354,509和US 8,900,587中描述之派姆利珠單抗、MEDI0608(US 8,609,089)、匹利珠單抗(pidilizumab)(US 8,686,119)和西米普利單抗(cemiplimab)。
本發明中所使用之抗PDL1 MAb均為特異地結合PDL1並阻斷抑制途徑PD1/PDL1者。這些抗PDL1 MAb包括:美國專利案8,217,149中描述之阿替利珠單抗(atezolizumab)、德瓦魯單抗(durvalumab)(US 8,779,108)、美國專利案9,624,298中描述之阿維魯單抗(avelumab)和MDX-1105 (US 7943743)。
另外,根據本發明,抑制PD1/PDL1交互作用之低分子量抑制劑可與降低EGF濃度之藥劑組合。這些抑制劑包括BMS1166、BMS202和CA-170。
本發明提供之降低EGF之濃度的藥劑均為誘導產生針對自體人EGF的特異性Ab之疫苗組成物。該等抗體阻斷EGF與EGF受體之交互作用,這有助於降低和/或消除血清EGF之水準。該等疫苗組成物之實例均為包含人類重組EGF(EGFhr)與轉運蛋白之共軛物作為活性成分者。該轉運蛋白可為:霍亂毒素 B、破傷風類毒素、KLH和來自腦膜炎雙球菌(Neisseria meningitidis)之P64k,但不限於此。此外,該等疫苗組成物包括選自下列者之佐劑:不完全弗氏佐劑(Freund's adjuvant)、基於角鯊烯之佐劑、合成起源之佐劑、礦物質起源之佐劑、植物起源之佐劑、動物起源之佐劑、顆粒化蛋白質性佐劑和脂質體。
識別和 / 或選擇病患之方法
某位病患是否屬於待藉由本發明方法治療之病患群體可使用本技藝已知之常規實驗來評估。例如,為了測定上皮腫瘤是否表現野生型KRAS,通常從待評估之病患取得腫瘤樣本,且分別從樣本取得KRAS核酸序列及擴增,並進行測序。或者,聚合酶鏈反應可檢測是否存有KRAS基因。
另一方法與血漿或血清樣本有關,其中具有KRAS致癌基因之循環腫瘤細胞可使用膜微陣列檢測。在這方面,血漿或血清中之KRAS正突變表明該腫瘤中存在KRAS突變,而血漿或血清中不存在KRAS突變並不一定證明胰臟腫瘤組織中缺乏類似之突變。
此外,或另外地,野生型KRAS之表現可藉由檢測腫瘤樣本中之突變和/或野生型KRAS多肽來測定,例如藉由使用分別與特異於野生型或突變型KRAS之表位結合的特異性抗體。設想選擇患有表現野生型KRAS之上皮腫瘤的病患來治療,而不選擇表現突變型KRAS之病患進行治療。
患有表現突變型KRAS,尤其是患有如本文他處陳述之一或多個突變的KRAS之上皮腫瘤的病患被認為對本發明方法中所使用之治療性組成物的治療反應較小或無反應。因此,本發明亦提供區分攜帶上皮腫瘤之病患的方法。當在本文中使用時,“區分”係指將患有上皮腫瘤之病患區分為可能受益於使用本發明之治療性組成物治療的病患及可能無法受益的病患。設想其上皮腫瘤不表現野生型KRAS之病患,特別是其上皮腫瘤表現突變型KRAS之病患不太可能受益於使用本文所描述之治療性組成物進行的治療(對使用本文所描述之治療性組成物的治療有反應)。
反之,其PDAC腫瘤表現如本文他處定義之野生型KRAS、HRAS或NRAS之病患可能受益於如本文所描述之治療(對如本文所描述之治療有反應)。該“野生型”KRAS較佳為具有對應於SEQ ID NO:1或SEQ ID NO:2之序列。
