TWI663983B - 用於治療癌症之pd-1拮抗劑及vegfr抑制劑之組合 - Google Patents
用於治療癌症之pd-1拮抗劑及vegfr抑制劑之組合 Download PDFInfo
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- TWI663983B TWI663983B TW104103603A TW104103603A TWI663983B TW I663983 B TWI663983 B TW I663983B TW 104103603 A TW104103603 A TW 104103603A TW 104103603 A TW104103603 A TW 104103603A TW I663983 B TWI663983 B TW I663983B
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Classifications
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Abstract
本發明闡述包含計畫性死亡1受體(PD-1)拮抗劑及VEGFR抑制劑之組合療法及該等組合療法之用途,其用於治療癌症,且具體而言用於治療表現PD-L1之癌症。
Description
本申請案主張於2014年2月4日提出申請之美國臨時申請案第61/935,809號之權益,該申請案之全文以引用方式併入本文中。
本申請案含有以ASCII格式電子提交之序列表且其全部內容以引用方式併入本文中。於2015年1月29日創建之該ASCII拷貝命名為PCFC-956-WO1_SL.txt且大小為32,535個字節。
本發明係關於可用於治療癌症之組合療法。具體而言,本發明係關於包含計畫性死亡1蛋白質(PD-1)拮抗劑及血管內皮生長因子受體(VEGFR)途徑之抑制劑之組合療法。
認為PD-1在免疫調節及周邊耐受性之維持中起重要作用。PD-1在初始T、B及NKT細胞上適度表現且藉由在淋巴球、單核球及髓樣細胞上之T/B細胞受體信號傳導上調(1)。
PD-1之兩種已知配體PD-L1(B7-H1)及PD-L2(B7-DC)在各種組織中產生之人類癌症中表現。在(例如)卵巢癌、腎癌、結腸直腸癌、胰臟癌、肝癌及黑色素瘤之大的試樣組中,顯示PD-L1表現與較差預後相關且降低整體存活而與隨後治療無關(2-13)。類似地,發現腫瘤
浸潤淋巴球上之PD-1表現標記乳癌及黑色素瘤中之功能異常T細胞(14-15)且與腎癌中之較差預後相關(16)。因此,已提出表現PD-L1之腫瘤細胞與表現PD-1之T細胞相互作用以減弱T細胞活化及免疫監視之逃避,藉此促進針對腫瘤之受損免疫反應。
若干抑制PD-1與其配體PD-L1及PD-L2中之一者或二者之間之相互作用的單株抗體在臨床研發中用於治療癌症。已提出若與其他已批准或實驗癌症療法(例如放射、手術、化學治療劑、靶向療法、抑制在腫瘤中失調之其他信號傳導途徑之藥劑及其他免疫增強藥劑)組合投與,該等抗體之功效可得以增強。
蛋白酪胺酸激酶已鑑別為癌症之治療性治療中之重要靶標。腫瘤血管生成及生長需要生長因子配體及其各別受體酪胺酸激酶。血管內皮生長因子(VEGF)係導致在血管生成期間形成新血管之內皮細胞分支、擴張及存活之過程中的關鍵組份。不期望之血管生成係若干疾病(例如視網膜病、牛皮癬、類風濕性關節炎、年齡相關性黃斑變性(AMD)及癌症(包括實體瘤))之標誌,Folkman,Nature Med.,1,27-31(1995)。
血管內皮生長因子受體(VEGFR)抑制劑已批准用於治療各種類型之癌症(包括晚期及轉移性腎細胞癌、胃腸道間質瘤及肝細胞癌),且繼續在臨床環境中經研究。已提出若與其他已批准或實驗癌症療法(例如放射、手術、化學治療劑、靶向療法、抑制在腫瘤中失調之其他信號傳導途徑之藥劑及其他免疫增強藥劑)組合投與,該等抑制劑之功效可得以增強。
在一個實施例中,本發明提供用於治療個體之癌症之方法,其包含向該個體投與包含PD-1拮抗劑及VEGFR抑制劑之組合療法。
在另一實施例中,本發明提供包含與VEGFR抑制劑組合用於治
療癌症之PD-1拮抗劑的藥劑其。
在又一實施例中,本發明提供包含與PD-1拮抗劑組合用於治療癌症之VEGFR抑制劑的藥劑。
其他實施例提供PD-1拮抗劑之用途(其用於製造在與VEGFR抑制劑組合投與時用於治療個體之癌症之藥劑)及VEGFR抑制劑之用途(其用於製造在與PD-1拮抗劑組合投與時用於治療個體之癌症之藥劑)。
在再一實施例中,本發明提供PD-1拮抗劑及VEGFR抑制劑之用途,其用於製造用於治療個體之癌症之藥劑。在一些實施例中,藥劑包含套組,且套組亦包含包括與VEGFR抑制劑組合使用PD-1拮抗劑以治療個體之癌症的說明書之包裝插頁。
在所有上述治療方法、藥劑及用途中,PD-1拮抗劑抑制PD-L1與PD-1結合,且較佳亦抑制PD-L2與PD-1結合。在上述治療方法、藥劑及用途之一些實施例中,PD-1拮抗劑係單株抗體或其抗原結合片段,其特異性結合至PD-1或PD-L1且阻斷PD-L1與PD-1結合。在一個實施例中,PD-1拮抗劑係包含重鏈及輕鏈之抗PD-1抗體,且其中重鏈及輕鏈包含圖6中所示之胺基酸序列(SEQ ID NO:21及SEQ ID NO:22)。
在本文之治療方法、藥劑及用途之所有上述實施例中,VEGFR抑制劑係N-甲基-2-[3-((E)-2-吡啶-2-基-乙烯基)-1H-吲唑-6-基硫基]-苯甲醯胺或其醫藥上可接受之鹽。
在本發明之上述治療方法、藥劑及用途之一些實施例中,個體係人類且癌症係實體瘤且在一些實施例中,實體瘤係膀胱癌、乳癌、透明細胞腎癌、頭/頸鱗狀細胞癌、肺鱗狀細胞癌、惡性黑色素瘤、非小細胞肺癌(NSCLC)、卵巢癌、胰臟癌、前列腺癌、腎細胞癌、小細胞肺癌(SCLC)或三重陰性乳癌。在一些實施例中,癌症係腎細胞癌(RCC)。在一些實施例中,癌性係透明細胞腎癌。
在本發明之上述治療方法、藥劑及用途之其他實施例中,個體
係人類且癌症係血紅素惡性腫瘤且在一些實施例中,血紅素惡性腫瘤係急性淋巴母細胞性白血病(ALL)、急性骨髓性白血病(AML)、慢性淋巴球性白血病(CLL)、慢性骨髓性白血病(CML)、彌漫性大B細胞淋巴瘤(DLBCL)、EBV陽性DLBCL、原發性縱隔大B細胞淋巴瘤、富含T細胞/組織細胞之大B細胞淋巴瘤、濾泡性淋巴瘤、何傑金氏淋巴瘤(Hodgkin’s lymphoma,HL)、套細胞淋巴瘤(MCL)、多發性骨髓瘤(MM)、骨髓性細胞白血病-1蛋白質(Mcl-1)、骨髓發育不良症候群(MDS)、非何傑金氏淋巴瘤(NHL)或小淋巴球性淋巴瘤(SLL)。
同樣,在上述治療方法、藥劑及用途中之任一者之一些實施例中,癌症之PD-L1及PD-L2中之一者或二者之表現經測試呈陽性。在又一些實施例中,癌症具有升高之PD-L1表現。
在上述治療方法、藥劑及用途之一個實施例中,個體係人類且癌症係經測試對人類PD-L1呈陽性之RCC。
在上述治療方法、藥劑及用途之另一實施例中,癌症係具有透明細胞亞型之晚期RCC且存於先前未治療RCC之人類中。
圖1顯示可用於本發明中之例示性抗PD-1單株抗體之輕鏈及重鏈CDR的胺基酸序列(SEQ ID NO:1-6)。
圖2顯示可用於本發明中之另一例示性抗PD-1單株抗體之輕鏈及重鏈CDR的胺基酸序列(SEQ ID NO:7-12)。
圖3顯示可用於本發明中之例示性抗PD-1單株抗體之重鏈可變區及全長重鏈的胺基酸序列(SEQ ID NO:13及SEQ ID NO:14)。
圖4顯示可用於本發明中之例示性抗PD-1單株抗體之替代輕鏈可變區的胺基酸序列(SEQ ID NO:15-17)。
圖5A-5B顯示可用於本發明中之例示性抗PD-1單株抗體之替代輕鏈的胺基酸序列,其中圖5A顯示K09A-L-11及K09A-L-16輕鏈之胺基
酸序列(分別為SEQ ID NO:18及19),且圖5B顯示K09A-L-17輕鏈之胺基酸序列(SEQ ID NO:20)。
圖6顯示MK-3475之重鏈及輕鏈之胺基酸序列(分別為SEQ ID NO:21及22)。
圖7顯示尼沃魯單抗(nivolumab)之重鏈及輕鏈之胺基酸序列(分別為SEQ ID NO:23及24)。
縮略語.貫穿本發明之詳細說明及實例,使用以下縮略語:
為了可更易於瞭解本發明,下文具體定義某些技術及科學術語。除非本文件中別處另有說明,否則本文所用所有技術及科學術語皆具有由本發明所屬之熟習此項技術者通常所瞭解之含義。
「約」在用於修飾數值定義之參數(例如,PD-1拮抗劑或VEGFR抑制劑之劑量或利用本文所述組合療法之治療時間長度)時意指該參數可變化高達低於或高於該參數之所述數值之10%。舉例而言,約5mg/kg之劑量可在4.5mg/kg與5.5mg/kg之間變化。
如本文(包括隨附申請專利範圍)所用,除非上下文明確表指示,否則諸如「一(a、an)」及「該(the)」等單詞之單數形式包括其相應複數個指示物。
「投與」及「處理」在應用於動物、人類、實驗個體、細胞、組織、器官或生物流體時係指外源性醫藥、治療、診斷試劑或組合物與動物、人類、個體、細胞、組織、器官或生物流體接觸。細胞之處理涵蓋試劑與細胞接觸、以及試劑與流體接觸,其中流體與細胞接觸。「投與」及「處理」亦意指(例如)細胞由試劑、診斷、結合化合物或由另一細胞之活體外及離體處理。術語「個體」包括任何生物體,較佳動物,更佳哺乳動物(例如,大鼠、小鼠、狗、貓、兔)且最
佳人類。
本文所用術語「抗體」係指展現期望生物或結合活性之任一形式的抗體。因此,其以最廣泛含義使用且特定而言涵蓋但不限於單株抗體(包括全長單株抗體)、多株抗體、多特異性抗體(例如,雙特異性抗體)、人類化全長人類抗體、嵌合抗體及駱駝化單一結構域抗體。「親代抗體」係在改良抗體用於預期用途(例如人類化抗體用作人類治療劑)之前藉由將免疫系統保留於抗原獲得之抗體。
一般而言,基本抗體結構單元包含四聚物。每一四聚物包括兩對相同多肽鏈,每一對具有一個「輕」鏈(約25kDa)及一條「重」鏈(約50-70kDa)。每一鏈之胺基末端部分包括約100至110或更多個胺基酸的可變區,其主要負責抗原識別。重鏈之羧基末端部分可定義主要負責效應子功能之恆定區。通常,人類輕鏈分類為κ及λ輕鏈。此外,人類重鏈通常分類為μ、δ、γ、α或ε,且將抗體之同種型分別定義為IgM、IgD、IgG、IgA及IgE。在輕鏈及重鏈內,可變區及恆定區由約12或更多個胺基酸之「J」區連接,其中該重鏈亦包括約10或更多個胺基酸之「D」區。通常參見Fundamental Immunology Ch.7(Paul,W.編輯,第2版,Raven Press,N.Y.(1989)。
每一輕鏈/重鏈對之可變區形成抗體結合位點。因此,一般而言,完整抗體具有兩個結合位點。除在雙功能或雙特異性抗體中外,兩個結合位點通常相同。
通常,重鏈及輕鏈二者之可變結構域包含三個超變區,亦稱作互補決定區(CDR),其位於相對保守之框架區(FR)內。CDR通常由框架區比對,從而使得能夠結合至特異性表位。一般而言,自N末端至C末端,輕鏈及重鏈可變結構域二者皆包含FR1、CDR1、FR2、CDR2、FR3、CDR3及FR4。胺基酸與每一結構域之比對通常係根據如下之定義:Sequences of Proteins of Immunological Interest,Kabat
等人;National Institutes of Health,Bethesda,Md.;第5版;NIH出版號91-3242(1991);Kabat(1978)Adv.Prot.Chem.32:1-75;Kabat等人,(1977)J.Biol.Chem.252:6609-6616;Chothia等人,(1987)J Mol.Biol.196:901-917或Chothia等人,(1989)Nature 342:878-883。
