TWI802902B - 含有抗間皮素抗體的抗體-藥物共軛物及其用途 - Google Patents
含有抗間皮素抗體的抗體-藥物共軛物及其用途 Download PDFInfo
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- TWI802902B TWI802902B TW110120509A TW110120509A TWI802902B TW I802902 B TWI802902 B TW I802902B TW 110120509 A TW110120509 A TW 110120509A TW 110120509 A TW110120509 A TW 110120509A TW I802902 B TWI802902 B TW I802902B
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Abstract
本發明提供一種免疫共軛物,其包括抗體,該抗體包含與間皮素中之抗原決定基特異性結合的抗原結合片段、N-聚糖結合域及N-聚糖;與該N-聚糖連接之連接子;及分別與該連接子共軛之有效負載A及有效負載B;其中該有效負載A及該有效負載B為相同或不同的。本發明亦提供一種包含該免疫共軛物之醫藥組合物及一種治療癌症之方法。
Description
本發明係關於一種抗間皮素抗體-藥物共軛物,其中該共軛物中所包含之糖蛋白包含一或多個三甘露糖基核心。本發明亦關於一種治療有需要之個體之疾病諸如癌症的方法,其包含向該個體投與抗間皮素抗體-藥物共軛物。
抗體-藥物共軛物(ADC)通常包含與特異性靶向標誌物(例如腫瘤標誌物)之抗體偶合的抗癌藥物(例如細胞毒素)。抗體在體內追蹤此等標誌物且使其自身附接至癌細胞表面。抗體與目標標誌物(抗原)之間的結合在腫瘤細胞中觸發信號,腫瘤細胞隨後將ADC內化。在ADC內化之後,細胞毒性藥物可釋放且殺死癌細胞。歸因於特異性靶向,藥物之副作用可能會降低。
間皮素(MSLN)為一種腫瘤分化抗原,在數種人類腫瘤中過度表現,包括間皮瘤、胰臟癌、卵巢癌、胰臟腺癌、肺腺癌、膽管癌、肝外膽管癌、肺癌及上皮樣間皮瘤。因此,間皮素為一種有前景的診斷/治療目標。
儘管許多針對間皮素之抗體正在開發中,諸如SS1P (一種由靶向抗體片段與綠膿桿菌(
Pseudomonas)外毒素A之截短片段基因融合構成的抗間皮素免疫毒素)、阿奈妥單抗(Anetumab) (一種單株抗體)及阿奈妥單抗拉夫坦辛(Anetumab Ravtansin) (一種抗體-藥物共軛物),但仍需要使用抗間皮素抗體之改良治療劑。
本發明係關於含有抗間皮素抗體的抗體-藥物共軛物及其在療法中之用途。
本發明之一個態樣係關於免疫共軛物。根據本發明之一個實施例的免疫共軛物包括:
抗體,其包含與間皮素中之抗原決定基特異性結合的抗原結合片段、N-聚糖結合域及具有式(1)之結構的N-聚糖;
式(1)
其中「*」表示鍵或保護基;
連接子,其在「*」表示鍵時與N-聚糖中之各「*」連接;及
獨立地與連接子共軛之有效負載A及有效負載B;其中有效負載A及有效負載B為相同或不同的。
在本發明之一些實施例中,抗體為單株抗體、人源化抗體、人類抗體、來自裂解抗體之抗體Fab片段、F(ab')
2、Fv片段或Fc片段、scFv-Fc片段、微型抗體、雙功能抗體或scFv。
在本發明之一些實施例中,抗原結合片段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區、CDRH2區及CDRH3區,且輕鏈可變區之互補決定區包含CDRL1區、CDRL2區及CDRL3區;其中CDRH1區包含SEQ ID NO: 1之胺基酸序列;CDRH2區包含SEQ ID NO: 2之胺基酸序列;CDRH3區包含SEQ ID NO: 3之胺基酸序列;CDRL1區包含SEQ ID NO: 4之胺基酸序列;CDRL2區包含SEQ ID NO: 5之胺基酸序列;且CDRL3區包含SEQ ID NO: 6之胺基酸序列。在本發明之一個實施例中,抗體包含有包含SEQ ID NO: 7之胺基酸序列的重鏈可變區及包含SEQ ID NO: 8之胺基酸序列的輕鏈可變區。在本發明之一個實施例中,抗體包含有包含SEQ ID NO: 9之胺基酸序列的重鏈可變區及包含SEQ ID NO: 10之胺基酸序列的輕鏈可變區。在本發明之一個實施例中,抗體包含有包含SEQ ID NO: 11之胺基酸序列的重鏈可變區及包含SEQ ID NO: 12之胺基酸序列的輕鏈可變區。
在本發明之一些實施例中,抗體包含重鏈恆定區,且N-聚糖結合域位於重鏈恆定區中。
在本發明之一些實施例中,抗體包含兩個N-聚糖。
本發明之免疫共軛物之有效量的某些實施例為範圍介於約0.01 mg/kg至800 mg/kg、0.05 mg/kg至600 mg/kg、0.1 mg/kg至500 mg/kg、0.5 mg/kg至400 mg/kg、1 mg/kg至300 mg/kg、5 mg/kg至200 mg/kg、10 mg/kg至100 mg/kg、15 mg/kg至80 mg/kg、20 mg/kg至60 mg/kg、25 mg/kg至50 mg/kg的彼等實施例。
在本發明之一些實施例中,連接子係選自由以下組成之群:具有2至20個碳原子之直鏈或分支鏈烷基、環烷基、烯基、環烯基、炔基、芳香基、雜芳香基、烷氧基、醯基、烷胺基、芳胺基、醚、酯、醯胺、胺基甲酸酯、碳酸酯、式(3)至式(7)、含雙硫鍵之連接子、酸不穩定連接子、光不穩定連接子、肽酶不穩定連接子及酯酶不穩定連接子或其組合。
在本發明之一些實施例中,有效負載A及有效負載B獨立地選自治療劑及標記。
治療劑之實例包括但不限於抗代謝物、烷基化劑、類烷基化劑、DNA小溝烷基化劑、蒽環黴素(anthracyclines)、抗生素、卡奇黴素(calicheamicins)、抗有絲分裂劑、拓樸異構酶抑制劑、蛋白酶體抑制劑、放射性同位素及同位素螯合劑。治療劑之具體化合物的實例包括但不限於單甲基奧瑞他汀E (monomethyl auristatin E,MMAE)、單甲基奧瑞他汀F (MMAF)、類美登素(maytansinoids)、多卡黴素-羥基苯甲醯胺氮雜吲哚(duocarmycin-hydroxy benzamide azaindole,DUBA)、二伸乙基三胺-N,N,N',N",N"-五乙酸酯(DTPA)、依昔替康(exatecan)及Dxd2。
標記之實例包括但不限於螢光標記、發色標記、電子緻密標記、化學發光標記、放射性標記、酶標記及正子發射體。
保護基之一個實例為疊氮基。
本發明之一個態樣係關於一種醫藥組合物,其包含上述免疫共軛物及醫藥學上可接受之載劑。
本發明之一個態樣係關於一種用於治療癌症之方法。根據本發明之一個實施例的方法可包含向需要癌症治療之個體投與治療有效量之上述免疫共軛物。
在本發明之一些實施例中,癌症為表現間皮素之癌症。癌症之實例包括但不限於卵巢癌、間皮瘤、胰臟癌、非小細胞肺癌、食道癌、胃癌、膽管癌、結腸直腸癌、子宮內膜癌及乳癌。
熟習此項技術者應瞭解,治療有效量視許多因素而定,諸如患者病況、年齡、疾病狀態、給藥途徑等,且此類有效量可在常規實踐中基於此等因素確定而無需過度實驗。
本發明之其他態樣將藉由以下描述而變得顯而易見。
應注意,如本文及隨附申請專利範圍中所用,單數形式「一(a/an)」及「該」包括複數個指示物,除非上下文另有明確規定。同樣,術語「一(a/an)」、「一或多個」及「至少一個」在本文中可互換使用。亦應注意,術語「包含」、「包括」及「具有」可互換使用。
除非另外定義,否則本文所用之所有科學或技術術語具有與一般熟習本發明所屬技術者所理解相同之含義。與本文所述之方法及材料類似或等效的任何方法及材料可由一般熟習此項技術者理解及使用以實踐本發明。
必須注意,如本說明書及隨附申請專利範圍中所用,單數形式「一(a/an)」及「該」包括複數個指示物,除非上下文另有明確規定。因此,除非上下文另有要求,否則單數術語應包括複數且複數術語應包括單數。
術語「及/或」用於指兩種事物或所提及之兩種事物中之任一者。
如本文所用,術語「免疫共軛物」係指包括至少一個效應部分(諸如有效負載A及B)及抗體的多肽分子。在某些實施例中,免疫共軛物包含不超過一個效應部分。根據本發明之特定免疫共軛物基本上由一個效應部分及藉由一或多個連接子接合之抗體組成。
如本文所用,術語「抗體」意謂包含至少一個與特定抗原(例如間皮素)特異性結合或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」包括免疫球蛋白分子以及其多聚體(例如IgM),該等免疫球蛋白分子包含藉由雙硫鍵互連之四條多肽鏈,亦即兩條重(H)鏈及兩條輕(L)鏈。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區及V
L區可進一步細分為高變區,稱為互補決定區(CDR),其穿插有更保守區,稱為構架區(FR)。各V
H及V
L由三個CDR及四個FR構成,自胺基端至羧基端按以下順序排列:FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4。在本發明之不同實施例中,抗α-毒素抗體(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。胺基酸共同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「單株抗體」不限於經由融合瘤技術產生之抗體。單株抗體係藉由任何可用或此項技術中已知的手段衍生自單一株,包括任何真核、原核或噬菌體株。
非人類抗體之「人源化」形式為含有來源於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,人源化抗體將包含基本上所有的至少一個且通常兩個可變域,其中所有或基本上所有的CDR區對應於非人類免疫球蛋白之CDR區且所有或基本上所有的FR區為人類免疫球蛋白序列之FR區。
如本文所用,術語「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。CDR已由Kabat等人, J. Biol. Chem. 252:6609-6616 (1977);Kabat等人, 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)描述,其中定義包括相互比較時之胺基酸殘基的重疊或子集。
如本文所用,術語抗體之「抗原結合片段」及其類似物包括任何天然存在、可酶促獲得、合成或經基因工程改造之多肽或糖蛋白,其特異性結合抗原以形成複合物。
如本文所用,術語「間皮素」係指40 kDa蛋白質間皮素,其藉由糖基磷脂醯肌醇(GPI)鍵錨定於細胞膜及胺基端31 kDa脫落片段,稱為巨核細胞增強因子(MPF)。兩個片段均含有N-糖基化位點。較佳地,該術語係指人類間皮素及其天然裂解部分,例如表現於細胞膜(例如癌細胞膜)上。特定言之,間皮素之片段含有間皮素之N端區。
如本文所用,術語「抗原決定基」係指抗體所結合之抗原上的位點。
如本文所用,術語「N-聚糖」係指N-連接之寡醣,例如藉由天冬醯胺-N-乙醯基葡糖胺鍵附接至多肽之天冬醯胺殘基的寡醣。N-聚醣具有Man
3GlcNAc
2之共同五醣核心(「Man」係指甘露糖;「Glc」係指葡萄糖;且「NAc」係指N-乙醯基;GlcNAc係指N-乙醯基葡糖胺)。關於N-聚糖使用之術語「三甘露糖核心」亦指結構Man
3GlcNAc
2(「Man
3」)。N-聚醣在包含添加至Man
3核心結構之外周糖(例如海藻糖及唾液酸)之分支(觸角)數目方面有所不同。
如本文所用,術語「醫藥組合物」係指包含具有生物或藥理學活性之活性成分及醫藥學上可接受之載劑的調配物或製劑。醫藥組合物可呈溶液、懸浮液、錠劑、散劑、小丸劑、珠粒、顆粒劑、微球體、膠囊、丸劑等形式。
術語「治療(treatment/treating/treat)」一般係指獲得所需藥理學及/或生理學效果。該效果就完全或部分預防疾病、病症或其症狀而言可為預防性的,且就部分或完全治癒疾病、病症及/或歸因於其之症狀而言可為治療性的。本文所用之「治療」涵蓋對哺乳動物,較佳人類之疾病的任何治療,且包括(1)抑制個體之疾病、病症或其症狀的發展或(2)緩解或改善個體之疾病、病症或其症狀。
如本文所用,術語「個體」為可受益於投與如本文所揭示之化合物或組合物的任何動物。在一些實施例中,個體為哺乳動物,例如人類、靈長類動物、犬、貓、馬、牛、豬、嚙齒動物,諸如大鼠或小鼠。通常,哺乳動物為人類。
如本文所提供之活性成分之術語「有效量」意謂該成分之足以提供所需功能之所需調節的量。如以下將指出,所需精確量將因個體而異,視個體之疾病狀態、身體條件、年齡、性別、物種及體重、組合物之特定特性及調配物等而定。可調整給藥方案以誘導最佳治療反應。舉例而言,可每天投與若干分次劑量,或可如治療情況之緊急程度所指示按比例減少劑量。因此,不可能指定確切的「有效量」。然而,適當有效量可由一般熟習此項技術者僅使用常規實驗來確定。
如本文所用,術語「醫藥學上可接受」係指在合理醫學判斷範疇內適用於與個體(人類或非人類動物)組織接觸而無過度毒性、刺激、過敏性反應或其他問題或併發症,與合理益處/風險比相稱的化合物、物質、組合物及/或劑型。在與調配物之其他成分相容的意義上,各載劑、賦形劑等必須亦為「可接受的」。適合之載劑、賦形劑等可見於標準醫藥學文本中。
本發明之免疫共軛物可與「載劑」一起調配。如本文所用,「載劑」包括任何溶劑、分散介質、媒劑、包衣、稀釋劑、抗細菌劑及/或抗真菌劑、等張劑、吸收延遲劑、緩衝劑、載體溶液、懸浮液、膠體及其類似物。對醫藥活性物質使用此類介質及/或藥劑為此項技術中眾所周知的。舉例而言,醫藥組合可專門調配成以固體或液體形式投與,包括適於以下之形式:(1)經口投與,例如灌藥(水性或非水性溶液或懸浮液)、口含錠、糖衣藥丸、膠囊、丸劑、錠劑(例如靶向經頰、舌下及全身性吸收之錠劑)、大丸劑、散劑、顆粒劑、施用於舌頭之糊劑;(2)非經腸投與,例如藉由以例如無菌溶液或懸浮液或持續釋放調配物形式皮下、肌肉內、靜脈內或硬膜外注射;(3)局部施用,例如以乳膏、洗劑、凝膠、軟膏或控制釋放貼片或噴霧劑形式施用於皮膚;(4)陰道內或直腸內,例如以子宮托、乳膏、栓劑或泡沫形式;(5)舌下;(6)經眼;(7)經皮;(8)經黏膜;或(9)經鼻。
抗體-藥物共軛物(ADC)為一類治療劑,其中藥物(或有效負載)附接至抗體或其抗原結合片段。ADC中之抗體與選定目標(通常為細胞上之目標)結合,從而將藥物帶至目標附近,產生高度選擇性治療效果。ADC之一個實例可為靶向癌細胞上表現之蛋白質的抗體,且有效負載可為細胞毒性劑。本發明之一個實施例係關於一種免疫共軛物(抗體-藥物共軛物),其含有抗間皮素抗體或其結合片段及兩個或更多個有效負載。在本發明之一個實施例中,免疫共軛物包含
抗體,其包含與間皮素中之抗原決定基特異性結合的抗原結合片段、N-聚糖結合域及具有式(1)之結構的N-聚糖;
式(1)
其中「*」表示鍵或保護基;
連接子,其在「*」表示鍵時與N-聚糖中之各「*」連接;及
獨立地與連接子共軛之有效負載A及有效負載B;其中有效負載A及有效負載B為相同或不同的。
在本發明之另一個實施例中,有效負載A及有效負載B為相同或不同的。
根據本發明之實施例,抗間皮素抗體或其結合片段能夠識別且與間皮素或其片段結合。本文中之術語抗體係以其最廣泛意義使用且具體包括單株抗體、多株抗體、二聚體、多聚體、多特異性抗體(例如雙特異性抗體)、抗體片段以及雙鏈及單鏈抗體。術語「抗體」在本文中亦意謂包括人類抗體、人源化抗體、嵌合抗體及特異性結合間皮素之抗體。術語「抗體」意謂包括完整抗體,以及抗體之片段,例如來自裂解抗體之抗體Fab片段、F(ab')
2、Fv片段或Fc片段、scFv-Fc片段、微型抗體、雙功能抗體或scFv。此外,該術語包括抗體之經基因工程改造之衍生物。抗體、抗體片段及經基因工程改造之抗體可藉由此項技術中已知之方法獲得。
如本文所述之抗體包含N-聚醣結合域。在一個實施例中,抗體包含重鏈恆定區,且N-聚糖結合域位於重鏈恆定區中。在一些實施例中,如所述之抗體在Fc區之C