在本文提供之治療方法的背景下,術語“有反應的”係指在投予如本文定義之治療性組成物後,病患或腫瘤顯示出根據臨床試驗之反應評估標準(iRECIST)中的完全反應、部分反應或疾病穩定。如本文所使用之術語“非反應性”係指在投予如本文定義之治療性組成物後,病患或腫瘤顯示出根據iRECIST之穩定的疾病或進行性疾病。iRECIST描述於Seymour L y cols. RECIST working group (2017) Lancet Oncol. 18(3):e143-e152中。
因此,本文亦提供選擇待治療之病患或病患群體的方法。此係藉由測定各病患之上皮腫瘤樣本中是否存在突變型和/或野生型KRAS來達成。在其腫瘤樣本中檢測到突變型KRAS和/或未檢測到野生型KRAS之病患被認為不符合治療條件,而在其腫瘤樣本中檢測到野生型KRAS和/或未檢測到突變型KRAS的病患被認為符合條件,因此,被選擇根據本發明進行治療。
此外,如前述,本發明提供用於預測患有PDAC或上皮腫瘤之病患對使用如本文所描述之治療性組成物的治療為反應者或非反應者之方法。如前述,可使用本技藝已知和本文他處描述之常規方法評估病患之腫瘤樣本中是否存有突變型和/或野生型KRAS。上皮腫瘤中之突變型KRAS的表現表明該病患或上皮腫瘤將對治療無反應,而上皮腫瘤中之野生型KRAS的表現表明該病患將對使用如本文所描述之治療性組成物的治療有反應。
於本發明之另一較佳實施態樣中,對治療有反應之病患將為那些表現天然KRAS者,因而,藉由免疫組織化學技術測得之腫瘤樣本中的PDL1水準低於1%。
治療方法
可使用本文所描述之治療性組成物治療的癌症類型為,但不限於:NSCLC、頭頸部之鱗狀細胞癌、尿道上皮癌、結腸直腸癌、胃癌、食道癌、子宮頸癌、肝細胞癌、默克爾細胞癌、腎細胞癌、子宮內膜癌、乳癌、鱗狀皮膚癌。此外,本發明包括使用本發明之組合可抑制其生長之難治性或復發之腫瘤。
較佳地,包含EGF作為活性成分之疫苗組成物將投予在肌肉內;前四個劑量為每14天投予一次,其餘為每28天投予一次,容許之時間範圍為3天。這些組成物所使用之劑量範圍將包含20至70 μL/kg體重或每公斤體重20至70μg總蛋白質或高達5 mg之總蛋白質,較推薦的為30至60μg/kg。該治療階段之最短持續時間為6個月,然後根據所得之結果,隨後之維持階段的頻率和劑量可有所變化。考量所產生之Ab效價及臨床症狀之改善和/或穩定,可將該維持期優化,其先決條件為保證血清EGF濃度降低。該等血清EGF濃度可藉由用於此目的之任何可商購的診斷裝置來測量。
抗PD1和抗PDL1 MAb將以用於各案例之推薦劑量和排程投予。在抗PD1 MAb之案例中,將經由靜脈內途徑投予劑量範圍在100至500 mg的總蛋白,頻率為2至6 週。在抗PDL1 MAb之案例中,將經由靜脈內途徑投予劑量範圍在600至1800 mg之總蛋白,頻率為2至5週。疫苗和MAb之投予將經過調整以配合阻斷PD1/PD1L傳訊和抑制由EGF介導之傳訊的作用。遵循此原則,該投予可為伴隨的或依序的。特別是,該疫苗組成物之投予可能與該MAb之投予方案重疊。
本發明藉由下列實施例和附圖進一步闡述。然而,這些實施例不應被解釋為對本發明範圍之限制。
實施例
1.