本文所用術語「超變區」係指負責抗原結合之抗體胺基酸殘基。超變區包含「互補決定區」或「CDR」之胺基酸殘基(即輕鏈可變結構域中之CDRL1、CDRL2及CDRL3及重鏈可變結構域中之CDRH1、CDRH2及CDRH3)。參見Kabat等人,(1991)Sequences of Proteins of Immunological Interest,第5版,Public Health Service,National Institutes of Health,Bethesda,Md.(藉由序列定義抗體之CDR區);亦參見Chothia及Lesk(1987)J.Mol.Biol.196:901-917(藉由結構定義抗體之CDR區)。本文所用術語「框架」或「FR」殘基係指彼等不同於本文定義為CDR殘基之超變區殘基的可變結構域殘基。
除非另外指示,否則如本文所用「抗體片段」或「抗原結合片段」係指抗體之抗原結合片段,即保留特異性結合至由全長抗體結合之抗原之能力之抗體片段,例如保留一或多個CDR區之片段。抗體結合片段之實例包括(但不限於)Fab、Fab'、F(ab')2及Fv片段;雙鏈抗體;線性抗體;單鏈抗體分子(例如sc-Fv);奈米抗體及自抗體片段形成之多特異性抗體。
「特異性結合至」指定靶標蛋白之抗體係與其他蛋白質相比展現優先結合至該靶標之抗體,但此特異性無需絕對結合特異性。若抗體之結合決定試樣中靶標蛋白質之存在而不(例如)產生不期望結果(例如假陽性),則認為抗體對其預期靶標具有「特異性」。可用於本發明中之抗體或其結合片段將以與非靶標蛋白質之親和力之至少兩倍、較佳至少10倍、更佳至少20倍且最佳至少100倍之親和力結合至靶標蛋白質。如本文所用,若抗體結合至包含給定胺基酸序列(例如成熟
人類PD-1或人類PD-L1分子之胺基酸序列)之多肽但不結合至無該序列之蛋白質,則據稱該抗體特異性結合至包含該序列之多肽。
「嵌合抗體」係指如下抗體以及該等抗體之片段:其中重鏈及/或輕鏈之一部分與源自特定物種(例如人類)或屬特定抗體種類或亞類之抗體中相應序列相同或同源,而鏈之其餘部分與源自另一物種(例如小鼠)或屬另一抗體種類或亞類之抗體中相應序列相同或同源,只要其展現期望生物活性即可。
「人類抗體」係指僅包含人類免疫球蛋白蛋白質序列之抗體。若人類抗體係在小鼠、小鼠細胞或源自小鼠細胞之雜交瘤中產生,則其可含有鼠類碳水化合物鏈。類似地,「小鼠抗體」或「大鼠抗體」係指僅分別包含小鼠或大鼠免疫球蛋白序列之抗體。
「人類化抗體」係指含有來自非人類(例如,鼠類)抗體以及人類抗體之序列的抗體形式。該等抗體含有源自非人類免疫球蛋白之最小序列。通常,人類化抗體將包含實質上全部的至少一個且通常兩個可變結構域,其中全部或實質上全部超變環對應於非人類免疫球蛋白之超變環,且全部或實質上全部FR區為人類免疫球蛋白序列之FR區。人類化抗體視情況亦包含免疫球蛋白恆定區(Fc)(通常為人類免疫球蛋白恆定區)的至少一部分。在需要區分人類化抗體與親代齧齒類動物抗體時,將前綴「hum」、「hu」或「h」添加至抗體純系名稱。齧齒類動物抗體之人類化形式通常將包含親代齧齒類動物抗體之相同CDR序列,但可包括某些胺基酸取代以增加親和力、增加人類化抗體之穩定性或用於其他原因。
術語「癌症」、「癌性」或「惡性」係指或描述哺乳動物中特徵通常在於細胞生長失調之生理學病況。癌症之實例包括(但不限於)癌、淋巴瘤、白血病、胚細胞瘤及肉瘤。該等癌症之更特定實例包括鱗狀細胞癌、骨髓瘤、小細胞肺癌、非小細胞肺癌、膠質瘤、何傑金
氏淋巴瘤、非何傑金氏淋巴瘤、急性骨髓性白血病(AML)、多發性骨髓瘤、胃腸(道)癌、腎癌、卵巢癌、肝癌、淋巴母細胞性白血病、淋巴球性白血病、結腸直腸癌、子宮內膜癌、腎癌、前列腺癌、甲狀腺癌、黑色素瘤、軟骨肉瘤、神經母細胞瘤、胰臟癌、多形性神經膠質母細胞瘤、子宮頸癌、腦癌、胃癌、膀胱癌、肝細胞瘤、乳癌、結腸癌及頭頸癌。癌症之另一特定實例包括腎細胞癌。癌症之又一特定實例包括透明細胞腎癌。可根據本發明治療之癌症包括彼等特徵在於測試組織試樣中PD-L1及PD-L2之一者或二者之表現升高者。
「生物治療劑」意指在支持腫瘤維持及/或生長或阻抑抗腫瘤免疫反應之任何生物途徑中阻斷配體/受體信號傳導的生物分子,例如抗體或融合蛋白。
除非另外指示,否則如本文所用「CDR」或「CDRs」意指免疫球蛋白可變區中使用Kabat編號系統定義之互補決定區。
「化學治療劑」係可用於治療癌症之化學化合物。化學治療劑之類別包括(但不限於):烷基化劑、抗代謝藥、激酶抑制劑、紡錘體毒劑植物鹼、細胞毒性/抗腫瘤抗生素、拓撲異構酶抑制劑、光敏化劑、抗雌激素及選擇性雌激素受體調節劑(SERM)、抗孕酮劑、雌激素受體下調劑(ERD)、雌激素受體拮抗劑、促黃體激素釋放激素促效劑、抗雄激素劑、芳香酶抑制劑、EGFR抑制劑、VEGF抑制劑及抑制參與異常細胞增殖或腫瘤生長之基因表現的反義寡核苷酸。可用於本發明治療方法中之化學治療劑包括細胞生長抑制劑及/或細胞毒性劑。
如本文所用「Chothia」意指Al-Lazikani等人,JMB 273:927-948(1997)中所述之抗體編號系統。
「保守修飾變體」或「保守取代」係指蛋白質中之胺基酸經具有類似特性(例如電荷、側鏈大小、疏水性/親水性、主鏈構象及剛性
等)之其他胺基酸取代,使得通常可進行變化而不改變蛋白質之生物活性或其他期望性質,例如抗原親和力及/或特異性。彼等熟習此項技術者應認識到,一般而言,在多肽之非必需區中之單一胺基酸取代不會實質上改變生物活性(例如,參見Watson等人(1987)Molecular Biology of the Gene,The Benjamin/Cummings Pub.公司,第224頁(第4版))。另外,結構或功能類似之胺基酸之取代較不可能破壞生物活性。例示性保守取代闡述於下表1中。
如整個說明書及申請專利範圍所用,「基本上由……組成(consists essentially of)」或變化形式(例如「consist essentially of」或「consisting essentially of」)指示包括任何所列舉之成份或成份組,且視情況包括具有與所列舉之成份類似或不同性質且不會實質上改變特定給藥方案、方法或組合物之基本或新穎性質之其他成份。作為非限制性實例,基本上由所列舉胺基酸序列組成之PD-1拮抗劑亦可包括一或多種不會實質上影響結合化合物之性質的胺基酸(包括一或多種胺基酸殘基之取代)。
「診斷性抗PD-L單株抗體」意指特異性結合至在某些哺乳動物細胞表面上表現之指定PD-L之成熟形式(PD-L1或PDL2)的mAb。成熟PD-L無前分泌前導序列,亦稱作前導肽。術語「PD-L」及「成熟PD-L」在本文中可互換使用,且除非另外指示或子上下文易於明瞭,否則應理解為意指相同分子。
如本文所用,診斷性抗人類PD-L1 mAb或抗hPD-L1 mAb係指特異性結合至成熟人類PD-L1之單株抗體。成熟人類PD-L1分子由以下序列之胺基酸19-290組成:
SKKQSDTHLEET(SEQ ID NO:25)。
適用於在免疫組織化學(IHC)中作為診斷性mAb供檢測經過福爾馬林固定、石蠟包埋(FFPE)之腫瘤組織切片中PD-L1表現之診斷性抗人類PD-L1 mAb之具體實例係抗體20C3及抗體22C3,其闡述於於
2013年12月18日提出申請且於2014年6月26日公開為WO2014/100079之共同待決之國際專利申請案PCT/US13/075932。據報導另一種可用於IHC供檢測FFPE組織切片中PD-L1表現之抗人類PD-L1 mAb(Chen,B.J.等人,Clin Cancer Res 19:3462-3473(2013))係可自Sino Biological公司(Beijing,P.R.China;目錄編號10084-R015)公開獲得之兔抗人類PD-L1 mAb。
如本文所用「框架區」或「FR」意指不包括CDR區之免疫球蛋白可變區。
「同源性」係指兩種多肽序列在最佳比對時其之間之序列類似性。在兩個比較序列中,二者同一位置由相同胺基酸單體亞單位佔據時,例如,若兩種不同Ab之輕鏈CDR中之位置由丙胺酸佔據,則兩種Ab在該位置處係同源性。同源性%係由兩個序列共享之同源位置之數目除以比較位置之總數目×100。舉例而言,若兩個序列經最佳比對時序列中10個位置中之8個匹配或同源,則兩個序列係80%同源。通常,在兩個序列經比對以產生最大同源性%時進行比較。舉例而言,可藉由BLAST算法進行比較,其中選擇算法之參數,以在各別參考序列之整個長度範圍內各別序列之間產生最大匹配。
以下參考文獻係關於通常用於序列分析之BLAST算法:BLAST算法:Altschul,S.F.等人,(1990)J.Mol.Biol.215:403-410;Gish,W.等人,(1993)Nature Genet.3:266-272;Madden,T.L.等人,(1996)Meth.Enzymol.266:131-141;Altschul,S.F.等人,(1997)Nucleic Acids Res.25:3389-3402;Zhang,J.等人,(1997)Genome Res.7:649-656;Wootton,J.C.等人,(1993)Comput.Chem.17:149-163;Hancock,J.M.等人,(1994)Comput.Appl.Biosci.10:67-70;比對評分系統(ALIGNMENT SCORING SYSTEMS):Dayhoff,M.O.等人,「A model of evolutionary change in proteins.」in Atlas of Protein
Sequence and Structure,(1978),第5卷,增刊3.M.O.Dayhoff(編輯),第345-352頁,Natl.Biomed.Res.Found.,Washington,DC;Schwartz,R.M.等人,「Matrices for detecting distant relationships.」in Atlas of Protein Sequence and Structure,(1978),第5卷,增刊3。」M.O.Dayhoff(編輯),第353-358頁,Natl.Biomed.Res.Found.,Washington,DC;Altschul,S.F.,(1991)J.Mol.Biol.219:555-565;States,D.J.等人,(1991)Methods 3:66-70;Henikoff,S.等人,(1992)Proc.Natl.Acad.Sci.USA 89:10915-10919;Altschul,S.F.等人,(1993)J.Mol.Evol.36:290-300;比對統計學:Karlin,S.等人,(1990)Proc.Natl.Acad.Sci.USA 87:2264-2268;Karlin,S.等人,(1993)Proc.Natl.Acad.Sci.USA 90:5873-5877;Dembo,A.等人,(1994)Ann.Prob.22:2022-2039;及Altschul,S.F.「Evaluating the statistical significance of multiple distinct local alignments.」in Theoretical and Computational Methods in Genome Research(S.Suhai編輯),(1997),第1-14頁,Plenum,New York。
「分離之抗體」及「分離之抗體片段」係指純化狀態且在該情況下意指所指名之分子實質上無其他生物分子,例如核酸、蛋白質、脂質、碳水化合物或其他材料(例如細胞碎片及生長培養基)。通常,術語「經分離」並無意指完全沒有該材料或沒有水、緩衝液或鹽,除非其含量會實質上干擾如本文所述結合化合物之實驗或治療用途。
如本文所用「Kabat」意指由Elvin A.Kabat((1991)Sequences of Proteins of Immunological Interest,第5版,Public Health Service,National Institutes of Health,Bethesda,Md.)提出之免疫球蛋白比對及編號系統。
如本文所用「單株抗體」或「mAb」或「Mab」係指實質上同源抗體之群體,即,包含該群體之抗體分子之胺基酸序列相同,只是可
