TW202328204A - Nectin細胞黏附分子4之特異性抗體及其用途 - Google Patents
Nectin細胞黏附分子4之特異性抗體及其用途 Download PDFInfo
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Abstract
本發明係關於一種對nectin細胞黏附分子4 (nectin-4)具有特異性之經修飾之抗體或其抗原結合片段。本發明亦關於一種偵測或診斷個體是否患有腫瘤或具有罹患腫瘤之風險或評估腫瘤預後的方法,及一種用於在罹患腫瘤之個體中治療、預防性治療及/或預防該腫瘤的醫藥組合物。
Description
本發明係關於一種抗體或其抗原結合片段,其對nectin細胞黏附分子4 (nectin-4)具有特異性,用於偵測及/或治療腫瘤。
癌症為世界範圍內死亡之主要原因之一。若病例在早期偵測到且得到治療,則癌症死亡率可降低,因此急需針對一般人群之可行篩檢選項。
免疫療法為癌症治療中最有前景的進展之一。癌症免疫療法用於產生及增強抗腫瘤免疫反應,例如藉由用腫瘤細胞上之抗原的特異性抗體、抗原呈現細胞與腫瘤細胞之融合體進行治療或藉由活化抗腫瘤T細胞。在患者體內募集免疫細胞(例如T細胞)針對腫瘤細胞之能力提供對抗直至最近一直被視為不可治癒的癌症類型及轉移的治療模態。
當癌在早期診斷出且疾病限於起源器官時,存活率顯著改善。實際上,用於篩檢之物理方法,如子宮頸癌中之抹片檢查及乳癌中之乳房攝影術已顯著降低死亡率。因此,已鼓勵關於開發可容易獲取的體液,諸如血清、尿液或唾液中之新早期偵測生物標記的研究。一些熟知生物標記在疾病晚期階段可靠地偵測到,但對早期癌症診斷缺乏足夠敏感度,尤其特異性,且因此主要用於預後、分期、監測及選擇療法。
因此,需要開發一種治療及偵測癌症之新穎方法。
本發明提供一種抗體或其抗原結合片段,其特異性結合至抗原或其片段中之抗原決定基,用於治療及偵測癌症。
在一個態樣中,本發明提供一種對nectin細胞黏附分子4或其片段中之抗原決定基具有特異性的抗體或其抗原結合片段;其包含重鏈可變區之互補決定區(CDR)及輕鏈可變區之CDR,其中重鏈可變區之CDR包含CDRH1、CDRH2及CDRH3區,且輕鏈可變區之CDR包含CDRL1、CDRL2及CDRL3區,且其中:
CDRH1區包含選自由SEQ ID NO: 2至6組成之群的胺基酸序列或具有至少90%序列一致性之基本相似序列;CDRH2區包含選自由SEQ ID NO: 8至12組成之群的胺基酸序列或具有至少90%序列一致性之基本相似序列;CDRH3區包含選自由SEQ ID NO: 14至18組成之群的胺基酸序列或具有至少90%序列一致性之基本相似序列;且
CDRL1區包含選自由SEQ ID NO: 20至24組成之群的胺基酸序列或具有至少90%序列一致性之基本相似序列;CDRL2區包含選自由SEQ ID NO: 26至30組成之群的胺基酸序列或具有至少90%序列一致性之基本相似序列;CDRL3區包含選自由SEQ ID NO: 32至36組成之群的胺基酸序列或具有至少90%序列一致性之基本相似序列。
在本發明之一個實施例中,nectin-4為人類nectin-4。
在本發明之一些實施例中,該抗體或其抗原結合片段對nectin-4或其片段之細胞外域中之抗原決定基具特異性;nectin-4片段之實例包括但不限於nectin-4-Q96NY8 (PVRL4_HUMAN)之胺基酸94至435、94至732或94至957。
在本發明之一個實施例中,抗體NECTIN4-scFv-L1或其抗原結合片段包含以下:包含SEQ ID NO: 2或具有至少90%序列一致性之基本相似序列的CDRH1區、包含SEQ ID NO: 8或具有至少90%序列一致性之基本相似序列的CDRH2區、包含SEQ ID NO: 14或具有至少90%序列一致性之基本相似序列的CDRH3區、包含SEQ ID NO: 20或具有至少90%序列一致性之基本相似序列的CDRL1區、包含SEQ ID NO: 26或具有至少90%序列一致性之基本相似序列的CDRL2區及包含SEQ ID NO: 32或具有至少90%序列一致性之基本相似序列的CDRL3區。在一個實施例中,重鏈可變區包含SEQ ID NO: 37之胺基酸序列或具有至少90%序列一致性之基本相似序列;且輕鏈可變區包含SEQ ID NO: 38之胺基酸序列或具有至少90%序列一致性之基本相似序列。
在本發明之一個實施例中,抗體NECTIN4-scFv-S2或其抗原結合片段包含以下:包含SEQ ID NO: 3或具有至少90%序列一致性之基本相似序列的CDRH1區、包含SEQ ID NO: 9或具有至少90%序列一致性之基本相似序列的CDRH2區、包含SEQ ID NO: 15或具有至少90%序列一致性之基本相似序列的CDRH3區、包含SEQ ID NO: 21或具有至少90%序列一致性之基本相似序列的CDRL1區、包含SEQ ID NO: 27或具有至少90%序列一致性之基本相似序列的CDRL2區及包含SEQ ID NO: 33或具有至少90%序列一致性之基本相似序列的CDRL3區。在一個實施例中,重鏈可變區包含SEQ ID NO: 39之胺基酸序列或其基本相似序列;且輕鏈可變區包含SEQ ID NO: 40之胺基酸序列或其基本相似序列。
在本發明之一個實施例中,抗體NECTIN4-scFv-S6或其抗原結合片段包含以下:包含SEQ ID NO: 4或具有至少90%序列一致性之基本相似序列的CDRH1區、包含SEQ ID NO: 10或具有至少90%序列一致性之基本相似序列的CDRH2區、包含SEQ ID NO: 16或具有至少90%序列一致性之基本相似序列的CDRH3區、包含SEQ ID NO: 22或具有至少90%序列一致性之基本相似序列的CDRL1區、包含SEQ ID NO: 28或具有至少90%序列一致性之基本相似序列的CDRL2區及包含SEQ ID NO: 34或具有至少90%序列一致性之基本相似序列的CDRL3區。在一個實施例中,重鏈可變區包含SEQ ID NO: 41之胺基酸序列或具有至少90%序列一致性之基本相似序列;且輕鏈可變區包含SEQ ID NO: 42之胺基酸序列或具有至少90%序列一致性之基本相似序列。
在本發明之一個實施例中,抗體NECTIN4-scFv-S8或其抗原結合片段包含以下:包含SEQ ID NO: 5或具有至少90%序列一致性之基本相似序列的CDRH1區、包含SEQ ID NO: 11或具有至少90%序列一致性之基本相似序列的CDRH2區、包含SEQ ID NO: 17或具有至少90%序列一致性之基本相似序列的CDRH3區、包含SEQ ID NO: 23或具有至少90%序列一致性之基本相似序列的CDRL1區、包含SEQ ID NO: 29或具有至少90%序列一致性之基本相似序列的CDRL2區及包含SEQ ID NO: 35或具有至少90%序列一致性之基本相似序列的CDRL3區。在一個實施例中,重鏈可變區包含SEQ ID NO: 43之胺基酸序列或具有至少90%序列一致性之基本相似序列;且輕鏈可變區包含SEQ ID NO: 44之胺基酸序列或具有至少90%序列一致性之基本相似序列。
在本發明之一個實施例中,抗體NECTIN4-scFv-S21或其抗原結合片段包含以下:包含SEQ ID NO: 6或具有至少90%序列一致性之基本相似序列的CDRH1區、包含SEQ ID NO: 12或具有至少90%序列一致性之基本相似序列的CDRH2區、包含SEQ ID NO: 18或具有至少90%序列一致性之基本相似序列的CDRH3區、包含SEQ ID NO: 24或具有至少90%序列一致性之基本相似序列的CDRL1區、包含SEQ ID NO: 30或具有至少90%序列一致性之基本相似序列的CDRL2區及包含SEQ ID NO: 36或具有至少90%序列一致性之基本相似序列的CDRL3區。在一個實施例中,重鏈可變區包含SEQ ID NO: 45之胺基酸序列或其基本相似序列;且輕鏈可變區包含SEQ ID NO: 46之胺基酸序列或其基本相似序列。
在本發明之一些實施例中,抗體或其片段為單株抗體、嵌合抗體、人類化抗體、人類抗體或scFv抗體或其片段。
在本發明之一些實施例中,該抗體或其抗原結合片段與治療劑結合。治療劑之實例包括但不限於抗代謝物、烷化劑、類烷化劑、DNA小溝烷化劑、蒽環黴素、抗生素、卡奇黴素(calicheamicin)、抗有絲分裂劑、拓樸異構酶抑制劑、HDAC抑制劑、蛋白酶體抑制劑及放射性同位素。
在本發明之一些實施例中,該抗體或其抗原結合片段表現於細胞之表面上。該細胞可為免疫細胞、癌症幹細胞或幹細胞。在本發明之一個實施例中,該免疫細胞為T細胞。
本發明亦提供一種編碼抗體或其抗原結合片段之載體。
本發明亦提供一種表現該抗體或其抗原結合片段或含有該載體之經基因工程改造之細胞。
本發明亦提供一種醫藥組合物,其包含有效量之該抗體或其抗原結合片段或該經基因工程改造之細胞。
在另一態樣中,本發明提供一種偵測或診斷個體是否患有腫瘤或具有罹患腫瘤之風險或評估腫瘤預後的方法,其包含使來源於該個體之樣品與該抗體或其抗原結合片段接觸。
本發明提供一種用於偵測樣品中之nectin-4的方法,其包含使該樣品與該抗體或其抗原結合片段接觸。
本發明亦提供一種用於偵測樣品中之nectin-4的套組,其中該套組包含該抗體或其抗原結合片段。