聯合投予
CIMAvax-EGF
和抗
PD1 mAb
納武利尤單抗
為
安全的且誘導有效之抗人
EGF Ab
反應。
在紐約州水牛城羅斯威爾帕克(Roswell Park)綜合癌症中心進行之第I/II期臨床試驗(NCT02955290) 中,使用包含疫苗組成物CIMAvax-EGF和抗PD1 mAb納武利尤單抗之治療性組成物治療末期NSCLC病患。
該研究具有第I期劑量遞增和第II期療效評估。總共納入29名患有轉移性NSCLC之病患。納武利尤單抗之使用劑量為每2週經由靜脈內途徑投予240 mg。在誘導期(4個劑量)之期間,每2週經由肌肉內途徑投予劑量為2.4 mg之CIMAvax-EGF疫苗組成物,然後在維持期每月注射。前6名病患接受一半劑量之CIMAvax-EGF(1.2 mg)。
安全性變化形廓良好且沒有與該施用之療法相關的嚴重不良反應。CIMAvax-EGF在所有病患中均誘導出良好之反應,此係由抗EGF Ab效價等於或大於 1:4000(血清稀釋度(圖1))定義。
在藉由ELISA(人EGF Quantikine ELISA套組,R&D Systems)測量時,使用CIMAvax-EGF和mAb 納武利尤單抗治療之病患中亦觀察到病患血清中之EGF濃度快速降低(圖2)。
接受治療之29名病患之中位總生存期為10.36個月。一年之總生存率為44%。
實施例 2. 聯合投予 CIMAvax-EGF 和抗 PD1 mAb 納武利尤單抗 顯著有益於天然 KRAS 病患。
於實施例1中描述之試驗中,根據腫瘤中是否存有KRAS基因之突變來區分該病患以進行分析。使用新一代測序分析來驗證KRAS基因是否存有突變及副本數,該新一代測序分析係使用基於多參數PCR之DNA測序。令人驚訝地,具有天然KRAS之病患的存活情況明顯高於具有突變型KRAS之病患(圖3)。
具有天然KRAS之病患的中位生存期為22.06個月,而具有突變型KRAS之病患的中位生存期為10.26個月。具有天然KRAS之病患的一年生存率為69%,而具有突變型KRAS之病患為37%。
此外,在聯合療法後,具有天然KRAS之病患的疾病控制率顯著提高(根據irRECIST標準,病患之疾病至少穩定(Seymour L et al. RECIST working group (2017) Lancet Oncol. 18 (3):e143-e152)。相較於具有包含突變型KRAS之腫瘤的病患,在具有天然KRAS之病患中,使用CIMAvax-EGF和納武利尤單抗之聯合療法後的疾病控制率為56.3%,而含有突變型KRAS之腫瘤的病患之疾病控制率為12.5%。
使用聯合療法後,在具有天然KRAS之病患中觀察到之生存情形具有臨床相關性,根據文獻,根據KRAS突變進行的區分不會影響僅使用納武利尤單抗治療之病患的生存率。在這些罹患末期NSCLC之病患中,使用納武利尤單抗之單藥療法導致具有突變型或天然KRAS的病患之中位生存期分別為11.2個月和10個月(Passiglia F et al.(2019)Br J Cancer 120(1): 57- 62)。
實施例 3. 聯合投予 CIMAvax-EGF 和抗 PD1 Ab 納武利尤單抗 明顯有益於具有天然 KRAS 腫瘤且 PDL1<1% 之 病患。
鑑於文獻中已知的歷史:其腫瘤中之PDL1表現低的病患對使用抗PD1 mAb之單一療法的反應較低,對其腫瘤不表現PDL1(PDL1<1%)的病患重複進行實施例2之分析。使用用於測定PDL1之pharmDx分析28-8測定PDL1之表現。
令人驚訝地,觀察到根據KRAS中之突變來區分病患再次區分出病患之存活率。具有天然KRAS之病患的中位生存期為22.06個月,而具有突變型KRAS之病患的中位生存期為10.26個月。在具有天然KRAS之病患中的一年生存率為80%,非常高(圖4)。
[
圖 1]使用CIMAvax-EGF和納武利尤單抗處理之病患血清中的抗EGF Ab效價。
[
圖 2]使用CIMAvax-EGF和納武利尤單抗處理之病患血清中的EGF水準。
[
圖 3]在患有天然KRAS和突變型KRAS腫瘤之病患中,使用CIMAvax-EGF和納武利尤單抗治療之病患隨著時間推移的累積生存期。
[
圖 4]在PD-L1腫瘤(其為天然KRAS或突變型KRAS)<1%之病患中,使用CIMAvax-EGF和納武利尤單抗治療之病患隨著時間推移的累積生存期。