存在微量之可能天然存在之突變。相比之下,習用(多株)抗體製劑通常包括多種在其可變結構域、尤其其CDR(其通常對不同表位具有特異性)中具有不同胺基酸序列之不同抗體。修飾詞「單株」指示抗體之特徵在於自實質上同源之抗體群體獲得,且不應理解為需要藉由任一特定方法來產生該抗體。舉例而言,欲根據本發明使用之單株抗體可藉由由Kohler等人(1975)Nature 256:495首次闡述之雜交瘤方法製得,或可藉由重組DNA方法製得(參見,例如,美國專利第4,816,567號)。「單株抗體」亦可使用以下中所述之技術自噬菌體抗體庫分離:例如,Clackson等人(1991)Nature 352:624-628及Marks等人(1991)J.Mol.Biol.222:581-597。亦參見Presta(2005)J.Allergy Clin.Immunol.116:731。
「患者」或「個體」係指需要醫療法或參與臨床試驗、流行病學研究或用作對照之任一單一個體,包括人類及哺乳動物獸醫患者,例如牛、馬、狗及貓。
「PD-1拮抗劑」意指阻斷表現於癌細胞上之PD-L1與表現於免疫細胞(T細胞、B細胞或NKT細胞)上之PD-1的結合且較佳亦阻斷表現於癌細胞上之PD-L2與免疫細胞表現之PD-1的結合的任何化學化合物或生物分子。PD-1及其配體之替代名稱或同義詞包括:對於PD-1而言為PDCD1、PD1、CD279及SLEB2;對於PD-L1而言為PDCD1L1、PDL1、B7H1、B7-4、CD274及B7-H;且對於PD-L2而言為PDCD1L2、PDL2、B7-DC、Btdc及CD273。在治療人類個體之任何本發明治療方法、藥劑及用途中,PD-1拮抗劑阻斷人類PD-L1與人類PD-1之結合,且較佳阻斷人類PD-L1與PD-L2二者與人類PD1之結合。人類PD-1胺基酸序列可參見NCBI位點編號:NP_005009。人類PD-L1及PD-L2胺基酸序列可分別參見NCBI位點編號:NP_054862及NP_079515。
可用於任何本發明治療方法、藥劑及用途之PD-1拮抗劑包括單株抗體(mAb)或其抗原結合片段,其特異性結合至PD-1或PD-L1,且較佳地特異性結合至人類PD-1或人類PD-L1。mAb可為人類抗體、人類化抗體或嵌合抗體,且可包括人類恆定區。在一些實施例中,人類恆定區係選自由IgG1、IgG2、IgG3及IgG4恆定區組成之群,且在較佳實施例中,人類恆定區係IgG1或IgG4恆定區。在一些實施例中,抗原結合片段係選自由Fab、Fab'-SH、F(ab')2、scFv及Fv片段組成之群。
結合至人類PD-1且可用於本發明之治療方法、藥劑及用途中之mAb之實例闡述於US7488802、US7521051、US8008449、US8354509、US8168757、WO2004/004771、WO2004/072286、WO2004/056875及US2011/0271358中。在本發明之治療方法、藥劑及用途中可用作PD-1拮抗劑之特異性抗人類PD-1 mAb包括:MK-3475(一種具有WHO Drug Information,第27卷,第2期,第161-162頁(2013)中所述之結構且包含圖6中所示之重鏈及輕鏈胺基酸序列的人類化IgG4 mAb)、尼沃魯單抗(BMS-936558)(一種具有WHO Drug Information,第27卷,第1期,第68-69頁(2013)中所述之結構且包含圖7中所示之重鏈及輕鏈胺基酸序列的人類IgG4 mAb);人類化抗體h409A11、h409A16及h409A17(其闡述於WO2008/156712中)及AMP-514(其由MedImmune研發)。
結合至人類PD-L1且可用於本發明之治療方法、藥劑及用途中之mAb之實例闡述於WO2013/019906、W02010/077634 A1及US8383796中。在本發明之治療方法、藥劑及用途中可用作PD-1拮抗劑之特定抗人類PD-L1 mAb包括MPDL3280A、BMS-936559、MEDI4736、MSB0010718C及分別包含WO2013/019906之SEQ ID NO:24及SEQ ID NO:21之重鏈及輕鏈可變區的抗體。
可用於本發明之治療方法、藥劑及用途中之任一者中之其他PD-1拮抗劑包括特異性結合至PD-1或PD-L1、且較佳特異性結合至人類PD-1或人類PD-L1之免疫黏附素,例如含有融合至恆定區(例如免疫球蛋白分子之Fc區)之PD-L1或PD-L2之細胞外或PD-1結合部分的融合蛋白。特異性結合至PD-1之免疫黏附分子之實例闡述於WO2010/027827及WO2011/066342中。在本發明之治療方法、藥劑及用途中用作PD-1拮抗劑之特異性融合蛋白包括AMP-224(亦稱作B7-DCIg),其係PD-L2-FC融合蛋白且結合至人類PD-1。
在本發明之治療方法、藥劑及用途之一些較佳實施例中,PD-1拮抗劑係單株抗體或其抗原結合片段,其包含:(a)輕鏈CDR SEQ ID NO:1、2及3及重鏈CDR SEQ ID NO:4、5及6;或(b)輕鏈CDR SEQ ID NO:7、8及9及重鏈CDR SEQ ID NO:10、11及12。
在本發明之治療方法、藥劑及用途之其他較佳實施例中,PD-1拮抗劑係單株抗體或其抗原結合片段,其特異性結合至人類PD-1且包含(a)包含SEQ ID NO:13或其變體之重鏈可變區,及(b)包含選自由以下組成之群之胺基酸序列之輕鏈可變區:SEQ ID NO:15或其變體;SEQ ID NO:16或其變體;及SEQ ID NO:17或其變體。重鏈可變區序列之變體除在框架區中(即,在CDR外部)具有至多17個保守胺基酸取代外與參考序列相同,且在框架區中較佳具有小於10、9、8、7、6或5個保守胺基酸取代。輕鏈可變區序列之變體除在框架區中(即,在CDR外部)具有至多5個保守胺基酸取代外與參考序列相同,且在框架區中較佳具有小於4、3或2個保守胺基酸取代。
在本發明之治療方法、藥劑及用途之另一較佳實施例中,PD-1拮抗劑係特異性結合至人類PD-1且包含(a)包含SEQ ID NO:14之重鏈及(b)包含SEQ ID NO:18、SEQ ID NO:19或SEQ ID NO:20之輕鏈的單株抗體。
在本發明之治療方法、藥劑及用途之又一較佳實施例中,PD-1拮抗劑係特異性結合至人類PD-1且包含(a)包含SEQ ID NO:14之重鏈及(b)包含SEQ ID NO:18之輕鏈的單株抗體。
下表2提供用於本發明之治療方法、藥劑及用途中之例示性抗PD-1 mAb之胺基酸序列的列表,且序列示於圖1-5中。
如本文所用之「PD-L1」表現或「PD-L2」表現意指細胞表面上之指定PD-L蛋白質或細胞或組織內之指定PD-L mRNA之任何可檢測之表現程度。PD-L蛋白質表現可利用診斷性PD-L抗體在腫瘤組織切片之IHC分析中或藉由流式細胞術檢測。或者,由腫瘤細胞之PD-L蛋白質表現可藉由PET成像使用特異性結合至期望PD-L靶標(例如,PD-L1或PD-L2)之結合劑(例如,抗體片段、親和體及諸如此類)檢測。用於檢測及量測PD-L mRNA表現之技術包括RT-PCR及實時定量RT-PCR。
已闡述若干用於在腫瘤組織切片之IHC分析中定量PD-L1蛋白質表現之方法。參見(例如)Thompson,R.H.等人,PNAS 101(49);17174-17179(2004);Thompson,R.H.等人,Cancer Res. 66:3381-3385(2006);Gadiot,J.等人,Cancer 117:2192-2201(2011);Taube,J.M.等人,Sci Transl Med 4,127ra37(2012);及Toplian,S.L.等人,New Eng.J Med. 366(26):2443-2454(2012)。
一種方法採用PD-L1表現呈陽性或陰性之簡單二元終點,其中陽性結果在展現細胞表面膜染色之組織學證據之腫瘤細胞百分比方面加以定義。將腫瘤組織切片計數為總腫瘤細胞之至少1%且較佳5%之PD-L1表現呈陽性。
在另一方法中,在腫瘤細胞中以及在浸潤免疫細胞(其主要包含淋巴球)中定量腫瘤組織切片中之PD-L1表現。將展現膜染色之腫瘤細胞及浸潤免疫細胞之百分比單獨地定量為<5%、5%至9%及隨後以10%增量直至100%。對於腫瘤細胞,若評分<5%評分,則將PD-L1表現計數為陰性,且若評分5%則為陽性。免疫浸潤中之PD-L1表現報導為稱作經調節發炎評分(AIS)之半定量量測,該評分係藉由使膜染色細胞之百分比乘以浸潤之強度測定,其分級為無(0)、輕度(評分為1,稀少淋巴球)、中度(評分為2,由淋巴組織細胞聚集物之腫瘤之
局灶浸潤)或嚴重(評分為3,彌漫性浸潤)。若AIS係5,則藉由免疫浸潤將腫瘤組織切片計數為PD-L1表現呈陽性。
可比較PD-L mRNA表現程度與一或多種常用於定量RT-PCR中之參考基因(例如泛素C)之mRNA表現程度。
在一些實施例中,基於與由適當對照之PD-L1表現程度(蛋白質及/或mRNA)的比較,由惡性細胞及/或由腫瘤內之浸潤免疫細胞之PD-L1表現程度(蛋白質及/或mRNA)測定為「過表現」或「升高」。舉例而言,對照PD-L1蛋白質或mRNA表現程度可為相同類型之非惡性細胞中或來自匹配正常組織之切片中定量的程度。在一些較佳實施例中,若試樣中之PD-L1蛋白質(及/或PD-L1 mRNA)較對照中大至少10%、20%或30%,則腫瘤試樣中之PD-L1表現測定為升高。
如本文所用「RECIST 1.1反應準則」意指Eisenhauer等人、E.A.等人,Eur.J Cancer 45:228-247(2009)若需要基於所量測反應之背景針對靶標損傷或非靶標損傷所述之定義。
「持續反應」意指在停止用本文所述治療劑或組合療法治療後之持續治療效應。在一些實施例中,持續反應具有至少與治療持續時間相同或係治療持續時間之至少1.5、2.0、2.5或3倍之持續時間。
「組織切片」係指組織試樣之單一部分或片,例如,自正常組織或腫瘤之試樣切割之組織薄片。
如本文所用「治療」(「treat」或「treating」)癌症意指向患有癌症或經診斷患有癌症之個體投與PD-1拮抗劑與VEGFR抑制劑之組合療法以達成至少一種陽性治療效應(例如,癌細胞數目減少、腫瘤大小減小、癌細胞浸潤至周邊器官之速率降低或腫瘤轉移或腫瘤生長之速率降低)。癌症中之陽性治療效應可以多種方式量測(參見W.A.Weber,J.Nucl.Med.50:1S-10S(2009))。舉例而言,關於腫瘤生長抑制,根據NCI標準,T/C≦42%係抗腫瘤活性之最小量。認為T/C<
10%係高抗腫瘤活性量,其中T/C(%)=經治療腫瘤體積中值/對照腫瘤體積中值×100。在一些實施例中,藉由本發明組合達成之治療係PR、CR、OR、PFS、DFS及OS中之任一者。PFS(亦稱作「至腫瘤進展之時間」)指示治療期間及之後癌症不生長之時間長度,且包括患者經歷CR或PR之時間量以及患者經歷SD之時間量。DFS係指治療期間及之後患者仍無疾病之時間長度。OS係指與初始或未經治療之個體或患者相比預期壽命之延長。在一些較佳實施例中,對本發明組合之反應係PR、CR、PFS、DFS、OR或OS中之任一者,其係使用RECIST 1.1反應準則評定。有效治療癌症患者之本發明組合之治療方案可根據多種因素(例如患者之疾病狀態、年齡及體重及療法激發個體之抗癌反應之能力)而變。儘管本發明之任何態樣之實施例可不在每個個體中有效達成陽性治療效應,但在統計上顯著之數目之個體中應有效達成陽性治療效應,如藉由業內已知之任何統計測試(例如Student’s測試、chi2-測試、根據Mann及Whitney之U-測試、Kruskal-Wallis測試(H-測試)、Jonckheere-Terpstra-測試及Wilcoxon-測試)所測定。
術語「治療方案」、「投藥方案」(「dosing protocol」)及投藥方案(dosing regimen)可互換使用,係指本發明組合中每一治療劑之投與劑量及定時。