H2恆定域之重鏈中具有N-糖基化天冬醯胺殘基。在一個實施例中,抗體包含兩條重鏈及兩個N-聚糖,各N-聚糖與一條重鏈結合。特定言之,如式(1)所示之N-聚糖中之第一GlcNAc (GlcNAc
1)與抗體結合。
在本發明之一個實施例中,抗體DCBPR2002之抗原結合片段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區、CDRH2區及CDRH3區,且輕鏈可變區之互補決定區包含CDRL1區、CDRL2區及CDRL3區;其中CDRH1區包含SEQ ID NO: 1之胺基酸序列;CDRH2區包含SEQ ID NO: 2之胺基酸序列;CDRH3區包含SEQ ID NO: 3之胺基酸序列;CDRL1區包含SEQ ID NO: 4之胺基酸序列;CDRL2區包含SEQ ID NO: 5之胺基酸序列;且CDRL3區包含SEQ ID NO: 6之胺基酸序列。
在本發明之一個實施例中,抗體為小鼠抗體。已開發小鼠抗間皮素抗體株SS1用於臨床試驗中之癌症治療。抗體SS1包含有包含SEQ ID NO: 7之胺基酸序列的重鏈可變區及包含SEQ ID NO: 8之胺基酸序列的輕鏈可變區,如US7081518 B1中所揭示。
據觀察,SS1在患者中誘導強效免疫原性及抗藥物抗體。因此,SS1之人源化為進一步藥物開發之必需及關鍵步驟。對於人源化SS1 4D5 (HdSS1)製備,人類受體構架係選自臨床中已驗證之構架。在本發明之一個實施例中,抗體HdSS1包含有包含SEQ ID NO: 9之胺基酸序列的重鏈可變區及包含SEQ ID NO: 10之胺基酸序列的輕鏈可變區。
在本發明之一些實施例中,抗體包含與mAb SS1構架區具有最高程度同源性之人類生殖系VL及VH序列。特定言之,人源化抗體HuSS1 (DCBPR2002)包含有包含SEQ ID NO: 11之胺基酸序列的重鏈可變區及包含SEQ ID NO: 12之胺基酸序列的輕鏈可變區,如圖1所示。
序列列於表1中。
表1
序列 | SEQ ID NO. | |
CDRH1 | GYSFTGYTMN | 1 |
CDRH2 | LITPYNGASSYNQKFRG | 2 |
CDRH3 | GGYDGRGFDY | 3 |
CDRL1 | SASSSVSYMH | 4 |
CDRL2 | DTSKLAS | 5 |
CDRL3 | QQWSKHPLT | 6 |
SS1之重鏈可變區 | QVQLQQSGPELEKPGASVKISCKASGYSFTGYTMNWVKQSHGKSLEWIGLITPYNGASSYNQKFRGKATLTVDKSSSTAYMDLLSLTSEDSAVYFCARGGYDGRGFDYWGQGTTVTVSS | 7 |
SS1之輕鏈可變區 | DIELTQSPAIMSASPGEKVTMTCSASSSVSYMHWYQQKSGTSPKRWIYDTSKLASGVPGRFSGSGSGNSYSLTISSVEAEDDATYYCQQWSKHPLTFGAGTKLEIKR | 8 |
HdSS1之重鏈可變區 | EVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALITPYNGASSYNQKFRGRFTISRDDSKNTLYLQMNSLRAEDTAVYYCARGGYDGRGFDYWGQGTLVTVSS | 9 |
HdSS1之輕鏈可變區 | DIQMTQSPSSLSASVGDRVTITCSASSSVSYMHWYQQKPGKAPKLLIYDTSKLASGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQWSKHPLTFGQGTKVEIKR | 10 |
HuSS1 (DCBPR2002)之重鏈可變區 | QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYTMNWVRQAPGQGLEWMGLITPYNGASSYNQKFRGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARGGYDGRGFDYWGQGTLVTVSS | 11 |
HuSS1 (DCBPR2002)之輕鏈可變區 | EIVLTQSPATLSLSPGERATLSCSASSSVSYMHWYQQKPGQAPRLLIYDTSKLASGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQWSKHPLTFGQGTKVEIKR | 12 |
如本文所用,「GlcNAc
1」、「GlcNAc
2」、「GlcNAc
3」及「GlcNAc
4」分別表示觸角形聚糖部分之不同位置處的GlcNAc糖。
如本文所用,「
」表示包含三個甘露糖之三甘露糖基結構,其中第一甘露糖(Man
1)與GlcNAc糖連接;且第二及第三甘露糖(Man
2及Man
3)分別經由α-1,3及α-1,6糖苷鍵與Man
1連接。
如本文所用,「-(Fuc)
0-1」表示海藻糖為視情況存在的,且當存在時,僅存在一個海藻糖。
如本文所述之N-聚醣具有式(1)之結構。如式(2)所示之N-聚糖、連接子、有效負載A及B的合成方法可至少在WO2018/126092A1中看到。
如本文所用,「-(CH
2)
0-8-」表示-CH
2-可存在或可不存在,且當存在時,其可獨立地為1、2、3、4、5、6、7或8個-CH
2-基團。
在一些實施例中,連接子具有能夠連接共軛劑及有效負載之官能基。此類連接子之實例包括但不限於不可裂解連接子及可裂解連接子。在一些實施例中,不可裂解連接子包括但不限於具有2至20個碳原子之直鏈或分支鏈烷基、環烷基、烯基、環烯基、炔基、芳香基、雜芳香基、烷氧基、醯基、烷胺基或芳胺基。在一些實施例中,可裂解連接子包括但不限於含雙硫鍵之連接子、酸不穩定連接子、光不穩定連接子、肽酶不穩定連接子及酯酶不穩定連接子。連接子之實例包括但不限於具有2至20個碳原子之直鏈或分支鏈烷基、環烷基、烯基、環烯基、炔基、芳香基、雜芳香基、烷氧基、醯基、烷胺基、芳胺基、醚、酯、醯胺、胺基甲酸酯、碳酸酯、式(3)至式(7)、含雙硫鍵之連接子、酸不穩定連接子、光不穩定連接子、肽酶不穩定連接子及酯酶不穩定連接子。上述實例中之多於一者可以任何順序同時使用。
式(3)
式(4)
在式(3)及式(4)中:
R
1獨立地選自由以下組成之群:氫、鹵素、-OR
5、-NO
2、-CN、-S(O)
2R
5、C
1- C
24烷基、C
6- C
24(雜)芳香基、C
7- C
24烷基(雜)芳香基及C
7- C
24(雜)芳烷基,且
其中烷基、(雜)芳香基、烷基(雜)芳香基及(雜)芳烷基視情況經取代,
兩個取代基R
1可連接在一起以形成增環環烷基或增環(雜)芳烴取代基,且
R
5獨立地選自由以下組成之群:氫、鹵素、C
1- C
24烷基、C
6- C
24(雜)芳香基、C
7- C
24烷基(雜)芳香基及C
7- C
24(雜)芳烷基;
X為C(R
1)
2、O、S或NR
2,其中R
2為R
1;a為0、1、2、3、4、5、6、7或8;a'為0、1、2、3、4、5、6、7或8;且a+a' < 10;且
L係選自由以下組成之群:具有2至20個碳原子之直鏈或分支鏈烷基、環烷基、烯基、環烯基、炔基、芳香基、雜芳香基、烷氧基、醯基、烷胺基、芳胺基、醚、酯、醯胺、胺基甲酸酯、碳酸酯、含雙硫鍵之連接子、酸不穩定連接子、光不穩定連接子、肽酶不穩定連接子及酯酶不穩定連接子或其組合。
式(5)
在式(5)中:
R
1及L如式(3)及式(4)中所定義;
R
3獨立地選自由以下組成之群:氫、鹵素、C
1- C
24烷基、C
6- C
24(雜)芳香基、C
7- C
24烷基(雜)芳香基及C
7- C
24(雜)芳烷基;
R
4係選自由以下組成之群:氫、鹵素、C
1- C
24烷基、C
6- C
24(雜)芳香基、C
7- C
24烷基(雜)芳香基及C
7- C
24(雜)芳烷基,烷基視情況雜有一或多個選自由O、N及S組成之群之雜原子,其中烷基、(雜)芳香基、烷基(雜)芳香基及(雜)芳烷基獨立地視情況經取代。
式(6)
式(7)
在式(6)及式(7)中,L如式(3)及式(4)中所定義。
在一些實施例中,當免疫共軛物用於治療個體之疾病時,因此有效負載A及B可獨立地為治療劑。治療劑可為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(methotrexate)、甲醯四氫葉酸(leucovorin)、羥基尿素(hydroxyurea)、硫鳥嘌呤(6-TG)、巰基嘌呤(6-MP)、阿糖胞苷(cytarabine)、噴司他丁(pentostatin)、磷酸氟達拉濱(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(azathioprine)、胞嘧啶甲胺喋呤(cytosine methotrexate)、甲氧苄啶(trimethoprim)、乙胺嘧啶(pyrimethamine)或培美曲塞(pemetrexed));烷基化劑(例如美法侖(cmelphalan)、苯丁酸氮芥(chlorambucil)、白消安(busulfan)、噻替派(thiotepa)、異環磷醯胺(ifosfamide)、卡莫司汀(carmustine)、洛莫司汀(lomustine)、司莫司汀(semustine)、鏈佐星(streptozocin)、達卡巴嗪(dacarbazine)、絲裂黴素C (mitomycin C)、環磷醯胺(cyclophosphamide)、二氯甲基二乙胺(mechlorethamine)、烏拉莫司汀(uramustine)、二溴甘露醇(dibromomannitol)、四硝酸酯(tetranitrate)、丙卡巴肼(procarbazine)、六甲蜜胺(altretamine)、米托唑胺(mitozolomide)或替莫唑胺(temozolomide));類烷基化劑(例如順鉑(cisplatin)、卡鉑(carboplatin)、奈達鉑(nedaplatin)、奧沙利鉑(oxaliplatin)、沙鉑(satraplatin)或特瑞鉑(triplatin));DNA小溝烷基化劑(例如倍癌黴素(duocarmycins)諸如CC-1065及其任何類似物或衍生物;吡咯并苯并二氮呯(pyrrolobenzodiazapenes)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)或戊柔比星(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)、短桿菌肽D (gramicidin D)、絲裂黴素(mitomycins) (例如絲裂黴素C);卡奇黴素(calicheamicins);抗有絲分裂劑(包括例如類美登素(maytansinoids) (諸如DM1、DM3及DM4)、奧瑞他汀(auristatins) (包括例如單甲基奧瑞他汀E (MMAE)及單甲基奧瑞他汀F (MMAF))、海兔毒素(dolastatins)、念珠藻素(cryptophycins)、長春花生物鹼(vinca alkaloids) (例如長春新鹼(vincristine)、長春花鹼(vinblastine)、長春地辛(vindesine)、長春瑞賓(vinorelbine))、紫杉烷(taxanes) (例如紫杉醇(paclitaxel)、多烯紫杉醇(docetaxel)或新穎紫杉烷)、妥布賴森(tubulysins)及秋水仙鹼(colchicines));拓樸異構酶抑制劑(例如伊立替康(irinotecan)、拓朴替康(topotecan)、喜樹鹼(camptothecin)、司拉替康(silatecan)、科西替康(cositecan)、依昔替康(exatecan)、勒托替康(lurtotecan)、吉馬替康(gimatecan)、貝洛替康(belotecan)、魯比替康(rubitecan)、SN38、DXd、DXd2、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)、帕比諾他(panobinostat)或貝利司他(belinostat));蛋白酶體抑制劑(例如肽基酉朋酸(peptidyl boronic acids));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
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)。
特定言之,如本文所用之治療劑為單甲基奧瑞他汀E、單甲基奧瑞他汀F、類美登素、多卡黴素-羥基苯甲醯胺氮雜吲哚、二伸乙基三胺-N,N,N',N",N"-五乙酸酯、依昔替康或Dxd2。
在一些實施例中,當免疫共軛物用於偵測時,有效負載A及B可獨立地為標記。標記包括但不限於直接偵測之標記或部分(諸如螢光標記、發色標記、電子緻密標記、化學發光標記及放射性標記),以及例如經由酶促反應或分子相互作用間接偵測之部分,諸如酶或配體。例示性標記包括但不限於放射性同位素P
32、C
14、I
125、H
3及I
131;螢光團,諸如稀土螯合物或螢光素及其衍生物;若丹明(rhodamine)及其衍生物;丹醯基(dansyl);傘酮(umbelliferone);螢光素酶,例如螢火蟲螢光素酶及細菌螢光素酶;螢光素;2,3-二氫呔𠯤二酮;山葵過氧化酶(HRP);鹼性磷酸酶;β-半乳糖苷酶;葡萄糖澱粉酶;溶菌酶;醣氧化酶,例如葡萄糖氧化酶、半乳糖氧化酶及葡萄糖-6-磷酸去氫酶;雜環氧化酶,諸如尿酸酶及黃嘌呤氧化酶,其與採用過氧化氫氧化染料前體之酶(諸如HRP、乳過氧化酶或微過氧化酶)偶合;生物素/抗生物素蛋白;自旋標記;噬菌體標記;穩定自由基及類似標記。在另一個實施例中,標記為正子發射體。正子發射體包括但不限於Ga
68、F
18、Cu
64、Y
86、Br
76、Zr
89及I
124。
在本發明之一些實施例中,免疫共軛物可不完全裝有有效負載A及B以及連接子,且N-聚醣可直接與保護基結合。保護基可進一步經治療劑或標記置換。保護基之一個實例為疊氮基。
本發明之一個實施例係關於一種醫藥組合物,其包含本發明之免疫共軛物及醫藥學上可接受之載劑。
本發明之一個實施例係關於使用本發明之免疫共軛物治療疾病或病症之方法。該疾病可為癌症。特定言之,癌症為表現間皮素之癌症。「表現間皮素之癌症」係指具有表現間皮素之細胞的任何癌症。間皮素一般在實體腫瘤上表現,包括與肺、胸膜、卵巢、乳房、胃、膽管、子宮及胸腺相關之實體腫瘤。因此,表現間皮素之癌症的實例包括但不限於卵巢癌、間皮瘤、胰臟癌、非小細胞肺癌、食道癌、胃癌、膽管癌、結腸直腸癌、子宮內膜癌及乳癌。特定言之,癌症為卵巢癌。
在一些實施例中,基於活體內藥物動力學概況,免疫共軛物顯示出比隨機共軛免疫共軛物相對穩定的共軛連接。
在一些實施例中,在異種移植動物模型中,具有N-聚糖之免疫共軛物顯示出比隨機共軛免疫共軛物更好的功效。
本發明之實施例將藉由以下特定實例來說明。熟習此項技術者應瞭解,此等實例僅用於說明且其他修改及變化在不脫離本發明之範疇的情況下係可能的。
實例
除非另外指明,否則各
1H NMR資料在500 MHz下獲得。除非另外規定,否則本文所用之縮寫如下:Az:疊氮基;Bu:丁基;Bn:苯甲基;BOC:三級丁氧基羰基;BOP:六氟磷酸苯并三唑-1-基氧基三/二甲胺基-鏻;DBCO:二苯并環辛炔基;DCC:二環己基碳二亞胺;DCM:二氯甲烷;DIPEA:
N,