在另一態樣中,本發明提供一種用於在罹患腫瘤之個體中治療、預防性治療及/或預防該腫瘤的方法,其包含向該個體投與該醫藥組合物。替代地,本發明提供一種用於在罹患腫瘤之個體中治療、預防性治療及/或預防該腫瘤的醫藥組合物,其包含有效量之如本文所揭示之抗體或其抗原結合片段或經基因工程改造之細胞。腫瘤之實例包括但不限於鱗狀細胞癌、肺癌、腹膜癌、肝細胞癌、胃癌(gastric/stomach cancer)、胰臟癌、神經膠質母細胞瘤、子宮頸癌、卵巢癌、肝癌(liver cancer)、膀胱癌、肝腫瘤、乳癌、大腸癌、大腸直腸癌、子宮內膜癌或子宮癌、唾液腺癌、腎癌(kidney/renal cancer)、前列腺癌、外陰癌、甲狀腺癌、肝癌(hepatic carcinoma)、頭頸癌、B細胞淋巴瘤、慢性淋巴球性白血病(CLL)、急性淋巴母細胞性白血病(ALL)、毛細胞白血病及慢性骨髓母細胞性白血病。特定言之,腫瘤為三陰性乳癌、膀胱癌、肺癌、胰臟癌、卵巢癌、頭/頸癌或食道癌。
在以下部分中詳細描述本發明。本發明之其他特徵、目的及優勢可見於實施方式及申請專利範圍中。
在以下描述中,使用許多術語且提供以下定義以有助於理解所主張之主題。本文中未明確定義之術語根據其普通且一般含義使用。
除非另外規定,否則「一(a/an)」意謂「一或多個」。
如本文所用,術語「抗原決定基」係指抗體結合至抗原之位點。
如本文所用,術語「抗體」意謂包含至少一個特異性結合至特定抗原(例如nectin-4)與其相互作用之互補決定區(CDR)的任何抗原結合分子或分子複合物。術語「抗體」包括包含四個多肽鏈,亦即藉由雙硫鍵互連之兩個重(H)鏈及兩個輕(L)鏈的免疫球蛋白分子,以及其多聚體(例如IgM)。各重鏈包含重鏈可變區(本文中縮寫為HCVR或V
H)及重鏈恆定區。重鏈恆定區包含三個域,亦即C
H1、C
H2及C
H3。各輕鏈包含輕鏈可變區(本文中縮寫為LCVR或V
L)及輕鏈恆定區。輕鏈恆定區包含一個域(C
L1)。V
H及V
L區可進一步細分成稱為互補決定區(CDR)之高變區,其間穿插有稱為構架區(FR)之保守性較高之區域。各V
H及V
L係由自胺基端至羧基端按以下順序排列的三個CDR及四個FR構成:FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4。在本發明之不同實施例中,抗nectin-4抗體(或其抗原結合部分)之FR可與人類生殖系序列一致,或可經天然或人工修飾。胺基酸共通序列可基於兩個或更多個CDR之並列分析來定義。
如本文所用,術語「特異性」意謂抗體不與其他抗原決定基發生顯著程度的交叉反應。
如本文所用,術語「互補決定區」(CDR)係指在重鏈及輕鏈多肽之可變區內發現的非連續抗原組合位點。Kabat等人,J.Biol.Chem.252:6609-6616(1977);Kabat等人,美國衛生及人類服務部(U.S.Dept.of Health and Human Services),「Sequences of proteins of immunological interest」(1991);Chothia等人,J.Mol .Biol.196:901-917(1987);及MacCallum等人,J.Mol.Biol.262:732-745(1996)已經描述CDR,其中定義包括彼此對照比較時胺基酸殘基的重疊或子集。
當應用於多肽時,術語「基本相似性」或「基本相似」意謂兩個肽序列在諸如藉由程式GAP或BESTFIT,使用預設空位權重最佳地比對時,共有至少90%、91%、92%、93%、94%、95%、96%、97%、98%或99%序列一致性,甚至更佳地至少98%或99%序列一致性。不一致殘基位置之差異較佳為保守性胺基酸取代。「保守性胺基酸取代」為一種胺基酸取代,其中胺基酸殘基經側鏈(R基團)具有類似化學特性(例如電荷或疏水性)之另一個胺基酸殘基取代。一般而言,保守性胺基酸取代不實質上改變蛋白質之功能特性。在其中兩個或更多個胺基酸序列彼此間差異為保守性取代之情況下,可上調序列一致性或相似度百分比以根據保守取代性質加以校正。進行此調節之方式為熟習此項技術者所熟知。具有化學特性類似之側鏈之胺基酸組的實例包括(1)脂族側鏈:甘胺酸、丙胺酸、纈胺酸、白胺酸及異白胺酸;(2)脂族羥基側鏈:絲胺酸及蘇胺酸;(3)含醯胺側鏈:天冬醯胺及麩醯胺酸;(4)芳族側鏈:苯丙胺酸、酪胺酸及色胺酸;(5)鹼性側鏈:離胺酸、精胺酸及組胺酸;(6)酸性側鏈:天冬胺酸及麩胺酸;及(7)含硫側鏈為半胱胺酸及甲硫胺酸。較佳的保守性胺基酸取代組為:纈胺酸-白胺酸-異白胺酸、苯丙胺酸-酪胺酸、離胺酸-精胺酸、丙胺酸-纈胺酸、麩胺酸-天冬胺酸及天冬醯胺-麩醯胺酸。替代地,保守性置換為在以引用之方式併入本文中之Gonnet等人(1992) Science 256: 1443-1445中所揭示之PAM250對數似然性矩陣中具有正值之任何變化。「適度保守」置換為在PAM250對數似然性矩陣中具有非負值之任何變化。
如本文所用之術語「單株抗體」不限於經由融合瘤技術產生之抗體。單株抗體係藉由此項技術中任何可用或已知的手段衍生自單一純系,包括任何真核、原核或噬菌體純系。
如本文所用,術語「嵌合」抗體係指具有衍生自以下之可變序列的抗體:非人類免疫球蛋白及人類免疫球蛋白恆定區,通常選自人類免疫球蛋白模板。
非人類抗體之「人類化」形式為含有衍生自非人類免疫球蛋白之最小序列的嵌合免疫球蛋白。一般而言,人類化抗體將包含實質上所有的至少一個且通常兩個可變域,其中所有或實質上所有的CDR區對應於非人類免疫球蛋白之CDR區且所有或實質上所有的FR區為人類免疫球蛋白序列之FR區。
如本文所用,術語抗體之「抗原結合部分」、抗體之「抗原結合片段」及其類似術語包括特異性結合抗原以形成複合物的任何天然存在的、可以酶方式獲得的、合成的或經基因工程改造的多肽或醣蛋白。
如本發明中所用,術語「治療劑」意謂適用於向哺乳動物(例如人類)投與之具有治療或藥理作用的任何化合物、物質、藥物、前藥或活性成分。
如本文所用,術語「載體」意指能夠轉運其已連接之另一核酸的核酸分子。一種類型之載體為「質體」,其係指可與額外DNA片段連接之環形雙股DNA環。另一類型之載體為病毒載體,其中額外DNA片段可與病毒基因體連接。某些載體能夠在其所引入之宿主細胞中自主複製(例如具有細菌複製起點之細菌載體及游離型哺乳動物載體)。其他載體(例如非游離型哺乳動物載體)可在引入宿主細胞中時整合至宿主細胞之基因體中,且藉此與宿主基因體一起複製。此外,某些載體能夠引導與其操作性連接之基因之表現。此類載體在本文中稱為「重組表現載體」(或簡言之,「表現載體」)。一般而言,用於重組DNA技術中之表現載體常常呈質體形式。由於質體為載體之最常用形式,因而在本說明書中,「質體」與「載體」可互換使用。然而,本發明意欲包括提供等效功能之此類其他形式之表現載體,諸如病毒載體(例如,複製缺陷反轉錄病毒、腺病毒及腺相關病毒)。
術語「經基因工程改造之」細胞或細胞之「基因工程改造」意謂使用遺傳物質操縱基因以改變細胞中之基因複本及/或基因表現量。遺傳物質可呈DNA或RNA形式。遺傳物質可藉由包括病毒轉導及非病毒轉染之各種方式轉移至細胞中。在經基因工程改造之後,細胞中某些基因之表現量可永久或暫時改變。
如本發明中所用,術語「醫藥組合物」意謂含有向哺乳動物(例如人類)投與以預防、治療或消除哺乳動物所患之特定疾病或病理性病狀的治療劑的混合物。
如本文所用,術語「治療有效量」或「靈驗量」係指當投與哺乳動物或其他個體用於治療疾病時,足以實現對該疾病之該治療的抗體之量。
如本文所用,術語「治療(treatment/treating)」及其類似術語涵蓋對哺乳動物,尤其人類之疾病的任何治療,且包括:(a)預防疾病在可易患該疾病但尚未診斷患有其之個體中發生;(b)抑制疾病,亦即遏制其發展;及(c)緩解疾病,亦即促使疾病消退。
術語「預防(preventing/prevention)」在此項技術中為公認的,且當與病狀相關使用時,其包括在該病狀發作之前投與藥劑,以相對於未接受該藥劑之個體,降低個體之醫學病狀的頻率或嚴重程度或延遲其症狀發作。
如本文中可互換地使用,術語「個人」、「個體」、「宿主」及「患者」係指哺乳動物,包括但不限於鼠類(大鼠、小鼠)、非人類靈長類動物、人類、犬科動物、貓科動物、有蹄動物(例如馬科動物、牛科動物、綿羊、豬科動物、山羊)等。
如本文所用,術語「需要治療」係指由照護者(例如在人類之情況下,為醫師、護士、護理從業者或個人;在動物(包括非人類之哺乳動物)之情況下,為獸醫)作出的判斷,該判斷為個體需要治療或將受益於治療。除包括知曉個體由於可由本發明化合物治療之病狀而患病或將患病以外,此判斷係基於照護者之專項知識領域內的各種因素作出。
「癌症」、「腫瘤」及類似術語包括癌變前、贅生性、轉型及癌性細胞,且可指實體腫瘤,或非實體癌症(參見例如Edge等人AJCC Cancer Staging Manual (第7版,2009);Cibas及Ducatman Cytology: Diagnostic principles and clinical correlates (第3版,2009))。癌症包括良性贅瘤及惡性贅瘤(異常生長)兩者。「轉型」係指自發的或誘導的表型變化,例如,細胞之不朽化、形態變化、異常細胞生長、減少的接觸抑制及固著及/或惡性病(參見Freshney, Culture of Animal Cells a Manual of Basic Technique (第3版,1994))。儘管轉型可由經轉型病毒之感染及新基因體DNA之併入或外源DNA之攝入引起,其亦可以自發方式或在暴露於誘癌物之後產生。
如本文所用,術語「樣品」涵蓋獲自個人、個體或患者之多種樣品類型,其可用於診斷性或監測分析。該定義涵蓋血液及生物來源之其他液體樣品;固體組織樣品,諸如生檢樣本或組織培養物或源自其之細胞及其後代。
本發明提供一種特異性結合至nectin-4或其片段中之抗原決定基的抗體或其抗原結合片段。
在一個實施例中,抗體或其抗原結合片段(抗nectin-4)包含重鏈可變區之互補決定區(CDR)及輕鏈可變區之互補決定區,其中重鏈可變區之互補決定區包含CDRH1、CDRH2及CDRH3區,且輕鏈可變區之互補決定區包含CDRL1、CDRL2及CDRL3區,且其中:
CDRH1區包含選自由SEQ ID NO: 2至6組成之群的胺基酸序列或具有至少90%、至少95%、至少98%或至少99%序列一致性之基本相似序列;CDRH2區包含選自由SEQ ID NO: 8至12組成之群的胺基酸序列或具有至少90%、至少95%、至少98%或至少99%序列一致性之基本相似序列;CDRH3區包含選自由SEQ ID NO: 14至18組成之群的胺基酸序列或具有至少90%、至少95%、至少98%或至少99%序列一致性之基本相似序列;且
CDRL1區包含選自由SEQ ID NO: 20至24組成之群的胺基酸序列或具有至少90%、至少95%、至少98%或至少99%序列一致性之基本相似序列;CDRL2區包含選自由SEQ ID NO: 26至30組成之群的胺基酸序列或具有至少90%、至少95%、至少98%或至少99%序列一致性之基本相似序列;CDRL3區包含選自由SEQ ID NO: 32至36組成之群的胺基酸序列或具有至少90%、至少95%、至少98%或至少99%序列一致性之基本相似序列。
Nectin細胞黏附分子4 (nectin-4),亦稱為脊髓灰白質炎病毒受體相關4 (PVRL4),係第I型跨膜蛋白及nectin家族相關類免疫球蛋白黏附分子之成員。已知nectin-4位於細胞表面上且能夠與其他細胞或細胞外基質(ECM)結合。在人類中,nectin-4主要在發育期間在氣管、肺及皮膚之上皮黏附接合區處表現(JBC 2001, 276(46):43205-43215)。表現在成人中降低,此時其他nectin之表現在成人組織中繼續。然而,nectin-4在包括乳癌之各種癌中再表現為具有原致癌特性之腫瘤相關抗原。在腫瘤中,nectin-4及ADAM17/TACE金屬蛋白酶之活性形式過度表現,且在細胞質中觀測到裂解nectin-4 (可溶性形式) (JBC 2005, 280(20):19543-50;BMC Cancer 2007, 7:73)。特定言之,如本文所揭示之nectin-4為人類nectin-4。
在本發明之一些實施例中,抗體或其抗原結合片段對nectin-4或其片段之細胞外域中之抗原決定基具有特異性;nectin-4片段之實例包括但不限於nectin-4-Q96NY8 (PVRL4_HUMAN,NCBI參考序列:NM_030916.3,UniProtKB/Swiss-Prot (Q96NY8.1))之胺基酸94至435、94至732或94至957。
在本發明之一個實施例中,抗體NECTIN4-scFv-L1或其抗原結合片段包含以下:包含SEQ ID NO: 2或具有至少90%、至少95%、至少98%或至少99%序列一致性之基本相似序列的CDRH1區、包含SEQ ID NO: 8或具有至少90%、至少95%、至少98%或至少99%序列一致性之基本相似序列的CDRH2區、包含SEQ ID NO: 14或具有至少90%、至少95%、至少98%或至少99%序列一致性之基本相似序列的CDRH3區、包含SEQ ID NO: 20或具有至少90%、至少95%、至少98%或至少99%序列一致性之基本相似序列的CDRL1區、包含SEQ ID NO: 26或具有至少90%、至少95%、至少98%或至少99%序列一致性之基本相似序列的CDRL2區及包含SEQ ID NO: 32或具有至少90%、至少95%、至少98%或至少99%序列一致性之基本相似序列的CDRL3區。在一個實施例中,重鏈可變區包含SEQ ID NO: 37之胺基酸序列或具有至少90%、至少95%、至少98%或至少99%序列一致性之基本相似序列;且輕鏈可變區包含SEQ ID NO: 38之胺基酸序列或具有至少90%、至少95%、至少98%或至少99%序列一致性之基本相似序列。
在本發明之一個實施例中,抗體NECTIN4-scFv-S2或其抗原結合片段包含以下:包含SEQ ID NO: 3或具有至少90%、至少95%、至少98%或至少99%序列一致性之基本相似序列的CDRH1區、包含SEQ ID NO: 9或具有至少90%、至少95%、至少98%或至少99%序列一致性之基本相似序列的CDRH2區、包含SEQ ID NO: 15或具有至少90%、至少95%、至少98%或至少99%序列一致性之基本相似序列的CDRH3區、包含SEQ ID NO: 21或具有至少90%、至少95%、至少98%或至少99%序列一致性之基本相似序列的CDRL1區、包含SEQ ID NO: 27或具有至少90%、至少95%、至少98%或至少99%序列一致性之基本相似序列的CDRL2區及包含SEQ ID NO: 33或具有至少90%、至少95%、至少98%或至少99%序列一致性之基本相似序列的CDRL3區。在一個實施例中,重鏈可變區包含SEQ ID NO: 39之胺基酸序列或具有至少90%、至少95%、至少98%或至少99%序列一致性之基本相似序列;且輕鏈可變區包含SEQ ID NO: 40之胺基酸序列或具有至少90%、至少95%、至少98%或至少99%序列一致性之基本相似序列。
在本發明之一個實施例中,抗體NECTIN4-scFv-S6或其抗原結合片段包含以下:包含SEQ ID NO: 4或具有至少90%、至少95%、至少98%或至少99%序列一致性之基本相似序列的CDRH1區、包含SEQ ID NO: 10或具有至少90%、至少95%、至少98%或至少99%序列一致性之基本相似序列的CDRH2區、包含SEQ ID NO: 16或具有至少90%、至少95%、至少98%或至少99%序列一致性之基本相似序列的CDRH3區、包含SEQ ID NO: 22或具有至少90%、至少95%、至少98%或至少99%序列一致性之基本相似序列的CDRL1區、包含SEQ ID NO: 28或具有至少90%、至少95%、至少98%或至少99%序列一致性之基本相似序列的CDRL2區及包含SEQ ID NO: 34或具有至少90%、至少95%、至少98%或至少99%序列一致性之基本相似序列的CDRL3區。在一個實施例中,重鏈可變區包含SEQ ID NO: 41之胺基酸序列或具有至少90%、至少95%、至少98%或至少99%序列一致性之基本相似序列;且輕鏈可變區包含SEQ ID NO: 42之胺基酸序列或具有至少90%、至少95%、至少98%或至少99%序列一致性之基本相似序列。
在本發明之一個實施例中,抗體NECTIN4-scFv-S8或其抗原結合片段包含以下:包含SEQ ID NO: 5或具有至少90%、至少95%、至少98%或至少99%序列一致性之基本相似序列的CDRH1區、包含SEQ ID NO: 11或具有至少90%、至少95%、至少98%或至少99%序列一致性之基本相似序列的CDRH2區、包含SEQ ID NO: 17或具有至少90%、至少95%、至少98%或至少99%序列一致性之基本相似序列的CDRH3區、包含SEQ ID NO: 23或具有至少90%、至少95%、至少98%或至少99%序列一致性之基本相似序列的CDRL1區、包含SEQ ID NO: 29或具有至少90%、至少95%、至少98%或至少99%序列一致性之基本相似序列的CDRL2區及包含SEQ ID NO: 35或具有至少90%、至少95%、至少98%或至少99%序列一致性之基本相似序列的CDRL3區。在一個實施例中,重鏈可變區包含SEQ ID NO: 43之胺基酸序列或具有至少90%、至少95%、至少98%或至少99%序列一致性之基本相似序列;且輕鏈可變區包含SEQ ID NO: 44之胺基酸序列或具有至少90%、至少95%、至少98%或至少99%序列一致性之基本相似序列。
在本發明之一個實施例中,抗體NECTIN4-scFv-S21或其抗原結合片段包含以下:包含SEQ ID NO: 6或具有至少90%、至少95%、至少98%或至少99%序列一致性之基本相似序列的CDRH1區、包含SEQ ID NO: 12或具有至少90%、至少95%、至少98%或至少99%序列一致性之基本相似序列的CDRH2區、包含SEQ ID NO: 18或具有至少90%、至少95%、至少98%或至少99%序列一致性之基本相似序列的CDRH3區、包含SEQ ID NO: 24或具有至少90%、至少95%、至少98%或至少99%序列一致性之基本相似序列的CDRL1區、包含SEQ ID NO: 30或具有至少90%、至少95%、至少98%或至少99%序列一致性之基本相似序列的CDRL2區及包含SEQ ID NO: 36或具有至少90%、至少95%、至少98%或至少99%序列一致性之基本相似序列的CDRL3區。在一個實施例中,重鏈可變區包含SEQ ID NO: 45之胺基酸序列或具有至少90%、至少95%、至少98%或至少99%序列一致性之基本相似序列;且輕鏈可變區包含SEQ ID NO: 46之胺基酸序列或具有至少90%、至少95%、至少98%或至少99%序列一致性之基本相似序列。
序列表展示於表1中。
表1:
SEQ ID NO | 名稱 | 序列 |
1 | 雞scFv CDRH1 | SYDML |
2 | NECTIN4-scFv-L1 CDRH1 | SHGMF |
3 | NECTIN4-scFv-S2 CDRH1 | SNGMA |
4 | NECTIN4-scFv-S6 CDRH1 | SNGMA |
5 | NECTIN4-scFv-S8 CDRH1 | DYGMG |
6 | NECTIN4-scFv-S21 CDRH1 | SYAMM |
7 | 雞scFv CDRH2 | GIDNTGSYTHYGAAVKG |
8 | NECTIN4-scFv-L1 CDRH2 | GISDAGSWTGYGAAVKG |
9 | NECTIN4-scFv-S2 CDRH2 | GVNAAGSWTGYGAAVKG |
10 | NECTIN4-scFv-S6 CDRH2 | GVNAAGSWTGYGAAVKG |
11 | NECTIN4-scFv-S8 CDRH2 | GISGSGSYTDYGAAVKG |