「腫瘤」在應用於經診斷患有或懷疑患有癌症之個體時係指惡性或潛在惡性贅瘤或任何大小之組織塊,且包括原發性腫瘤及繼發性贅瘤。實體瘤係通常不含囊腫或液體區域之組織之異常生長或塊。不同類型之實體係瘤針對形成其之細胞類型來命名。實體瘤之實例係肉瘤、癌及淋巴瘤。白血病(血液癌)通常不會形成實體瘤(National Cancer Institute,Dictionary of Cancer Terms)。
「腫瘤負荷(Tumor burden)」亦稱為「腫瘤負荷(tumor load)」,
係指分佈於整個體內之腫瘤物質之總量。腫瘤負荷係指整個體內(包括淋巴結及骨髓)之癌細胞之總數目或腫瘤之總大小。腫瘤負荷可藉由此項技術中已知之多種方法測定,例如在腫瘤自個體移除後(例如)使用卡尺、或在體內時使用成像技術(例如超音波、骨掃描、電腦斷層攝影(CT)或磁共振成像(MRI)掃描)量測其尺寸。
術語「腫瘤大小」係指腫瘤之總大小,其可量測為腫瘤之長度及寬度。腫瘤大小可藉由此項技術中已知之多種方法測定,例如在腫瘤自個體移除後(例如)使用卡尺、或在體內時使用成像技術(例如骨掃描、超音波、CT或MRI掃描)量測其尺寸。
如本文中所用「可變區」或「V區」或「V鏈」意指不同抗體間之序列可變之IgG鏈的區段。其延伸至輕鏈中之Kabat殘基109及重鏈中之113。
「VEGFR抑制劑」意指血管內皮生長因子(VEGF)受體之小分子抑制劑或針對血管內皮生長因子(VEGF)之單株抗體。在實施例中,「VEGFR抑制劑」意指血管內皮生長因子(VEGF)受體之小分子抑制劑。在本發明之治療方法、藥劑及用途中用作VEGFR抑制劑之具體VEGFR抑制劑包括阿西替尼(axitinib)、舒尼替尼(sunitinib)、索拉非尼(sorafenib)、替沃紮尼(tivozanib)及貝伐單抗(bevacizumab)。在實施例中,在本發明之治療方法、藥劑及用途中用作VEGFR抑制劑之具體VEGFR抑制劑包括阿西替尼、舒尼替尼、索拉非尼及替沃紮尼。
在本發明之治療方法、藥劑及用途之實施例中,VEGFR抑制劑係具有以下結構之化合物N-甲基-2-[3-((E)-2-吡啶-2-基-乙烯基)-1H-吲唑-6-基硫基]-苯甲醯胺或6-[2-(甲基胺甲醯基)苯基硫基]-3-E-[2-(吡啶-2-基)乙烯基]吲唑:
其稱作阿西替尼或AG-013736。
阿西替尼係血管內皮生長因子(VEGF)受體1、2及3之有效選擇性抑制劑。該等受體參與病理性血管生成、腫瘤生長及癌症之轉移性進展。阿西替尼已顯示有效抑制VEGF調介之內皮細胞增殖及存活(Hu-Lowe,D.D.等人,Clin Cancer Res 14:7272-7283(2008);Solowiej,S.等人,Biochemistry 48:7019-31(2009))。臨床試驗目前正在進行或實施以研究阿西替尼用於治療各種癌症(包括肝癌、黑色素瘤、間皮瘤、非小細胞肺癌、前列腺癌、腎細胞癌、軟組織肉瘤及實體瘤)之用途。Inlyta®(阿西替尼)已在美國、歐洲、日本及其他管轄區域批准用於治療腎細胞癌。
阿西替尼以及其醫藥上可接受之鹽闡述於美國專利第6,534,524號中。製備阿西替尼之方法闡述於美國專利第6,884,890號及第7,232,910號、美國公開案第2006-0091067號及第2007-0203196號及國際公開案第WO 2006/048745號中。阿西替尼之劑型闡述於美國公開案第2004-0224988號中。阿西替尼之多晶型式及醫藥組合物亦闡述於美國專利第8,791,140號及美國公開案第2006-0094763號、第2008-0274192號及第2014-0248347號中。阿西替尼之用途(包括用作單一藥劑或用於組合治療)闡述於美國專利第7,141,581號及美國公開案第2014-0288125號中。上文列舉之專利及專利申請案以引用方式併入本文中。
應瞭解,除非另外指明,否則阿西替尼包括提及其鹽。阿西替尼本質上係鹼性且能夠與各種無機及有機酸形成多種鹽。如本文所用
術語「鹽」表示與無機及/或有機酸形成之酸性鹽。阿西替尼之醫藥上可接受之鹽可(例如)藉由使阿西替尼與一定量(例如等效量)之酸在介質(例如鹽於其中沈澱者)或水性介質中反應、之後凍乾來形成。
阿西替尼之例示性酸加成鹽包括乙酸鹽、抗壞血酸鹽、苯甲酸鹽、苯磺酸鹽、硫酸氫鹽、硼酸鹽、丁酸鹽、檸檬酸鹽、樟腦酸鹽、樟腦磺酸鹽、富馬酸鹽、鹽酸鹽、氫溴酸鹽、氫碘酸鹽、乳酸鹽、馬來酸鹽、甲磺酸鹽、萘磺酸鹽、硝酸鹽、草酸鹽、磷酸鹽、丙酸鹽、水楊酸鹽、琥珀酸鹽、硫酸鹽、酒石酸鹽、硫氰酸鹽、甲苯磺酸鹽(toluenesulfonate,亦稱作tosylate)及諸如此類。另外,通常視為適於自鹼性醫藥化合物形成醫藥上有用之鹽的酸係論述於以下中:例如,S.Berge等人,Journal of Pharmaceutical Sciences(1977)66(1)1-19;P.Gould,International J.of Pharmaceutics(1986)33 201-217;Anderson等人,The Practice of Medicinal Chemistry(1996),Academic Press,New York;及The Orange Book(Food & Drug Administration,Washington,D.C.,在其網站上)。該等揭示內容以引用方式併入本文中。
出於本發明之目的,所有該等酸性鹽皆意欲係如用於本發明中之屬阿西替尼之範疇內之醫藥上可接受之鹽,且認為所有酸性鹽皆等效於相應化合物之游離形式。
阿西替尼之前藥亦預期用於本發明之方法、藥劑及用途中。如本文所用術語「前藥」表示係在投與個體後藉由代謝或化學過程經歷化學轉化以產生阿西替尼或其鹽的藥物前體之化合物。前藥之論述提供於以下中:T.Higuchi及V.Stella,Pro-drugs as Novel Delivery Systems(1987)14 of the A.C.S.Symposium Series,及Bioreversible Carriers in Drug Design,(1987)Edward B.Roche編輯,American Pharmaceutical Association and Pergamon Press,二者皆以引用方式併
入本文中。
在本發明之一個態樣中,本發明提供用於治療個體之癌症之方法,其包含向個體投與包含PD-1拮抗劑及VEGFR抑制劑之組合療法。
組合療法亦可包含一或多種額外治療劑。額外治療劑可為(例如)除VEGFR抑制劑外之化學治療劑、生物治療劑(包括但不限於針對VEGF、EGFR、Her2/neu、其他生長因子受體、CD20,CD40、CD-40L、CTLA-4、OX-40、4-1BB及ICOS之抗體)、免疫試劑(例如,減毒癌細胞、腫瘤抗原、抗原呈遞細胞(例如經腫瘤衍生之抗原或核酸脈衝之樹突細胞)、免疫刺激細胞因子(例如,IL-2、IFN α2、GM-CSF)及經編碼免疫刺激細胞因子(例如但不限於GM-CSF)之基因轉染之細胞)。
化學治療藥劑之實例包括烷基化劑,例如噻替哌(thiotepa)及環磷醯胺;磺酸烷基酯,例如白消安(busulfan)、英丙舒凡(improsulfan)及哌泊舒凡(piposulfan);氮丙啶,例如苯并多巴(benzodopa)、卡波醌(carboquone)、米得哌(meturedopa)及烏得哌(uredopa);伸乙基亞胺及甲基密胺,包括六甲密胺(altretamine)、三伸乙基密胺、三伸乙基磷醯胺、三伸乙基硫化磷醯胺及三羥甲基密胺;番荔枝內酯(acetogenin)(尤其係布拉他辛(bullatacin)及布拉他辛酮(bullatacinone));喜樹鹼(camptothecin)(包括合成類似物托泊替康(topotecan));苔蘚抑制素(bryostatin);卡利抑制素(callystatin);CC-1065(包括其合成類似物阿多來新(adozelesin)、卡折來新(carzelesin)及比折來新(bizelesin));克利特非辛(cryptophycin)(尤其係克利特非辛1及克利特非辛8);多拉司他汀(dolastatin);多卡米星(duocarmycin)(包括合成類似物KW-2189及CBI-TMI);艾榴塞洛素(eleutherobin);
水鬼蕉鹼(pancratistatin);匍枝珊瑚醇(sarcodictyin);海綿素(spongistatin);氮芥(nitrogen mustards),例如苯丁酸氮芥(chlorambucil)、萘氮芥(chlornaphazine)、氯磷醯胺、雌氮芥(estramustine)、異環磷醯胺(ifosfamide)、雙氯乙基甲胺(mechlorethamine)、雙氯乙基甲胺氧化物鹽酸鹽、美法倉(melphalan)、新氮芥(novembichin)、苯乙酸氮芥膽甾醇酯(phenesterine)、潑尼莫司汀(prednimustine)、曲磷胺(trofosfamide)、尿嘧啶氮芥;亞硝基脲,例如卡莫司汀(carmustine)、氯脲菌素(chlorozotocin)、福莫司汀(fotemustine)、洛莫司汀(lomustine)、尼莫司汀(nimustine)、雷莫司汀(ranimnustine);抗生素,例如烯二炔抗生素(例如,卡奇黴素(calicheamicin),尤其卡奇黴素γ 1I及卡奇黴素phiI1(參見,例如,Agnew,Chem Intl.Ed.Engl.,33:183-186(1994));達內黴素(dynemicin),包括達內黴素A;雙膦酸鹽類,例如氯膦酸鹽(clodronate);埃斯培拉黴素(esperamicin);以及新製癌菌素髮色團(neocarzinostatin chromophore)及相關色蛋白烯二炔抗生素發色團)、阿克拉黴素(aclacinomysin)、放線菌素(actinomycin)、安麯黴素(authramycin)、偶氮絲胺酸(azaserine)、博萊黴素(bleomycin)、放線菌素C(cactinomycin)、卡拉黴素(carabicin)、洋紅黴素(caminomycin)、嗜癌黴素(carzinophilin)、色黴素(chromomycin)、放線菌素D(dactinomycin)、柔紅黴素(daunorubicin)、地托比星(detorubicin)、6-重氮基-5-側氧基-L-正白胺酸、多柔比星(doxorubicin)(包括嗎啉基-多柔比星、氰嗎啉基-多柔比星、2-吡咯啉基-多柔比星及去氧多柔比星)、表柔比星(epirubicin)、依索比星(esorubicin)、伊達比星(idarubicin)、麻西羅黴素(marcellomycin)、絲裂黴素(mitomycin)(例如絲裂黴素C)、黴酚酸、諾拉黴素(nogalamycin)、橄欖黴素(olivomycin)、培洛黴素(peplomycin)、泊非