N-二異丙基乙胺;DMF:N,N-二甲基甲醯胺;DMAP:4-二甲胺基吡啶;EDC:1-(3-二甲胺基丙基)3-乙基碳化二亞胺鹽酸鹽;EtOAc:乙酸乙酯;eq.:當量;GlcNAc:N-乙醯基葡糖胺;GlcNAz:疊氮基-N-乙醯基葡糖胺;HBTU:3-[雙(二甲胺基)甲基鎓基]-3H-苯并三唑-1-氧化物六氟磷酸鹽;六氟磷酸苯并三唑四甲基釒尿;HOBt:羥基苯并三唑;HOSu:N-羥基丁二醯亞胺;HATU:1-[雙(二甲胺基)亞甲基]-1H-1,2,3-三唑并[4,5-b]吡錠3-氧化物六氟磷酸鹽;六氟磷酸氮雜苯并三唑四甲基釒尿;LAH:氫化鋰鋁;MeOH:甲醇;MES:4-嗎啉乙磺酸;MGAT-1:甘露糖基(α-1,3-)-糖蛋白β-1,2-N-乙醯基葡糖胺基轉移酶;MGAT-2:甘露糖基(α-1,6-)-糖蛋白β-1,2-N-乙醯基葡糖胺基轉移酶;MHz:百萬赫;MMAE:單甲基奧瑞他汀E;MS(ES):質譜儀-電子噴霧;NMP:N-甲基吡咯啶酮;Ph:苯基;Pr:丙基;TEA:三乙胺;TFA:三氟乙酸;THF:四氫呋喃;TLC:薄層層析;Tetrakis:肆(三苯基膦)鈀;UDP:尿苷二磷酸。
實例
1
抗間皮素
SS1 mAb
之人源化
人類
V
區構架序列之選擇:
藉由使用小鼠單株抗體SS1 (其序列揭示於US 7,081,518 B1中)作為親本抗體,根據Kabat定義之SS1 mAb CDR序列描述於圖1A中(SEQ ID NO: 7及8)。
對於人源化SS1 4D5 (HdSS1)製備,人類受體構架係選自臨床中已驗證之構架。VH亞組III (IGHV3-66*04)及VL κ亞組I (IGKV1-39*01)中之人類重鏈及輕鏈構架序列已在臨床中得到驗證,且亦成功地用於許多人源化抗體中。
如圖1A所示,IGHV3-66*04重鏈構架區之序列與mAb SS1中之序列相差35個胺基酸(加下劃線的殘基),其相當於42.68% (構架區中總殘基之35/82)的變異。另外,IGKV1-39*01 (VL)輕鏈構架區之序列與mAb SS1中之序列相差25個胺基酸(加下劃線的殘基),其相當於30.86% (構架區中總殘基之25/81)的變異。
對於人源化SS1 IMGT (HuSS1)製備,自IMGT資料庫(International immunogenetics Information System®)鑑別與mAb SS1構架區具有最高程度同源性之人類生殖系VL及VH序列。同源性搜尋可用BLAST或類似方法進行。此等研究分別將人類生殖系基因IGHV1-2*02 (VH)及IGVK3-11*01 (VL)鑑別為與mAb SS1中相應的重鏈及輕鏈構架序列最同源的VH及VL序列。
如圖1B所示,IGHV1-2*02重鏈構架區之序列與mAb SS1中之序列相差25個胺基酸(加下劃線的殘基),其相當於30.49% (構架區中總殘基之25/82)的變異。如圖1B所示,IGVK3-11*01 (VL)輕鏈構架區之序列與mAb SS1中之序列相差27個胺基酸(加下劃線的殘基),其對應於33.33% (構架區中總殘基之27/81)的變異。
此兩對輕鏈及重鏈序列(hum 4D5及hum IMGT)用作構築針對人類間皮素之人源化抗體的實例。(SEQ ID NO: 9、10、11及12)
實例
2
人源化抗體之結合親和力分析
全長抗體之表現
為了確認小鼠抗體人源化後的親和力變化,分別藉由核苷酸合成方法直接生成IMGT及4D5版本之人源化輕鏈及人源化重鏈的可變區。將小鼠可變區、人源化版本之IMGT (SEQ ID NO: 11及12)及4D5 (SEQ ID NO: 9及10)可變區次選殖至如圖2所示之人類Fc嵌合體抗體表現載體pTCAE8中,引入宿主細胞中以製備重組抗體表現細胞。作為表現之宿主細胞,使用FreeStyle293細胞(由Invitrogen製造)。
以下程序用於將如此構築之載體轉染至30 ml體積之FreeStyle™ 293細胞懸浮液中。在轉染期間,細胞可保持在FreeStyle™ 293表現培養基中。在轉染前約24小時,將FreeStyle™ 293細胞以2×10
6個細胞/毫升傳遞15 ml。將燒瓶置於含有8% CO
2之37℃培育箱中。隨後,將37.5 µg質體DNA稀釋於1.5 ml無菌150 mM NaCl中,總體積為1.5 ml。在另一管中,將37.5 µl PEI (2.0 mg/ml)稀釋於1.5 ml無菌150 mM NaCl中。使DNA及PEI溶液在室溫下靜置5分鐘。藉由將管倒置平緩地混合溶液,且隨後使管在室溫下靜置約10-20分鐘。將DNA-PEI混合物添加至F293細胞中,且將經轉染細胞在以135-150 rpm旋轉之定軌震盪器平台上,在37℃、8% CO
2之培育箱中培育4小時。隨後,添加等體積的新鮮培養基,總體積為30 ml,且培養細胞5-7天。隨後收穫細胞用於抗體純化及定量。
收集的上清液經由0.2微米過濾器(由Millpore製造)過濾以移除污染物。含有抗體之培養上清液用蛋白質A (由Millipore製造)、1.5 M甘胺酸/NaOH緩衝液、3 M NaCl (pH 9.0)作為吸收緩衝液,及0.2 M甘胺酸/HCl緩衝液(pH 2.5)作為溶離緩衝液進行親和純化。藉由添加1 M Tris/HCl緩衝液(pH 9.0)將溶離份調整至約pH 6.0~7.0。使用透析膜(10,000 MW截止值,由Spectrum Laboratories製造)用PBS替換所製備之抗體溶液,且經由孔徑為0.22微米之膜濾器(由Millpore製造)過濾滅菌,以產生純化抗體。純化抗體之濃度係藉由量測在280 nm下之吸光度來測定,且基於1.45最佳密度轉換量測值,等於1 mg/ml。
藉由
ELISA
測定抗體結合親和力
ELISA盤塗有每孔1~2 μg/100 μl間皮素蛋白。孔用PBS沖洗3次,且用每孔300 μl 5% MPBS在37℃下阻斷2小時。在用PBS洗滌後,將孔與在5% MPBS中連續稀釋之間皮素抗體在37℃下培育1.5小時。洗滌培養盤且向各孔中添加山羊多株抗人類IgG-HRP抗體(1:10,000) (Jackson ImmunoResearch)。如上文所述量測吸光度,且用Prism軟體(GraphPad)藉由非線性回歸計算抗體之結合親和力。
在構架區高度變異的情況下,藉由將來自mAb SS1之CDR序列移植至IGHV3-66*04及IGVK1-39*01序列中生成之HdSS1 (HH)顯示出對間皮素低得多的親和力(KD = 2.61E-08 M) (用於比較,mAB SS1,KD = 8.36E-11M) (圖3),(下表2)。
與HdSS1相比,在構架區高度變異的情況下,藉由將來自mAb SS1之CDR序列移植至IGHV1-2*02及IGVK3-11*01序列中生成之HuSS1 (HH)對間皮素具有相對良好的親和力(KD = 4.99E-11 M) (用於比較,mAB SS1,KD = 8.36E-11M) (圖3) (下表2)。
此等結果表明IGHV1-2*02重鏈構架區及IGVK3-11*01輕鏈構架區優越地容忍相對較高程度的變異而不影響CDR區構形。
表2
ELISA KD (M) | |
SS1 MM | 8.36E-11 |
HdSS1 HH | 2.61E-08 |
HuSS1-HH | 4.99E-11 |
使用
BIAcore
之親和力量測及動力學分析
為了知曉個別抗體之間的結合動力學差異,如先前所述(Karlsson及Falt, (1997) J. Immunol Methods 200:121-133)使用BIAcore T200 (Cytiva Inc.)進行表面電漿共振(SPR)量測。根據供應商的說明書,用N-乙基-N'-(3-二甲胺基丙基)-碳化二亞胺鹽酸鹽(EDC)及N-羥基丁二醯亞胺(NHS)活化羧基甲基化葡聚糖生物感測器晶片(CM5,Cytiva Inc.)。間皮素蛋白用10 mM乙酸鈉pH 4.0稀釋至5 μg/ml,隨後以10 μL/min之流動速率注射,以獲得約1500個反應單位(RU)的偶合蛋白,接著注射1 M乙醇胺以阻斷未反應之基團。對於動力學量測,將抗間皮素mAb之兩倍連續稀釋液(0.3125 nM至40 nM)在25℃下以30 μL/min之流動速率注射至由製造商(Cytiva Inc.)提供之HBS-EP+ Biacore運行緩衝液中,且藉由減去空白流動槽之反應來校正間皮素蛋白之結合反應。使用簡單的一對一朗格繆爾結合模型(Langmuir binding model)計算締合速率(kon或ka)及解離速率(koff或kd),且使用kon及koff之單獨擬合。(Cytiva.TM. Biacore Insight Evaluation Software)。
結果展示於圖4及表3 (如下)中。嵌合體SS1 mAb與間皮素結合之kon及koff分別為3.415E6及1.194E-5,且KD為3.496E-12 mol/L。HuSS1mAb (IMGT版本)與間皮素結合之kon及koff分別為4.493E6及1.124E-5,且KD為2.501E-12。
根據圖4之結果,表明人源化抗體HuSS1 (DCBPR2002)可識別人類間皮素蛋白,且在人源化後,IMGT版本之親和力類似於小鼠SS1抗體且具有良好的親和力,KD值為約2.501E-12。
表3
ka(1/Ms) | kd(1/s) | KD(M) | Rmax(RU) | Chi 2(RU 2) | |
SS1 | 3.415E+6 | 1.194E-5 | 3.496E-12 | 218.2 | 20.3 |
HuSS1 | 4.493E+6 | 1.124E-5 | 2.501E-12 | 180.6 | 17.9 |
實例
3
三甘露糖基
-DCBPR2002 (DCBPR2002-TM)
之
製備
為了自DCBPR2002移除N-聚糖之半乳糖及唾液酸部分,將10 mg DCBPR2002用20 μl β1,4-半乳糖苷酶(NEB,P0745L,8單位/微升)及5 μl α2-3,6,8神經胺糖酸酶(NEB,P0720L,50單位/微升)在1X GlycoBuffer (NEB,總體積1 mL)中在37℃下處理24小時。向反應物中進一步添加10 μl β1,4-半乳糖苷酶(NEB,P0745L,8單位/微升),且使反應在37℃下再進行24小時以獲得G0F/G0抗體樣品。藉由使用rProtein A Sepharose Fast Flow (GE Healthcare,17-1279-02)純化抗體樣品。在純化後,對抗體樣品進行折合質量層析分析。
DCBPR2002-2Az
之
製備
(
圖
21A)
MGAT-1將UDP-疊氮基-N-乙醯基葡糖胺轉移至三甘露糖基核心蛋白各臂之末端甘露糖中之一者。為了證實抗體中之此現象,將三甘露糖基-DCBPR2002 (5 mg)及UDP-GlcNAz (最終濃度為2.5 mg)在1000 μl 1X緩衝液SP (25 mM MES (4-嗎啉乙磺酸),10 mM MnCl
2,pH 6.5)中在MGAT-1 (0.1 mg;R&D,8334-GT或自製)存在下在37℃下培育16小時。對產物DCBPR2002-2Az進行折合質量層析分析。
DCBPR2002-4Az
之
製備
(
圖
21B)
將三甘露糖基-DCBPR2002 (5 mg)及UDP-GlcNAz (2.5 mg)在800 μl 1X緩衝液SP (25 mM MES,10 mM MnCl
2,pH 6.5)中在兔MGAT-1 (0.2 mg)及大鼠MGAT-2 (0.05 mg)存在下在37℃下培育16小時。在培育後,對反應產物DCBPR2002-4Az進行折合質量層析分析及完整質量層析分析。
實例
4
DBCO-vc-MMAE (
化合物
5)
之製備
將DBCO-CO
2H (1) (200 mg,1 eq)、EDC (226 mg,3 eq)及HOSu (376 mg,3 eq)之混合物溶解於二氯甲烷(5 mL)中,且在室溫下攪拌3小時。在反應完成後,反應混合物用二氯甲烷及水萃取。隨後,有機層用鹽水洗滌且經MgSO
4乾燥。在減壓下移除有機溶劑,得到化合物2,其不經進一步純化。
將DIPEA (170 mg,2 eq)添加至化合物2 (1 eq)及3-(2-(2-(2-胺基乙氧基)乙氧基)乙氧基)丙酸(174 mg,1.2 eq)於二氯甲烷(5 mL)中之混合物中。在室溫下攪拌反應混合物隔夜。在反應完成後,反應混合物用二氯甲烷及1 N HCl(aq)萃取。隨後,有機層用鹽水洗滌且經MgSO
4乾燥。藉由管柱層析用甲醇/二氯甲烷純化殘餘物,得到棕色液體化合物3 (54%產率)。
1H NMR (600 MHz, DMSO) δ 7.69 (dd, J = 7.7, 1.3 Hz, 1H), 7.63 (d, J = 7.4 Hz, 1H), 7.53 - 7.44 (m, 3H), 7.39 (td, J = 7.5, 1.6 Hz, 1H), 7.35 (td, J = 7.5, 1.3 Hz, 1H), 7.30 (dd, J = 7.4, 1.6 Hz, 1H), 5.04 (d, J = 14.0 Hz, 1H), 3.62 (d, J = 14.0 Hz, 1H), 3.58 (t, J = 6.4 Hz, 2H), 3.48 - 3.43 (m, 8H), 3.29 (dd, J = 5.9, 2.3 Hz, 2H), 3.13 - 3.04 (m, 2H), 2.61 - 2.55 (m, 1H), 2.42 (t, J = 6.4 Hz, 2H), 2.24 (dt, J = 15.5, 7.8 Hz, 1H), 2.00 (ddd, J = 15.4, 8.2, 5.7 Hz, 1H), 1.76 (ddd, J = 16.3, 8.0, 5.7 Hz, 1H)。LC-MS(ESI): m/z [C
28H
32N
2O
7]計算值509.2 [M +1]
+,實驗值509.2[M +1]
+。
將DIPEA (145 mg,2 eq)添加至化合物3 (286 mg,1 eq)、vc-MMAE (化合物4) (630 mg,1.1 eq)及HATU (428 mg,2 eq)於DCM: DMF 2:1 (6 mL)中之混合物中。在室溫下攪拌混合物1小時。在反應完成後,反應混合物用二氯甲烷及水萃取。隨後,有機層用鹽水洗滌且經MgSO
4乾燥。在減壓下移除有機溶劑。藉由管柱層析用甲醇/二氯甲烷純化殘餘物,得到淡黃色固體化合物5 (71%產率)。
1H NMR (600 MHz, MeOD) δ 7.66 (d, J = 7.4 Hz, 1H), 7.61 (d, J = 3.5 Hz, 3H), 7.51 - 7.44 (m, 3H), 7.42 - 7.37 (m, 3H), 7.33 (dt, J = 15.5, 8.2 Hz, 5H), 7.26 (d, J = 7.3 Hz, 1H), 7.23 (t, J = 7.4 Hz, 1H), 5.23 - 5.07 (m, 3H), 4.71 - 4.48 (m, 4H), 4.29 - 4.15 (m, 4H), 3.75 - 3.69 (m, 3H), 3.63 - 3.54 (m, 8H), 3.46 - 3.39 (m, 3H), 3.36 (s, 4H), 3.30 (d, J = 16.5 Hz, 3H), 3.26 - 3.23 (m, 2H), 3.23 - 3.16 (m, 2H), 3.12 (s, 2H), 2.96 (dd, J = 17.0, 10.0 Hz, 3H), 2.75 - 2.68 (m, 1H), 2.57 - 2.46 (m, 4H), 2.38 (dt, J = 15.0, 7.5 Hz, 1H), 2.28 - 2.04 (m, 5H), 2.04 - 1.66 (m, 8H), 1.66 - 1.49 (m, 4H), 1.45 (d, J = 29.4 Hz, 2H), 1.19 (dd, J = 6.6, 3.0 Hz, 3H), 1.15 (dd, J = 12.8, 6.8 Hz, 3H), 1.03 - 0.70 (m, 24H)。
實例
5
DBCO-S-DM1
(
化合物
11)
之
製備
將1,2-二(吡啶-2-基)雙硫烷(1.83 g,2 eq)添加至4-巰基丁酸(0.5 g,1 eq)於甲醇(10 mL)中之溶液中。在室溫下攪拌混合物隔夜。在反應完成後,在減壓下移除有機溶劑。藉由管柱層析用己烷/乙酸乙酯純化殘餘物,得到無色液體化合物6 (14%產率)。
