TWI746473B - 針對細胞內抗原之單域抗體 - Google Patents
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Abstract
本發明提供一種不使用外源性靶向序列或化學組合物而治療病症或疾病之組合物及方法。本發明係有關於針對引起病症或疾病的標靶之單域抗體(sdAbs)、蛋白質及包括有該單域抗體的多肽。本發明亦包含編碼該單域抗體、蛋白質及多肽之核酸，以及包括該單域抗體之組合物。本發明包含該等核酸、單域抗體及編碼該單域抗體之核酸在預防性、治療性或診斷性目的上之用途。
Description
本申請案主張2015年11月2日提出之美國臨時專利申請案第62/210,795號之權益，其內容全文係以引用方式併入本文中。
本申請案係與一電子格式的序列表一起提交。所述序列表係以一於2016年10月27日建立、標題為「序列表」的檔案提供，其大小為58千位元組。所述電子格式的序列表中的資訊整體係以引用方式併入本文中。
本發明係有關一種針對細胞內抗原之單域抗體。
在習知抗體或抗體片段的使用上，使用單域抗體(sdAbs)做為單抗原結合蛋白或做為較大蛋白質或多肽中的抗原結合域可提供許多優點。sdAbs的優點包含：僅需一個單一結構域來高親合力地及高選擇性地結合一抗原；可由單一個基因表現sdAbs且不需要轉譯後修飾；sdAbs對於熱、pH、蛋白水解酶及其他變性劑或變性條件具有高穩定性；sdAbs的製備便宜；且sdAbs可接近習知抗體無法接近的標靶及表位。
有許多由異常的細胞內或穿膜成分(諸如核苷酸及蛋白質)所引起的疾病或病症，諸如病毒感染或癌症。可利用將該等異常成分消除
以預防或治療疾病或病症。有許多藥物化合物可用於這類疾病的治療，但該等化合物可能是無效的、無法遞送的或對未受影響的細胞有毒性。
其他的治療方法包含使用含有一外源性靶向序列的治療性蛋白質或試劑，使得治療性試劑可以在細胞膜中被受體識別，從而使治療性試劑可穿過細胞膜並進入細胞。一旦治療劑在細胞內，該治療性試劑可以與標靶成分交互作用以治療疾病。然而，使用外源性靶向序列可能會限制被治療性試劑靶向的細胞類型，且增加製造該治療性試劑的成本。
出於上述原因，需要有不依賴於為了進入細胞之外源性靶向序列或化學組合物、且能有效地僅靶向體內受影響的細胞之組合物及方法來治療或預防疾病。
本發明係有關單域抗體(sdAbs)以及包括該單域抗體之蛋白質或多肽。該單域抗體係針對會導致病症或疾病的標靶。本發明亦包含編碼該單域抗體、蛋白質及多肽之核酸，以及包括該單域抗體的組合物。本發明包含為預防、治療或診斷目的之該組合物、單域抗體、蛋白質或多肽的用途。本發明亦包含針對本發明之單域抗體的單株抗體的用途。
本發明係涉及用以治療或預防病症或疾病之單域抗體。其一實施例係涉及抗人類免疫不全病毒第一型(HIV-1)反轉錄酶之單域抗體(sdAb)。在一態樣中，所述抗HIV-1反轉錄酶之單域抗體係包括SEQ ID NO：27中陳述的胺基酸序列。本發明亦包含一種在一個體中使用抗HIV-1反轉錄酶之單域抗體而治療疾病、預防疾病發生或預防疾病復發之方法，其係藉由對一個體施予其所需之有效量的抗HIV-1反轉錄酶之單域抗體。該個體係可為哺乳動物，諸如人類。所述抗HIV-1反轉錄酶之單域抗體係可與一或多種化合物(諸如(例如)蛋白水解酶抑制劑)結合施予。對一個體所需之
有效量的抗HIV-1反轉錄酶之單域抗體的施予係可通過靜脈內投藥、肌肉內投藥、口服投藥、直腸投藥、經腸投藥、腸胃外投藥、眼內投藥、皮下投藥、經皮投藥、以眼藥水投藥、以鼻噴劑投藥、藉由吸入或噴霧投藥、局部投藥及以一可植入式藥物投藥。
於另一實施例中，本發明係涉及一種經分離多肽，其具有SEQ ID NO：27中陳述的胺基酸序列。於另一實施例中，本發明包含一種針對SEQ ID NO：27之多肽的抗體。
亦可以預期到本發明包含一種測量來自一個體的一樣本中之抗HIV-1反轉錄酶之單域抗體的數量之方法，該方法包括下列步驟：a)產生一針對一包括有SEQ ID NO：27中陳述之胺基酸序列的多肽的一或多個結構域之小鼠單株抗體；b)由該個體獲得一樣本；c)以該小鼠單株抗體與該樣本執行一定量免疫測定，以判定在一個體中該單域抗體的數量；以及d)定量該個體中該單域抗體的數量。在一態樣中，該定量免疫測定係包括酵素連接免疫吸附測定(ELISA)、特異性分析物標記及再捕獲法(SALRA)、液相色層分析、質譜分析、螢光活化細胞分選或其組合。
本發明之另一實施例係涉及一種抗伊波拉VP24之單域抗體。在一態樣中，所述抗伊波拉VP24之單域抗體係包括SEQ ID NO：55中陳述的胺基酸序列。本發明亦包含一種在一個體中使用抗伊波拉VP24之單域抗體而治療疾病、預防疾病發生或預防疾病復發之方法，其係藉由對一個體施予其所需之有效量的抗伊波拉VP24之單域抗體。該個體係可為哺乳動物，諸如人類。所述抗伊波拉VP24之單域抗體係可與一或多種化合物(諸如(例如)蛋白水解酶抑制劑)結合施予。對一個體所需之有效量的抗伊波拉VP24之單域抗體的施予係可通過靜脈內投藥、肌肉內投藥、口服投藥、直腸投藥、經腸投藥、腸胃外投藥、眼內投藥、皮下投藥、經皮投藥、以
眼藥水投藥、以鼻噴劑投藥、藉由吸入或噴霧投藥、局部投藥及以一可植入式藥物投藥。
於另一實施例中，本發明係涉及一種經分離多肽，其具有SEQ ID NO：55中陳述的胺基酸序列。於另一實施例中，本發明包含一種針對SEQ ID NO：55之多肽的抗體。