黴素(potfiromycin)、嘌呤黴素(puromycin)、三鐵阿黴素(quelamycin)、羅多比星(rodorubicin)、鏈黑菌素(streptonigrin)、鏈脲菌素(streptozocin)、殺結核菌素(tubercidin)、烏苯美司(ubenimex)、淨司他丁(zinostatin)、佐柔比星(zorubicin);抗代謝物,例如胺甲蝶呤(methotrexate)及5-氟尿嘧啶(5-FU);葉酸類似物,例如二甲葉酸(denopterin)、胺甲喋呤、蝶羅呤(pteropterin)、曲美沙特(trimetrexate);嘌呤類似物,例如氟達拉濱(fludarabine)、6-巰基嘌呤、硫咪嘌呤(thiamiprine)、硫鳥嘌呤;嘧啶類似物,例如安西他濱(ancitabine)、阿紮胞苷(azacitidine)、6-阿紮尿苷(6-azauridine)、卡莫氟(carmofur)、阿糖胞苷(cytarabine)、二去氧尿苷、去氧氟尿苷(doxifluridine)、依諾他濱(enocitabine)、氟尿苷(floxuridine);雄激素,例如卡普睪酮(calusterone)、丙酸屈他雄酮(dromostanolone propionate)、環硫雄醇(epitiostanol)、美雄烷(mepitiostane)、睪內酯(testolactone);抗腎上腺素,例如胺魯米特(aminoglutethimide)、米托坦(mitotane)、曲洛司坦(trilostane);葉酸補充劑,例如亞葉酸;乙醯葡醛酸內酯(aceglatone);醛磷醯胺糖苷(aldophosphamide glycoside);胺基乙醯丙酸(aminolevulinic acid);恩尿嘧啶(eniluracil);安吖啶(amsacrine);百思布希(bestrabucil);比生群(bisantrene);依達曲沙(edatraxate);地磷醯胺(defofamine);秋水仙胺(demecolcine);地吖醌(diaziquone);依氟鳥胺酸(eflornithine);依利乙銨(elliptinium acetate);埃博黴素(epothilone);依託格魯(etoglucid);硝酸鎵;羥基脲;香菇多糖(lentinan);氯尼達明(lonidainine);類美坦辛(maytansinoid),例如美坦辛(maytansine)及柄型菌素(ansamitocin);米托脲腙(mitoguazone);米托蒽醌(mitoxantrone);莫哌達醇(mopidamol);尼群克林(nitraerine);噴托他汀(pentostatin);蛋胺氮芥(phenamet);吡柔比星(pirarubicin);洛索蒽醌(losoxantrone);鬼臼
酸;2-乙基醯肼;丙卡巴肼(procarbazine);雷佐生(razoxane);根黴素(rhizoxin);西佐喃(sizofiran);鍺螺胺(spirogermanium);細格孢氮雜酸(tenuazonic acid);三亞胺醌(triaziquone);2,2',2"-三氯三乙胺;單端孢黴烯(trichothecene)(尤其係T-2毒素、疣皰菌素A(verrucarin A)、桿孢菌素(roridin A)及蛇形菌素(anguidine));烏拉坦(urethane);長春地辛(vindesine);達卡巴嗪(dacarbazine);甘露莫司汀(mannomustine);二溴甘露醇(mitobronitol);二溴衛矛醇(mitolactol);哌泊溴烷(pipobroman);噶薩托辛(gacytosine);阿拉伯糖苷(arabinoside)(「Ara-C」);環磷醯胺;噻替哌;紫杉烷(taxoid),例如紫杉醇(paclitaxel)及多西紫杉醇(doxetaxel);苯丁酸氮芥;吉西他濱(gemcitabine);6-硫鳥嘌呤;巰基嘌呤;胺甲喋呤;鉑類似物,例如順鉑(cisplatin)及卡鉑(carboplatin);長春花鹼(vinblastine);鉑;依託泊苷(etoposide)(VP-16);異環磷醯胺;米托蒽醌;長春新鹼(vincristine);長春瑞濱(vinorelbine);諾安托(novantrone);替尼泊苷(teniposide);依達曲沙(edatrexate);道諾黴素(daunomycin);胺基蝶呤(aminopterin);希羅達(xeloda);伊班膦酸鹽(ibandronate);CPT-11;拓撲異構酶抑制劑RFS 2000;二氟甲基鳥胺酸(DMFO);類視色素,例如視黃酸;卡培他濱(capecitabine);及上述藥劑中任一者之醫藥上可接受之鹽、酸或衍生物。亦包括用於調節或抑制激素對腫瘤之作用之抗激素劑,例如抗雌激素及選擇性雌激素受體調節劑(SERM),包括(例如)他莫昔芬(tamoxifen)、雷洛昔芬(raloxifene)、屈洛昔芬(droloxifene)、4-羥基他莫昔芬、曲沃昔芬(trioxifene)、雷洛昔芬(keoxifene)、LY117018、奧那司酮(onapristone)及托瑞米芬(toremifene)(Fareston);抑制酶芳香酶之芳香酶抑制劑,其調節腎上腺中之雌激素產生,例如4(5)-咪唑、胺魯米特、乙酸甲地孕酮(megestrol acetate)、依西美坦(exemestane)、福美
坦(formestane)、法倔唑(fadrozole)、伏氯唑(vorozole)、來曲唑(letrozole)及阿那曲唑(anastrozole);及抗雄激素,例如氟他胺(flutamide)、尼魯米特(nilutamide)、比卡魯胺(bicalutamide)、亮丙瑞林(leuprolide)及戈舍瑞林(goserelin);及上述藥劑中任一者之醫藥上可接受之鹽、酸或衍生物。
根據標準醫藥實踐,本發明之組合療法中之每一治療劑可單獨投與或於藥劑(本文中亦稱作醫藥組合物)中投與,該藥劑包含治療劑及一或多種醫藥上可接受之載劑、賦形劑及稀釋劑。
本發明之組合療法中之每一治療劑可同時投與(即,在同一藥劑中)、並行投與(即,在單獨藥劑中,以任何次序一個接一個地投與)或以任何次序依序投與。在組合療法中之治療劑呈不同劑型(一種藥劑係錠劑或膠囊且另一藥劑係無菌液體)及/或以不同投藥時間表(例如,化學治療劑至少每日投與且生物治療劑較不頻繁(例如每週一次、每兩週一次或每三週一次)投與)時,依序投與尤其有用。
在一些實施例中,VEGFR抑制劑係在投與PD-1拮抗劑之前投與,而在其他實施例中,VEGFR抑制劑係在投與PD-1拮抗劑之後投與。
在一些實施例中,在藥劑作為單一療法用於治療相同癌症時,組合療法中之治療劑中之至少一者係使用相同給藥方案(劑量、頻率及治療持續時間)投與。在其他實施例中,與在藥劑用作單一療法時相比,患者服用較低總量之組合療法中之治療劑中之至少一者,例如,較小劑量、較小頻率給藥及/或較短治療持續時間。
本發明之組合療法中之每一小分子治療劑可經口或非經腸(包括靜脈內、肌內、腹膜內、皮下、經直腸、局部及經皮投與途徑)投與。
本發明之組合療法可在手術之前或之後使用以移除腫瘤且可在
療法之前、期間或之後使用。
在一些實施例中,將本發明之組合療法投與先前未經生物治療劑或化學治療劑治療(即,先前未經治療)之患者。在其他實施例中,將組合療法投與在用生物治療劑或化學治療劑之先前療法後不能達成持續反應(即,經歷治療)之患者。
通常使用本發明之組合療法來治療足夠大以藉由觸診或藉由此項技術中熟知之成像技術(例如MRI、超音波或CAT掃描)發現之腫瘤。在一些較佳實施例中,使用本發明之組合療法來治療具有至少約200mm3、300mm3、400mm3、500mm3、750mm3或最高1000mm3之尺寸之晚期腫瘤。
本發明之組合療法較佳投與患有PD-L1表現經測試呈陽性之癌症之人類患者。在一些較佳實施例中,在IHC分析中在自患者移除之腫瘤試樣之FFPE或冷凍組織切片上使用診斷性抗人類PD-L1抗體或其抗原結合片段檢測PD-L1表現。通常,患者之醫師將安排診斷性測試以測定在用PD-1拮抗劑及VEGFR抑制劑治療起始之前自患者移除之腫瘤組織試樣中的PD-L1表現,但設想醫師可在起始治療後之任何時間(例如在完成治療週期後)安排首次或隨後診斷性測試。
針對本發明之組合療法選擇給藥方案(本文中亦稱作投藥方案)取決於若干因素,包括實體之血清或組織轉換率、症狀之程度、實體之免疫原性及所治療個體中之靶標細胞、組織或器官之可達性。較佳地,給藥方案配合可接受之負效應程度來遞送最大量之各治療劑給患者。因此,組合中之每一生物治療劑及化學治療劑之劑量及投藥頻率部分取決於特定治療劑、所治療癌症之嚴重程度及患者特性。可以取得選擇抗體、細胞因子及小分子之適當劑量的指引。參見(例如)Wawrzynczak(1996)Antibody Therapy,Bios Scientific Pub.有限公司,Oxfordshire,UK;Kresina(編輯)(1991)Monoclonal Antibodies, Cytokines and Arthritis,Marcel Dekker,New York,NY;Bach(編輯)(1993)Monoclonal Antibodies and Peptide Therapy in Autoimmune Diseases,Marcel Dekker,New York,NY;Baert等人(2003)New Engl.J.Med.348:601-608;Milgrom等人(1999)New Engl.J.Med.341:1966-1973;Slamon等人(2001)New Engl.J.Med.344:783-792;Beniaminovitz等人(2000)New Engl.J.Med.342:613-619;Ghosh等人(2003)New Engl.J.Med.348:24-32;Lipsky等人(2000)New Engl.J.Med.343:1594-1602;Physicians' Desk Reference 2003(Physicians' Desk Reference,第57版);Medical Economics公司;ISBN:1563634457;第57版(2002年11月)。可由臨床醫師(例如)使用業內已知或懷疑會影響治療或預期會影響治療之參數或因子決定適當給藥方案,且將取決於(例如)患者之臨床病史(例如,先前療法)、欲治療之癌症之類型及階段及對組合療法中之一或多種治療劑之反應之生物標記。
本發明之組合療法中之生物治療劑可藉由連續輸注或藉由間隔劑量(例如每日、每隔一天、每週三次或每週一次、兩週、三週、每月、每兩個月等)投與。總每週劑量通常係至少0.05μg/kg、0.2μg/kg、0.5μg/kg、1μg/kg、10μg/kg、100μg/kg、0.2mg/kg、1.0mg/kg、2.0mg/kg、10mg/kg、25mg/kg、50mg/kg體重或更多。參見(例如)Yang等人(2003)New Engl.J.Med.349:427-434;Herold等人(2002)New Engl.J.Med.346:1692-1698;Liu等人(1999)J.Neurol.Neurosurg.Psych.67:451-456;Portielji等人(20003)Cancer Immunol.Immunother.52:133-144。
在採用抗人類PD-1 mAb作為組合療法中之PD-1拮抗劑的一些實施例中,投藥方案將包含在整個治療過程中以1mg/kg、2mg/kg、3mg/kg、5mg/kg或10mg/kg之劑量以約14天(±2天)或約21天(±2天)
或約30天(±2天)之間隔投與抗人類PD-1 mAb。
在採用抗人類PD-1 mAb作為組合療法中之PD-1拮抗劑的其他實施例中,投藥方案將包含以約0.005mg/kg至約10mg/kg之劑量投與抗人類PD-1 mAb,其中同一患者劑量增大。在其他增加劑量實施例中,劑量之間之間隔可逐漸縮短,例如第一與第二劑量之間約30天(±2天),第二與第三劑量之間約14天(±2天)。在某些實施例中,對於第二劑量後之劑量,投藥間隔將為約14天(±2天)。
在某些實施例中,向個體投與靜脈內(IV)輸注包含本文所述PD-1拮抗劑中之任一者之藥劑。
在本發明之一個較佳實施例中,組合療法中之PD-1拮抗劑係尼沃魯單抗,其係以選自由以下組成之群之劑量靜脈內投與:1mg/kgQ2W、2mg/kg Q2W、3mg/kg Q2W、5mg/kg Q2W、10mg Q2W、1mg/kg Q3W、2mg/kg Q3W、3mg/kg Q3W、5mg/kg Q3W及10mg Q3W。
在本發明之另一較佳實施例中,組合療法中之PD-1拮抗劑係MK-3475,其係以選自由以下組成之群之劑量在液體藥劑中投與:1mg/kg Q2W、2mg/kg Q2W、3mg/kg Q2W、5mg/kg Q2W、10mg Q2W、1mg/kg Q3W、2mg/kg Q3W、3mg/kg Q3W、5mg/kg Q3W、10mg Q3W及該等劑量中之任一者之固定劑量當量,即,例如200mg Q3W。在一些尤佳實施例中,MK-3475係以液體藥劑形式投與,該液體藥劑包含pH 5.5之10mM組胺酸緩衝液中之25mg/ml MK-3475、7%(w/v)蔗糖、0.02%(w/v)聚山梨醇酯80,且在約30分鐘之時間段內藉由IV輸注投與藥劑之選擇劑量。