1H NMR (600 MHz, CDCl
3) δ 8.49 (ddd,
J= 4.8, 1.8, 0.9 Hz, 1H), 7.72 (dt,
J= 8.1, 1.0 Hz, 1H), 7.69 - 7.61 (m, 1H), 7.12 (ddd,
J= 7.3, 4.9, 1.1 Hz, 1H), 2.88 (t,
J= 7.1 Hz, 2H), 2.53 (t,
J= 7.2 Hz, 2H), 2.07 (p,
J= 7.2 Hz, 2H)。
將DIPEA (145 mg,2 eq)添加至化合物6 (286 mg,1 eq)、vc-MMAE (4) (630 mg,1.1 eq)及HATU (428 mg,2 eq)於DCM (5 mL)中之混合物中。在室溫下攪拌混合物1小時。在反應完成後,反應混合物用二氯甲烷及水萃取。隨後,有機層用鹽水洗滌且經MgSO
4乾燥。在減壓下移除有機溶劑。藉由管柱層析用甲醇/二氯甲烷純化殘餘物,得到淡黃色固體化合物7 (71%產率)。1H NMR (600 MHz, DMSO) δ 7.18 (d, J = 1.5 Hz, 1H), 6.90 (s, 1H), 6.62 - 6.56 (m, 1H), 6.56 - 6.52 (m, 1H), 5.94 (s, 1H), 5.56 (dd, J = 14.8, 9.0 Hz, 1H), 5.31 (q, J = 6.8 Hz, 1H), 4.52 (dd, J = 12.0, 2.7 Hz, 1H), 4.06 (t, J = 12.3 Hz, 1H), 3.92 (s, 3H), 3.52 - 3.45 (m, 2H), 3.25 (s, 3H), 3.13 (s, 3H), 2.93 - 2.78 (m, 4H), 2.72 (s, 3H), 2.21 (t, J = 7.2 Hz, 2H), 2.04 (dd, J = 14.4, 2.4 Hz, 1H), 1.69 (p, J = 7.4 Hz, 2H), 1.59 (s, 3H), 1.50 - 1.40 (m, 2H), 1.14 (dd, J = 28.7, 6.6 Hz, 6H), 0.97 (d, J = 6.4 Hz, 6H), 0.78 (s, 3H)。
將HBTU (0.92 g,1.5 eq)及DIPEA (0.57 mL,2 eq)添加至化合物1 (0.5 g,1 eq)及化合物8 (0.62 g,1.3 eq)於DMF (8 mL)中之混合物中。在室溫下攪拌反應混合物2小時。在反應完成後,反應混合物用乙酸乙酯及水萃取。隨後,有機層用鹽水洗滌且經MgSO
4乾燥。藉由管柱層析用甲醇/二氯甲烷純化殘餘物,得到橙色液體化合物9 (76%產率)。LC-MS(ESI): m/z [C
32H
41N
3O
7]計算值579.68 [M +1]
+,實驗值479.95[M +1]
+。
化合物
10
之合成
在冰浴下,將TFA (2.85 mL)添加至化合物9 (0.72 g,1 eq)於二氯甲烷(15 mL)中之溶液中。在室溫下攪拌反應混合物3小時。在反應完成後,在減壓下移除有機溶劑。藉由管柱層析用甲醇/二氯甲烷純化殘餘物,得到棕色固體化合物10 (69%產率)。H NMR (600 MHz, DMSO) δ 7.78 - 7.74 (m, 2H), 7.69 - 7.66 (m, 1H), 7.62 (d, J = 7.4 Hz, 1H), 7.52 - 7.45 (m, 2H), 7.40 - 7.33 (m, 2H), 7.30 (dd, J = 7.4, 1.2 Hz, 1H), 5.03 (d, J = 14.1 Hz, 1H), 3.62 (d, J = 14.0 Hz, 1H), 3.57 - 3.53 (m, 6H), 3.49 - 3.44 (m, 6H), 3.30 (td, J = 6.0, 1.8 Hz, 2H), 3.12 - 3.04 (m, 2H), 2.96 (dd, J = 10.7, 5.5 Hz, 2H), 2.59 (ddd, J = 24.2, 9.8, 4.7 Hz, 1H), 2.23 (dt, J = 15.4, 7.6 Hz, 1H), 2.04 - 1.96 (m, 1H), 1.76 (ddd, J = 16.4, 8.0, 5.8 Hz, 1H)。LC-MS(ESI): m/z [C
27H
33N
3O
5]計算值479.57 [M +1]
+,實驗值480.1 [M +1]
+。
將HBTU (77 mg,1.5 eq)及DIPEA (0.047 mL,2 eq)添加至化合物7 (70 mg,1 eq)及化合物10 (100 mg,0.9 eq)於DMF (7 mL)中之混合物中。在室溫下攪拌反應混合物隔夜。在反應完成後,反應混合物用乙酸乙酯及水萃取。隨後,有機層用鹽水洗滌且經MgSO
4乾燥。藉由管柱層析用甲醇/二氯甲烷純化殘餘物,得到橙色固體化合物11 (DBCO-S-DM1) (54%產率)。1H NMR (600 MHz, DMSO) δ 7.86 (t, J = 5.6 Hz, 1H), 7.76 (t, J = 5.6 Hz, 1H), 7.70 - 7.66 (m, 1H), 7.62 (d, J = 7.3 Hz, 1H), 7.52 - 7.43 (m, 2H), 7.40 - 7.32 (m, 2H), 7.29 (d, J = 7.4 Hz, 1H), 7.17 (s, 1H), 6.90 (s, 1H), 6.63 - 6.56 (m, 1H), 6.55 - 6.52 (m, 1H), 5.94 (s, 1H), 5.56 (dd, J = 14.8, 9.0 Hz, 1H), 5.31 (q, J = 6.8 Hz, 1H), 5.02 (d, J = 14.0 Hz, 1H), 4.52 (dd, J = 12.1, 2.7 Hz, 1H), 4.06 (t, J = 12.3 Hz, 1H), 3.93 (d, J = 8.8 Hz, 3H), 3.61 (d, J = 14.0 Hz, 1H), 3.47 (s, 9H), 3.37 (t, J = 5.9 Hz, 2H), 3.29 (td, J = 5.9, 2.2 Hz, 2H), 3.24 (s, 3H), 3.17 (dt, J = 11.6, 9.2 Hz, 3H), 3.12 (s, 2H), 3.10 - 3.02 (m, 2H), 2.88 (ddd, J = 15.9, 12.2, 5.3 Hz, 2H), 2.84 - 2.81 (m, 1H), 2.81 - 2.78 (m, 1H), 2.71 (s, 2H), 2.60 - 2.53 (m, 2H), 2.53 - 2.51 (m, 5H), 2.48 - 2.44 (m, 3H), 2.23 (dt, J = 15.5, 7.8 Hz, 1H), 2.07 (td, J = 7.0, 2.7 Hz, 2H), 2.00 (ddd, J = 15.3, 12.4, 8.4 Hz, 2H), 1.76 (ddd, J = 16.4, 7.9, 5.7 Hz, 1H), 1.71 - 1.65 (m, 2H), 1.59 (s, 2H), 1.50 - 1.41 (m, 2H), 1.24 (dd, J = 6.9, 5.8 Hz, 2H), 1.17 (d, J = 6.8 Hz, 3H), 1.12 (d, J = 6.4 Hz, 3H), 0.84 (ddd, J = 13.1, 9.9, 6.7 Hz, 1H), 0.78 (s, 2H)。LC-MS(ESI): m/z [C
66H
85ClN
6O
16S
2]計算值1317.99 [M +1]
+,實驗值1299.41 [M -18]
+。
實例
6
DBCO-vc-seco DUBA
(
化合物
20)
之製備
化合物
12
之合成
如Beusker, P. H. (Mol. Pharmaceutics 2015, 12, 1813−1835)所述製備化合物12。
在冰浴下,將碳酸雙(4-硝基苯基)酯(0.858 g,2 eq)及三甲胺(0.983 mL,5 eq)添加至化合物12 (0.805 g,1 eq)於THF (40 mL)中之溶液中。在室溫下攪拌反應混合物8小時,且隨後在冰浴下,將化合物13 (1.85 g,5 eq)添加至反應混合物中。在室溫下攪拌反應混合物隔夜。在反應完成後,在減壓下移除有機溶劑。隨後,有機層用鹽水洗滌且經MgSO
4乾燥。藉由管柱層析用甲醇/二氯甲烷純化殘餘物,得到化合物14 (21.7%產率)。1H NMR (600 MHz, DMSO) δ 10.33 (s, 1H), 9.47 (s, 1H), 8.70 (s, 1H), 8.40 - 8.31 (m, 1H), 7.99 (d, J = 8.8 Hz, 2H), 7.74 (d, J = 9.6 Hz, 2H), 7.58 (d, J = 11.7 Hz, 1H), 7.42 (s, 1H), 7.36 (s, 1H), 7.18 (d, J = 8.8 Hz, 2H), 5.30 (s, 2H), 5.16 (t, J = 4.2 Hz, 1H), 4.69 - 4.61 (m, 2H), 4.47 (d, J = 2.7 Hz, 1H), 3.83 (d, J = 11.8 Hz, 1H), 3.80 - 3.64 (m, 3H), 3.64 - 3.60 (m, 1H), 3.60 - 3.51 (m, 4H), 3.52 - 3.43 (m, 3H), 3.41 (s, 4H), 3.33 (s, 1H), 2.96 - 2.92 (m, 1H), 2.88 - 2.81 (m, 3H), 2.81 - 2.73 (m, 2H), 1.47 - 1.21 (m, 9H)。LC-MS(ESI): m/z [C
44H
51ClN
6O
10]計算值859.36 [M +1]
+,實驗值859.7 [M +1]
+。
在冰浴下,將DIPEA (0.34 mL,2 eq)添加至化合物1 (0.3 g,1 eq)、HBTU (0.56 g,1.5 eq)、2-(2-胺基乙氧基)乙-1-醇(0.12 g,1.2 eq)於DMF (4 mL)中之混合物中。在室溫下攪拌反應混合物隔夜。在反應完成後,反應混合物用乙酸乙酯及水萃取。隨後,有機層用鹽水洗滌且經MgSO
4乾燥。藉由管柱層析用甲醇/二氯甲烷純化殘餘物,得到化合物15 (70%產率)。1H NMR (600 MHz, MeOD) δ 7.55 (d, J = 7.4 Hz, 1H), 7.51 - 7.47 (m, 1H), 7.38 - 7.33 (m, 3H), 7.24 (dtd, J = 22.1, 7.5, 1.2 Hz, 2H), 7.14 (dd, J = 7.5, 1.4 Hz, 1H), 5.02 (t, J = 10.9 Hz, 1H), 3.66 - 3.56 (m, 2H), 3.56 - 3.50 (m, 2H), 3.39 - 3.36 (m, 2H), 3.36 - 3.28 (m, 2H), 3.16 - 3.11 (m, 2H), 2.59 (dt, J = 16.4, 7.6 Hz, 1H), 2.25 (dt, J = 15.1, 7.5 Hz, 1H), 2.10 - 2.01 (m, 1H), 1.90 - 1.82 (m, 1H)。LC-MS(ESI): m/z [C
23H
24N
2O
4]計算值392.45 [M +1]
+,實驗值393.39 [M +1]
+。
化合物
16
之合成
在惰性氛圍下,將碳酸雙(4-硝基苯基)酯(0.47 g,3 eq)及DIPEA (0.2 mL,3 eq)添加至化合物15 (0.2 g,1 eq)於DMF/CH
2Cl
2(6/2 mL)中之溶液中。在室溫下攪拌反應混合物隔夜。在反應完成後,反應混合物用乙酸乙酯及水萃取。隨後,有機層用鹽水洗滌且經MgSO
4乾燥。合併有機溶劑且在減壓下移除。藉由管柱層析用甲醇/二氯甲烷純化殘餘物,得到化合物16 (70%產率)。1H NMR (600 MHz, CDCl3) δ 8.30 - 8.27 (m, 2H), 7.70 (d, J = 7.5 Hz, 1H), 7.53 - 7.50 (m, 1H), 7.44 - 7.38 (m, 5H), 7.37 (dd, J = 7.5, 1.4 Hz, 1H), 7.32 (td, J = 7.5, 0.8 Hz, 1H), 7.27 (d, J = 1.2 Hz, 1H), 5.17 (d, J = 13.9 Hz, 1H), 4.43 (t, J = 4.6 Hz, 2H), 3.81 - 3.72 (m, 2H), 3.69 (d, J = 13.9 Hz, 1H), 3.57 - 3.44 (m, 2H), 3.43 - 3.32 (m, 2H), 2.83 (ddd, J = 16.9, 8.6, 5.9 Hz, 1H), 2.45 (ddd, J = 14.7, 8.6, 5.8 Hz, 1H), 2.21 (dt, J = 15.2, 6.1 Hz, 1H), 1.97 (dt, J = 17.0, 6.1 Hz, 1H)。LC-MS(ESI): m/z [C
30H
27N
3O
8]計算值557.55 [M +1]
+,實驗值558.58 [M +1]
+。
化合物
18
之合成
將DIPEA (0.134 mL,2.2 eq)添加至化合物16 (0.2 g,1 eq)、化合物17 (0.2 g,1.5 eq)及HOBt (0.11 g,2.2 eq)於DMF (5 mL)中之混合物中。在室溫下攪拌反應混合物隔夜。在反應完成後,反應混合物用乙酸乙酯及水萃取。隨後,有機層用鹽水洗滌且經MgSO
4乾燥。合併有機溶劑且在減壓下移除。藉由管柱層析用甲醇/二氯甲烷純化殘餘物,得到化合物18 (36%產率)。
化合物
19
之合成
在惰性氛圍下,將碳酸雙(4-硝基苯基)酯(0.08 g,3 eq)及DIPEA (0.043 mL,3 eq)添加至化合物18 (0.05 g,1 eq)於DMF (3 mL)中之溶液中。在室溫下攪拌反應混合物隔夜。在反應完成後,反應混合物用乙酸乙酯及水萃取。隨後,有機層用鹽水洗滌且經MgSO
4乾燥。合併有機溶劑且在減壓下移除。藉由管柱層析用甲醇/二氯甲烷純化殘餘物,得到化合物19 (33%產率)。
在冰浴下,將TFA (11.2 mL,3 eq)添加至化合物14 (0.263 g,1 eq)於CH
2Cl
2(11.2 mL)中之溶液中。在室溫下攪拌反應混合物1小時。在反應完成後,在減壓下移除有機溶劑。將殘餘物溶解於DMF (7.6 mL)中。在冰浴下,將化合物19 (0.324 g,1.1 eq)及TEA (0.21 mL,5 eq)添加至混合物中。在室溫下攪拌反應混合物隔夜。在反應完成後,在減壓下移除有機溶劑。用二氯甲烷及水萃取殘餘物。隨後,有機層用鹽水洗滌且經MgSO
4乾燥。藉由管柱層析用甲醇/二氯甲烷純化殘餘物,得到化合物20 (DBCO-vc-seco DUBA) (55.2%產率)。
化合物
21
之合成
將HOSu (226 mg,3 eq)添加至DBCO-CO
2H (1) (200 mg,1 eq)、EDC (376 mg,3 eq)於二氯甲烷(5 mL)中之混合物中。在室溫下攪拌混合物2小時。在反應完成後,反應混合物用DCM及水萃取。隨後,有機層用鹽水洗滌且經MgSO
4乾燥。在減壓下移除有機溶劑,得到淡黃色液體。
將黃色液體逐滴添加至乙二胺於二氯甲烷中之溶液中持續20分鐘。在室溫下攪拌混合物隔夜。在反應完成後,反應混合物用DCM及NaHCO
3(aq.)萃取。隨後,有機層用鹽水洗滌且經MgSO
4乾燥。在減壓下移除有機溶劑。藉由管柱層析用甲醇/二氯甲烷純化殘餘物,得到黃色油狀物(產率:58.9%)。