亦可以預期到本發明包含一種測量來自一個體的一樣本中之抗伊波拉VP24之單域抗體的數量之方法，該方法包括下列步驟：a)產生一針對一包括有SEQ ID NO：55中陳述之胺基酸序列的多肽的一或多個結構域之小鼠單株抗體；b)由該個體獲得一樣本；c)以該小鼠單株抗體與該樣本執行一定量免疫測定，以判定在一個體中該單域抗體的數量；以及d)定量該個體中該單域抗體的數量。在一態樣中，該定量免疫測定係包括ELISA、SALRA、液相色層分析、質譜分析、螢光活化細胞分選或其組合。
本發明之又一實施例係涉及一種抗花生四烯酸-12-脂肪加氧酶(ALOX12)之單域抗體。在一態樣中，所述抗ALOX12之單域抗體係包括SEQ ID NO：49、SEQ ID NO：50、SEQ ID NO：51或SEQ ID NO：52中陳述的胺基酸序列。本發明亦包含一種在一個體中使用抗ALOX12之單域抗體而治療疾病、預防疾病發生或預防疾病復發之方法，其係藉由對一個體施予其所需之有效量的抗ALOX12之單域抗體。該個體係可為哺乳動物，諸如人類。所述抗ALOX12之單域抗體係可與一或多種化合物(諸如(例如)蛋白水解酶抑制劑)結合施予。對一個體所需之有效量的抗ALOX12之單域抗體的施予係可通過靜脈內投藥、肌肉內投藥、口服投藥、直腸投藥、經腸投藥、腸胃外投藥、眼內投藥、皮下投藥、經皮投藥、以眼藥水投藥、以鼻噴劑投藥、藉由吸入或噴霧投藥、局部投藥及以一可植入式藥物投藥。
於另一實施例中，本發明係涉及一種經分離多肽，其具有
SEQ ID NO：49、SEQ ID NO：50、SEQ ID NO：51或SEQ ID NO：52中陳述的胺基酸序列。於另一實施例中，本發明包含一種針對SEQ ID NO：49、SEQ ID NO：50、SEQ ID NO：51或SEQ ID NO：52之多肽的抗體。
亦可以預期到本發明包含一種測量來自一個體的一樣本中之抗ALOX12之單域抗體的數量之方法，該方法包括下列步驟：a)產生一針對一包括有SEQ ID NO：49、SEQ ID NO：50、SEQ ID NO：51或SEQ ID NO：52中陳述之胺基酸序列的多肽的一或多個結構域之小鼠單株抗體；b)由該個體獲得一樣本；c)以該小鼠單株抗體與該樣本執行一定量免疫測定，以判定在一個體中該單域抗體的數量；以及d)定量該個體中該單域抗體的數量。在一態樣中，該定量免疫測定係包括ELISA、SALRA、液相色層分析、質譜分析、螢光活化細胞分選或其組合。
參考以下描述、所附申請專利範圍及附圖，本發明之此等及其他特徵、態樣與優點將變得更加容易理解，其中：第1及2圖係描繪使用HIV1-9抗HIV-1 RT之單域抗體(SEQ ID NO.27)的ELISA結果；第3及4圖係描繪使用HIV1-9抗HIV-1 RT之單域抗體(SEQ ID NO.27)之連續稀釋液的ELISA結果；第5至8圖係描繪使用VP24-5抗伊波拉VP24之單域抗體(SEQ ID NO.55)的ELISA結果；以及第9及10圖係描繪使用VP24-5抗伊波拉VP24單域抗體(SEQ ID NO.55)的連續稀釋液之ELISA結果。
如本文中所用，下列術語及其變體具有下文中給出的含義，
除非使用這類術語的上下文明確指出其有不同的含義。
本文中使用的術語「一(a)」、「一個(an)」與「該(the)」以及相似的指代應被解釋為涵蓋單數及複數，除非它們在上下文中用於指示其他含義。
術語「抗原決定子」是指在抗原上被抗原結合分子(諸如本發明之單域抗體或多肽)、更特別是被該抗原結合分子之抗原結合位點所辨識的表位。術語「抗原決定子」及「表位」亦可交換地使用。對於特定的抗原決定子、表位、抗原或蛋白質係可以結合、具有親合力及/或具有特異性的胺基酸序列係被認為是「抗(against)」或「針對(directed against)」該抗原決定子、表位、抗原或蛋白質。
如本文中所用，術語「包括(comprise)」和該術語的變化形(諸如"comprising"及"comprises”)並非意欲排除其他附加物、成分、整體或者步驟。
可以預期到本文中所述之該等單域抗體、多肽及蛋白質可包含所謂的「保守」胺基酸取代，其通常可以描述為其中的胺基酸殘基被具有相似化學結構的另一胺基酸殘基取代，且對該多肽的功能、活性或其他生物特性幾乎沒有或基本上沒有影響之胺基酸取代。保守胺基酸取代是本技術領域中眾所周知的。保守取代即為下列群組(a)-(e)內的一個胺基酸被同群組內的另一胺基酸所取代：(a)小的脂肪族、非極性或弱極性的殘基：Ala、Ser、Thr、Pro及Gly；(b)極性、帶負電荷的殘基及其(不帶電荷的)醯胺：Asp、Asn、Glu及和Gln；(c)極性、帶正電荷的殘基：His、Arg及Lys；(d)大的脂肪族、非極性殘基：Met、Leu、Ile、Val及Cys；以及(e)芳香族殘基：Phe、Tyr及Trp。其他的保守取代包含：Ala取代成Gly或取代成Ser；Arg取代成Lys；Asn取代成Gln或取代成His；Asp取代成Glu；Cys取代成Ser；Gln
取代成Asn；Glu取代成Asp；Gly取代成Ala或取代成Pro；His取代成Asn或取代成Gln；Ile取代成Leu或取代成Val；Leu取代成Ile或取代成Val；Lys取代成Arg、取代成Gln或取代成Glu；Met取代成Leu、取代成Tyr或取代成Ile；Phe取代成Met、取代成Leu或取代成Tyr；Ser取代成Thr；Thr取代成Ser；Trp取代成Tyr；Tyr取代成Trp；及/或Phe取代成Val、取代成Ile或取代成Leu。