可藉由該等藥劑中之一者或二者之劑量增加鑑別與阿西替尼組合之MK-3475之最佳劑量。在一個實施例中,阿西替尼係以5mg BID投與且MK-3475係以2mg/kg Q2W之起始劑量投與,且若患者不耐受
此劑量組合,則將MK-3475之劑量降低至10mg/kg Q2W之劑量,而若患者不耐受起始劑量組合,則將MK-3475之劑量降低至1mg/kg Q2W。
在另一實施例中,阿西替尼係以5mg BID投與且MK-3475係以2mg/kg Q3W之起始劑量投與,且若患者不耐受此起始劑量組合,則將MK-3475之劑量降低至1mg/kg Q3W。
在另一實施例中,阿西替尼係以5mg BID投與且MK-3475係以2mg/kg Q3W之起始劑量投與,且若患者不耐受此劑量組合,則將阿西替尼之劑量降低至3mg BID。
在實施例中,與食物一起或無食物BID投與5mg阿西替尼,其中所投與每一劑量間隔約12小時。在MK-3475投與當天,阿西替尼可在MK-3475投與之前或之後給予。
在一些實施例中,在即將投與MK-3475及阿西替尼組合之前先採用單一藥劑阿西替尼之7天導入期治療患者。
在一些實施例中,治療週期始於組合治療之第一天且持續2週。在該等實施例中,在患者達成CR後,組合療法較佳投與至少12週(6個治療週期)、更佳至少24週且甚至更佳至少2週。
在一些較佳實施例中,若患者耐受阿西替尼而無與藥物相關之等級>2之不利事件連續2週,則在6個週期後增加阿西替尼之劑量。阿西替尼之劑量可每一週期增加2mg BID,直至10mg BID之最大劑量。
在一些實施例中,選擇用於接受本發明組合療法治療之患者係經診斷患有具有主要透明細胞亞型且切除原發性腫瘤之晚期RCC患者。較佳地,患者過去未曾接受過針對晚期RCC之全身療法。
本發明亦提供包含如上文所述PD-1拮抗劑及醫藥上可接受之賦形劑的藥劑。在PD-1拮抗劑係生物治療劑(例如mAb)時,可使用習用
細胞培養及回收/純化技術在CHO細胞中產生拮抗劑。
在一些實施例中,包含作為PD-1拮抗劑之抗PD-1抗體之藥劑可呈液體調配物提供或由凍乾粉末在使用之前使用注射用無菌水重組後製得。WO 2012/135408闡述包含MK-3475且適用於本發明中之液體及凍乾藥劑的製備。在一些較佳實施例中,包含MK-3475之藥劑提供於含有約50mg MK-3475之玻璃小瓶中。
本發明亦提供包含阿西替尼及醫藥上可接受之賦形劑之藥劑。
本文所述抗PD-1及VEGFR抑制劑藥劑可呈包含第一容器及第二容器及包裝插頁之套組提供。第一容器含有至少一個劑量之包含抗PD-1拮抗劑之藥劑,第二容器含有至少一個劑量之包含VEGFR抑制劑之藥劑,且包裝插頁或標籤包含使用藥劑治療患者癌症之說明書。第一及第二容器可包括相同或不同形狀(例如,小瓶、注射器及瓶)及/或材料(例如,塑膠或玻璃)。套組可進一步包含可用於投與藥劑之其他材料,例如稀釋劑、濾紙、IV袋及線、針及注射器。在套組之一些較佳實施例中,抗PD-1拮抗劑係抗PD-1抗體且說明書陳述,藥劑意欲用於治療患有癌症之患者,該癌症之PD-L1表現藉由IHC分析來測試呈陽性。
本發明之該等及其他態樣(包括下文列舉之例示性具體實施例)自其中含有之教示將明瞭。
1.一種用於治療個體之癌症之方法,其包含向該個體投與包含PD-1拮抗劑及VEGFR抑制劑之組合療法。
2.如實施例1之方法,其中該PD-1拮抗劑係單株抗體或其抗原結合片段。
3.如實施例1或2之方法,其中該VEGFR抑制劑係化合物N-甲基-2-[3-((E)-2-吡啶-2-基-乙烯基)-1H-吲唑-6-基硫基]-苯甲醯胺或其醫藥
上可接受之鹽。
4.一種藥劑,其包含與VEGFR抑制劑組合用於治療個體之癌症之PD-1拮抗劑,其中該PD-1拮抗劑係單株抗體或其抗原結合片段。
5.一種藥劑,其包含與PD-1拮抗劑組合用於治療個體之癌症之VEGFR抑制劑。
6.如實施例4或5之藥劑,其進一步包含醫藥上可接受之賦形劑。
7.一種PD-1拮抗劑之用途,其用於製造在與VEGFR抑制劑組合投與時用於治療個體之癌症的藥劑。
6.一種VEGFR抑制劑化合物之用途,其用於製造在與PD-1拮抗劑組合投與時用於治療個體之癌症的藥劑。
7.一種PD-1拮抗劑及VEGFR抑制劑之用途,其用於製造用於治療個體之癌症的藥劑。
8.一種套組,其包含第一容器、第二容器及包裝插頁,其中該第一容器包含至少一個劑量之包含抗PD-1拮抗劑之藥劑,該第二容器包含至少一個劑量之包含VEGFR抑制劑之藥劑,且該包裝插頁包含使用該等藥劑治療個體癌症之說明書。
9.如實施例8之套組,其中該等說明書陳述,該等藥劑意欲用於治療患有癌症之個體,該癌症之PD-L1表現藉由免疫組織化學(IHC)分析來測試呈陽性。
10.如實施例1至9中任一項之方法、藥劑、用途或套組,其中該個體係人類且該PD-1拮抗劑係單株抗體或其抗原結合片段,其特異性結合至人類PD-L1且阻斷人類PD-L1與人類PD-1結合。
11.如實施例9之方法、藥劑、用途或套組,其中該PD-1拮抗劑係MPDL3280A、BMS-936559、MEDI4736、MSB0010718C或分別包含WO2013/019906之SEQ ID NO:24及SEQ ID NO:21之重鏈及輕鏈可變區的單株抗體。
12.如實施例1至9中任一項之方法、藥劑、用途或套組,其中該個體係人類,且該PD-1拮抗劑係單株抗體或其抗原結合片段,其特異性結合至人類PD-1且阻斷人類PD-L1與人類PD-1結合。
13.如實施例12之方法、藥劑、用途或套組,其中該PD-1拮抗劑亦阻斷人類PD-L2與人類PD-1結合。
14.如實施例13之方法、藥劑、用途或套組,其中該單株抗體或其抗原結合片段包含:(a)SEQ ID NO:1、2及3之輕鏈CDR及SEQ ID NO:4、5及6之重鏈CDR;或(b)SEQ ID NO:7、8及9之輕鏈CDR及SEQ ID NO:10、11及12之重鏈CDR。
15.如實施例13之方法、藥劑、用途或套組,其中該單株抗體或其抗原結合片段包含SEQ ID NO:7、8及9之輕鏈CDR及SEQ ID NO:10、11及12之重鏈CDR。
16.如實施例13之方法、藥劑、用途或套組,其中該PD-1拮抗劑係包含重鏈及輕鏈之抗PD-1單株抗體,且其中該重鏈包含SEQ ID NO:21且該輕鏈包含SEQ ID NO:22。
17.如實施例13之方法、藥劑、用途或套組,其中該PD-1拮抗劑係包含重鏈及輕鏈之抗PD-1單株抗體,且其中該重鏈包含SEQ ID NO:23且該輕鏈包含SEQ ID NO:24。
18.如實施例10至17中任一項之方法、藥劑、用途或套組,其中該癌症係實體瘤。
19.如實施例10至17中任一項之方法、藥劑、用途或套組,其中該癌症係膀胱癌、乳癌、透明細胞腎癌、頭/頸鱗狀細胞癌、肺鱗狀細胞癌、惡性黑色素瘤、非小細胞肺癌(NSCLC)、卵巢癌、胰臟癌、前列腺癌、腎細胞癌、小細胞肺癌(SCLC)或三重陰性乳癌。
20.如實施例10至17中任一項之方法、藥劑、用途或套組,其中該癌症係晚期腎細胞癌。
21.如實施例10至17中任一項之方法、藥劑、用途或套組,其中該個體先前未治療晚期腎細胞癌。
22.如實施例10至17中任一項之方法、藥劑、用途或套組,其中該癌症係透明細胞腎癌。
23.如實施例10至17中任一項之方法、藥劑、用途或套組,其中該癌症係急性淋巴母細胞性白血病(ALL)、急性骨髓性白血病(AML)、慢性淋巴球性白血病(CLL)、慢性骨髓性白血病(CML)、彌漫性大B細胞淋巴瘤(DLBCL)、濾泡性淋巴瘤、何傑金氏淋巴瘤(HL)、套細胞淋巴瘤(MCL)、多發性骨髓瘤(MM)、骨髓性細胞白血病-1蛋白質(Mcl-1)、骨髓發育不良症候群(MDS)、非何傑金氏淋巴瘤(NHL)或小淋巴球性淋巴瘤(SLL)。
24.如實施例10至23中任一項之方法、藥劑、用途或套組,該癌症之人類PD-L1經測試呈陽性。
25.如實施例24之方法、藥劑、用途或套組,其中該人類PD-L1表現升高。
26.如實施例13之方法、藥劑、用途或套組,其中該PD-1拮抗劑係MK-3475或尼沃魯單抗。
27.如實施例26之方法、藥劑、用途或套組,其中該MK-3475調配為液體藥劑,該液體藥劑包含pH 5.5之10mM組胺酸緩衝液中之25mg/ml MK-3475、7%(w/v)蔗糖、0.02%(w/v)聚山梨醇酯80。
28.如實施例1至27中任一項之方法、藥劑、用途或套組,其中該VEGR抑制劑係舒尼替尼、索拉非尼或替沃紮尼。
29.如實施例1至27中任一項之方法、藥劑、用途或套組,其中該VEGR抑制劑係N-甲基-2-[3-((E)-2-吡啶-2-基-乙烯基)-1H-吲唑-6-基硫基]-苯甲醯胺或其醫藥上可接受之鹽。
30.如實施例1至27中任一項之方法、藥劑、用途或套組,其中
該VEFR抑制劑係阿西替尼且調配為1mg錠劑或5mg錠劑。
31.一種治療經診斷患有癌症之人類個體之方法,其包含向該個體投與包含MK-3475及阿西替尼之組合療法,其中(a)阿西替尼係以5mg BID之劑量投與且MK-3475係以選自由1mg/kg Q3W、2mg/kg Q3W及200mg Q3W組成之群之劑量投與,或(b)阿西替尼係以3mg BID之劑量投與且MK-3475係以選自由1mg/kg Q3W、2mg/kg Q3W及200mg Q3W組成之群之劑量投與。
32.一種藥劑,其包含與阿西替尼組合用於治療人類個體之癌症之MK-3475,該治療係藉由包含以下方法來進行:向該個體投與(a)5mg BID之劑量之阿西替尼及選自由1mg/kg Q3W、2mg/kg Q3W及200mg/kg Q3W組成之群之劑量之MK-3475,或(b)3mg BID之劑量之阿西替尼及選自由1mg/kg Q3W、2mg/kg Q3W及200mg Q3W組成之群之劑量之MK-3475。
33.一種藥劑,其包含與MK-3475組合用於治療人類個體之癌症之阿西替尼,該治療係藉由包含以下方法來進行:向該個體投與(a)5mg BID之劑量之阿西替尼及選自由1mg/kg Q3W、2mg/kg Q3W及200mg/kg Q3W組成之群之劑量之MK-3475,或(b)3mg BID之劑量之阿西替尼及選自由1mg/kg Q3W、2mg/kg Q3W及200mg Q3W組成之群之劑量之MK-3475。
34.如實施例31至33中任一項之方法或藥劑,其中阿西替尼係以5mg BID之劑量投與且MK-3475係以1mg/kg Q3W投與。
35.如實施例31至33中任一項之方法或藥劑,其中阿西替尼係以5mg BID之劑量投與且MK-3475係以2mg/kg Q3W投與。
36.如實施例31至33中任一項之方法或藥劑,其中阿西替尼係以3mg BID之劑量投與且MK-3475係以1mg/kg Q3W投與。
37.如實施例31至33中任一項之方法或藥劑,其中阿西替尼係
以3mg BID之劑量投與且MK-3475係以2mg/kg Q3W投與。
38.如實施例31至33中任一項之方法或藥劑,其中阿西替尼係以3mg BID之劑量投與且MK-3475係以200mg Q3W投與。
39.如實施例31至38中任一項之方法或藥劑,其中該癌症係腎細胞癌。
40.如實施例39之方法或藥劑,其中該個體先前未治療腎細胞癌。
41.如實施例31至38中任一項之方法或藥劑,其中該癌症係透明細胞腎癌。
42.如實施例31至41中任一項之方法或藥劑,其中在投與該組合療法之前自該個體移除之該癌症之組織切片的PD-L1表現經測試呈陽性。
43.如實施例42之方法或藥劑,其中該組織切片中至少50%腫瘤細胞之PD-L1表現藉由免疫組織化學(IHC)分析來測試呈陽性。
44.如實施例43之方法或藥劑,其中該IHC分析採用抗體22C3以檢測PD-L1表現。
45.如實施例31至44中任一項之方法或藥劑,其中MK-3475係藉由IV輸注投與。