1H NMR (600 MHz, MeOD) δ 7.63 (d, J = 7.4 Hz, 1H), 7.61 - 7.56 (m, 1H), 7.47 - 7.41 (m, 3H), 7.32 (dtd, J = 23.9, 7.5, 1.2 Hz, 2H), 7.23 (dd, J = 7.5, 1.3 Hz, 1H), 5.08 (d, J = 14.0 Hz, 1H), 3.63 (d, J = 14.0 Hz, 1H), 3.14 (dtd, J = 19.7, 13.5, 6.2 Hz, 2H), 2.74 (ddd, J = 16.6, 8.0, 6.8 Hz, 1H), 2.68 - 2.54 (m, 2H), 2.31 (ddd, J = 14.8, 8.0, 6.6 Hz, 1H), 2.16 (dt, J = 15.2, 6.5 Hz, 1H), 1.95 (dt, J = 16.7, 6.4 Hz, 1H)。LC-MS (ESI): m/z [C
21H
21N
3O
2]計算值348.16 [M +1]
+,實驗值348.03 [M +1]
+。
DBCO-DTPA (
化合物
22)
之合成
將市售DTPA (26 mg,1.1 eq)添加至化合物21 (13 mg,1 eq.)於H
2O:DMF 3:1 (3 mL)中之溶液中。在室溫下攪拌混合物隔夜。在反應完成後,反應混合物用二氯甲烷及水萃取。隨後,有機層用鹽水洗滌且經MgSO
4乾燥。在減壓下移除有機溶劑,得到黃色固體DBCO-DTPA (20 mg)。LC-MS (ESI): m/z [C
43H
49N
7O
12S]計算值888.32 [M +1]
+,實驗值888.47 [M +1]
+。
化合物
23
之合成
將DIPEA (0.082 mL,2.5 eq)添加至依昔替康甲磺酸鹽(0.11 g,1.1 eq)及Fmoc-vc-PAB-PNP (0.144 g,1 eq)於DMF (3 mL)中之混合物中。在室溫下攪拌反應混合物隔夜。在反應完成後,在減壓下移除DMF。用乙醚及二氯甲烷洗滌殘餘物,得到0.2 g灰色固體(化合物23),其不經進一步純化。
化合物
24
之合成
將二乙胺(0.082 mL,2.5 eq)添加至化合物23於DMF (3 mL)中之溶液中。在室溫下攪拌反應混合物隔夜。在反應完成後,在減壓下移除DMF。用乙醚及二氯甲烷洗滌殘餘物,得到0.14 g黑色固體(化合物24),其不經進一步純化。
1H NMR (600 MHz, DMSO) δ 10.18 (s, 1H), 8.45 (s, 1H), 8.08 (d,
J= 9.0 Hz, 1H), 7.96 (s, 1H), 7.79 (d,
J= 10.8 Hz, 1H), 7.61 (d,
J= 8.4 Hz, 2H), 7.38 (d,
J= 8.4 Hz, 2H), 7.32 (s, 1H), 6.55 (s, 1H), 6.03 (t,
J= 5.6 Hz, 1H), 5.46 (s, 2H), 5.45 (s, 2H), 5.34 - 5.22 (m, 3H), 5.14 - 5.04 (m, 2H), 4.54 - 4.45 (m, 1H), 4.13 (dt,
J= 6.9, 6.2 Hz, 1H), 3.28 - 3.21 (m, 1H), 3.19 - 3.15 (m, 1H), 3.15 - 3.07 (m, 1H), 3.06 - 3.00 (m, 1H), 2.98 - 2.93 (m, 1H), 2.39 - 2.35 (m, 3H), 2.25 - 2.18 (m, 1H), 2.18 - 2.11 (m, 1H), 2.04 - 1.98 (m, 1H), 1.93 - 1.83 (m, 2H), 1.74 - 1.67 (m, 1H), 1.64 - 1.56 (m, 1H), 1.50 - 1.42 (m, 1H), 1.42 - 1.34 (m, 1H), 0.96 - 0.91 (m, 3H), 0.91 - 0.85 (m, 6H)。LC-MS (ESI): m/z [C
43H
49FN
8O
9]計算值841.36 [M +1]
+,實驗值841.34 [M +1]
+。
化合物
25
之合成
將DIPEA (13.7 uL,3 eq)添加至化合物3 (13 mg,1 eq)、化合物24 (33 mg,1.5 eq)及HATU (30 mg,3 eq)於DCM:DMF 2:1 (3 mL)中之混合物中。在室溫下攪拌混合物2小時。在反應完成後,反應混合物用DCM及水萃取。隨後,有機層用鹽水洗滌且經MgSO
4乾燥。在減壓下移除有機溶劑。藉由管柱層析用甲醇/二氯甲烷純化殘餘物,得到淡黃色固體化合物25 (66.7%產率)。
1H NMR (600 MHz, DMSO) δ 10.00 (s, 1H), 8.69 (s, 1H), 8.47 (d,
J= 8.9 Hz, 1H), 8.14 (d,
J= 7.7 Hz, 1H), 8.07 (t,
J= 9.0 Hz, 1H), 7.88 (d,
J= 8.8 Hz, 1H), 7.82 - 7.74 (m, 2H), 7.68 (dd,
J= 7.6, 1.0 Hz, 1H), 7.64 - 7.60 (m, 2H), 7.52 - 7.43 (m, 3H), 7.37 (d,
J= 8.5 Hz, 2H), 7.35 - 7.27 (m, 2H), 6.54 (s, 1H), 5.99 (t,
J= 7.1 Hz, 1H), 5.45 (s, 1H), 5.43 (s, 2H), 5.32 - 5.27 (m, 2H), 5.10 - 5.06 (m, 1H), 5.02 (d,
J= 14.1 Hz, 1H), 4.38 (dd,
J= 13.0, 7.7 Hz, 1H), 4.26 - 4.20 (m, 1H), 3.64 - 3.56 (m, 3H), 3.51 - 3.41 (m, 7H), 3.31 - 3.19 (m, 4H), 3.18 - 2.91 (m, 6H), 2.62 (dt,
J= 3.6, 1.8 Hz, 1H), 2.61 - 2.54 (m, 1H), 2.40 - 2.33 (m, 4H), 2.27 - 2.11 (m, 3H), 2.03 - 1.92 (m, 2H), 1.91 - 1.81 (m, 2H), 1.80 - 1.65 (m, 3H), 1.63 - 1.59 (m, 1H), 1.59 - 1.54 (m, 1H), 1.52 - 1.40 (m, 2H), 1.38 - 1.32 (m, 1H), 0.91 - 0.79 (m, 9H)。LC-MS(ESI): m/z [C
71H
79FN
10O
15]計算值1331.57 [M +1]
+,實驗值1331.72 [M +1]
+。
化合物
27
之合成
將市售Boc-GGFG-OH (化合物26) (415 mg,1 eq)添加至EDCI (273 mg,1.5 eq)及HOSu (164 mg,1.5 eq)於二氯甲烷(18 mL)中之混合物中。在室溫下攪拌混合物3.5小時。將反應混合物逐滴添加至依昔替康甲磺酸鹽(343 mg,0.83 eq)及三乙胺(0.2 mL,1.5 eq)之混合DMF溶液中。在室溫下攪拌反應混合物隔夜。在反應完成後,在減壓下移除有機溶劑。藉由管柱層析用甲醇/二氯甲烷純化殘餘物,得到淡黃色固體化合物27 (507 mg,63%產率)。LC-MS(ESI): m/z [C
44H
48FN
7O
10]計算值853.91 [M +1]
+,實驗值854.35 [M +1]
+。875.91[M + Na]
+,實驗值875.52[M + Na]
+。
化合物
28
之合成
將三氟乙酸(4 mL)添加至化合物27 (507 mg,1 eq)於二氯甲烷(4 mL)中之溶液中。在室溫下攪拌混合物3小時。在反應完成後,在減壓下移除有機溶劑。用二氯甲烷洗滌殘餘物,得到黃色固體化合物28 (378 mg,85%產率)。LC-MS(ESI): m/z [C
39H
40FN
7O
8]計算值753.79 [M +1]
+,實驗值754.18 [M +1]
+。
化合物
29
之合成
將DIPEA (0.18 mL, 20 eq)添加至化合物28 (40 mg,1 eq)於DMF (1 mL)中之溶液中。在冰浴下攪拌反應混合物15分鐘。將反應混合物逐滴添加至化合物3 (48 mg,1.2 eq)及HBTU (30 mg,1.5 eq)之混合DMF溶液(1 mL)中。在室溫下攪拌混合物2小時。在反應完成後,在減壓下移除有機溶劑。藉由管柱層析用甲醇/二氯甲烷純化殘餘物,得到淺黃色固體化合物29 (44 mg,67%產率)。LC-MS(ESI): m/z [C
67H
70FN
9O
14]計算值1244.34 [M +1]
+,實驗值1244.56 [M +1]
+。1266.34[M + Na]
+,實驗值1266.83[M + Na]
+。
化合物
30
之合成
將DIPEA (0.7 mL,2 eq)添加至化合物2及NH
2-PEG12-COOH (1217 mg,1.0 eq)於二氯甲烷/DMF (8 mL/8 mL)中之混合物中。在室溫下攪拌反應混合物隔夜。在反應完成後,在減壓下移除有機溶劑。藉由管柱層析用甲醇/二氯甲烷純化殘餘物,得到黏性液體DBCO-PEG12-GGFG-依昔替康(化合物31) (401 mg,23%產率)。LC-MS(ESI): m/z[C
46H
68N
2O
16]計算值905.05 [M]
+,實驗值905.53 [M]
+。
化合物
31
之合成
將DIPEA (0.14 mL,20 eq)添加至化合物28 (30 mg,1 eq)於DMF (1 mL)中之混合物中。在冰浴下攪拌反應混合物15分鐘。將反應混合物逐滴添加至化合物30 (43 mg,1.2 eq)及HBTU (23 mg,1.5 eq)於DMF中之混合溶液(1 mL)中。在室溫下攪拌反應混合物2小時。在反應完成後,在減壓下移除有機溶劑。藉由管柱層析用甲醇/二氯甲烷純化殘餘物,得到黃色固體化合物31 (17 mg,26%產率)。LC-MS(ESI): m/z [C
85H
106FN
9O
23]計算值1640.82 [M +1]
+,實驗值1641.07 [M +1]
+。
化合物
32
之合成
將HOSu (170 mg,1.5 eq)添加至N-(三級丁氧基羰基)-4-胺基丁酸(200 mg,1.0 eq)及EDCI (283 mg,1.5 eq)於DCM (5 mL)中之混合物中。在室溫下在N
2氛圍下攪拌反應混合物2小時。在反應完成後,反應混合物用二氯甲烷及水萃取。有機層用鹽水洗滌且經MgSO
4乾燥。在減壓下移除有機溶劑。將殘餘物添加至依昔替康甲磺酸鹽(434 mg,0.83 eq)及Et
3N (0.21 mL,1.5 eq)於DMF (5 mL)中之混合溶液中。在室溫下攪拌反應混合物12小時。在減壓下移除有機溶劑。藉由管柱層析純化殘餘物,得到黃色固體化合物32 (402 mg,79%產率)。LC-MS (ESI): m/z C
33H
37FN
4O
7[M + H]
+計算值:621.26,實驗值:621.01。
化合物
33
之合成
將化合物32添加至DCM/TFA = 1/1 (9.5 mL/9.5 mL)之混合溶液中。在室溫下在N
2氛圍下攪拌反應混合物2小時。在反應完成後,在減壓下移除有機溶劑。藉由管柱層析(DCM/MeOH)純化殘餘物,得到黃色固體化合物33 (23 mg,69%產率)。LC-MS (ESI): m/z C
28H
29FN
4O
5[M + H]
+計算值:521.21,實驗值:521.09。
1H NMR (600 MHz, DMSO) δ 8.53 (d,
J= 8.7 Hz, 1H), 7.82 (d,
J= 10.8 Hz, 1H), 7.32 (s, 3H), 6.56 (s, 1H), 5.65 - 5.53 (m, 1H), 5.43 (s, 2H), 5.25 (d,
J= 18.7 Hz, 1H), 5.15 (d,
J= 18.7 Hz, 1H), 3.17 (t,
J= 6.0 Hz, 2H), 2.81 (t,
J= 7.6 Hz, 2H), 2.42 - 2.37 (m, 3H), 2.26 (t,
J= 7.1 Hz, 2H), 2.14 (d,
J= 5.3 Hz, 2H), 1.99 - 1.70 (m, 4H), 0.87 (t,
J= 7.3 Hz, 3H)。
化合物
34
之合成
將化合物26 (252 mg,1.3 eq)添加至EDCI (104 mg,1.5 eq)及HOSu (77 mg,1.5 eq)於DCM (9 mL)中之混合物中。在室溫下在N
2氛圍下攪拌反應混合物2小時。在反應完成後,反應混合物用二氯甲烷及水萃取。有機層用鹽水洗滌且經MgSO
4乾燥。在減壓下移除有機溶劑。將殘餘物添加至化合物33 (231 mg,1.0 eq)及Et
3N (0.1 mL,1.5 eq)之混合溶液中。在室溫下在N
2氛圍下攪拌反應混合物12小時。在反應完成後,在減壓下移除有機溶劑。藉由管柱層析(DCM/MeOH)純化殘餘物,得到黃色固體化合物34 (153 mg,28%產率)。LC-MS (ESI): m/z C
48H
55FN
8O
11[M + H]
+計算值:939.4,實驗值:939.68。
化合物
35
之合成
將化合物34添加至DCM/TFA = 1/1 (3 mL/3 mL)之混合溶液中。在室溫下在N
2氛圍下攪拌反應混合物2小時。在反應完成後,在減壓下移除有機溶劑。藉由管柱層析(DCM/MeOH)純化殘餘物,得到黃色固體化合物35 (90 mg,65%產率)。LC-MS (ESI): m/z C
43H
47FN
8O
9[M + H]
+計算值:839.35,實驗值:839.22。
將化合物35 (20 mg,1 eq)添加至化合物3 (13.3 mg,1.1 eq)、DIPEA (0.083 mL,20 eq)及HBTU (13.6 mg,1.5 eq)於DMF (2 mL)中之混合物中。在室溫下在N
2氛圍下攪拌反應混合物1.5小時。在反應完成後,在減壓下移除有機溶劑。藉由管柱層析(DCM/MeOH)純化殘餘物,得到黃色固體化合物36 (18 mg,58%產率)。LC-MS (ESI): m/z C
71H
77FN
10O
15[M + H]
+計算值:1329.43,實驗值:1329.69。
將化合物35 (20 mg,1 eq)添加至化合物30 (19 mg,0.9 eq)、DIPEA (0.083 mL,20 eq)及HBTU (13.6 mg,1.5 eq)於DMF (2 mL)中之混合物中。在室溫下在N
2氛圍下攪拌反應混合物1.5小時。在反應完成後,在減壓下移除有機溶劑。藉由管柱層析(DCM/MeOH)純化殘餘物,得到黃色固體化合物37 (6.4 mg,17%產率)。LC-MS (ESI): m/z C
89H
113FN
10O
24[M + H]
+計算值:1726.9,實驗值:1726.6。
化合物
39
之合成
將DIPEA (0.5 mL,3 eq)添加至市售化合物38 (300 mg,1 eq)及NH
2-PEG3-COOH (273 mg,1.3 eq)於二氯甲烷/DMF (3 mL/3 mL)中之混合物中。在室溫下攪拌反應混合物18小時。在反應完成後,在減壓下移除有機溶劑。藉由管柱層析(DCM/MeOH)純化殘餘物,得到黏性液體化合物39 (235 mg,62%產率)。LC-MS(ESI): m/z [C
20H
31NO
7]計算值397.47 [M +1]
+,實驗值397.39 [M +1]
+。420.47[M + Na]
+,實驗值420.07[M + Na]
+。
化合物
40
之合成