12 | NECTIN4-scFv-S21 CDRH2 | GIRSDGRYTYYGAAVKG |
13 | 雞scFv CDRH3 | AK-----------RTAGS |
14 | NECTIN4-scFv-L1 CDRH3 | AK-----SAGDWY-GADD |
15 | NECTIN4-scFv-S2 CDRH3 | AK-----TADDWY-GADD |
16 | NECTIN4-scFv-S6 CDRH3 | AK-----TADDWY-GADD |
17 | NECTIN4-scFv-S8 CDRH3 | AK-----GSNSAYPDAAD |
18 | NECTIN4-scFv-S21 CDRH3 | AKSGVTDTSSSTYSSASN |
19 | 雞scFv CDRL1 | SGDSS-YYG |
20 | NECTIN4-scFv-L1 CDRL1 | SGGSSNYYG |
21 | NECTIN4-scFv-S2 CDRL1 | SGDDSRYYG |
22 | NECTIN4-scFv-S6 CDRL1 | SGSSGYGYG |
23 | NECTIN4-scFv-S8 CDRL1 | SGGSGYGYG |
24 | NECTIN4-scFv-S21 CDRL1 | SGGSG-SYG |
25 | 雞scFv CDRL2 | DNTNRPS |
26 | NECTIN4-scFv-L1 CDRL2 | NNNKRPS |
27 | NECTIN4-scFv-S2 CDRL2 | YNDKRPS |
28 | NECTIN4-scFv-S6 CDRL2 | SNDKRPS |
29 | NECTIN4-scFv-S8 CDRL2 | SNDKRPS |
30 | NECTIN4-scFv-S21 CDRL2 | ANTNRPS |
31 | 雞scFv CDRL3 | ASTDSSS-TAGI |
32 | NECTIN4-scFv-L1 CDRL3 | GGWDKSA---GI |
33 | NECTIN4-scFv-S2 CDRL3 | GAYDSTTHSGSA |
34 | NECTIN4-scFv-S6 CDRL3 | GGYDSSASYVGI |
35 | NECTIN4-scFv-S8 CDRL3 | GGYDSSASYVGI |
36 | NECTIN4-scFv-S21 CDRL3 | GSRDSS--YVGI |
37 | NECTIN4-scFv-L1 VH | AVTLDESGGGLQAPGGGLSLVCRASGFTFSSHGMFWVRQAPGKGLEFVAGISDAGSWTGYGAAVKGRATISRDSGQSTVRLQLNNLRAEDTGIYYCAK-----SAGDWY-GADDIDAWGHGTEVIVSS |
38 | NECTIN4-scFv-L1 VL | ALTQPSSVSANPGETVKITCSGGSSNYYGWYQQKSPGSAPVTLIYNNNKRPSDIPSRFSASKSGSTHTLTITGVRAEDEAVYFCGGWDKSA---GIFGAGTTLTVL |
39 | NECTIN4-scFv-S2 VH | TVTLDESGGGLQTPGGGLSLVCKGSGFTFSSNGMAWVRQAPGKGLEFVGGVNAAGSWTGYGAAVKGRATISRDNGQSTVRLQLNDLRAEDTGTYYCAK-----TADDWY-GADDIDAWGHGTEVIVSS |
40 | NECTIN4-scFv-S2 VL | ALTQPSSVSANPGETVEVTCSGDDSRYYGWYQQKSPGSAPVTVIYYNDKRPSDIPSRFSGSKSGSTGTLTITGVQAEDEAVYFCGAYDSTTHSGSAFGAGTTLTVL |
41 | NECTIN4-scFv-S6 VH | TVTLDESGGGLQTPGGGLSLVCKGSGFTFSSNGMAWVRQAPGKGLEFVAGVNAAGSWTGYGAAVKGRATISRDNGQSTVRLQLNDLRAEDTGTYYCAK-----TADDWY-GADDIDAWGHGTEVIVSS |
42 | NECTIN4-scFv-S6 VL | ALTQPSSVSTNLGETVEITCSGSSGYGYGWYQQKSPGSAPVTVIYSNDKRPSDIPSRFSGSASGSTATLTITGVRAEDEAVYLCGGYDSSASYVGIFGAGTTLTVL |
43 | NECTIN4-scFv-S8 VH | TVTLDESGGGLQTPGGGLSLVCKASGFTFNDYGMGWMRQAPGKGLEWVAGISGSGSYTDYGAAVKGRAIISRDNGQSTVRLQLNNLRAEDTGTYVCAK-----GSNSAYPDAADIDAWGHGTEVIVSS |
44 | NECTIN4-scFv-S8 VL | ALTQPSSVSANLGGTVEITCSGGSGYGYGWYQQKSPGSAPVTVIYSNDKRPSDIPSRFSGSASGSTATLTITGVRAEDEAVYFCGGYDSSASYVGIFGAGTTLTVL |
45 | NECTIN4-scFv-S21 VH | AVTLDESGGGLQTPGGALSLVCKASGFTFSSYAMMWVRQAPGKGLEYIAGIRSDGRYTYYGAAVKGRATISRDNGQSTVRLQLNNLRAEDTGTYYCAKSGVTDTSSSTYSSASNIDAWGHGTEVIVSS |
46 | NECTIN4-scFv-S21 VL | ALTQPSSVSANLGGTVKITCSGGSG-SYGWYQQKSPGSAPVTLIYANTNRPSDIPSRFSGSKSGSTSTLTITGVQAEDVAVYYCGSRDSS--YVGIFGAGTTLTVL |
47 | 短連接子 | GQSSRSS |
48 | 長連接子1 | GQSSRSSSGGGSSGGGGS |
49 | 長連接子2 | GQSSRSSGGGGSSGGGGS |
50 | S21之結合區 | GELETSDVVTVVLGQDAKLPCFYRGDSGEQVGQVAWARVDAGEGAQELALLHSKYGLHVSPAYEGRVEQPPPPRNPLDGSVLLRNAVQADEGEYECRVSTFPAGSFQARLRLRV |
根據本發明之抗體可為全長(例如,IgG1或IgG4抗體)或可僅包含抗原結合部分(例如,Fab、F(ab')
2或scFv片段),且可視需要經修飾以影響功能性。
可使用一般熟習此項技術者已知的各種技術以判定抗體是否「特異性結合至多肽或蛋白質內之一或多個胺基酸」。例示性技術包括例如常規交叉阻斷分析,諸如Antibodies, Harlow及Lane (Cold Spring Harbor Press, Cold Spring Harb., NY)中所描述;丙胺酸掃描突變分析;肽墨點分析(Reineke, 2004, Methods Mol Biol 248:443-463)及肽裂解分析。另外,可採用諸如抗原決定基切除、抗原決定基提取及抗原化學修飾之方法(Tomer, 2000, Protein Science 9:487-496)。可用於鑑別與抗體特異性結合之多肽內之胺基酸的另一方法為藉由質譜偵測之氫/氘交換。一般而言,氫/氘交換方法涉及氘標記相關蛋白質,繼而使抗體與氘標記之蛋白質結合。隨後,將蛋白質/抗體複合物轉移至水中以允許氫-氘交換在除了經抗體保護之殘基(其保持經氘標記)以外的所有殘基處發生。在抗體解離之後,對目標蛋白質進行蛋白酶裂解及質譜分析,藉此展現對應於與抗體相互作用之特定胺基酸的氘標記殘基。參見例如Ehring (1999) Analytical Biochemistry 267 (2):252-259;Engen及Smith (2001) Anal. Chem. 73:256A-265A。
藉由使用此項技術中已知之常規方法,可容易地確定抗體是否與參考抗nectin-4抗體特異性結合至相同抗原決定基或競爭結合。舉例而言,為了確定測試抗體是否與本發明之參考抗nectin-4抗體結合至相同抗原決定基,使參考抗體結合至nectin-4蛋白。接下來,評估測試抗體與nectin-4分子結合之能力。若在與參考抗nectin-4抗體飽和結合之後測試抗體能夠結合至nectin-4,則可得出以下結論:測試抗體與參考抗nectin-4抗體結合至不同抗原決定基。另一方面,若在與參考抗nectin-4抗體飽和結合之後測試抗體不能結合至nectin-4分子,則測試抗體可結合至與本發明之參考抗nectin-4抗體所結合之抗原決定基相同的抗原決定基。隨後可進行額外常規實驗(例如肽突變及結合分析),以確認所觀測到之測試抗體之結合缺失實際上是否係由於與參考抗體結合至同一抗原決定基,或是否係空間阻斷(或另一現象)負責所觀測到之結合缺乏。此類實驗可使用ELISA、RIA、Biacore、流動式細胞測量術或此項技術中可用之任何其他定量或定性抗體結合分析來進行。根據本發明之某些實施例,如競爭性結合分析中所量測,若例如1倍、5倍、10倍、20倍或100倍過量之一種抗體抑制另一種抗體之結合至少50%但較佳地75%、90%或甚至99%,則兩種抗體結合至相同的(或重疊)抗原決定基。或者,若降低或消除一種抗體之結合的抗原中之基本上所有胺基酸突變降低或消除另一種抗體之結合,則將兩種抗體視為結合至相同抗原決定基。若僅一個子集的降低或消除一種抗體之結合的胺基酸突變降低或消除另一種抗體之結合,則將兩種抗體視為具有「重疊抗原決定基」。