分子生物中之標準方法闡述於以下中:Sambrook、Fritsch及Maniatis(1982及1989年第2版,2001年第3版)Molecular Cloning,A Laboratory Manual,Cold Spring Harbor Laboratory Press,Cold Spring Harbor,NY;Sambrook及Russell(2001)Molecular Cloning,第3版,Cold Spring Harbor Laboratory Press,Cold Spring Harbor,NY;Wu(1993)Recombinant DNA,第217卷,Academic Press,San Diego,CA)。標準方法亦出現於以下中:Ausbel等人(2001)Current Protocols in Molecular Biology,第1-4卷,John Wiley and Sons公司,New York,NY,其闡述在細菌細胞中之選殖及DNA誘變(第1卷)、哺乳動物細胞及酵母中之選殖(第2卷)、糖偶聯物及蛋白質表現(第3卷)及生物資訊學(第4卷)。
闡述包括免疫沈澱、層析、電泳、離心及結晶之蛋白質純化之方法(Coligan等人(2000)Current Protocols in Protein Science,第1卷,John Wiley and Sons公司,New York)。闡述化學分析、化學修飾、轉譯後修飾、融合蛋白之產生、蛋白質之糖基化(參見,例如,Coligan等人(2000)Current Protocols in Protein Science,第2卷,John Wiley and Sons公司,New York;Ausubel等人(2001)Current Protocols in Molecular Biology,第3卷,John Wiley and Sons公司,NY,NY,第16.0.5-16.22.17頁;Sigma-Aldrich公司(2001)Products for Life Science Research,St.Louis,MO;第45-89頁;AmershamPharmacia Biotech(2001)BioDirectory,Piscataway,N.J.,第384-391頁)。闡述多株及單株抗體之產生、純化及斷裂(Coligan等人(2001)Current Protcols in Immunology,第1卷,John Wiley and Sons公司,New York;Harlow及Lane(1999)Using Antibodies,Cold Spring Harbor Laboratory Press,Cold Spring Harbor,NY;Harlow及Lane,同上)。可獲得表徵配體/受體相互作用之標準技術(參見,例如,Coligan等人(2001)Current Protocols in Immunology,第4卷,John Wiley公司,New York)。
可製備單株、多株及人類化抗體(參見,例如,Sheperd及Dean(編輯)(2000)單株Antibodies,Oxford Univ.Press,New York,NY;Kontermann及Dubel(編輯)(2001)Antibody Engineering,Springer-Verlag,New York;Harlow及Lane(1988)Antibodies A Laboratory Manual,Cold Spring Harbor Laboratory Press,Cold Spring Harbor,NY,
第139-243頁;Carpenter等人(2000)J.Immunol.165:6205;He等人(1998)J.Immunol.160:1029;Tang等人(1999)J.Biol.Chem.274:27371-27378;Baca等人(1997)J.Biol.Chem.272:10678-10684;Chothia等人,(1989)Nature 342:877-883;Foote及Winter(1992)J.Mol.Biol.224:487-499;美國專利第6,329,511號)。
人類化之替代方式係使用在噬菌體上展現之人類抗體庫或轉基因小鼠中之人類抗體庫(Vaughan等人,(1996)Nature Biotechnol.14:309-314;Barbas(1995)Nature Medicine 1:837-839;Mendez等人(1997)Nature Genetics 15:146-156;Hoogenboom及Chames(2000)Immunol.Today 21:371-377;Barbas等人(2001)Phage Display:A Laboratory Manual,Cold Spring Harbor Laboratory Press,Cold Spring Harbor,New York;Kay等人(1996)Phage Display of Peptides and Proteins:A Laboratory Manual,Academic Press,San Diego,CA;de Bruin等人(1999)Nature Biotechnol.17:397-399)。
抗原之純化並非生成抗體所必需的。可將動物用攜載所關注抗原之細胞進行免疫。隨後可將脾細胞自經免疫動物分離,且脾細胞可與骨髓瘤細胞系融合以產生雜交瘤(參見,例如,Meyaard等人,(1997)Immunity 7:283-290;Wright等人(2000)Immunity 13:233-242;Preston等人,同上;Kaithamana等人(1999)J.Immunol.163:5157-5164)。
抗體可偶聯至(例如)小藥物分子、酶、脂質體、聚乙二醇(PEG)。抗體可用於治療、診斷、套組或其他目的,且包括偶合至(例如)染料、放射性同位素、酶或金屬(例如膠態金)之抗體(參見,例如,Le Doussal等人,(1991)J.Immunol.146:169-175;Gibellini等人(1998)J.Immunol.160:3891-3898;Hsing及Bishop(1999)J.Immunol.162:2804-2811;Everts等人(2002)J.Immunol.168:883-889)。
可獲得用於流式細胞術之方法,包括螢光活化細胞分選(FACS)(參見,例如,Owens等人(1994)Flow Cytometry Principles for Clinical Laboratory Practice,John Wiley and Sons,Hoboken,NJ;Givan(2001)Flow Cytometry,第2版;Wiley-Liss,Hoboken,NJ;Shapiro(2003)Practical Flow Cytometry,John Wiley and Sons,Hoboken,NJ)。可獲得用作(例如)診斷性試劑之適於修飾核酸(包括核酸引物及探針)、多肽及抗體的螢光試劑(Molecular Probesy(2003)Catalogue,Molecular Probes公司,Eugene,OR;Sigma-Aldrich(2003)Catalogue,St.Louis,MO)。
闡述免疫系統之組織學之標準方法(參見,例如,Muller-Harmelink(編輯)(1986)Human Thymus:Histopathology and Pathology,Springer Verlag,New York,NY;Hiatt等人(2000)Color Atlas of Histology,Lippincott,Williams及Wilkins,Phila,PA;Louis等人(2002)Basic Histology:Text and Atlas,McGraw-Hill,New York,NY)。
可獲得用於測定(例如)抗原片段、前導序列、蛋白質摺疊、功能結構域、糖基化位點及序列比對之軟體包裝及數據庫(參見,例如,GenBank,Vector NTI® Suite(Informax公司,Bethesda,MD);GCG Wisconsin Package(Accelrys公司,San Diego,CA);DeCypher®(TimeLogic公司,Crystal Bay,Nevada);Menne等人(2000)Bioinformatics 16:741-742;Menne等人(2000)Bioinformatics Applications Note 16:741-742;Wren等人(2002)Comput.Methods Programs Biomed.68:177-181;von Heijne(1983)Eur.J.Biochem.133:17-21;von Heijne(1986)Nucleic Acids Res.14:4683-4690)。
此研究將評估阿西替尼與MK-3475之組合在患有RCC之人類患者
中之功效。患者將用5mg或3mg BID之阿西替尼及1mg/kg或2mg/kg之MK-3475藉由靜脈內輸注每三週治療一次,持續18個月之時段。
BID:每日兩次;q3wk:每3週。
根據以下結果量度中之至少一者,預計阿西替尼與MK-3475之組合將較單獨治療更有效:反應之持續時間(DR)[時間範圍:18個月]-自客觀腫瘤反應首次記載至客觀腫瘤進展或由於任何癌症死亡的時間(週)。腫瘤反應之持續時間將計算為(客觀腫瘤進展首次記載或由於癌症而死亡之日期減去隨後將確認之首次CR或PR之日期加上1)除以7。針對具有確認客觀腫瘤反應之參與者之亞組計算DR。
具有客觀反應之參與者之百分比[時間範圍:18個月]-根據實體瘤反應評估準則(RECIST),基於OR之評定確認完全緩解(CR)或確認部分緩解(PR)之參與者之百分比。確認緩解係彼等重複骨髓測試顯示以下情況持續至少2個月者:骨髓母細胞小於百分之五(5%),且所有細胞系正常成熟,且周邊血液之絕對值正常。PR係彼等除胚細胞相對於處理前減少至少50%外,符合所有CR準則者。
進展-無存活(PFS)[時間範圍:18個月]-自研究處理之第一劑量至客觀腫瘤進展首次記載或由於任何原因死亡之時間中值,以先達到者為準。PFS計算為(週)=(第一事件日期減去第一劑量日期加上1)除以7。
整體存活(OS)[時間範圍:5年]-整體存活將為自募集至死亡之
持續時間。對於活著之參與者,在最後一次接觸時設限整體存活。
美國東岸癌症臨床研究合作組織(Eastern Cooperative Oncology Group[ECOG])體能狀態[時間範圍:最多2.5年]-治療中量測之ECOG-PS(30天延遲之第一劑量與最後劑量日期之間之時間)以5分標度評定參與者之體能狀態:0=完全活動/能夠繼續所有患病前活動而不受限制;1=無法做劇烈的活動,但可以走動/從事輕鬆或坐著的工作;2=可以走動(>50%清醒hr),能夠完全自理,不能從事任何工作活動;3=能夠僅限制性自理,臥床/坐輪椅>50%清醒hr;4=完全失能,不能從事任何自理,完全臥床/坐輪椅;5=死亡。
血液生物標記之存在(比率)或不存在[時間範圍:最多2.5年]-為鑑別完全反應及復發/進展(若發生)之生物標記(FGF、IL8、VEGF...)。
研究之患者合格性將根據以下準則測定:適於研究之年齡:18歲及以上。
適於研究之性別:二者
接受健康志願者:否
組織學上或細胞學上確認之具有主要透明細胞亞型且切除原發性腫瘤之晚期RCC;至少一個可量測病灶,如藉由實體瘤反應評估準則(RECIST)1.1版所定義;美國東岸癌症臨床研究合作組織體能狀態0或1;及受控高血壓。
表4提供序列表中序列之簡單說明。
Sharpe, A.H、Wherry, E.J.、Ahmed R.及Freeman G.J. The
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9. Inman等人,PD-L1 (B7-H1) expression by urothelial carcinoma