將DIPEA (69 ul,4 eq)添加至化合物39 (41 mg,1 eq)、化合物4 (135 mg,1.2 eq)及HATU (57 mg,1.5 eq)於DMF (3 mL)中之混合物中。在室溫下攪拌反應混合物18小時。在反應完成後,在減壓下移除有機溶劑。藉由管柱層析(DCM/MeOH)純化殘餘物,得到黃色固體化合物40 (41 mg,27%產率)。LC-MS(ESI): m/z [C
78H
123N
11O
18]計算值1502.90 [M +1]
+,實驗值1503.13 [M +1]
+。1524.90[M + Na]
+,實驗值1525.43[M + Na]
+。
化合物
41
之合成
將DIPEA (0.5 mL,3 eq)添加至市售化合物38 (300 mg,1 eq)及NH
2-PEG12-COOH (587 mg,1.0 eq)於二氯甲烷/DMF (4 mL/4 mL)中之混合物中。在室溫下攪拌反應混合物18小時。在反應完成後,在減壓下移除有機溶劑。藉由管柱層析(DCM/MeOH)純化殘餘物,得到黏性液體化合物41 (598 mg,79%產率)。LC-MS(ESI): m/z [C
38H
67NO
16]計算值793.95 [M +1]
+,實驗值794.25 [M +1]
+。
BCN-PEG12-GGFG-
依昔替康
(
化合物
42)
之合成
將DIPEA (0.14 mL,20 eq)添加至化合物28 (30 mg,1 eq)、化合物41 (38 mg,1.2 eq)及HBTU (23 mg,1.5 eq)於DMF (2 mL)中之混合物中。在室溫下攪拌反應混合物2小時。在反應完成後,在減壓下移除有機溶劑。藉由管柱層析(DCM/MeOH)純化殘餘物,得到黃色固體化合物42 (10.9 mg,18%產率)。LC-MS(ESI): m/z [C
77H
105FN
8O
23]計算值1529.72 [M +1]
+,實驗值1530.9 [M +1]
+。
將DIPEA (0.14 mL,20 eq)添加至化合物28 (30 mg,1 eq)、化合物39 (19 mg,1.2 eq)及HBTU (23 mg,1.5 eq)於DMF (2 mL)中之混合物中。在室溫下攪拌反應混合物2小時。在反應完成後,在減壓下移除有機溶劑。藉由管柱層析(DCM/MeOH)純化殘餘物,得到黃色固體化合物43 (7.4 mg,16%產率)。LC-MS(ESI): m/z [C
59H
69FN
8O
14]計算值1133.24 [M +1]
+,實驗值1133.63 [M +1]
+。
將DIPEA (0.14 mL,20 eq)添加至化合物35 (34 mg,1 eq)、化合物39 (29 mg,0.9 eq)及HBTU (23 mg,1.5 eq)於DMF (2 mL)中之混合物中。在室溫下攪拌反應混合物1.5小時。在反應完成後,在減壓下移除有機溶劑。藉由管柱層析(DCM/MeOH)純化殘餘物,得到黃色固體化合物44 (19 mg,32%產率)。LC-MS (ESI): m/z C
81H
112FN
9O
24[M + H]
+計算值:1615.8,實驗值:1615.42。
化合物
45
之合成
將化合物3 (490 mg,1 eq)添加至EDC (552 mg,3 eq)及HOSu (333 mg,3 eq)於無水二氯甲烷/無水DMF (2.4 mL/2.4 mL)中之混合物中。在室溫下在N
2氛圍下攪拌反應混合物18小時。在反應完成後,反應混合物用二氯甲烷及水萃取。隨後,有機層用鹽水洗滌且經MgSO
4乾燥。在減壓下移除有機溶劑,得到黏性液體化合物45 (856 mg),其不經進一步純化。
化合物
47
之合成
將DIPEA (621.7 mg,5 eq)添加至化合物46 (856 mg)及NH-雙(PEG3-CO
2H) (574 mg,1.4 eq)於二氯甲烷/DMF (4.8 mL/4.8 mL)中之混合物中。在室溫下攪拌反應混合物隔夜。在反應完成後,在減壓下移除有機溶劑。藉由管柱層析(DCM/MeOH)純化殘餘物,得到黏性液體化合物47 (485 mg,54%產率)。LC-MS(ESI): m/z [C
46H
65N
3O
16]計算值916.03 [M]
+,實驗值916.3 [M]
+。1H NMR (600 MHz, DMSO) δ 12.17 (s, 2H), 7.77 (t, J = 5.6 Hz, 1H), 7.68 (dd, J = 7.7, 1.3 Hz, 1H), 7.62 (d, J = 7.3 Hz, 1H), 7.48 (m, 3H), 7.36 (m, 2H), 7.30 (dd, J = 7.4, 1.4 Hz, 1H), 5.02 (d, J = 14.1 Hz, 1H), 3.61 - 3.56 (m, 8H), 3.54 - 3.32 (m, 39H), 3.31 - 3.26 (m, 2H), 3.16 (d, J = 4.9 Hz, 1H), 3.13 - 3.03 (m, 3H), 2.63 - 2.54 (m, 4H), 2.43 (td, J = 6.3, 2.7 Hz, 4H), 2.23 (dt, J = 15.5, 7.7 Hz, 1H), 1.99 (m, 1H), 1.75 (m, 1H), 1.24 (d, J = 5.9 Hz, 9H)。
DBCO-PEG3-2(PEG3-VC-PAB-MMAE) (
化合物
48)
之合成
將DIPEA (22 mg,3.2 eq)添加至化合物47 (49 mg,1 eq)、化合物4 (72 mg,1.2 eq)及HBTU (51 mg,2.5 eq)於DMF (0.43 mL)中之混合物中。在室溫下攪拌反應混合物24小時。在反應完成後,在減壓下移除有機溶劑。藉由管柱層析(DCM/MeOH)純化殘餘物,得到黏性液體化合物48 (41 mg)。LC-MS (TOF): m/z [C
162H
249N
23O
38]計算值3126.9 [M]
+,實驗值1042.95 [M]
3+, 1563.92 [M]
2+
實例
18 DCBPR2002-4(DBCO-vc-MMAE)
之
製備
(
圖
21C)
MES pH6.5緩衝液之製備:將4.881 g MES游離酸(2-嗎啉基乙磺酸,CAS 4432-31-9)懸浮於750 mL dH2O中。藉由10 N NaOH(aq)將pH值調整至6.5。隨後,將蒸餾水添加至懸浮液中直至體積達到1 L。
將5.78 mL DBCO-vc-MMAE (10 mM於DMSO中)緩慢添加至DCBPR2002-4Az (34 mL,2.5 mg/mL)於緩衝液(MES pH 6.5)中之溶液中。在氬氣下在37℃下攪拌反應混合物18小時。藉由在檸檬酸鈉pH6.5緩衝液中使用具有30 kDa NMWL之Amicon Ultra-15離心過濾裝置對抗體製劑進行脫鹽及濃縮,得到DCBPR2002-4(DBCO-vc-MMAE)。藉由LC-MS量測ADC之藥物與抗體比(DAR):3.89。
實例
19 DCBPR2002-4(DBCO-S-DM1)
之
製備
(
圖
21D)
將4.48 mL DBCO-S-DM1 (10 mM於DMA中)緩慢添加至DCBPR2002-4Az (11.2 mL,2.5 mg/mL)於緩衝液(MES pH 6.5)中之溶液中。在氬氣下在37℃下攪拌反應混合物6小時。藉由在檸檬酸鈉pH6.5緩衝液中使用具有30 kDa NMWL之Amicon Ultra-15離心過濾裝置對抗體製劑進行脫鹽及濃縮,得到DCBPR2002-4(DBCO-S-DM1)。藉由LC-MS量測ADC之藥物與抗體比(DAR):~4。
實例
20 DCBPR2002-4(DBCO-vc-seco DUBA)
之
製備
(
圖
21E)
將0.4 mL DBCO-vc-seco DUBA (10 mM於DMA中)及1.2 mL DMA緩慢添加至DCBPR2002-4Az (4 mL,5 mg/mL)於緩衝液(MES pH 6.5)中之溶液中。在氬氣下在37℃下攪拌反應混合物20小時。藉由在檸檬酸鈉pH6.5緩衝液中使用具有30 kDa NMWL之Amicon Ultra-15離心過濾裝置對抗體製劑進行脫鹽及濃縮,得到DCBPR2002-4(DBCO-vc-seco DUBA)。藉由LC-MS量測ADC之藥物與抗體比(DAR):~4。
實例
21 DCBPR2002-4(DBCO-PEG4-vc-PAB-MMAF)
之
製備
(
圖
21F)
DBCO-PEG4-VC-PAB-MMAF為市售連接子-有效負載。
將0.4 mL DBCO-PEG4-VC-PAB-MMAF (10 mM於DMSO中)及0.4 mL DMSO緩慢添加至DCBPR2002-4Az (4 mL,5 mg/mL)於緩衝液(MES pH 6.5)中之溶液中。在氬氣下在37℃下攪拌反應混合物18小時。藉由在檸檬酸鈉pH6.5緩衝液中使用具有30 kDa NMWL之Amicon Ultra-15離心過濾裝置對抗體製劑進行脫鹽及濃縮,得到DCBPR2002-4(DBCO-PEG4-vc-PAB-MMAF)。藉由LC-MS量測ADC之藥物與抗體比(DAR):~4。
實例
22
DCBPR2002-4(DBCO-DTPA)
之
製備
(
圖
21G)
將0.24 mL DBCO-DTPA (10 mM於ddH
2O中)緩慢添加至DCBPR2002-4Az (2.4 mL,5 mg/mL)於緩衝液(MES pH 6.5)中之溶液中。在氬氣下在37℃下攪拌反應混合物18小時。藉由在檸檬酸鈉pH6.5緩衝液中使用具有30 kDa NMWL之Amicon Ultra-15離心過濾裝置對抗體製劑進行脫鹽及濃縮,得到DCBPR2002-4(DBCO-DTPA)。藉由LC-MS量測ADC之藥物與抗體比(DAR):~4。
實例
23 DCBPR2002-4(DBCO-PEG3-vc-
依昔替康
)
之
製備
(
圖
21H)
將0.04 mL DBCO-PEG3-VC-依昔替康(10 mM於DMA中)及0.12 mL DMA緩慢添加至DCBPR2002-4Az (0.4 mL,5 mg/mL)於緩衝液(MES pH 6.5)中之溶液中。在氬氣下在37℃下攪拌反應混合物18小時。藉由在MES pH6.5緩衝液中使用具有30 kDa NMWL之Amicon Ultra-15離心過濾裝置對抗體製劑進行脫鹽及濃縮,得到DCBPR2002-4(DBCO-PEG3-VC-依昔替康)。藉由LC-MS量測ADC之藥物與抗體比(DAR):3.77。
實例
24 DCBPR2002-4(DBCO-PEG3-GGFG-
依昔替康
)
之
製備
(
圖
21I)
將0.02 mL DBCO-PEG3-GGFG-依昔替康(10 mM於DMA中)及0.06 mL DMA緩慢添加至DCBPR2002-4Az (0.2 mL,5 mg/mL)於緩衝液(MES pH 6.5)中之溶液中。在氬氣下在37℃下攪拌反應混合物18小時。藉由在MES pH6.5緩衝液中使用具有30 kDa NMWL之Amicon Ultra-15離心過濾裝置對抗體製劑進行脫鹽及濃縮,得到DCBPR2002-4(DBCO-PEG3-GGFG-依昔替康)。藉由LC-MS量測ADC之藥物與抗體比(DAR):3.21。
實例
25 DCBPR2002-4(DBCO-PEG12-GGFG-
依昔替康
)
之
製備
(
圖
21J)
將0.02 mL DBCO-PEG12-GGFG-依昔替康(10 mM於DMA中)及0.02 mL DMA緩慢添加至DCBPR2002-4Az (0.1 mL,10 mg/mL)於緩衝液(MES pH 6.5)中之溶液中。在氬氣下在37℃下攪拌反應混合物18小時。藉由在MES pH6.5緩衝液中使用具有30 kDa NMWL之Amicon Ultra-15離心過濾裝置對抗體製劑進行脫鹽及濃縮,得到DCBPR2002-4(DBCO-PEG12-GGFG-依昔替康)。藉由LC-MS量測ADC之藥物與抗體比(DAR):3.91。
實例
26 DCBPR2002-4(DBCO-PEG3-GGFG-DXd2)
之
製備
(
圖
21K)
將0.02 mL DBCO-PEG3-GGFG-DXd2 (10 mM於DMA中)及0.06 mL DMA緩慢添加至DCBPR2002-4Az (0.213 mL,4.7 mg/mL)於緩衝液(MES pH 6.5)中之溶液中。在氬氣下在37℃下攪拌反應混合物18小時。藉由在MES pH6.5緩衝液中使用具有30 kDa NMWL之Amicon Ultra-15離心過濾裝置對抗體製劑進行脫鹽及濃縮,得到DCBPR2002-4(DBCO-分支鏈PEG3-GGFG-依昔替康)。藉由LC-MS量測ADC之藥物與抗體比(DAR):3.12。
實例
27 DCBPR2002-4(DBCO-PEG12-GGFG-DXd2)
之
製備
(
圖
21L)
將0.02 mL DBCO-PEG12-GGFG-DXd2 (10 mM於DMA中)及0.06 mL DMA緩慢添加至DCBPR2002-4Az (0.213 mL,4.7 mg/mL)於緩衝液(MES pH 6.5)中之溶液中。在氬氣下在37℃下攪拌反應混合物18小時。藉由在MES pH6.5緩衝液中使用具有30 kDa NMWL之Amicon Ultra-15離心過濾裝置對抗體製劑進行脫鹽及濃縮,得到DCBPR2002-4(DBCO-PEG12-GGFG-DX8951)。藉由LC-MS量測ADC之藥物與抗體比(DAR):3.52。
實例
28 DCBPR2002-4(BCN-PEG3-VC-PAB-MMAE)
之
製備
(
圖
21M)
將0.0067 mL BCN-PEG3-VC-PAB-MMAE (10 mM於DMSO中)及0.0333 mL DMSO緩慢添加至DCBPR2002-4Az (0.2 mL,5 mg/mL)於緩衝液(MES pH 6.5)中之溶液中。在氬氣下在37℃下攪拌反應混合物18小時。藉由在MES pH6.5緩衝液中使用具有30 kDa NMWL之Amicon Ultra-15離心過濾裝置對抗體製劑進行脫鹽及濃縮,得到DCBPR2002-4(BCN-PEG3-VC-PAB-MMAE)。藉由LC-MS量測ADC之藥物與抗體比(DAR):2.67。
實例
29 DCBPR2002-4(BCN-PEG12-GGFG-
依昔替康
)
之
製備
(
圖
21N)
將0.02 mL BCN-PEG12-GGFG-依昔替康(10 mM於DMA中)及0.01 mL DMA緩慢添加至DCBPR2002-4Az (0.05 mL,10 mg/mL)於緩衝液(MES pH 6.5)中之溶液中。在氬氣下在37℃下攪拌反應混合物42小時。藉由在MES pH6.5緩衝液中使用具有30 kDa NMWL之Amicon Ultra-15離心過濾裝置對抗體製劑進行脫鹽及濃縮,得到DCBPR2002-4(BCN-PEG12-GGFG-依昔替康)。藉由LC-MS量測ADC之藥物與抗體比(DAR):3.51。
實例
30 DCBPR2002-4(BCN-PEG3-GGFG-
依昔替康
)
之
製備
(
圖
21O)
將0.01 mL BCN-PEG3-GGFG-依昔替康(10 mM於DMA中)及0.01 mL DMA緩慢添加至DCBPR2002-4Az (0.05 mL,10 mg/mL)於緩衝液(MES pH 6.5)中之溶液中。在氬氣下在37℃下攪拌反應混合物18小時。藉由在MES pH6.5緩衝液中使用具有30 kDa NMWL之Amicon Ultra-15離心過濾裝置對抗體製劑進行脫鹽及濃縮,得到DCBPR2002-4(BCN-PEG3-GGFG-依昔替康)。藉由LC-MS量測ADC之藥物與抗體比(DAR):3.73。
實例
31 DCBPR2002-4(BCN-PEG12-GGFG-DXd2)
之
製備
(
圖
21P)