抗體亦包括完整抗體分子之抗原結合片段。抗體之抗原結合片段可使用任何適合之標準技術衍生自例如完整抗體分子,諸如涉及編碼抗體可變域及視情況存在之恆定域之DNA之操縱及表現的蛋白水解消化或重組基因工程改造技術。該DNA為已知的及/或可易於自例如商業來源、DNA庫(包括例如噬菌體-抗體庫)獲得,或可經合成。DNA可以化學方式或藉由使用分子生物學技術定序及操縱,例如以將一或多個可變域及/或恆定域配置為適合之組態,或引入密碼子,產生半胱胺酸殘基,修飾、添加或缺失胺基酸等。
抗原結合片段之非限制性實例包括:(i) Fab片段;(ii) F(ab')
2片段;(iii) Fd片段;(iv) Fv片段;(v)單鏈Fv (scFv)分子;(vi) dAb片段;以及(vii)由胺基酸殘基組成的模擬抗體高變區之最小識別單元(例如經分離之互補決定區(CDR),諸如CDR3肽),或受限制之FR3-CDR3-FR4肽。其他經工程改造之分子,諸如域特異性抗體、單域抗體、域缺失抗體、嵌合抗體、CDR移植抗體、雙功能抗體、三功能抗體、四功能抗體、微型抗體、奈米抗體(例如單價奈米抗體、二價奈米抗體等)、小模組免疫藥物(SMIP)及鯊魚可變IgNAR域亦涵蓋在如本文所使用之表述「抗原結合片段」內。
抗體之抗原結合片段通常包含至少一個可變域。可變域可具有任何尺寸或胺基酸組成,且一般將包含至少一個與一或多個構架序列相鄰或同框之CDR。在具有與V
L域相關聯的V
H域的抗原結合片段中,V
H和V
L域可以任何適合的配置相對於彼此定位。舉例而言,可變區可為二聚體且含有V
H-V
H、V
H-V
L或V
L-V
L二聚體。或者,抗體之抗原結合片段可含有單體V
H及V
L域。
在某些實施例中,抗體之抗原結合片段可含有與至少一個恆定域共價連接之至少一個可變域。可見於本發明之抗體之抗原結合片段內的可變域及恆定域之非限制性例示性組態包括:(i) V
H-C
H1;(ii) V
H-C
H2;(iii) V
H-C
H3;(iv) V
H-C
H1-C
H2;(v) V
H-C
H1-C
H2-C
H3, (vi) V
H-C
H2-C
H3;(vii) V
H-C
L;(viii) V
L-C
H1;(ix) V
L-C
H2;(x) V
L-C
H3;(xi) V
L-C
H1-C
H2;(xii) V
L-C
H1-C
H2-C
H3;(xiii) V
L-C
H2-C
H3;及(xiv) V
L-C
L。在可變域及恆定域之任何組態,包括上文所列之例示性組態中之任一者中,可變域及恆定域可直接彼此連接或可藉由完全或部分鉸鏈區或連接區連接。鉸鏈區可由至少2個(例如5、10、15、20、40、60個或更多個)胺基酸組成,該等胺基酸在單一多肽分子中之相鄰可變域及/或恆定域之間產生可撓性或半可撓性連接。此外,本發明之抗體之抗原結合片段可包含上文所列之可變域及恆定域組態中之任一者的均二聚體或雜二聚體(或其他多聚體),該等組態彼此及/或與一或多個單體V
H或V
L域非共價締合(例如藉由雙硫鍵)。
與衍生出抗體之相應生殖系序列相比,本文所揭示之抗nectin-4抗體可在重鏈及輕鏈可變域之構架區及/或CDR區中包含一或多個胺基酸取代、插入及/或缺失。此類突變可藉由比較本文中所揭示之胺基酸序列與獲自例如公共抗體序列資料庫之生殖系序列來容易地確定。本發明包括衍生自本文所揭示之任何胺基酸序列的抗體及其抗原結合片段,其中一或多個構架區及/或CDR區內之一或多個胺基酸突變成衍生出抗體之生殖系序列的相應殘基,或突變成另一哺乳動物生殖系序列之相應殘基,或突變成相應生殖系殘基之保守性胺基酸取代(此類序列變化在本文中統稱為「生殖系突變」)。一般熟習此項技術者自本文所揭示之重鏈及輕鏈可變區序列開始,可容易地產生許多包含一或多個個別生殖系突變或其組合之抗體及抗原結合片段。在某些實施例中,V
H及/或V
L域內之所有構架及/或CDR殘基均突變回衍生出抗體之初始生殖系序列中所發現之殘基。在其他實施例中,僅某些殘基突變回初始生殖系序列,例如僅在FR1的前8個胺基酸內或在FR4的最後8個胺基酸內發現的突變殘基,或僅在CDR1、CDR2或CDR3內發現的突變殘基。在其他實施例中,構架及/或CDR殘基中之一或多者突變成不同生殖系序列(亦即,不同於最初衍生出抗體之生殖系序列的生殖系序列)的相應殘基。此外,本發明之抗體可含有構架區及/或CDR區內兩個或更多個生殖系突變之任何組合,例如其中某些個別殘基突變為特定生殖系序列之相應殘基,而與原始生殖系序列不同之某些其他殘基維持不變或突變為不同生殖系序列之相應殘基。一旦獲得,即可針對一或多種所需特性容易地測試含有一或多個生殖系突變之抗體及抗原結合片段,該等特性諸如改良的結合特異性、增加的結合親和力、改良或增強的拮抗或促效生物特性(視具體情況而定)、減小的免疫原性等。本發明內涵蓋以此一般方式獲得之抗體及抗原結合片段。
本發明亦包括一種抗nectin-4抗體,其包含本文所揭示之V
H、V
L及/或CDR胺基酸序列中之任一者之具有一或多個保守性取代的變異體。舉例而言,本發明包括一種抗nectin-4抗體,其具有相對於本文所揭示之V
H、V
L及/或CDR胺基酸序列中之任一者,具有10個或更少、8個或更少、6個或更少、4個或更少等保守性胺基酸取代的V
H、V
L及/或CDR胺基酸序列。
在本發明之一些實施例中,根據本發明之抗體為人類化抗體。為改良根據本發明之人類化抗體之結合親和力,人類構架區中之一些胺基酸殘基經CDR之物種(例如嚙齒動物)中的相應胺基酸殘基置換。
本發明之抗體可為單特異性、雙特異性或多特異性的。多特異性抗體可對一種目標多肽之不同抗原決定基具有特異性,或可含有對超過一種目標多肽具有特異性之抗原結合域。本發明之抗nectin-4抗體可連接至另一功能性分子(例如另一肽或蛋白質)或與另一功能性分子共表現。舉例而言,抗體或其片段可功能上連接(例如藉由化學偶合、遺傳融合、非共價締合或以其他方式)至一或多個其他分子實體(諸如另一抗體或抗體片段)以產生具有第二結合特異性之雙特異性或多特異性抗體。舉例而言,本發明包括雙特異性抗體,其中免疫球蛋白之一條臂對nectin-4或其片段具有特異性,且免疫球蛋白之另一條臂對第二治療目標具有特異性或與治療部分結合。
在本發明之一個實施例中,抗體或其抗原結合片段與治療劑結合。
在本發明之一些實施例中,治療劑表示細胞生長抑制劑或細胞毒性劑或具有相應放射性同位素之同位素螯合劑。細胞生長抑制劑或細胞毒性劑之實例包括但不限於抗代謝物(例如,氟尿嘧啶(5-FU)、氟尿苷(5-FUdR)、甲胺喋呤、甲醯四氫葉酸、羥脲、硫鳥嘌呤(6-TG)、巰基嘌呤(6-MP)、阿糖胞苷、噴司他丁(pentostatin)、氟達拉濱磷酸鹽(fludarabine phosphate)、克拉屈濱(cladribine) (2-CDA)、天冬醯胺酶、吉西他濱(gemcitabine)、卡培他濱(capecitibine)、硫唑嘌呤、胞嘧啶甲胺喋呤、曲美普林(trimethoprim)、嘧啶甲胺(pyrimethamine)或培美曲塞(pemetrexed));烷化劑(例如,c美法倫(cmelphalan)、氮芥苯丁酸、白消安(busulfan)、噻替派(thiotepa)、異環磷醯胺、卡莫司汀(carmustine)、洛莫司汀(lomustine)、司莫司汀(semustine)、鏈脲菌素、達卡巴嗪(dacarbazine)、絲裂黴素C、環磷醯胺、甲基二(氯乙基)胺、烏拉莫司汀(uramustine)、二溴甘露醇、四硝酸酯、丙卡巴肼(procarbazine)、六甲蜜胺、米托唑胺(mitozolomide)或替莫唑胺(temozolomide));類烷化劑(例如,順鉑(cisplatin)、卡鉑(carboplatin)、奈達鉑(nedaplatin)、奧沙利鉑(oxaliplatin)、賽特鉑(satraplatin)或特瑞鉑(triplatin));DNA小溝烷化劑(例如,倍癌黴素(duocarmycin),諸如CC-1065及其任何類似物或衍生物;吡咯并苯并二氮雜卓(pyrrolobenzodiazapene)或其任何類似物或衍生物);蒽環黴素(例如,道諾黴素(daunorubicin)、小紅莓(doxorubicin)、表柔比星(epirubicin)、艾達黴素(idarubicin)或伐柔比星(valrubicin));抗生素(例如,放線菌素d (dactinomycin)、博萊黴素(bleomycin)、光神黴素(mithramycin)、安麴黴素(anthramycin)、鏈佐黴素(streptozotocin)、短桿菌素D (gramicidin D)、絲裂黴素(例如,絲裂黴素C);卡奇黴素;抗有絲分裂劑(包括例如,類美登素(maytansinoid) (諸如DM1、DM3及DM4)、奧瑞他汀(auristatin) (包括例如,單甲基奧瑞他汀E (MMAE)及單甲基奧瑞他汀F (MMAF))、尾海兔素(dolastatin)、念珠藻素(cryptophycin)、長春花屬生物鹼(例如,長春新鹼(vincristine)、長春鹼(vinblastine)、長春地辛(vindesine)、長春瑞濱(vinorelbine))、紫杉烷(例如,太平洋紫杉醇、多西他賽(docetaxel)或新穎紫杉烷)、特吡萊辛(tubulysin)及秋水仙鹼);拓樸異構酶抑制劑(例如,伊立替康(irinotecan)、拓朴替康(topotecan)、喜樹鹼(camptothecin)、依託泊苷(etoposide)、替尼泊苷(teniposide)、安吖啶(amsacrine)或米托蒽醌(mitoxantrone));HDAC抑制劑(例如,伏立諾他(vorinostat)、羅米地辛(romidepsin)、西達本胺(chidamide)、帕比司他(panobinostat)或貝林諾他(belinostat));蛋白酶體抑制劑(例如,肽基硼酸(peptidyl boronic acid));以及放射性同位素,諸如At
211、I
131、I
125、Y
90、Re
186、Re
188、Sm
153、Bi
212或Bi