如本文中所用之術語「結構域」通常指抗體鏈的球狀區域，特別是指重鏈抗體的球狀區域，或指基本上由這類球狀區域組成的多肽。
單域結構的胺基酸序列與結構一般係由四個構架區(或「FR」)所組成，該等構架區分別稱為「構架區1」或「FR1」；「構架區2」或「FR2」；「構架區3」或「FR3」；及「構架區4」或「FR4」。該等構架區間雜有三個「互補決定區」(或「CDR」)，其分別稱為「互補決定區1」(或「CDR1」)；「互補決定區2」(或「CDR2」)；及「互補決定區3」(或「CDR3」)。
如本文中所用，術語「人類化單域抗體」係表示一個單域抗體之天然存在的VHH序列的胺基酸序列中已有一或多個胺基酸殘基，被來自於人類的習知四鏈抗體的VH結構域中之對應位置處存在的一或多個胺基酸殘基所取代。這可由本領域中所熟知的方法進行。例如，該等單域抗體的FR係可被人類變異FR所取代。
如本文中所用，「經分離」核酸或胺基酸係已與其通常相關聯的至少一種其他成分分離，諸如其來源或培養基、另一核酸、另一蛋白質/多肽、另一生物成分或大分子或污染物、雜質或次要組分。
術語「哺乳動物」定義為一屬於哺乳動物網之個體，包括(但不限於)人、家畜及農場動物，及動物園、體育及寵物動物，諸如牛、馬、羊、狗及貓。
如本文中所用，「藥學上可接受之載體」係意欲包含任何及
所有與藥物施用相容的溶劑、分散介質、包衣、抗菌及抗真菌劑、等滲透壓及吸收延遲劑等。適宜的載體係描述在最新版本的Remington's Pharmaceutical Sciences，其為本技術領域中的標準參考文獻。這類載體或稀釋劑之較佳實例包含(但不限於)水、鹽水、生理鹽水、林格氏溶液(Ringer's solution)、右旋葡萄糖溶液、PBS(磷酸鹽緩衝鹽水)及5%的人類血清白蛋白。也可使用脂質體、陽離子脂質及非水性媒劑(諸如非揮發性油)。用於藥學活性物質之這類介質及試劑在本技術領域中是眾所周知的。除非到任何習用介質或試劑與如上述所定義之治療性試劑不相容的程度，可預期其使用在本發明的組合物中。
「定量免疫測定」係指任何藉由使用一抗體測量存在於一樣本中的抗原數量之手段。用以執行定量免疫測定的方法包含(但不限於)酵素連接免疫吸附測定(ELISA)、特異性分析物標記及再捕獲法(SALRA)、液相色層分析、質譜分析、螢光活化細胞分選及其組合。
術語「溶液」係指一包括溶劑及溶質的組合物，且其包含真溶液和懸浮液。溶液的實例包含括溶解在一液體中的固體、液體或氣體以及懸浮在一液體中的顆粒或微胞。
術語「特異性」是指特定的抗原結合分子或抗原結合蛋白分子可以結合的不同類型的抗原或抗原決定子的數目。一抗原結合蛋白的特異性可以依據親合力及/或結合性來判定。親合力係由抗原與抗原結合蛋白的解離平衡常數(KD)所表示，其為抗原決定子和該抗原結合蛋白上抗原結合位點之間的結合強度的量度：KD值越小，抗原決定子和抗原結合分子之間的結合強度越強(或者，親合力亦可以表示為親合常數(Ka)，其為1/KD)。本領域技術人員應該清楚，親合力可以取決於感興趣的特定抗原來判定。結合性係為抗原結合分子及該抗原之間的結合強度的量度。結合性係與抗
原決定子及其在抗原結合分子上的抗原結合位點之間的親合力以及在該抗原結合分子上存在的相關結合位點的數目有關。抗原結合蛋白與抗原或抗原決定子的特異性結合可由任何已知方法來判定，例如，斯卡查德分析(Scatchard analysis)及/或競爭結合測定，諸如放射性免疫測定(RIA)、酵素免疫測定(EIA)及夾心式(sandwich)競爭測定。
如本文中所用，術語「重組」係指使用用以產生本發明之單域抗體的基因工程方法(例如，選殖，及擴增)。
術語「單域抗體」、「sdAb」或「VHH」通常可定義為一包括由四個間雜有三個互補決定區的構架區所組成的胺基酸序列之多肽或蛋白質。其係以FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4表示。本發明之sdAb亦包含一包括有該sdAb胺基酸序列之多肽或蛋白質。通常，sdAb係於諸如美洲駝之駱駝科動物中產生，但也可使用本領域中熟知的技術來合成產生。如本文中所用，存在於天然存在重鏈抗體中的可變區也將被稱為「VHH結構域」，以便將它們與存在於習知4鏈抗體中的重鏈可變結構域(稱為「VH結構域」)，及存在於習知4鏈抗體中的輕鏈可變結構域(稱為「VL結構域」)相區分。「VHH」與「單域抗體(sdAb)」在本文中係可互換使用。單域抗體或多肽的胺基酸殘基編號係根據Kabat等人(「Sequence of proteins of immunological interest」，US Public Health Services,NIH Bethesda,MD，出版號91)提供之用於VH結構域的通用編號來編號。根據此編號方式，單域抗體的FR1包括位置1-30的胺基酸殘基，單域抗體的CDR1包括位置31-36的胺基酸殘基，單域抗體的FR2包括位置36-49的胺基酸殘基，單域抗體的CDR2包括位置50-65的胺基酸殘基，單域抗體的FR3包括位置66-94的胺基酸殘基，單域抗體的CDR3包括位置95-102的胺基酸殘基，而單域抗體的FR4包括位置103-113的胺基酸殘基。
術語「合成的」係指藉由活體外化學或酵素合成。