將0.02 mL BCN-PEG12-GGFG-DXd2 (10 mM於DMA中)及0.06 mL DMA緩慢添加至DCBPR2002-4Az (0.08 mL,10 mg/mL)於緩衝液(MES pH 6.5)中之溶液中。在氬氣下在37℃下攪拌反應混合物18小時。藉由在MES pH6.5緩衝液中使用具有30 kDa NMWL之Amicon Ultra-15離心過濾裝置對抗體製劑進行脫鹽及濃縮,得到DCBPR2002-4(DBCO-PEG12-GGFG-DXd2)。藉由LC-MS量測ADC之藥物與抗體比(DAR):3.51。
實例
32 DCBPR2002-4(DBCO-PEG3-2(PEG3-VC-PAB-MMAE))
之
製備
(
圖
21Q)
將0.02 mL DBCO-分支鏈-PEG-VC-MMAE-B (10 mM於DMA中)及0.113 mL DMA緩慢添加至DCBPR2002-4Az (0.333 mL,3 mg/mL)於緩衝液(MES pH 6.5)中之溶液中。在氬氣下在37℃下攪拌反應混合物18小時。藉由在MES pH6.5緩衝液中使用具有30 kDa NMWL之Amicon Ultra-15離心過濾裝置對抗體製劑進行脫鹽及濃縮,得到DCBPR2002-4(DBCO-PEG3-2(PEG3-VC-PAB-MMAE))。藉由LC-MS量測ADC之藥物與抗體比(DAR):5.68。
實例
33 DCBPR2002-2(DBCO-vc-MMAE)-2(DBCO-vc-seco DUBA)
之
製備
(
圖
21R)
DCBPR2002-2(DBCO-vc-MMAE)
之
合成
將2.04 mL DBCO-vc-MMAE (10 mM於DMSO中)緩慢添加至DCBPR2002-2Az (12 mL,5 mg/mL)於緩衝液(MES pH 6.5)中之溶液中。在氬氣下在37℃下攪拌反應混合物20小時。藉由在檸檬酸鈉pH6.5緩衝液中使用具有30 kDa NMWL之Amicon Ultra-15離心過濾裝置對抗體製劑進行脫鹽及濃縮,得到DCBPR2002-三甘露糖基-2(DBCO-vc-MMAE)。藉由LC-MS量測ADC之藥物與抗體比(DAR):~2。
DCBPR2002-2(
連接子
-
有效負載
)-2Az
之
通用合成
將5 mg DCBPR2002-2(連接子-有效負載)及UDP-GlcNAz (2.5 mg)在1000 μl 1X緩衝液SP (25 mM MES,10 mM MnCl
2,pH 6.5)中在大鼠MGAT-2 (0.05 mg)存在下在37℃下培育16小時。在反應後,經由Amicon Ultra-15離心過濾裝置純化抗體產物,以獲得DCBPR2002-2(連接子-有效負載),其中2個活性GlcNAz附接至重鏈中之其餘末端甘露糖。對產物進行折合質量層析分析。
DCBPR2002-2(DBCO-vc-MMAE)-2(DBCO-vc-seco DUBA)
之
合成
將4.08 mL DBCO-vc-seco DUBA (10 mM於DMA中)緩慢添加至DCBPR2002-2(DBCO-vc-MMAE)-2Az (10.2 mL,5 mg/mL)於緩衝液(MES pH 6.5)中之溶液中。在氬氣下在37℃下攪拌反應混合物18小時。藉由在檸檬酸鈉pH6.5緩衝液中使用具有30 kDa NMWL之Amicon Ultra-15離心過濾裝置對抗體製劑進行脫鹽及濃縮,得到DCBPR2002-2(DBCO-vc-MMAE)-2(DBCO-vc-seco DUBA)。藉由LC-MS量測ADC之藥物與抗體比(DAR):~4。
實例
34 DCBPR2002-2(DBCO-vc-MMAE)-2(DBCO-S-DM1)
之
製備
(
圖
21S)
DCBPR2002-2(DBCO-vc-MMAE)-2(DBCO-S-DM1)
之
合成
將2.08 mL DBCO-S-DM1 (10 mM於DMA中)緩慢添加至DCBPR2002-2(DBCO-vc-MMAE)-2Az (5.2 mL,5 mg/mL)於緩衝液(MES pH 6.5)中之溶液中。在氬氣下在37℃下攪拌反應混合物18小時。藉由在檸檬酸鈉pH6.5緩衝液中使用具有30 kDa NMWL之Amicon Ultra-15離心過濾裝置對抗體製劑進行脫鹽及濃縮,得到DCBPR2002-2(DBCO-vc-MMAE)-2(DBCO-S-DM1)。藉由LC-MS量測ADC之藥物與抗體比(DAR):~4。
實例
35 DCBPR2002-2(DBCO-vc-seco DUBA)-2(DBCO-S-DM1)
之
製備
(
圖
21T)
DCBPR2002-2(DBCO-vc-seco DUBA)
之
合成
將7.2 mL DBCO-vc-seco DUBA (10 mM於DMSO中)緩慢添加至DCBPR2002-2Az (18 mL,5 mg/mL)於緩衝液(MES pH 6.5)中之溶液中。在氬氣下在37℃下攪拌反應混合物20小時。藉由在檸檬酸鈉pH6.5緩衝液中使用具有30 kDa NMWL之Amicon Ultra-15離心過濾裝置對抗體製劑進行脫鹽及濃縮,得到DCBPR2002-2(DBCO-vc-seco DUBA)。藉由LC-MS量測ADC之藥物與抗體比(DAR):~2。
DCBPR2002-2(DBCO-vc-seco DUBA)-2(DBCO-S-DM1)
之
合成
將2.4 mL DBCO-S-DM1 (10 mM於DMA中)緩慢添加至DCBPR2002-2(DBCO-vc-seco DUBA)-2Az (6 mL,5 mg/mL)於緩衝液(MES pH 6.5)中之溶液中。在氬氣下在37℃下攪拌反應混合物18小時。藉由在檸檬酸鈉pH6.5緩衝液中使用具有30 kDa NMWL之Amicon Ultra-15離心過濾裝置對抗體製劑進行脫鹽及濃縮,得到DCBPR2002-2(DBCO-vc-seco DUBA)-2(DBCO-S-DM1)。藉由LC-MS量測ADC之藥物與抗體比(DAR):~4。
實例
36 SDS-PAGE
本發明之ADC可用此項技術中已知之技術,諸如SDS-PAGE及HPLC分析。舉例而言,抗MSLN mAb及抗MSLN ADC之溶液可藉由使用4-12%非還原及還原SDS-PAGE凝膠,隨後進行庫馬斯亮藍染色來分析。
實例
37
有效負載偶合分析
藥物與抗體比(DAR)之評估對於監測目標抗體上之有效負載共軛效率至關重要。藥物與抗體比可能會影響抗MSLN ADC產物之治療功效。液相層析-質譜法(LC-MS)為確定離胺酸連接之抗體-藥物共軛物(ADC)之藥物與抗體比(DAR)及藥物負載分佈的首選方法。峰面積百分比表示特定藥物負載ADC物種之相對分佈。隨後藉由使用峰面積百分比資訊及藥物負載數目計算加權平均DAR。
圖7示出本發明之ADC (DCBPR2002-4(DBCO-vc-MMAE))之質量分析的一個實例,其指示附接至抗體之各種數目之藥物的分佈,其中最豐富的物種具有4種藥物附接至抗體。此樣品中之平均藥物與抗體比(DAR)為4.07。
實例
38 ELISA
結合親和力
將100 μL濃度為1 μg/mL之含間皮素之塗佈緩衝液添加且塗佈於培養盤之各孔上。密封培養盤且在4℃下培育隔夜。抽吸孔且用300 μL PBST (0.05% Tween 20)洗滌3次。藉由添加200 μL PBS-5%脫脂奶來阻斷孔且在37℃下培育1小時。抽吸孔且用300微升/孔PBST (0.05% Tween 20)洗滌3次。向各孔中添加100 μL用PBS稀釋之400 ng ADC樣品,且隨後在37℃下培育培養盤1小時。抽吸孔且用300 μL PBST (0.05% Tween 20)洗滌3次。將50 μl抗人類κ輕鏈(1:5000)添加至各孔中,且在37℃下培育培養盤1小時。抽吸孔且用300微升/孔PBST (0.05% Tween 20)洗滌3次。將100 μl TMB添加至各孔中,且在室溫下培育培養盤15分鐘。藉由添加100 μL 1N HCl停止顯色。藉由使用ELISA讀取器在450-650 nm之吸光度下量測培養盤。資料展示於圖5中。
DCBPR2002 Kd=9.243e-011;DCBPR2002-4(DBCO-vc-MMAE) Kd= 1.329e-010;DCBPR2002-4(DBCO-s-DM1) Kd=1.449 e-010;DCBPR2002-4(DBCO-vc-seco-DUBA) Kd=9.747e-011;DCBPR2002-2(DBCO-vc-MMAE)-2(DBCO-s-DM1) Kd=1.355 e-010;DCBPR2002-2(DBCO-vc-MMAE)-2(DBCO-vc-seco-DUBA) Kd=1.580 e-010;及DCBPR2002-2(DBCO-vc-seco-DUBA)-2(DBCO-s-DM1) Kd=7.315 e-011。
實例
39
抗間皮素
ADC
之結合動力學
藉由表面電漿共振(Biacore® T100, Biacore, Inc., Piscataway, NJ)來確定抗間皮素ADC與間皮素相互作用之動力學常數。CM5晶片之流動槽用含約10,000個反應單位(RU)之抗人類IgG-Fc (Biacore®)之10 mM甘胺酸pH 5.0以10 μL/min固定600秒。以10 μL/min在CM5晶片上捕捉稀釋於TBS中之10 μg/mL抗間皮素抗體及抗間皮素ADC。在含有1 mM CaCl
2之PBS中記錄四種濃度(3.7至100 nM)之人類間皮素重組蛋白及零濃度(流動緩衝液)之100 μL/min結合3分鐘。量測複合物之解離10分鐘。藉由以10 μl/min注射3 M MgCl
2及3 mM EGTA 60秒來再生水表面。使用Biacore® T100評估軟體(Biacore®)將減去參照物及緩衝液信號後獲得之曲線納入1:1朗格繆爾結合模型中。Ka、Kd及KD展示於表4中。動力學分析顯示抗間皮素抗體與抗間皮素ADC具有類似ka(on)及kd(off)速率。
表4
分析物 | MSLN | ||||
抗體 | K a | K d | K D | Rmax(RU) | Chi 2(RU 2) |
DCBPR2002 | 5.091E+6 | 8.593E-5 | 1.688E-11 | 58.1 | 4.08 |
DCBPR2002-4(DBCO-vc-MMAE) | 5.395E+6 | 1.17E-4 | 2.168E-11 | 55.99 | 3.29 |
DCBPR2002-2(DBCO-vc-MMAE)-2(DBCO-vc-seco-DUBA) | 4.752E+6 | 1.218E-4 | 2.563E-11 | 50.98 | 2.40 |
實例
40
活體外細胞毒性研究
(KLM-1
及
OVCAR-3)
胰臟癌細胞株KUNK-1分別在補充有10%胎牛血清之RPMI 1640 Medium (ATCC改良)培養基中生長。卵巢癌細胞株OVCAR-3在補充有20%胎牛血清之RPMI 1640 Medium (ATCC改良)培養基中生長。KLM-1及OVCAR-3細胞株維持在37℃加濕培育箱之5% CO
2氛圍中。在處理前一天,收集細胞且接種於96孔盤中(每孔4,000個細胞)。在第二天,用3倍連續稀釋濃度之有毒有效負載及ADC處理細胞。各處理以八個一式三份資料點進行。在處理72小時後,根據製造商說明書藉由CellTiter-Glo
®套組(Promega)評定細胞活力。在培育結束時,使用SpectraMax i3x多模式偵測平台(Molecular Devices)來量測發光。與用0.05% PBS (ADC)或0.05% DMSO (有毒有效負載)處理之細胞相比,評估化合物細胞毒性。藉由使用GraphPad prism 5.0軟體以四參數對數方程式擬合活力資料來計算IC
50值。結果展示於表5中。
表5:有毒有效負載及ADC之IC
50值
相對IC 50(有毒有效負載/ADC之nM) | Cell Titer-Glo發光細胞活力分析 | |
MSLN+ | ||
KLM-1 | OVCAR-3 | |
DM1 | 2.1 | 1.6 |
MMAE | 0.3 | 0.3 |
seco-DUBA | 0.04 | 0.02 |
依昔替康 | 20.1 | |
DXd | >100 | |
DXd2 | >1000 | |
DCBPR2002-4(DBCO-vc-MMAE) | 101.3 | 1.0 |
DCBPR2002-4(DBCO-vc-seco-DUBA) | 19.4 | 23.9 |
DCBPR2002-4(DBCO-s-DM1) | 13.9 | 2.6 |
DCBPR2002-4(DBCO-PEG4-vc-PAB-MMAF) | 1.2 | |
DCBPR2002-4(DBCO-PEG3-vc-依昔替康) | 143 | |
DCBPR2002-4(DBCO-PEG3-GGFG-依昔替康) | 130.2 | |
DCBPR2002-4(DBCO-PEG12-GGFG-依昔替康) | >100 | |
DCBPR2002-4(DBCO-PEG3-GGFG-DXd2) | 19.7 | |
DCBPR2002-4(DBCO-PEG12-GGFG-DXd2) | 21.1 | |
DCBPR2002-4(BCN-PEG12-GGFG-依昔替康) | 15.6 | |
DCBPR2002-4(BCN-PEG3-GGFG-依昔替康) | >96.7 | |
DCBPR2002-4(BCN-PEG12-GGFG-DXd2) | >86.7 | |
DCBPR2002-2(DBCO-vc-MMAE)-2(DBCO-vc-seco-DUBA) | 46.0 | 43.3 |
DCBPR2002-2(DBCO-vc-seco-DUBA)-2(DBCO-s-DM1) | 27.0 | 36.3 |
DCBPR2002-2(DBCO-vc-MMAE)-2(DBCO-s-DM1) | 15.4 | 4.6 |
實例
41
內化分析
KLM-1或OVCAR3經胰蛋白酶處理,且隨後收穫並再懸浮於FAC緩衝液中。對照:將二級Ab抗人類IgG PE (1:200)添加至KLM-1或OVCAR3細胞中。細胞在4℃下培育0、0.5、2、5及24小時之時段,且隨後用1 mL FACS緩衝液洗滌。棄去上清液。測試組:將KLM-1或OVCAR3細胞與10 μg/mL含三甘露糖基抗間皮素ADC之FACS緩衝液一起在冰上預培育60分鐘,用FACS緩衝液洗滌三次,且隨後在37℃下培育0、0.5、2、5及24小時之時段。藉由流動式細胞測量術(BD LSRFortessa)分析細胞,且結果展示於圖6中。
實例
42
活體內
PK
此研究使用Meso Scale Discovery (MSD)電化學發光(ECL)方法對BALB/c小鼠及大鼠樣品進行DCBPR2002-4(DBCO-vc-MMAE)之藥物動力學分析。MSD分析可量測共軛及未共軛抗體。如此實例或總抗體分析中所示,培養盤塗有山羊抗人類IgG,其可捕捉所有人源化抗體(共軛及未共軛)。對於共軛抗體分析,培養盤塗有針對有效負載(藥物)之抗體,諸如抗MMAE抗體。
經由尾部靜脈以3 mg/kg之劑量投與小鼠。隨後在不同時間點獲得血液樣品,用於藉由MESO QuickPlex SQ 120方法測定小鼠中DCBPR2002-4(DBCO-vc-MMAE)之濃度。使用Phoenix™ for WinNonlin程式6.3版藉由非隔室分析來分析DCBPR2002-4(DBCO-vc-MMAE)之藥物動力學參數。
表6彙總PK研究之結果。總抗體MSD分析:量測共軛及未共軛抗體。共軛抗體MSD分析:僅量測共軛抗體。DCBPR2002-4(DBCO-vc-MMAE)之活體內半衰期為約87.2小時,此係因為與其他物種相比,在小鼠中觀察到的連接子蛋白水解程度較高可歸因於羧酸酯酶1C,吾等ADC上之纈胺酸-瓜胺酸連接子為該酶之受質。