<![CDATA[<110> 分子免疫學中心 (Centro De Inmunologia Molecular) ]]> 古巴商創新免疫治療聯盟公司 (Innovative Immunotherapy Alliance S.A.) <![CDATA[<120> 治療性組成物於治療患有上皮起源之腫瘤的病患之用途 ]]> <![CDATA[<140> TW 111119253]]> <![CDATA[<141> 2022-05-24]]> <![CDATA[<150> CU CU-2021-0045 ]]> <![CDATA[<151> 2021-05-26]]> <![CDATA[<160> 2 ]]> <![CDATA[<170> PatentIn 3.5版]]> <![CDATA[<210> 1]]> <![CDATA[<211> 189]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 1]]> Met Thr Glu Tyr Lys Leu Val Val Val Gly Ala Gly Gly Val Gly Lys 1 5 10 15 Ser Ala Leu Thr Ile Gln Leu Ile Gln Asn His Phe Val Asp Glu Tyr 20 25 30 Asp Pro Thr Ile Glu Asp Ser Tyr Arg Lys Gln Val Val Ile Asp Gly 35 40 45 Glu Thr Cys Leu Leu Asp Ile Leu Asp Thr Ala Gly Gln Glu Glu Tyr 50 55 60 Ser Ala Met Arg Asp Gln Tyr Met Arg Thr Gly Glu Gly Phe Leu Cys 65 70 75 80 Val Phe Ala Ile Asn Asn Thr Lys Ser Phe Glu Asp Ile His His Tyr 85 90 95 Arg Glu Gln Ile Lys Arg Val Lys Asp Ser Glu Asp Val Pro Met Val 100 105 110 Leu Val Gly Asn Lys Cys Asp Leu Pro Ser Arg Thr Val Asp Thr Lys 115 120 125 Gln Ala Gln Asp Leu Ala Arg Ser Tyr Gly Ile Pro Phe Ile Glu Thr 130 135 140 Ser Ala Lys Thr Arg Gln Arg Val Glu Asp Ala Phe Tyr Thr Leu Val 145 150 155 160 Arg Glu Ile Arg Gln Tyr Arg Leu Lys Lys Ile Ser Lys Glu Glu Lys 165 170 175 Thr Pro Gly Cys Val Lys Ile Lys Lys Cys Ile Ile Met 180 185 <![CDATA[<210> 2]]> <![CDATA[<211> 187]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 2]]> Met Thr Glu Tyr Lys Leu Val Val Val Gly Ala Gly Gly Val Gly Lys 1 5 10 15 Ser Ala Leu Thr Ile Gln Leu Ile Gln Asn His Phe Val Asp Glu Tyr 20 25 30 Asp Pro Thr Ile Glu Asp Ser Tyr Arg Lys Gln Val Val Ile Asp Gly 35 40 45 Glu Thr Cys Leu Leu Asp Ile Leu Asp Thr Ala Gly Gln Glu Glu Tyr 50 55 60 Ser Ala Met Arg Asp Gln Tyr Met Arg Thr Gly Glu Gly Phe Leu Cys 65 70 75 80 Val Phe Ala Ile Asn Asn Thr Lys Ser Phe Glu Asp Ile His His Tyr 85 90 95 