如本文中所用之術語「標靶」係指任何被該sdAb所辨識之成分、抗原或官能基。術語「細胞內標靶」係指任何存在於細胞內的成分、抗原或官能基。「穿膜標靶」係指任何位於細胞膜內的成分、抗原或官能基。「細胞外的標靶」係指位於細胞外面的成分、抗原或官能基。
如本文中所用之語「治療性組合物」係表示一意欲具有治療效果之物質，諸如醫藥組合物、基因物質、生物製劑及其它物質。基因物質包含意欲具有直接或間接的基因治療效果的物質，諸如基因載體、基因調控因子、基因結構因子、DNA、RNA等。生物製劑包含該等為生命物質或衍生自生命物質且意欲有治療效果的物質。
如本文中所用，詞語「治療有效用量」及「預防有效用量」係指在一疾病或該疾病之明顯症狀的治療、預防或管理上提供治療益處的用量。在治療、治愈、減輕、緩解、改變、矯正、改善、改進或影響疾病、疾病的症狀或患病傾向之目的上，該治療有效用量可治療一疾病或病症、一疾病的症狀或一患病傾向。治療有效的特定用量係可為一般開業醫生所容易判定，且可視本領域中已知的因素而改變，諸如(例如)疾病類型、病患病史及年齡、疾病的階段及其它治療性試劑的施用。
本發明係有關一種針對病毒及細胞內成分之單域抗體，也有關於包括有該等單域抗體之蛋白質及多肽以及編碼該等蛋白質與多肽之核苷酸。本發明亦可有關於針對細胞內、穿透細胞及細胞外之標靶或抗原的單域抗體。本發明亦包含編碼該等單域抗體、蛋白質及多肽的核酸，以及包括該單域抗體的組合物。本發明包含該等用於預防性、治療性或診斷性目的之組合物、單域抗體、蛋白質或多肽之使用。
單域抗體具有許多獨特的結構特徵與功能特性，其使得單域
抗體非常有利於用作為功能性抗原結合結構域或蛋白質。單域抗體在功能上係結合至不存在於輕鏈可變結構域中的抗原，且可以作用為一個單一的、相對小的功能性抗原結合結構單元、結構域或蛋白質。這將單域抗體與習用抗體的結構域區分開來，後者本身並不作用為抗原結合蛋白或結構域，但需要與習用抗體片段(諸如Fab片段或ScFv片段)結合以結合抗原。
單域抗體可使用本技術領域中所熟知的方法來取得。例如，一用於取得單域抗體的方法包含(a)以一或多個抗原對一駱駝科動物進行免疫接種、(b)自經免疫接種的駱駝科動物分離周邊淋巴細胞，取得總RNA及合成對應的cDNA、(c)構築一編碼VHH結構域之cDNA片段的基因庫、(d)使用PCR方法將步驟(c)中所獲得之該等編碼VHH結構域的cDNA轉錄成mRNA，將該mRNA轉換成核醣體表現型式，並由核醣體的表現選擇VHH結構域、以及(e)在一適宜的載體中表現該VHH結構域，並且，選擇性地純化所表現的VHH結構域。
另一種取得本發明之單域抗體的方法係藉由使用核酸合成技術來製備一編碼單域抗體的核酸，接著在體內或在體外表現該核酸。此外，本發明之單域抗體、多肽及蛋白質可使用用於製備蛋白質、多肽或其他胺基酸序列之合成或半合成技術來製備。
本發明之該等單域抗體通常將結合至該標靶所有天然存在的或合成的類似物、變體、突變體、對偶基因、部分及片段，或至少結合至該標靶之如下彼等類似物、變體、突變體、對偶基因、部分及片段：含有一或多個在野生型標靶中本發明該等單域抗體所結合之抗原決定子或表位基本上相同之抗原決定子或表位。本發明之該等單域抗體係可以與本發明該等單域抗體結合至野生型標靶之親合力與特異性相同(或較高或較低)之親合力與專一性來結合至這類類似物、變異體、突變體、對偶基因、部
分及片段。在本發明之範疇內亦可預期到本發明之該等單域抗體係結合至該標靶的某些類似物、變體、突變體、對偶基因、部分及片段而不結合其餘者。此外，本發明之單域抗體可經人類化，且可為單價或多價，及/或多特異性。另外，本發明之該等單域抗體可結合至磷酸化形式的標靶蛋白質以及非磷酸化形式的標靶蛋白質。單域抗體可連接其他諸如白蛋白或其他大分子的分子。
此外，多價的單域抗體係屬於本發明之範圍內，也就是說，該單域抗體可具有二或多個針對該標靶之二或多個不同表位的蛋白質或多肽。在這樣的多價單域抗體中，該蛋白質或多肽可(例如)針對相同的表位，實質上相等的表位，或不同的表位。該等不同的表位可位於相同的標靶上，或其可在二或多個不同的標靶上。
亦可設想到本發明之該一或多個單域抗體的序列可與一或多個連接子序列連接或接合。該連接子係可為(例如)一含有絲胺酸、甘胺酸及丙胺酸組合之蛋白質序列。
使用本發明單域抗體之部分、片段、類似物、突變體、變體、對偶基因及/或衍生物係亦屬於本發明之範圍，只要它們是適用於所述的用途。
由於本發明之該等單域抗體主要係用於治療及/或診斷的用途，其係針對哺乳動物，較佳地係以人做為標靶。然而，本文中所述之該等單域抗體有可能與來自其他物種的標靶交叉反應，例如與來自一或多個其它靈長類物種或其它動物(例如，小鼠、大鼠、兔、豬或狗)的標靶交叉反應，尤其在與該等標靶相關疾病有關之疾病及病症動物模型中。
在另一態樣中，本發明係有關一種編碼本發明之單域抗體的核酸。這類核酸係可(例如)呈一基因構築體形式。
在另一態樣中，本發明係有關一種表現或能夠表現本發明之單域抗體，及/或含有編碼本發明之單域抗體的核酸之宿主或宿主細胞。該等單域抗體的序列可用以插入任何生物體的基因體中而產生一基因改良生物體(GMO)。其實例包含(但不限於)植物、細菌、病毒及動物。
本發明更有關一種用於製備或產生該等單域抗體、編碼該等單域抗體的核酸、表現或能夠表現這類單域抗體的宿主細胞、含有本發明該等單域抗體的產物及組合物之方法。