213、P
32及Lu之放射性同位素,包括Lu
177。同位素螯合劑之實例包括但不限於乙二胺四乙酸(EDTA)、二伸乙基三胺-N,N,N',N",N"-五乙酸酯(DTPA)、1,4,7,10-四氮雜環十二烷-N,N',N",N"'-四乙酸酯(DOTA)、1,4,7,10-肆(2-羥丙基)-1,4,7,10-四氮雜環十二烷(THP)、三伸乙基四胺-N,N,N',N",N"',N"'-六乙酸酯(TTHA)、1,4,7,10-四氮雜環十二烷-N,N',N",N"'-肆(亞甲基膦酸酯) (DOTP)及巰基乙醯基三甘胺酸(MAG3)。
在本發明之一個實施例中,該抗體或其抗原結合片段表現於細胞之表面上。特定言之,細胞為T細胞或幹細胞,諸如iPSC。誘導性富潛能幹細胞可藉由將山中因子(Yamanaka factor)誘導至體細胞中來再程式化。如同胚胎幹細胞,iPSC能夠在無倫理問題之情況下分化成三胚層細胞。藉由此特性,iPSC展現有前景的臨床用途應用。
在本發明之一些實施例中,該抗體或其抗原結合片段呈嵌合抗原受體形式。
術語「嵌合抗原受體」或替代地「CAR」係指包含至少胞外抗原結合域、跨膜域及包含衍生自如下所定義之刺激分子之功能性信號傳導域之細胞質信號傳導域(在本文中亦稱為「胞內信號傳導域」)的重組多肽構築體。在一些實施例中,CAR多肽構築體中的域處於同一多肽鏈中,例如構成嵌合融合蛋白。在一些實施例中,CAR多肽構築體中之域彼此不相鄰,例如處於不同多肽鏈中。
抗體或其抗原結合片段可編碼於編碼抗體或其抗原結合片段之載體中。例示性載體為慢病毒載體。「慢病毒」係指能夠感染分裂細胞及非分裂細胞之反轉錄病毒屬。慢病毒之若干實例包括HIV (人類免疫缺乏病毒:包括第1型HIV及第2型HIV);馬傳染性貧血病毒;貓免疫缺乏病毒(FIV);牛免疫缺乏病毒(BIV);及猿猴免疫缺乏病毒(SIV)。
在另一態樣中,本發明提供表現抗體或其抗原結合片段或含有載體之經基因工程改造之細胞。經基因工程改造之細胞可為免疫細胞或幹細胞。此外,本發明提供一種免疫細胞,其自經基因工程改造之細胞分化。
本發明提供醫藥組合物,其包含本發明之抗體或其抗原結合片段、經基因工程改造之細胞或免疫細胞。本發明之醫藥組合物係藉由適合之稀釋劑、載劑、賦形劑及提供改良之轉移、遞送、耐受性及類似性質之其他藥劑調配。該等組合物可調配用於特定用途,諸如用於獸醫學用途或人類醫藥用途。所用組合物形式及賦形劑、稀釋劑及/或載劑將視抗體之預期用途及用於治療性用途之投藥模式而定。可於所有醫藥化學家已知之處方集中查詢眾多適當調配物:Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa。此等調配物包括例如散劑、糊劑、軟膏、膠凍、蠟、油、脂質、含有脂質(陽離子或陰離子)之囊泡(諸如LIPOFECTIN.TM., Life Technologies, Carlsbad, Calif.)、DNA結合物、無水吸收糊劑、水包油及油包水乳液、乳液卡波蠟(各種分子量之聚乙二醇)、半固體凝膠及含有卡波蠟之半固體混合物。亦參見Powell等人「Compendium of excipients for parenteral formulations」PDA (1998) J Pharm Sci Technol 52:238-311。
向患者投與之抗體的劑量可視患者之年齡及體型、目標疾病、病狀、投藥途徑及其類似者而變化。較佳劑量通常根據體重或體表面積計算。當本發明之抗體用於治療成年患者中與EPHA10相關之病狀或疾病時,靜脈內投與本發明之抗體可為有利的。可視病狀之嚴重程度而定來調節治療之頻率及持續時間。投與抗體之有效劑量及時程可憑經驗確定;舉例而言,可藉由週期性評估監測患者進展,且相應地調節劑量。此外,可使用此項技術中之熟知方法(例如Mordenti等人, 1991, Pharmaceut. Res. 8:1351)進行劑量之種間按比例調整。
各種遞送系統為吾人所知且可用於投與本發明之醫藥組合物,例如囊封於脂質體中、微粒、微膠囊、能夠表現突變病毒之重組細胞、受體介導之內飲作用(參見例如Wu等人, 1987, J. Biol. Chem. 262:4429-4432)。引入方法包括但不限於皮內、肌肉內、腹膜內、靜脈內、皮下、鼻內、硬膜外及經口途徑。組合物可藉由任何便利途徑投與,例如藉由輸注或彈丸注射、藉由經由上皮或黏膜皮膚內層(例如口腔黏膜、直腸黏膜及腸黏膜等)吸收且可與其他生物學活性劑一起投與。投藥可為全身性或局部的。
可使用標準針及注射器皮下或靜脈內遞送本發明之醫藥組合物。此外,關於皮下遞送,筆式遞送裝置易於在遞送本發明之醫藥組合物時應用。此類筆式遞送裝置可為可再用或拋棄式的。可再用的筆式遞送裝置通常利用含有醫藥組合物之可更換藥筒。一旦已投與藥筒內之全部醫藥組合物且藥筒為空,空藥筒可容易地丟棄且用含有醫藥組合物之新藥筒更換。隨後可再使用筆式遞送裝置。在拋棄式筆式遞送裝置中,不存在可更換藥筒。實際上,拋棄式筆式遞送裝置預填充有保存於裝置內的儲集器中的醫藥組合物。一旦儲集器中之醫藥組合物被清空,丟棄整個裝置。
在某些情形中,醫藥組合物可在控制釋放系統中遞送。在一個實施例中,可使用泵(參見Langer,見上文;Sefton 1987 CRC Crit. Ref. Biomed. Eng. 14: 201)。在另一實施例中,可使用聚合材料;參見Medical Applications of Controlled Release, Langer及Wise (編), 1974, CRC Pres., Boca Raton, Fla。在又另一實施例中,可將控制釋放系統接近組合物之目標置放,因此僅需要全身性劑量之一部分(參見例如Goodson, 1984, 於Medical Applications of Controlled Release, 見上文, 第2卷, 第115-138頁)。其他控制釋放系統論述於Langer, 1990, Science 249:1527-1533之綜述中。
可注射製劑可包括用於靜脈內、皮下、皮內及肌肉內注射、滴液輸液等之劑型。此等可注射製劑可藉由公開已知之方法來製備。舉例而言,可注射製劑可例如藉由將上文所描述之抗體或其鹽溶解、懸浮或乳化於習知地用於注射之無菌水性介質或油性介質中來製備。作為注射劑之水性介質,存在例如生理食鹽水、含有葡萄糖及其他輔助藥劑之等滲溶液等,其可與適當助溶劑組合使用,諸如醇(例如乙醇)、多元醇(例如丙二醇、聚乙二醇)、非離子界面活性劑[例如,聚山梨醇酯80、HCO-50 (氫化蓖麻油之聚氧化乙烯(50 mol)加合物)]等。採用例如芝麻油、大豆油等作為油性介質,其可與助溶劑(諸如苯甲酸苯甲酯、苄醇等)組合使用。較佳將由此製備之注射劑填充於適當安瓿中。
有利地,將用於上文所描述之經口或非經腸用途之醫藥組合物製備成呈適合於配合活性成分之劑量的單位劑量之劑型。此類呈單位劑量之劑型包括例如錠劑、丸劑、膠囊、注射劑(安瓿)、栓劑等。
在另一態樣中,本發明提供一種偵測或診斷個體是否患有腫瘤或具有罹患腫瘤之風險或評估腫瘤預後的方法,其包含使來源於該個體之樣品與該抗體或其抗原結合片段接觸。
本發明提供一種用於偵測樣品中之nectin-4的方法,其包含使該樣品與該抗體或其抗原結合片段接觸。
本發明亦提供一種用於偵測樣品中之nectin-4的套組,其中該套組包含該抗體或其抗原結合片段。
在另一態樣中,本發明提供一種用於在罹患腫瘤之個體中治療、預防性治療及/或預防該腫瘤的方法,其包含向該個體投與該醫藥組合物。替代地,本發明提供一種用於在罹患腫瘤之個體中治療、預防性治療及/或預防該腫瘤的醫藥組合物,其包含有效量之如本文所揭示之抗體或其抗原結合片段或經基因工程改造之細胞。
癌症之一個實例為實體腫瘤。癌症之另一實例為液體腫瘤,諸如淋巴瘤、白血病及血液科惡性病。本發明之癌症的其他實例包括三陰性乳癌、乳癌、乳癌轉移、本文所描述之任何癌症的轉移、大腸癌、大腸癌轉移、肉瘤、急性淋巴母細胞性白血病、急性骨髓性白血病、腎上腺皮質癌、愛滋病相關癌症諸如卡堡氏肉瘤(Kaposi sarcoma)、愛滋病相關淋巴瘤、原發性CNS淋巴瘤、肛門癌、闌尾癌、兒童星形細胞瘤、星形細胞瘤、兒童非典型類畸胎/橫紋肌瘤、CNS非典型類畸胎/橫紋肌瘤、非典型類畸胎/橫紋肌瘤、基底細胞癌、皮膚癌、膽管癌、膀胱癌、骨癌、尤文氏肉瘤(Ewing sarcoma)腫瘤家族、骨肉瘤、軟骨瘤、軟骨肉瘤、原發性及轉移性骨癌、惡性纖維組織細胞瘤、兒童腦幹神經膠質瘤、腦幹神經膠質瘤、腦腫瘤、腦及脊髓腫瘤、中樞神經系統胚胎性腫瘤、兒童中樞神經系統胚胎性腫瘤、中樞神經系統生殖細胞腫瘤、兒童中樞神經系統生殖細胞腫瘤、顱咽管瘤、兒童顱咽管瘤、室管膜瘤、兒童室管膜瘤、乳癌、支氣管腫瘤、兒童支氣管腫瘤、伯基特淋巴瘤(burkitt lymphoma)、類癌瘤、胃腸道癌、原發灶不明癌、心臟腫瘤、兒童心臟腫瘤、原發性淋巴瘤、子宮頸癌、膽管癌、脊索瘤、兒童脊索瘤、慢性淋巴球性白血病、慢性骨髓性白血病、慢性骨髓增生性腫瘤、大腸癌、大腸直腸癌、皮膚T細胞淋巴瘤、彌漫性中線神經膠質瘤、乳腺管原位癌、胚胎性腫瘤、子宮內膜癌、室管膜瘤、食道癌、敏感性神經胚細胞瘤、兒童敏感性神經胚細胞瘤、尤文氏肉瘤、顱外生殖細胞腫瘤、兒童顱外生殖細胞腫瘤、性腺外生殖細胞腫瘤、眼癌、眼內黑色素瘤、視網膜母細胞瘤、輸卵管癌、骨纖維組織細胞瘤、膽囊癌、胃癌、胃腸道類癌瘤、胃腸道基質瘤、卵巢癌、睪丸癌、妊娠期滋養細胞疾病、神經膠質瘤、多形性神經膠質母細胞瘤(GBM)、低度神經膠質瘤(LGG)、大腦神經膠質瘤病、毛細胞白血病、頭頸癌、肝細胞癌、組織細胞增生症、蘭格漢氏細胞(Langerhans cell)組織細胞增生症、霍奇金氏淋巴瘤(hodgkin lymphoma)、下咽癌、眼內黑色素瘤、黑色素瘤、黑色素瘤轉移、胰島細胞瘤、胰臟神經內分泌腫瘤、腎癌、腎細胞腫瘤、威爾姆氏瘤(Wilms tumor)、兒童腎腫瘤、唇及口腔癌、肝癌、肺癌、神經管母細胞瘤、非霍奇金氏淋巴瘤、巨球蛋白血症、瓦登斯特隆(Waldenstrom)巨球蛋白血症、男性乳癌、梅克爾細胞癌(merkel cell carcinoma)、潛藏原發轉移性鱗狀頸癌、涉及NUT基因之中線道癌、口腔癌、多發性內分泌瘤症候群、兒童多發性內分泌瘤症候群、多發性骨髓瘤/漿細胞腫瘤、蕈樣黴菌病、骨髓發育不良症候群、骨髓發育不良/骨髓增生性腫瘤、多發性骨髓瘤、骨髓增生性腫瘤、慢性骨髓增生性腫瘤、黏液乳頭型室管膜瘤、鼻腔及鼻竇癌、鼻咽癌、神經母細胞瘤、非小細胞肺癌、寡樹突神經膠質瘤、寡樹突星形細胞瘤、口咽癌、卵巢癌、低度惡性潛能腫瘤、胰臟癌、胰臟神經內分泌腫瘤、乳頭狀瘤症、兒童乳頭狀瘤症、副神經節瘤、副鼻竇及鼻腔癌、副甲狀腺癌、陰莖癌、嗜鉻細胞瘤、咽癌、毛狀星細胞瘤、垂體腫瘤、多形態黃星形細胞瘤(PXA)、胸膜肺母細胞瘤、兒童胸膜肺母細胞瘤、原發性腹膜癌、前列腺癌、直腸癌、妊娠相關癌症、橫紋肌肉瘤、兒童橫紋肌肉瘤、唾液腺癌、塞紮萊症候群(Sezary syndrome)、小細胞肺癌、小腸癌、軟組織肉瘤、鱗狀細胞癌、睪丸癌、咽喉癌、胸腺瘤、胸腺癌、甲狀腺癌、腎、骨盆及輸尿管移行細胞癌、子宮癌、尿道癌、子宮內膜癌、子宮肉瘤、陰道癌、血管腫瘤及外陰癌。