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10. Shimauchi T等人,Augmented expression of programmed death-1 in both neoplasmatic and nonneoplastic CD4+ T-cells in adult T-cell Leukemia/Lymphoma. Int. J. Cancer (2007): 121:2585-2590。
11. Gao等人,Overexpression of PD-L1 significantly associates with tumor aggressiveness and postoperative recurrence in human hepatocellular carcinoma. Clinical Cancer Research (2009) 15: 971-979。
12. Nakanishi J. Overexpression of B7-H1 (PD-L1) significantly associates with tumor grade and postoperative prognosis in human urothelial cancers. Cancer Immunol Immunother. (2007) 56: 1173-1182。
13. Hino等人,Tumor cell expression of programmed cell death-1 is a prognostic factor for malignant melanoma. Cancer (2010): 00: 1-9。
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本文所引用之所有參考文獻均以引用方式併入,其併入程度如同每一個別出版物、數據庫條目(例如,Genbank序列或GeneID條
目)、專利申請案或專利均特別且個別地指示以引用方式併入一般。申請者意欲依照37 C.F.R.§1.57(b)(1)使以引用方式併入之此聲明涉及每一及所有個別出版物、數據庫條目(例如Genbank序列或GeneID條目)、專利申請案或專利(其每一者皆按照37 C.F.R.§1.57(b)(2)明確鑑別),即使該引用未緊隨以引用方式併入之專用聲明。說明書內包括以引用方式併入之專用聲明(若存在)不會以任何方式弱化此以引用方式併入之一般聲明。本文中參考文獻之引用並不意欲承認參考文獻係相關先前技術,其亦不欲構成對該等出版物或文件之內容或日期之任何承認。
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Claims (14)
- 一種計畫性死亡1蛋白質(PD-1)拮抗劑之用途,其係用以製備治療個體癌症之藥物,其中該藥物係與血管內皮生長因子受體(VEGFR)抑制劑併用,且其中該PD-1拮抗劑係包含重鏈及輕鏈之抗PD-1單株抗體,其中該重鏈及輕鏈分別包含SEQ ID NO:21及SEQ ID NO:22,且另外其中該VEGFR抑制劑係N-甲基-2-[3-((E)-2-吡啶-2-基-乙烯基)-1H-吲唑-6-基硫基]-苯甲醯胺或其醫藥上可接受之鹽。
- 一種血管內皮生長因子受體(VEGFR)抑制劑之用途,其係用以製備治療個體癌症之藥物,其中該藥物係與計畫性死亡1蛋白質(PD-1)拮抗劑併用,且其中該VEGFR抑制劑係N-甲基-2-[3-((E)-2-吡啶-2-基-乙烯基)-1H-吲唑-6-基硫基]-苯甲醯胺或其醫藥上可接受之鹽,且另外其中該PD-1拮抗劑係包含重鏈及輕鏈之抗PD-1單株抗體,其中該重鏈及輕鏈分別包含SEQ ID NO:21及SEQ ID NO:22。
- 如請求項1或2之用途,其中該個體係人類。
- 如請求項1或2之用途,其中該癌症係實體瘤,其經過免疫組織化學(IHC)分析法測試之計畫性死亡1蛋白質(PD-L1)表現係呈陽性。
- 如請求項1或2之用途,其中該癌症係腎細胞癌。
- 如請求項1或2之用途,其中該PD-1拮抗劑係派姆單抗(pembrolizumab)且該VEGFR抑制劑係阿西替尼(axitinib)。
- 如請求項6之用途,其中該派姆單抗係調配為液體藥劑,該液體藥劑包含含在pH 5.5之10mM組胺酸緩衝液中之25mg/ml派姆單抗、7%(w/v)蔗糖、0.02%(w/v)聚山梨醇酯80,且阿西替尼係調配為1mg錠劑或5mg錠劑。
- 一種套組,其包含第一容器、第二容器及包裝插頁,其中該第一容器包含至少一個劑量之包含計畫性死亡1蛋白質(PD-1)拮抗劑之藥劑,該第二容器包含至少一個劑量之包含血管內皮生長因子受體(VEGFR)抑制劑之藥劑,且該包裝插頁包含使用該等藥劑治療個體癌症之說明書,其中該PD-1拮抗劑係包含重鏈及輕鏈之抗PD-1單株抗體,其中該等重鏈及輕鏈分別包含SEQ ID NO:21及SEQ ID NO:22;且另外其中該VEGFR抑制劑係N-甲基-2-[3-((E)-2-吡啶-2-基-乙烯基)-1H-吲唑-6-基硫基]-苯甲醯胺或其醫藥上可接受之鹽。
- 如請求項8之套組,其中該等說明書陳述該等藥劑意欲用於治療患有癌症之個體,其藉由免疫組織化學(IHC)分析法測試之計畫性死亡1蛋白質(PD-L1)表現係呈陽性。
- 如請求項8或9之套組,其中該個體係人類。
- 如請求項8或9之套組,其中該PD-1拮抗劑係調配為液體藥劑之派姆單抗且該VEGFR抑制劑係調配為1mg錠劑或5mg錠劑之阿西替尼。
- 如請求項8或9之套組,其中該癌症係膀胱癌、乳癌、透明細胞腎癌、頭/頸鱗狀細胞癌、肺鱗狀細胞癌、惡性黑色素瘤、非小細胞肺癌(NSCLC)、卵巢癌、胰臟癌、前列腺癌、腎細胞癌、小細胞肺癌(SCLC)、三重陰性乳癌、急性淋巴母細胞性白血病(ALL)、急性骨髓性白血病(AML)、慢性淋巴球性白血病(CLL)、慢性骨髓性白血病(CML)、彌漫性大B細胞淋巴瘤(DLBCL)、濾泡性淋巴瘤、何傑金氏淋巴瘤(Hodgkin’s lymphoma)(HL)、套細胞淋巴瘤(MCL)、多發性骨髓瘤(MM)、骨髓性細胞白血病-1蛋白質(Mcl-1)、骨髓發育不良症候群(MDS)、非何傑金氏淋巴瘤(NHL)或小淋巴球性淋巴瘤(SLL)。
- 如請求項12之套組,其中該癌症係晚期腎細胞癌。
- 一種套組,其包含:(a)用於與阿西替尼組合以供治療人類個體之癌症之派姆單抗,該治療所採用之方法包括:向該個體投與(i)一天兩次5mg(BID)之劑量之阿西替尼及選自由每三週1mg/kg(Q3W)、2mg/kg Q3W及200mg Q3W組成之群之劑量之派姆單抗,或(ii)3mg BID之劑量之阿西替尼及選自由1mg/kg Q3W、2mg/kg Q3W及200mg Q3W組成之群之劑量之派姆單抗;或(b)用於與派姆單抗組合以供治療人類個體之癌症之阿西替尼,其所採用之方法包括:向該個體投與(i)5mg BID之劑量之阿西替尼及選自由1mg/kg Q3W、2mg/kg Q3W及200mg Q3W組成之群之劑量之MK-3475,或(ii)3mg BID之劑量之阿西替尼及選自由1mg/kg Q3W、2mg/kg Q3W及200mg Q3W組成之群之劑量之派姆單抗。
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WO2015088847A1 (en) * | 2013-12-11 | 2015-06-18 | Glaxosmithkline Llc | Treating cancer with a combination of a pd-1 antagonist and a vegfr inhibitor |
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- 2015-02-03 TR TR2019/01507T patent/TR201901507T4/tr unknown
- 2015-02-03 EP EP15703439.8A patent/EP3102605B1/en not_active Revoked
- 2015-02-03 EP EP18205542.6A patent/EP3498734B1/en active Active
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2016
- 2016-07-13 IL IL246760A patent/IL246760A0/en unknown
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2019
- 2019-02-01 CY CY20191100147T patent/CY1121374T1/el unknown
- 2019-09-19 JP JP2019170177A patent/JP6894952B2/ja active Active
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2020
- 2020-01-14 US US16/742,657 patent/US20200325228A1/en not_active Abandoned
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2021
- 2021-06-03 JP JP2021093346A patent/JP2021130709A/ja active Pending
- 2021-11-29 CY CY20211101042T patent/CY1124785T1/el unknown
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2022
- 2022-04-20 US US17/725,240 patent/US20220324979A1/en active Pending
Non-Patent Citations (5)
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MCDERMOTT, David F. ATKINS, Michael B. PD‐1 as a potential target in cancer therapy. Cancer medicine, 2013, 2.5: 662-673. * |
MCDERMOTT, David F.; ATKINS, Michael B. PD‐1 as a potential target in cancer therapy. Cancer medicine, 2013, 2.5: 662-673. |
NCT02014636 : A Phase I/II Study to Assess the Safety and Efficacy of Pazopanib and MK 3475 in Patients With Advanced Renal Cell Carcinom. Clinical Trials.gov . First Posted: December 18, 2013. https://clinicaltrials.gov/ct2/show/NCT02014636 * |
NCT02133742: A Phase 1b, Open Label, Dose Finding Study To Evaluate Safety, Pharmacokinetics And Pharmacodynamics Of Axitinib (Ag-013736) In Combination With Pembrolizumab (Mk-3475) In Patients With Advanced Renal Cell Cancer. ClinicalTrials.gov archive, First Posted : May 8, 2014. https://clinicaltrials.gov/ct2/show/NCT02133742 * |
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