本發明更有關一種在本文中所述之單域抗體、編碼該單域抗體的核酸、宿主細胞、產物及組合物之應用及用途。這類產物或組合物係可為(例如)一用於治療或預防一疾病的醫藥組合物，或一用於診斷用途之產物或組合物。單域抗體可使用在各種側定之中(例如ELISA測定)及質譜分析測定中以測量該等單域抗體的血清及組織數量。
在另一態樣中，編碼本發明之一或多個單域抗體的核酸係可插入一生物體的基因體中以治療或預防疾病。
本發明大致上係有關單域抗體，以及包括或主要由一或多個這類單域抗體所組成而可用於預防性、治療性及/或診斷性目的之蛋白質或多肽。
於本發明中所詳述之該等方法單域及組合物係可用以治療本文中所述之疾病，且其可以本文中所述或其他已知之任何劑量及/或配方來使用，以及以本文中所述或其他本領域技術人員所知之任何給藥方式來使用。
本發明之單域抗體可用於治療及預防由病毒或異常細胞蛋白所引起的疾病。本發明之單域抗體亦可用於治療及預防疾病。本發明之單域抗體係可用於在細胞內分子過度表現時靶向疾病。其亦可藉由在被感
染的細胞中靶向細胞內的病毒蛋白而用於治療病毒感染。阻斷諸如(例如)HIV逆轉錄酶的病毒蛋白生成係可阻斷病毒的生命週期。
本發明之單域抗體也可以靶向細胞內的病毒蛋白(諸如Ebola VP24)，因而阻斷伊波拉病毒(Ebola)關閉宿主之抗病毒免疫反應的能力。
本發明之單域抗體可與一或多個化合物一起使用。例如，本發明之單域抗體可與JAK/STAT抑制劑一起使用，該等抑制劑諸如(例如)薑黃素(Curcumin)、白藜蘆醇(Resveratrol)、葫蘆素(Cucurbitacin)A,B,E,I,Q、黃酮吡醇Flavopiridol、去氧四角黴素(Deoxytetrangomycin)、環戊烯酮(Cyclopentenone)衍生物、N-酰基高丝氨酸內酯(N-Acylhomoserine Lactone)、靛玉紅(Indirubin)衍生物、甲異靛(Meisoindigo)、酪胺酸磷酸化抑制劑(Tyrphostins)、含白金之化合物(例如，IS3-295)、擬肽物(Peptidomimetics)、反義寡核苷酸、S3I-201、磷酸酪胺酸三肽(phosphotyrosin tripeptide)衍生物、HIV蛋白水解酶抑制劑(例如，nelfinavir、indinavir、saquinavir及ritornavir)、JSI-124、XpYL、Ac-pYLPQTV-NH2、ISS 610、CJ-1383、嘧啶甲胺(pyrimethamine)、二甲雙胍(Metformin)、阿替莫德(Atiprimod)、S3I-M2001、STX-0119；N-[2-(1,3,4-惡二唑基)]-4喹啉甲酰胺(N-[2-(1,3,4-oxadiazolyl)]-4 quinolinecarboxamide)衍生物、S3I-1757、LY5；5,8-二側氧基-6(吡啶-3-基氨基))-5,8,-二氫-荼-1-磺醯胺(5,8-dioxo-6(pyridin-3-ylamino)-5,8,-dihydro-naphthalene-1-sulfonamide)、withacinstin、Stattic、STA-21、LLL-3、LLL12、XZH-5、SF-1066、SF-1087、17o、隱丹參酮(Cryptotanshinone)、FLL32、FLL62、C188-9、BP-1108及BP-1075、肉盤菌內酯(Galiellalactone)、JQ1,5,15 DPP、WP1066、耐克螺(Niclosamide)、SD1008、硝呋齊特(Nifuroxazide)、隱丹參酮
(Cryptotanshinone)、BBI醌以及Ruxolitnib磷酸鹽。該等化合物中之一或多者係可增加治療反應並增強本發明之單域抗體的功效。本發明之單域抗體的功效可藉由與肽、擬肽、及其它藥物(諸如，例如(但不限於)希美替定(cimetidine)、阿托伐他汀(atorvastatin)、塞內昔布(celecoxib)、二甲雙胍及希美替定)結合而增加。
亦可預期到本發明該等單域抗體中之一或多者係可結合一起，或本發明該等單域抗體可與其他單域抗體結合。
可預期到本發明的某些單域抗體可不借助於在單域抗體上的額外靶向蛋白質序列，且可不借助於導引單域抗體結合至細胞表面受體及穿過細胞膜的外源性化合物，而穿過細胞膜進入細胞。
於穿過細胞膜之後，這些單域抗體可靶向穿膜或細胞內的分子或抗原。這些標靶係可為(例如)蛋白質、碳水化合物、脂質、核酸、突變蛋白質、病毒蛋白及傳染性蛋白顆粒。該等單域抗體的標靶可作用為酵素、細胞結構蛋白、細胞膜分子的胞內部分、胞器膜內的分子、任何類型的RNA分子、DNA或染色體的任何區域、甲基化或未甲基化的核酸、細胞合成機制內的部分組裝分子、第二信使分子以及細胞信息機制內的分子。該等標靶可包含於細胞質、細胞核、胞器及細胞膜中的所有分子。預定分泌或放置在細胞膜中的分子係可在離開細胞之前於細胞質內被靶向。
該等單域抗體的標靶可以在人、動物、植物、真菌、寄生蟲、原生動物、細菌、病毒、傳染性蛋白顆粒、原核細胞及真核細胞之中。可被本發明該等單域抗體靶向的細胞間及細胞內信息分子及蛋白質群的一些實例如下：致癌基因產物、內泌素、細胞介素、生長因子、神經傳導物質、激酶(包含酪胺酸激酶、絲胺酸激酶及蘇胺酸激酶)、磷酸酶、泛素、環核苷酸、環化酶(腺嘌呤基及甲脒基)、G蛋白、磷酸二酯酶、GTP酶超家族、