Nectin-4在61%乳腺管乳癌及6%小葉型乳癌中表現。雖然不希望受理論限制,但咸信聯合CEA/CA15.3/Nectin-4允許監測74%乳癌,與之相比,聯合CEA/CA15.3為67%。Nectin-4亦經由Pi3k/Akt軸上調EMT、轉移及WNT/β-連環蛋白路徑。臨床病理學資料展示乳房腫瘤轉移至腋下淋巴結時所誘導之nectin-4。在另一態樣中,nectin-4為乳癌幹細胞中之潛在血管生成生物標記。Nectin-4胞外域與整合素-β4物理相互作用且活化血管生成路徑。nectin-4與整合素-β4之相互作用經由Src、PI3K、AKT、iNOS路徑而非藉由磷酸-ERK或NF-κβ路徑促進血管生成。
提供以下實例以幫助熟習此項技術者實踐本發明。
實例
實例
1
:
重組
PVRL4
片段蛋白及抗
PVRL4
scFv
之表現及純化
抗原。簡言之,將Nectin-4-Q95NY8 (PVRL4_HUMAN)基因片段PVRL4_342 (94-435,342 bp,r342p)、PVRL4_639 (94-732,639 bp,r639p)、PVRL4_864 (94-957,864 bp,r864p)構築於pET-21a(+)質體中,且將所得載體轉型至大腸桿菌(
E . coli)中。來自單一群落之細菌培養物在5 ml含有胺苄青黴素(ampicillin) (50 μg/ml)之LB培養基中在37℃下生長隔夜,在相同LB培養基中稀釋100倍,且進一步生長直至OD
600達至0.4與0.8之間。為誘導PVRL4蛋白表現,添加異丙基-β-D-硫代哌喃半乳糖苷(IPTG)至培養物中達至1.0 mM之最終濃度。使細胞沈澱再懸浮於含有6 M尿素之His-結合緩衝液中且藉由音波處理溶解。在離心之後,將所得細胞溶解產物與Ni
2 +-瓊脂糖凝膠(GE™ Healthcare Life Science, Pittsburgh, PA, USA)一起培育,以根據製造商說明書純化重組PVRL4融合蛋白。
如圖1中所示,用SDS-PAGE分析蛋白質產物。
動物免疫接種。雌性白來亨雞(white leghorn chicken) (家雞(
Gallus domesticus))首先用含50 μg純化his-PVRL4_342或20 μg純化his-PVRL4_864之0.5 ml弗氏完全佐劑(Freund's complete adjuvant) (Sigma™, USA)藉由肌內注射進行免疫接種。以7或8之間隔用50 μg his-PVRL4_342進行三次額外免疫接種,接著在1個月後用30 μg his-PVRL4_342進行一次額外免疫接種。類似地,以7天之間隔用25 μg his-PVRL4_863進行第2次免疫接種,用20 μg his-PVRL4_863進行第3次免疫接種,且用15 μg his-PVRL4_863進行第4次免疫接種。各次免疫接種之後,蛋黃中之多株IgY抗體經部分純化且藉由酶聯免疫吸附分析(ELISA)滴定以確定體液抗PVRL4免疫反應之存在。使用10%硫酸聚葡萄糖自蛋黃純化IgY抗體。將經純化之IgY抗體溶解於5 ml含0.05%疊氮化鈉之TBS中且在−20°℃下儲存。
scFv 抗體庫之構築。簡言之,最終免疫接種之後自雞採集之脾即刻置放於Trizol中用於均質化。使用SuperScript RT套組(Invitrogen™, USA)將二十微克總RNA反轉錄成第一股cDNA。在使用雞特異性引子擴增之後,重鏈及輕鏈可變(VH及VL)區之PCR產物經歷第二輪PCR,以形成具有短連接子(諸如SEQ ID NO. 47)或長連接子(SEQ ID NO: 48或49)之全長scFv片段,其進一步選殖至pComb3X載體中。藉由電致孔將重組噬菌體DNA轉型至大腸桿菌ER2738菌株中。藉由添加野生型VCS-M13輔助噬菌體起始重組噬菌體之產生,該等噬菌體隨後用4%聚乙二醇8000及3% NaCl (w/v)沈澱,且最後再懸浮於1×磷酸鹽緩衝鹽水中。
基於細胞之噬菌體顯示淘選。將50 μl噬菌體庫(10
12-10
13)及150 μl含1% BSA之PBS在4℃下靜置1小時。將100 μl 10
6個BML01細胞及80 μl噬菌體在室溫下靜置30分鐘兩次以用於負向選擇。總上清液中添加10
6個BML01-Nectin4細胞且在4℃下靜置1小時以用於正向選擇。用PBS洗滌混合物5至8次。藉由將細胞與100 μl 0.2 M甘胺酸-HCl (pH 2.2)在室溫下一起培育10分鐘來溶離噬菌體。收集上清液且將其用15 μl 1 M Tris-HCl,pH 9.1中和。
用大腸桿菌ER2738測定且擴增噬菌體效價。噬菌體效價及擴增之結果展示於表2中。
表2
PFU/μl | 淘選1 | 擴增1 | 淘選2 | 擴增2 | 淘選3 |
長連接子 | 1×10 2 | 1×10 10 | 2.4×10 3 | 2×10 10 | 1.1×10 4 |
短連接子 | 1×10 4 | 4×10 10 | 1×10 4 | 2×10 2 | 2.99×10 5 |
與雞免疫球蛋白之重鏈及輕鏈可變區基因的scFv序列比對展示於圖2A及圖2B中。
基於細胞之 ELISA 。將BML01細胞或過度表現Nectin 4之BML01細胞以1×10
6個細胞/ml懸浮於10% FBS RPMI培養基中。將100 μl細胞接種於96孔圓底培養盤中且各孔添加50 μl候選噬菌體培養物。將混合物在室溫下以150 rpm振盪培育2小時,且隨後用PBS洗滌3次。混合物中添加100 μl抗M13-HRP (含1% BSA之PBS中1:5000稀釋)且在室溫下以150 rpm振盪培育2小時,且隨後用PBS洗滌6次。混合物中添加100 μl TMB且隨後藉由添加50 μl 2 N H
2SO
4停止反應。結果展示於圖3A及圖3B中。
抗HA抗體用於偵測候選噬菌體純系之結合活性。含1×10
5個細胞之100 μl流動緩衝液中添加20 μl候選噬菌體純系,且在室溫下培育30分鐘且洗滌兩次。隨後添加抗HA抗體且在室溫下培育30分鐘且洗滌兩次。混合物經歷流動式細胞測量術分析且展示圖4。
scFv之蛋白質表現展示於圖5中。抗PVRL4 scFv針對PVRL4 864之結合能力藉由西方墨點法分析且展示於圖6中。
用ELISA分析連續濃度之抗PVRL4 scFv針對PVRL4 864及BSA之結合能力。基於滴定抗PVRL4 scFv在OD450 nm值為1下之濃度展示於表3中。其展示S21對PVRL4 864具有最強親和力。
表3
排名 | 純系 | 濃度(μg/ml) |
1 | S21 | 0.02 |
2 | L1 | 0.04 |
3 | L4 | 0.16 |
4 | S6 | 0.31 |
藉由競爭性ELISA或ELISA進行的L1/S6/S21/L4針對r864p之結合分析的結果展示於圖7中。第一抗體為經純化之scFv;第二抗體為山羊抗雞輕鏈(1:3000);第三抗體為HRC結合之驢抗山羊IgG抗體(1:5000)。抗PVRL4 scFv之K
d 值展示於表4中。
純系 | 50%濃度(μg/ml) | K d 值(M) |
L4 (並非藉由競爭性ELISA) | 0.03 | 1.34×10 -9 |
S21 | 52.47 | 1.41×10 -6 |
S6 | 34.87 | 9.42×10 -7 |
L1 | 34.74 | 9.39×10 -7 |
吾人成功產生重組PVRL4片段蛋白及抗PVRL4_864 scFv。
實例
2
:抗
PVRL4
scFv
之表徵
西方墨點分析中單株抗PVRL4 scFv對MCF-7細胞之結合能力展示於圖8中。MDA-MB-231細胞充當陰性對照。第一抗體為經純化之scFv S2、S21及L4 (10 μg/ml);第二抗體為山羊抗雞輕鏈(1:3000);第三抗體為HRP結合之驢抗山羊抗體(1:5000)。
藉由免疫螢光進行的抗PVRL4 scFv針對乳癌細胞株之結合分析的結果展示於圖9A及圖9B中。共軛焦顯微鏡下S21針對乳癌細胞株MCF7之免疫螢光染色的結果展示於圖10中。第一抗體為經純化之scFv S21 (300 μg/ml);第二抗體為山羊抗雞輕鏈(1:400);第三抗體為TRIC結合之兔抗山羊IgG抗體(1:400);空白為第2及第3抗體,不含第1抗體。
染色分析中單株抗PVRL4 scFv之表徵結果展示於圖11中。S21用於對MCF-7細胞的免疫螢光染色(300 µg/ml),且用TRITC結合抗體視覺化(400×放大率;代表性資料)。