Arg Glu Gln Ile Lys Arg Val Lys Asp Ser Glu Asp Val Pro Met Val 100 105 110 Leu Val Gly Asn Lys Cys Asp Leu Pro Ser Arg Thr Val Asp Thr Lys 115 120 125 Gln Ala Gln Asp Leu Ala Arg Ser Tyr Gly Ile Pro Phe Ile Glu Thr 130 135 140 Ser Ala Lys Thr Arg Gln Gly Val Asp Asp Ala Phe Tyr Thr Leu Arg 145 150 155 160 Glu Ile Arg Lys His Lys Glu Lys Met Ser Lys Asp Gly Lys Lys Lys 165 170 175 Lys Lys Lys Ser Lys Thr Lys Cys Val Ile Met 180 185
Claims (14)
- 一種治療性組成物於治療上皮起源之腫瘤之用途,該治療性組成物包含誘導產生針對表皮生長因子(EGF)之特異性抗體(Ab)的疫苗組成物和阻斷PD1/PD1配體(PD-1L)傳訊路徑之化合物。
- 如請求項1之用途,其中該上皮起源之腫瘤表現野生型人類KRAS蛋白質。
- 如請求項2之用途,其中該野生型KRAS之特徵為具有選自由下列所組成之群組的序列:SEQ ID NO:1和SEQ ID NO:2。
- 如請求項1之用途,其中該誘導產生針對該EGF之抗體的疫苗組成物包含人類重組EGF與載體蛋白之共軛物以作為活性成分。
- 如請求項4之用途,其中該載體蛋白係選自由下列所組成之群組: - 霍亂毒素B次單位; - 破傷風類毒素; - KLH;及 - 腦膜炎雙球菌(Neisseria meningitidis)之P64k。
- 如請求項5之用途,其中該疫苗組成物另外具有選自由下列所組成之群組的佐劑: - 不完全弗氏佐劑(Freund's adjuvant); - 基於角鯊烯之佐劑; - 合成起源之佐劑; - 礦物質起源之佐劑; - 植物起源之佐劑; - 動物起源之佐劑; - 顆粒化蛋白質性佐劑;及 - 脂質體。
- 如請求項1之用途,其中阻斷PD1/PD-1L傳訊路徑之化合物係選自由下列所組成之群組: - 抗PD1抗體;及 - 抗PD-1L抗體。
- 如請求項7之用途,其中該抗PD1抗體係選自由下列所組成之群組:納武利尤單抗(nivolumab)、派姆利珠單抗(pembrolizumab)、西米普利單抗(cemiplimab)、MEDI0608和匹利珠單抗(pidilizumab)。
- 如請求項7之用途,其中該抗PD-1L抗體係選自由下列所組成之群組:阿替利珠單抗(atezolizumab)、德瓦魯單抗(durvalumab)、阿維魯單抗(avelumab)和MDX-1105。
- 如請求項1至9中任一項之用途,其中該病患之選擇係藉由測定該病患之腫瘤細胞的樣本中是否存有野生型KRAS,其中選擇腫瘤樣本中被檢測出野生型KRAS之病患接受治療。
- 如請求項1至10中任一項之用途,其係用於治療選自由下列所組成之群組的腫瘤:非小細胞肺癌、鱗狀細胞頭頸癌、尿道上皮癌(urothelial carcinoma)、結腸直腸癌、胃癌、食道癌、子宮頸癌、肝細胞癌、默克爾(Merkel)細胞癌、腎細胞癌、子宮內膜癌、乳癌和皮膚癌。
- 一種區分病患對使用治療性組成物之治療為反應者或非反應者之方法,該治療性組成物包含阻斷EGF之化合物和阻斷PD1/PD-1L傳訊路徑之抗體,其中該病患之選擇係藉由測定該病患之腫瘤細胞的樣本中是否存有野生型KRAS。
- 如請求項12之方法,其中若在該腫瘤樣本中檢測出野生型KRAS,則該病患被認為對治療有反應。
- 如請求項13之方法,其中在該病患之腫瘤樣本中PD-1L含量低於1%。
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KR101411165B1 (ko) | 2005-07-01 | 2014-06-25 | 메다렉스, 엘.엘.시. | 예정 사멸 리간드 1 (피디-엘1)에 대한 인간 모노클로날항체 |
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