免疫球蛋白(抗體、Fab片段、結合蛋白、單域抗體)、免疫球蛋白超家族、肌醇磷酸脂、類固醇受體、調鈣蛋白、CD群組(例如，CD4、CD8、CD28等)、轉錄因子、TGF-β、TNF-α及TNF-β、TNF配位體家族、凹槽受體信息分子、刺蝟受體信息分子、Wnt受體信息分子、類鐸受體信息分子、凋亡蛋白酶、肌動蛋白、肌球蛋白、肌肉生長抑制素、12-脂氧化酶、15-脂氧化酶、脂氧化酶超家族、逆轉錄酶、病毒及其蛋白質、澱粉樣蛋白、膠原蛋白、耦合G蛋白的受體、經突變的一般蛋白質、傳染性蛋白顆粒、Ras、Raf、Myc、Src、BCR/ABL、MEK、Erk、Mos、Tpl2、MLK3、TAK、DLK、MKK、p38、MAPK、MEKK、ASK、SAPK、JNK、BMK、MAP、JAK、PI3K、環氧化酵素、STAT1、STAT2、STAT3、STAT4、STAT5a、STAT5b、STAT6、Myc、p53、BRAF、NRAS、KRAS、HRAS及趨化介素。
HIV為一種在人類中引起後天性免疫不全症候群(AIDS)的反轉錄病毒。AIDS導致受感染個體免疫系統的漸進性破壞，這導致危及生命的伺機性感染與癌症的發生。在沒有治療的情形下，HIV感染後的平均存活時間估計為9至11年。
HIV係以有包膜的單鏈正義RNA病毒來傳播。在進入目標細胞內時，通過病毒編碼的反轉錄酶(RT)將病毒RNA基因體反轉錄為雙鏈DNA，所述反轉錄酶係與病毒顆粒中的病毒基因體一起傳遞。反轉錄酶為一種RNA依存型之DNA聚合酶並且也具有RNaseH的活性。所產生的病毒DNA接著被輸入到宿主細胞核內並藉由病毒編碼的整合酶與宿主輔助因子而整合到細胞DNA中。一旦整合後，病毒就可潛伏數月或數年。或者，病毒可經轉錄而產生新的RNA基因體與病毒蛋白，其係經包裝並從細胞中釋放而做為新的病毒顆粒。
已有兩種類型的HIV被鑑定：HIV-1及HIV-2。HIV-1毒性更
強，更具感染性，並且是全球大多數HIV感染的原因。HIV-2主要局限在西非。
抗HIV反轉錄酶之單域抗體係被開發為靶向HIV-1反轉錄酶。所述抗HIV-1 RT之單域抗體係可單獨地或與其他反轉錄病毒藥劑結合而成功治療感染HIV的個體。在使用本領域中所熟知的方法之情形下，重組HIV-1反轉錄酶蛋白(Creative Biomart,Shirley,NY)(SEQ ID NO.1)係經使用來產生可針對HIV-1反轉錄酶或結合HIV-1 RT之抗原決定區的單域抗體。
使用於對駱駝免疫接種重組HIV-1反轉錄酶蛋白(SEQ ID NO.1)之蛋白質序列為：
免疫接種的結果獲得了若干單域抗體並經篩選。抗HIV-1 RT之單域抗體的DNA序列如下所列：
HIV1-1(SEQ ID NO.2)：
HIV1-2(SEQ ID NO.3)：
HIV1-7(SEQ ID NO.4)：
HIV1-8(SEQ ID NO.5)：
HIV1-6(SEQ ID NO.6)：
HIV1_28(SEQ ID NO.7)：
HIV1-21(SEQ ID NO.8)：
HIV1-37(SEQ ID NO.9)：
HIV1-3(SEQ ID NO.10)：
HIV1-5(SEQ ID NO.11)：
HIV1-10(SEQ ID NO.12)：
HIV1_29(SEQ ID NO.13)：
HIV1_32(SEQ ID NO.14)：
HIV1-9(SEQ ID NO.15)：
HIV1-16(SEQ ID NO.16)：
HIV1-13(SEQ ID NO.17)：
HIV1_35(SEQ ID NO.18)：
HIV1-11(SEQ ID NO.19)：
HIV1_22(SEQ ID NO.20)：
HIV1-4(SEQ ID NO.21)：
HIV1_38(SEQ ID NO.22)：
HIV1_23(SEQ ID NO.23)：
HIV1_25(SEQ ID NO.24)：
抗HIV-1 RT之單域抗體的胺基酸序列如下所示：
HIV1-1(SEQ ID NO.25)
HIV1-2(SEQ ID NO.26)
HIV1-9(SEQ ID NO.27)：
HIV1-16(SEQ ID NO.28)：
HIV1-27(SEQ ID NO.29)
HIV1-30(SEQ ID NO.30)
HIV1-21(SEQ ID NO.31)
HIV1-4(SEQ ID NO.32)
HIV1-6(SEQ ID NO.33)
HIV1-7(SEQ ID NO.34)
HIV1-8(SEQ ID NO.35)
HIV1-11(SEQ ID NO.36)
HIV1-13(SEQ ID NO.37)
HIV1-23(SEQ ID NO.38)
HIV1-24(SEQ ID NO.39)
HIV1-25(SEQ ID NO.40)
HIV1-31(SEQ ID NO.41)
HIV1-38(SEQ ID NO.42)
HIV1-39(SEQ ID NO.43)
可針對本發明之抗HIV-1 RT之單域抗體的一或多個結構域來產生一或多個小鼠單株抗體。所述小鼠單株抗體可藉由本領域技術人員已知的方法產生，例如，該小鼠單株抗體可藉由小鼠融合瘤而產生。該小鼠單株抗體可使用於診斷分析之中，例如，該抗體可使用在一諸如ELISA或質譜分析測定之免疫測定中，以便測量該抗HIV-1 RT之單域抗體存在於病患樣本中的數量。