利用細胞ELISA進行的抗PVRL4 scFv針對乳癌細胞株MCF7之結合分析的結果展示於圖12中。第一抗體為經純化之scFv S21及L4,連續稀釋;第二抗體為山羊抗雞輕鏈(1:2000);第三抗體為HRC結合之驢抗山羊IgG抗體(1:4000);空白為第2及第3抗體,不含第1抗體;陰性對照(NC)為抗RT scFv S3 (RTS3)。
用抗PVRL4 scFv S21處理後MCF7之細胞增殖的結果展示於圖13中。
吾人發現S21可識別MCF7細胞株上之PVRL4且抑制其增殖。
實例
3
:用抗
PVRL4
scFv
對
PVRL4
進行抗原決定基定位
抗PVRL4 scFv S21之抗原決定基定位的結果展示於圖14中。第一抗體為經純化之scFv S21 (20 µg/ml)或抗r864第4次免疫接種之IgY (1:5000)作為陽性對照;第二抗體為山羊抗雞輕鏈(1:3000)或HRP結合之驢抗雞IgY (1:5000);第三抗體為HRC結合之驢抗山羊IgG抗體(1:5000)。S21之結合區為SEQ ID NO: 50。
雖然已結合上文所闡述之特定實施例來描述本發明,但對其之許多替代方案及其修改及變化對於一般熟習此項技術者而言將顯而易見。所有此類替代方案、修改及變化被視為屬於本發明之範疇內。
圖1展示實例1中PVRL4片段之表現。泳道1:Ni
+瓊脂糖凝膠結合之後的上清液;泳道2:所收集之洗滌緩衝液;泳道3:所收集之溶離緩衝液(咪唑);泳道4:溶離之後的Ni
+瓊脂糖凝膠。預測大小:r342p:15 kDa;r639p:48 kDa;r864p:34 kDa。
圖2A展示雞免疫球蛋白之輕鏈可變區的scFv序列比對。圖2B展示雞免疫球蛋白之重鏈可變區的scFv序列比對。
圖3A展示抗Nectin-4 M13噬菌體之親和力分析使用表現或不表現於BML01細胞上之Nectin-4。圖3B展示抗Nectin-4 M13噬菌體之親和力倍數(BML01-nectin-4 OD
450/BML01 OD
450)。
圖4展示使用抗HA抗體偵測候選噬菌體純系之結合活性的結果。
圖5展示scFv之蛋白質表現。
圖6展示藉由西方墨點法確定的抗PVRL4 scFv針對PVRL4 864之結合能力。
圖7展示藉由競爭性ELISA或ELISA進行的L1/S6/S21/L4針對r864p之結合分析的結果。
圖8展示西方墨點分析中單株抗PVRL4 scFv對MCF-7細胞之結合能力。
圖9A及圖9B展示藉由免疫螢光進行的抗PVRL4 scFv針對乳癌細胞株之結合分析的結果。圖9A:MCF7;圖9B:MCF10A。
圖10展示共軛焦顯微鏡下S21針對乳癌細胞株MCF7之免疫螢光染色結果。
圖11展示染色分析中單株抗PVRL4 scFv (S21)之表徵結果。
圖12展示使用ELISA確定的單株抗PVRL4 scFv對MCF-7細胞之結合能力(資料展示為平均值±SD,N=2)。
圖13展示用抗PVRL4 scFv S21處理後MCF7之細胞增殖結果。
圖14展示抗PVRL4 scFv S21之抗原決定基定位結果。
TW202328204A_112101454_SEQL.xml
Claims (20)
- 一種對nectin細胞黏附分子4 (nectin-4)或其片段中之抗原決定基具有特異性的抗體或其抗原結合片段;其包含重鏈可變區之互補決定區(CDR)及輕鏈可變區之CDR,其中該重鏈可變區之該等CDR包含CDRH1、CDRH2及CDRH3區,且該輕鏈可變區之該等CDR包含CDRL1、CDRL2及CDRL3區,且其中: 該CDRH1區包含選自由SEQ ID NO: 2至6組成之群的胺基酸序列;該CDRH2區包含選自由SEQ ID NO: 8至12組成之群的胺基酸序列;且該CDRH3區包含選自由SEQ ID NO: 14至18組成之群的胺基酸序列;且 該CDRL1區包含選自由SEQ ID NO: 20至24組成之群的胺基酸序列;該CDRL2區包含選自由SEQ ID NO: 26至30組成之群的胺基酸序列;且該CDRL3區包含選自由SEQ ID NO: 32至36組成之群的胺基酸序列。
- 如請求項1之抗體或其抗原結合片段,其中nectin-4為人類nectin-4。
- 如請求項1之抗體或其抗原結合片段,其對nectin-4或其該片段之細胞外域中之抗原決定基具有特異性。
- 如請求項1之抗體或其抗原結合片段,其對nectin-4-Q96NY8 (PVRL4_HUMAN)之胺基酸94至435、94至732或94至957具有特異性。
- 如請求項1之抗體或其抗原結合片段,其中 該CDRH1區包含SEQ ID NO: 2,該CDRH2區包含SEQ ID NO: 8,該CDRH3區包含SEQ ID NO: 14,該CDRL1區包含SEQ ID NO: 20,該CDRL2區包含SEQ ID NO: 26,且該CDRL3區包含SEQ ID NO: 32; 該CDRH1區包含SEQ ID NO: 3,該CDRH2區包含SEQ ID NO: 9,該CDRH3區包含SEQ ID NO: 15,該CDRL1區包含SEQ ID NO: 21,該CDRL2區包含SEQ ID NO: 27,且該CDRL3區包含SEQ ID NO: 33; 該CDRH1區包含SEQ ID NO: 4,該CDRH2區包含SEQ ID NO: 10,該CDRH3區包含SEQ ID NO: 16,該CDRL1區包含SEQ ID NO: 22,該CDRL2區包含SEQ ID NO: 28,且該CDRL3區包含SEQ ID NO: 34; 該CDRH1區包含SEQ ID NO: 5,該CDRH2區包含SEQ ID NO: 11,該CDRH3區包含SEQ ID NO: 17,該CDRL1區包含SEQ ID NO: 23,該CDRL2區包含SEQ ID NO: 29,且該CDRL3區包含SEQ ID NO: 35;或 該CDRH1區包含SEQ ID NO: 6,該CDRH2區包含SEQ ID NO: 12,該CDRH3區包含SEQ ID NO: 18,該CDRL1區包含SEQ ID NO: 24,該CDRL2區包含SEQ ID NO: 30,且該CDRL3區包含SEQ ID NO: 36。
- 如請求項1之抗體或其抗原結合片段,其中 該重鏈可變區包含SEQ ID NO: 37之胺基酸序列或具有至少90%序列一致性之基本相似序列;且該輕鏈可變區包含SEQ ID NO: 38之胺基酸序列或具有至少90%序列一致性之基本相似序列; 該重鏈可變區包含SEQ ID NO: 39之胺基酸序列或具有至少90%序列一致性之基本相似序列;且該輕鏈可變區包含SEQ ID NO: 40之胺基酸序列或具有至少90%序列一致性之基本相似序列; 該重鏈可變區包含SEQ ID NO: 41之胺基酸序列或具有至少90%序列一致性之基本相似序列;且該輕鏈可變區包含SEQ ID NO: 42之胺基酸序列或具有至少90%序列一致性之基本相似序列; 該重鏈可變區包含SEQ ID NO: 43之胺基酸序列或具有至少90%序列一致性之基本相似序列;且該輕鏈可變區包含SEQ ID NO: 44之胺基酸序列或具有至少90%序列一致性之基本相似序列;或 該重鏈可變區包含SEQ ID NO: 45之胺基酸序列或具有至少90%序列一致性之基本相似序列;且該輕鏈可變區包含SEQ ID NO: 46之胺基酸序列或具有至少90%序列一致性之基本相似序列。
- 如請求項1之抗體或其抗原結合片段,其為單株抗體、嵌合抗體、人類化抗體、人類抗體或scFv抗體或其片段。
- 如請求項1之抗體或其抗原結合片段,其與治療劑結合。
- 如請求項8之抗體或其抗原結合片段,其中該治療劑係選自由以下組成之群:抗代謝物、烷化劑、類烷化劑、DNA小溝烷化劑、蒽環黴素、抗生素、卡奇黴素(calicheamicin)、抗有絲分裂劑、拓樸異構酶抑制劑、HDAC抑制劑、蛋白酶體抑制劑及放射性同位素。
- 如請求項1之抗體或其抗原結合片段,其表現於細胞之表面上。
- 如請求項10之抗體或其抗原結合片段,其中該細胞為免疫細胞或幹細胞。
- 一種載體,其編碼如請求項1中任一項之抗體或其抗原結合片段。
- 一種經基因工程改造之細胞,其表現如請求項1之抗體或其抗原結合片段。
- 一種醫藥組合物,其包含有效量之如請求項1至11中任一項之抗體或其抗原結合片段或如請求項13之經基因工程改造之細胞。
- 一種偵測或診斷個體是否患有腫瘤或具有罹患腫瘤之風險或評估腫瘤預後的方法,其包含使來源於該個體之樣品與如請求項1至11中任一項之抗體或其抗原結合片段接觸。
- 一種用於偵測樣品中之nectin-4的方法,其包含使該樣品與如請求項1至11中任一項之抗體或其抗原結合片段接觸。
- 一種用於偵測樣品中之nectin-4的套組,其中該套組包含如請求項1至11中任一項之抗體或其抗原結合片段。
- 一種用於在罹患腫瘤之個體中治療、預防性治療及/或預防該腫瘤的醫藥組合物,其包含有效量之如請求項1至11中任一項之抗體或其抗原結合片段或如請求項13之經基因工程改造之細胞。
- 如請求項18之醫藥組合物,其中該腫瘤係選自由以下組成之群:鱗狀細胞癌、肺癌、腹膜癌、肝細胞癌、胃癌(gastric/stomach cancer)、胰臟癌、神經膠質母細胞瘤、子宮頸癌、卵巢癌、肝癌(liver cancer)、膀胱癌、肝腫瘤、乳癌、大腸癌、大腸直腸癌、子宮內膜癌或子宮癌、唾液腺癌、腎癌(kidney/renal cancer)、前列腺癌、外陰癌、甲狀腺癌、肝癌(hepatic carcinoma)、頭頸癌、B細胞淋巴瘤、慢性淋巴球性白血病(CLL)、急性淋巴母細胞性白血病(ALL)、毛細胞白血病及慢性骨髓母細胞性白血病。
- 如請求項19之醫藥組合物,其中該腫瘤為三陰性乳癌、膀胱癌、肺癌、胰臟癌、卵巢癌、頭/頸癌或食道癌。
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