針對重組花生四烯酸-12-脂肪加氧酶(ALOX12)的SdAb亦經產生。ALOX12也稱為血小板型12-脂肪加氧酶、花生四烯酸-氧12-氧化還原酶、Delta12-脂肪加氧酶、12Delta-脂肪加氧酶、C-12脂肪加氧酶、白三烯A4合成酶及LTA4合成酶。ALOX12是一種參與花生四烯酸代謝的脂肪加氧酶型酵素。ALOX12係牽涉於飲食誘導型及/或遺傳誘導型糖尿病、脂肪細胞/組織功能失常、以及肥胖的發生與併發症。ALOX12還被認為可調節血管的收縮、擴張、血壓、重塑及血管生成。ALOX12的抑制可預防血管形成的發生，ALOX12因而成為降低血管新生作用的標靶，而血管新生作用促進了動脈粥狀硬化、脂肪肝炎及其他關節炎疾病與癌症疾病。ALOX12數量的升高可能促成阿茲海默症的發生。
本發明提供了針對ALOX12蛋白的單域抗體、蛋白質及多肽。
可以預期到本發明之抗ALOX12之單域抗體及多肽可用於
預防及/或治療與ALOX12有關及/或由ALOX12介導的疾病與病症，諸如糖尿病、脂肪細胞功能失常、肥胖、動脈粥狀硬化、脂肪肝炎、關節炎及癌症。
重組人類ALOX12蛋白係用以產生針對ALOX12或可結合至ALOX12之抗原決定區的單域抗體。為產生抗ALOX12之單域抗體，重組人類ALOX12係在大腸桿菌中表現並做為目標抗原。
使用於駱駝的免疫接種之重組ALOX12蛋白(SEQ ID NO.44)序列為：
免疫接種的結果獲得了若干單域抗體並經篩選。該等單域抗體的DNA序列如下所列：
ALOX_21(SEQ ID NO.45)：
ALOX_41(SEQ ID NO.46)：
ALOX_43(SEQ ID NO.47)：
ALOX_46(SEQ ID NO.48)：
所產生的抗ALOX之單域抗體的蛋白序列如下：
ALOX_21(SEQ ID NO.49)：
ALOX_41(SEQ ID NO.50)：
ALOX_43(SEQ ID NO.51)：
ALOX_46(SEQ ID NO.52)：
可針對本發明之抗ALOX12單域抗體的一或多個結構域來產生一或多個小鼠單株抗體。所述小鼠單株抗體可藉由本領域技術人員已知的方法產生，例如，該小鼠單株抗體可藉由小鼠融合瘤而產生。該小鼠單株抗體可使用於診斷分析之中，例如，該抗體可使用在一諸如ELISA或質譜分析測定之免疫測定中，以便測量該抗ALOX12單域抗體存在於病患樣本中的數量。
伊波拉(Ebola)(也稱為伊波拉病毒病(EVD)及伊波拉出血熱(EHF))為一種由伊波拉病毒引起的人類及其他靈長類動物的病毒性出血熱。此疾病疾病具有高死亡風險，通常在症狀出現後6至16天導致25-90%的感染者死亡。
伊波拉干擾受感染個體的先天免疫系統的正常功能。伊波拉蛋白藉由干擾細胞產生及響應干擾素蛋白(諸如干擾素-α、干擾素-β及干擾
素γ)的能力而削弱免疫系統對病毒感染的反應。伊波拉的結構蛋白VP24及VP35在這干擾過程中扮演關鍵的角色。VP24蛋白阻斷了宿主細胞之抗病毒蛋白的產生。藉由抑制宿主的免疫反應，伊波拉可快速傳播到整個身體。
如本文中所述，抗VP24之單域抗體係被開發為靶向伊波拉VP24蛋白。所述抗VP24之單域抗體係可單獨地或與其他反轉錄病毒藥劑結合而成功治療感染伊波拉的個體。在使用本領域中所熟知的方法之情形下，重組VP24蛋白(SEQ ID NO.X)係經使用來產生可針對VP24或結合VP24之抗原決定區的單域抗體。
使用於對駱駝免疫接種重組VP24蛋白(SEQ ID NO.53)之蛋白質序列為：
免疫接種的結果獲得了抗VP24之單域抗體，VP24_5，並經篩選以用於結合VP24。VP24_5的DNA序列(SEQ ID.NO.54)如下：
VP24_5單域抗體的胺基酸序列(SEQ ID NO.55)如下所示，其CDR係加下劃線：
可針對本發明之抗VP24單域抗體的一或多個結構域來產生一或多個小鼠單株抗體。所述小鼠單株抗體可藉由本領域技術人員已知的方法產生，例如，該小鼠單株抗體可藉由小鼠融合瘤而產生。該小鼠單株抗體可使用於診斷分析之中，例如，該抗體可使用在一諸如ELISA或質譜分析測定之免疫測定中，以便測量該抗VP24單域抗體存在於病患樣本中的數量。
本發明之單域抗體係由經以若干蛋白免疫接種的駱駝所產生，該等蛋白包含ALOX12(SEQ ID NO.44)、VP24(SEQ ID NO.53)及HIV-1反轉錄酶(SEQ ID NO.1)。
在使用標準技術的情形下，使用pCDisplay-3M載體(Creative Biogene,Shirley,NY)及M13K07輔助噬菌體(New England Biolabs,Ipswich,MA)來建構一噬菌體表現資料庫。單域抗體的單選殖株係通過ELISA確認，且DNA序列及蛋白序列係使用標準方法來判定。
蛋白質結合實驗係於25℃下在Biacore 3000(General Electric Company,Fairfield,CT)上執行。分析緩衝液含有10mM HEPES緩衝液(pH 7.4)、150mM NaCl、3mM EDTA及0.05% P20。再生緩衝液含有10mM甘胺酸、HCl(pH 1.75)，而固定緩衝液含有10mM醋酸鈉(pH 5.0)。用於捕獲配位體的流速為5μl/min。用於動力學分析的流速為30μl/min。
用於蛋白質結合實驗的配位體為HIV1-9(SEQ ID NO.27)及STAT3-VHH 14(SEQ ID NO.56)。該等配位體係直接藉由胺共軛接合(EDC/NHS)來固定，感應晶片CM5之流動槽2及4的反應單位(RU)分別為1200及550。流動槽1保持空白並用於背景濾除。CM5晶片上未耦合的位置係以1M乙醇胺阻斷。對於結合分析，分析物rHIV-1(SEQ ID NO.1)係流過該感應晶片。以即時方式監測分析物與配位體的結合。親和力常數(KD=kd/ka)係由觀察到的締合速率(ka)與解離速率(kd)來計算，如表1所示。
蛋白質結合實驗之陰性控制組為抗STAT3之單域抗體
VHH14(SEQ ID NO.56)：
卡方檢驗(χ2)分析係於實際傳感圖與由BIAnalysis軟體產生的傳感圖之間進行，以判定分析的準確性。在1至2之間的χ2值係視為準確的，低於1的值係視為高度準確的。
完整的動力學分析係以表2中所示之分析物濃度進行，並以2倍連續稀釋最高的分析物濃度。HIV1-9抗RT之單域抗體皆與HIV-1及Ebola VP24分析物結合。
HIV1-9抗HIV-1 RT之單域抗體(SEQ ID NO.27)的兩個不同樣本係於ELISA中以1μg/mL的濃度針對棋盤式的披覆抗原、二級抗體與HRP濃度來評定。該披覆抗原為重組HIV-1 RT(Creative BioMart)(SEQ ID
NO.1)，每孔濃度為0.5、0.025、及0.125μg/mL。該二級抗體為以1：5,000及1：10,000稀釋之經生物素標記的兔子抗美洲駝抗體，而HRP係以1：2,5000及1：50,000稀釋。在若干濃度下係觀察到信噪比>20。ELISA的結果係顯示於第1及2圖中。
選擇三種組合來評估連續稀釋的HIV1-9抗HIV-1 RT之單域抗體(SEQ ID NO.27)(1μg/mL to 0.0001μg/mL)。
其結果係顯示於第3及4圖中。所使用的這兩個HIV1-9抗HIV-1 RT之單域抗體(SEQ ID NO.27)製品具有非常相似的結果。使用0.5μg/mL的披覆抗原、以1：5,000稀釋的二級抗體與以1：50,000稀釋的HRP之結果顯示了HIV1-9抗HIV-1 RT之單域抗體(SEQ ID NO.27)與HIV1 RT(SEQ ID NO：1)的結合係具有最高的信噪比及稍低的空白試驗值。
蛋白質結合實驗係以如實例2所述來執行。用於蛋白質結合實驗的配位體為VP24-5(SEQ ID NO.55)及STAT3-VHH 14(SEQ ID NO.56)。該等配位體係直接藉由胺共軛接合(EDC/NHS)來固定，感應晶片CM5之流動槽2及4的反應單位(RU)分別為427及550。流動槽1保持空白並用於背景濾除。CM5晶片上未耦合的位置係以1M乙醇胺阻斷。對於結合分析，分析物VP24(SEQ ID NO.53)係流過該感應晶片並以即時方式監測。親和力常數(KD=kd/ka)係由觀察到的締合速率(ka)與解離速率(kd)來計算，如表3所示。
完整的動力學分析係以不同的分析物濃度進行，並以2倍連續稀釋最高的分析物濃度，如表4中所示。
VP24-5抗伊波拉VP24之單域抗體(SEQ ID NO.55)的兩個不同樣本係於ELISA中以1μg/mL的濃度針對棋盤式的披覆抗原、二級抗體與HRP濃度來評定。該披覆抗原為重組伊波拉VP24(Creative BioMart)(SEQ ID NO.53)，每孔濃度為0.5、0.025、及0.125μg/mL。該二級抗體為以1：5,000及1：10,000稀釋之經生物素標記的兔子抗美洲駝抗體。HRP係以1：10,000及1：25,000稀釋使用。ELISA的結果係顯示於第5及6圖中。其信噪比低，且此分析係以較高濃度重複。
ELISA係以1及0.5μg/mL VP24-5抗伊波拉VP24之單域抗體(SEQ ID NO.55)重複進行。重組VP24(SEQ ID NO.53)係以每孔0.5或1μg/mL的濃度使用。二級抗體為以1：1,000、1：4,000及1：10,000稀釋之經生物素標記的兔子抗美洲駝抗體。HRP係以1：25,000及1：50,000稀釋使用。ELISA的結果係顯示於第7及8圖中。
選擇三種組合來評估連續稀釋的VP24-5抗伊波拉VP24之單域抗體(SEQ ID NO.55)(1μg/mL至0.0001μg/mL)。
其結果係顯示於第9及10圖中。所使用的這兩個VP24-5抗伊波拉VP24之單域抗體(SEQ ID NO.55)製品具有非常相似的結果，且顯示了VP24-5抗伊波拉VP24之單域抗體(SEQ ID NO.55)與重組VP24(SEQ ID NO.53)的結合。
儘管已經參考某些較佳實施例對本發明進行了相當詳細的討論，但也可以有其他的實施方式。本方法公開的步驟(例如)並非是限制性的，且其並非意欲指明每一個步驟對於該方法都一定是必要的，而是其僅僅是例示性的步驟。因此，所附申請專利範圍的範疇不應該限制於本公開內容所含之實施例的描述。本文所有引用的參考文獻之全文係以引用方式併入本文中。
<110> 辛生物科技股份有限公司/SINGH BIOTECHNOLOGY,LLC
<120> 單域抗體
<130> 7304-51293-9PCT
<150> US 62/249,868
<151> 2015-11-02
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Claims (2)
- 一種抗伊波拉VP24之單域抗體，其中所述抗伊波拉VP24之單域抗體係包括SEQ ID NO：55胺基酸序列。
- 一種經分離多肽，所述經分離多肽包括SEQ ID NO：55胺基酸序列。
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