活體內藥物動力學研究經設計以用於比較三甘露糖基共軛及半胱胺酸共軛之合成ADC (Adcetris)的連接子-有效負載穩定性。經由尾部靜脈以5 mg/kg之劑量向大鼠投與DCBPR2002-4(DBCO-vc-MMAE)及Adcetris。隨後在不同時間點獲得血清樣品,用於藉由MESO QuickPlex SQ 120方法測定大鼠中DCBPR2002-4(DBCO-vc-MMAE)及Adcetris之濃度。使用Phoenix™ for WinNonlin程式6.3版藉由非隔室分析來分析DCBPR2002-4(DBCO-vc-MMAE)及Adcetris之藥物動力學參數。
表7彙總PK研究之結果。總抗體MSD分析:量測共軛及未共軛抗體。共軛抗體MSD分析:僅量測共軛抗體。DCBPR2002-4(DBCO-vc-MMAE)之活體內半衰期對於總抗體為194 ± 35.0小時;共軛抗體之半衰期對於DCBPR2002-4(DBCO-vc-MMAE)為148±8.14小時且對於Adcetris為182 ± 10.9小時。(圖8)
表6
組 | C 0 | AUC (0-last) | AUC (0- ∞ ) | MRT | t 1/2 | CL | V ss | |
(ng/mL) | (ng*hr/mL) | (ng*hr/mL) | (hr) | (hr) | (mL/min/Kg) | (L/Kg) | ||
DCBPR2002-4(DBCO-vc-MMAE) (N=3) | 總 | 346 ±11.9 | 25963 ±6257 | 34112 ±10415 | 299 ±120 | 220 ±84.3 | 0.008 ±0.003 | 0.129 ±0.019 |
共軛 | 275 ±2.8 | 2264 ±49.3 | 2274 ±49.6 | 23.4 ±4.99 | 87.2 ±27.4 | 0.110 ±0.002 | 0.155 ±0.033 |
表7
組 | C 0 | AUC (0-last) | AUC (0- ∞ ) | MRT | t 1/2 | CL | V ss | |
(ng/mL) | (ng*hr/mL) | (ng*hr/mL) | (hr) | (hr) | (mL/min/Kg) | (L/Kg) | ||
DCBPR2002-4(DBCO-vc-MMAE) (N=3) | 總 | 94121 ± 1186 | 4013185 ± 216117 | 4363325 ± 298790 | 160 ± 26.3 | 194 ± 35.0 | 0.019 ± 0.001 | 0.183 ± 0.024 |
共軛 | 80955 ± 2308 | 2334505 ± 158551 | 2400450 ± 157340 | 85.6 ± 2.48 | 148 ± 8.14 | 0.035 ± 0.002 | 0.179 ± 0.017 | |
Adcetris (N=3) | 總 | 87418 | 6500218 | 9154784 | 405 | 351 | 0.009 | 0.224 |
± 7387 | ± 744720 | ± 1534447 | ± 4.33 | ± 10.0 | ± 0.002 | ± 0.035 | ||
共軛 | 84849 | 3863369 | 4274931 | 185 | 182 | 0.020 | 0.219 | |
± 10597 | ± 568713 | ± 600961 | ± 5.92 | ± 10.9 | ± 0.003 | ± 0.033 |
比較DCBPR2002-4(DBCO-vc-MMAE)及Adcetris之總抗體及共軛抗體的藥物動力學概況,總抗體與共軛抗體曲線之間的差異接近於DCBPR2002-4(DBCO-vc-MMAE)而非Adcetris。活體內結果表明,與半胱胺酸共軛(Adcetris)相比,所提出之三甘露糖基共軛在共軛連接子-有效負載之穩定性方面具有差異。
實例
43
抗
MSLN ADC
之異種移植模型
(
胰臟癌
)
此研究之目的為評估DCBPR2002-離胺酸-DBCO-vc-MMAE (DBCO-vc-MMAE經由疊氮基活化之離胺酸與抗體之多肽連接)及DCBPR2002-4(DBCO-vc-MMAE)在雄性NOD SCID小鼠KLM-1人類胰臟癌異種移植模型中之活體內抗腫瘤功效。
藉由用25 mM檸檬酸鈉緩衝液(pH 6.5)稀釋儲備液來調配分別包含測試物DCBPR2002離胺酸-DBCO-vc-MMAE、測試物DCBPR2002-4(DBCO-vc-MMAE)及相應媒劑之調配物。將各調配物靜脈內(IV)投與小鼠,每週一次,持續三週。
將KLM-1細胞作為單層培養物在37℃下5% CO
2之空氣氛圍中,在補充有10%胎牛血清之RPMI-1640培養基中活體外維持。腫瘤細胞每週藉由胰蛋白酶-EDTA處理常規繼代培養兩次。收穫生長在指數生長期之細胞且計數用於腫瘤接種。
6-7週齡之雄性NOD SCID小鼠係購自BioLasco Taiwan Co., LTD.且隔離一週。各籠中圈養五隻小鼠。所有動物均安置於19-25℃下12小時光/12小時暗循環之動物設施中。動物自由隨意獲取嚙齒動物顆粒狀食物及水。
將KLM-1細胞皮下(SC)植入雄性NOD SCID小鼠之右側腹中(含4 × 10
6個細胞之1:1 PBS/基質膠混合物,每隻小鼠0.1 mL)。當平均腫瘤體積達到約200 mm
3時,將小鼠隨機分為3組(每組N = 6)。靜脈內投與媒劑、DCBPR2002-離胺酸-DBCO-vc-MMAE (15 mg/kg)及DCBPR2002-4(DBCO-vc-MMAE) (15 mg/kg)中之每一者,每週一次,持續3週。
每週三次監測且記錄腫瘤體積、體重、死亡率及明顯毒性跡象,持續28天。腫瘤體積(mm
3)每週使用測徑規量測三次且根據下式計算:腫瘤體積= (
w 2×
l)/2,其中
w=腫瘤之寬度且
l=腫瘤之直徑長度(mm)。腫瘤生長抑制(TGI)百分比使用下式計算:TGI% = [1 - (T/C)] × 100%,其中T及C分別表示處理組及對照組之平均腫瘤體積。TGI (%)值≥58%視為顯著的抗腫瘤活性。應用單向ANOVA隨後進行鄧尼特檢驗(Dunnett's test)來比較媒劑及測試物處理組。在*P<0.05下,認為差異顯著。動物每週稱重三次,直至研究完成。
圖9展示KLM-1植入之雄性NOD SCID小鼠的腫瘤生長曲線。靜脈內投與測試物DCBPR2002-離胺酸-DBCO-vc-MMAE (15 mg/kg)及DCBPR2002-4(DBCO-vc-MMAE) (15 mg/kg)中之每一者,每週一次,持續3週。與媒劑組相比,腫瘤生長抑制(TGI) ≥ 58%視為顯著的抗腫瘤活性(#)。應用單向ANOVA隨後進行鄧尼特檢驗來比較媒劑及測試物處理組。在*P<0.05下,認為差異顯著。15 mg/kg之DCBPR2002-4(DBCO-vc-MMAE)自第7天至第28天顯著降低KLM-1腫瘤生長。15 mg/kg之DCBPR2002-離胺酸-DBCO-vc-MMAE未顯示出顯著的抗腫瘤活性。
圖10展示KLM-1植入之雄性NOD SCID小鼠的體重變化。靜脈內投與測試物DCBPR2002-離胺酸-DBCO-vc-MMAE (15 mg/kg)及DCBPR2002-4(DBCO-vc-MMAE) (15 mg/kg)中之每一者,每週一次,持續3週。在整個實驗中未觀察到體重減輕。
實例
44
抗
MSLN ADC
之異種移植模型
(
胰臟癌
)
此研究之目的為評估DCBPR2002及DCBPR2002-4(DBCO-vc-MMAE)在雄性NOD SCID小鼠KLM-1人類胰臟癌異種移植模型中之活體內抗腫瘤功效。
藉由用25 mM檸檬酸鈉緩衝液(pH 6.5)稀釋儲備液來調配分別包含測試物DCBPR2002、測試物DCBPR2002-4(DBCO-vc-MMAE)及相應媒劑之調配物。將各調配物靜脈內(IV)投與小鼠,每週一次,持續三週。
將KLM-1細胞作為單層培養物在37℃下5% CO
2之空氣氛圍中,在補充有10%胎牛血清之RPMI-1640培養基中活體外維持。腫瘤細胞每週藉由胰蛋白酶-EDTA處理常規繼代培養兩次。收穫生長在指數生長期之細胞且計數用於腫瘤接種。
6-7週齡之雄性NOD SCID小鼠係購自BioLasco Taiwan Co., LTD.且隔離一週。各籠中圈養五隻小鼠。所有動物均安置於19-25℃下12小時光/12小時暗循環之動物設施中。動物自由隨意獲取嚙齒動物顆粒狀食物及水。
將KLM-1細胞皮下(SC)植入雄性NOD SCID小鼠之右側腹中(含4 × 10
6個細胞之1:1 PBS/基質膠混合物,每隻小鼠0.1 mL)。當平均腫瘤體積達到200 mm
3時,將小鼠隨機分為4組(每組N = 6)。靜脈內投與媒劑、DCBPR2002-4(DBCO-vc-MMAE) (15及30 mg/kg)及裸抗體(DCBPR2002,30 mg/kg)中之每一者,每週一次,持續3週。
每週三次監測且記錄腫瘤體積、體重、死亡率及明顯毒性跡象,持續28天。腫瘤體積(mm
3)每週使用測徑規量測三次且根據下式計算:腫瘤體積= (
w 2×
l)/2,其中
w=腫瘤之寬度且
l=腫瘤之直徑長度(mm)。腫瘤生長抑制(TGI)百分比使用下式計算:TGI% = [1 - (T/C)] × 100%,其中T及C分別表示處理組及對照組之平均腫瘤體積。TGI (%)值≥58%視為顯著的抗腫瘤活性。應用單向ANOVA隨後進行鄧尼特檢驗來比較媒劑及測試物處理組。在*P<0.05下,認為差異顯著。動物每週稱重三次,直至研究完成。
圖11展示KLM-1植入之雄性NOD SCID小鼠的腫瘤生長曲線。靜脈內投與測試物DCBPR2002 (30 mg/kg)及DCBPR2002-4(DBCO-vc-MMAE) (15及30 mg/kg)中之每一者,每週一次,持續3週。與媒劑組相比,腫瘤生長抑制(TGI) ≥ 58%視為顯著的抗腫瘤活性(#)。應用單向ANOVA隨後進行鄧尼特檢驗來比較媒劑及測試物處理組。在*P<0.05下,認為差異顯著。15及30 mg/kg之DCBPR2002-4(DBCO-vc-MMAE)自第7天至第28天顯著降低KLM-1腫瘤生長。30 mg/kg之DCBPR2002未顯示出顯著的抗腫瘤活性。
圖12展示KLM-1植入之雄性NOD SCID小鼠的體重變化。靜脈內投與測試物DCBPR2002 (30 mg/kg)及DCBPR2002-4(DBCO-vc-MMAE) (15及30 mg/kg)中之每一者,每週一次,持續3週。在整個實驗中未觀察到體重減輕。
實例
45
抗
MSLN ADC
之異種移植模型
(
胰臟癌
)
此研究之目的為評估DCBPR2002-4(DBCO-vc-MMAE)、DCBPR2002-4(DBCO-vc-seco-DUBA)、DCBPR2002-4(DBCO-s-DM1)、DCBPR2002-2(DBCO-vc-MMAE)-2(DBCO-vc-seco-DUBA)、DCBPR2002-2(DBCO-vc-seco-DUBA)-2(DBCO-s-DM1)及DCBPR2002-2(DBCO-vc-MMAE)-2(DBCO-s-DM1)在雄性NOD SCID小鼠KLM-1人類胰臟癌異種移植模型中之活體內抗腫瘤功效。
藉由用25 mM檸檬酸鈉緩衝液(pH 6.5)稀釋儲備液來調配分別包含測試物DCBPR2002-4(DBCO-vc-MMAE)(15 mg/kg)、測試物DCBPR2002-4(DBCO-vc-seco-DUBA)(15 mg/kg)、測試物DCBPR2002-4(DBCO-s-DM1) (15 mg/kg)、測試物DCBPR2002-2(DBCO-vc-MMAE)-2(DBCO-vc-seco-DUBA) (15 mg/kg)、測試物DCBPR2002-2(DBCO-vc-MMAE)-2(DBCO-s-DM1) (15 mg/kg)、測試物DCBPR2002-2(DBCO-vc-seco-DUBA)-2(DBCO-s-DM1) (15 mg/kg)及相應媒劑的調配物。靜脈內(IV)投與各調配物,每週一次,持續三週。
將KLM-1細胞作為單層培養物在37℃下5% CO
2之空氣氛圍中,在補充有10%胎牛血清之RPMI-1640培養基中活體外維持。腫瘤細胞每週藉由胰蛋白酶-EDTA處理常規繼代培養兩次。收穫生長在指數生長期之細胞且計數用於腫瘤接種。
6-7週齡之雄性NOD SCID小鼠係購自BioLasco Taiwan Co., LTD.且隔離一週。各籠中圈養五隻小鼠。所有動物均安置於19-25℃下12小時光/12小時暗循環之動物設施中。動物自由隨意獲取嚙齒動物顆粒狀食物及水。
將KLM-1細胞皮下(SC)植入雄性NOD SCID小鼠之右側腹中(含4 × 10
6個細胞之1:1 PBS/基質膠混合物,每隻小鼠0.1 mL)。當平均腫瘤體積達到300 mm
3時,將小鼠隨機分為7組(每組N = 6)。以15 mg/kg靜脈內投與媒劑、DCBPR2002-4(DBCO-vc-MMAE)、DCBPR2002-4(DBCO-vc-seco-DUBA)、DCBPR2002-4(DBCO-s-DM1)、DCBPR2002-2(DBCO-vc-MMAE)-2(DBCO-vc-seco-DUBA)、DCBPR2002-2(DBCO-vc-MMAE)-2(DBCO-s-DM1)、DCBPR2002-2(DBCO-vc-seco-DUBA)-2(DBCO-s-DM1)中之每一者,每週一次,持續3週。
每週三次監測且記錄腫瘤體積、體重、死亡率及明顯毒性跡象,持續28天。腫瘤體積每週使用測徑規量測三次且根據下式計算:腫瘤體積= (w
2×l)/2,其中w
=腫瘤之寬度且l =腫瘤之直徑長度(mm)。腫瘤生長抑制(TGI)百分比使用下式計算:TGI% = [1 - (T/C)] × 100%,其中T及C分別表示處理組及對照組之平均腫瘤體積。TGI (%)值≥58%視為顯著的抗腫瘤活性。應用單向ANOVA隨後進行鄧尼特檢驗來比較媒劑及測試物處理組。在*P<0.05下,認為差異顯著。動物每週稱重三次,直至研究完成。
圖13展示KLM-1植入之雄性NOD SCID小鼠的腫瘤生長曲線。以15 mg/kg靜脈內投與測試物DCBPR2002-4(DBCO-vc-MMAE)、DCBPR2002-4(DBCO-vc-seco-DUBA)、DCBPR2002-4(DBCO-s-DM1)、DCBPR2002-2(DBCO-vc-MMAE)-2(DBCO-s-DM1)、DCBPR2002-2(DBCO-vc-MMAE)-2(DBCO-vc-seco-DUBA)及DCBPR2002-2(DBCO-vc-seco-DUBA)-2(DBCO-s-DM1)中之每一者,每週一次,持續3週。與媒劑組相比,腫瘤生長抑制(TGI) ≥ 58%視為顯著的抗腫瘤活性(#)。應用單向ANOVA隨後進行鄧尼特檢驗來比較媒劑及測試物處理組。在*P<0.05下,認為差異顯著。所有抗MSLN ADC均顯示出顯著的抗腫瘤活性。功效效力排名為DCBPR2002-4(DBCO-vc-seco-DUBA) = DCBPR2002-2(DBCO-vc-MMAE)-2(DBCO-vc-seco-DUBA) = DCBPR2002-2(DBCO-vc-seco-DUBA)-2(DBCO-s-DM1) > DCBPR2002-4(DBCO-vc-MMAE) > DCBPR2002-2(DBCO-vc-MMAE)-2(DBCO-s-DM1) > DCBPR2002-4(DBCO-s-DM1)。
圖14展示KLM-1植入之雄性NOD SCID小鼠的體重變化。以15 mg/kg靜脈內投與測試物DCBPR2002-4(DBCO-vc-MMAE)、DCBPR2002-4(DBCO-vc-seco-DUBA)、DCBPR2002-4(DBCO-s-DM1)、DCBPR2002-2(DBCO-vc-MMAE)-2(DBCO-s-DM1)、DCBPR2002-2(DBCO-vc-MMAE)-2(DBCO-vc-seco-DUBA)及DCBPR2002-2(DBCO-vc-seco-DUBA)-2(DBCO-s-DM1)中之每一者,每週一次,持續3週。在處理組中未觀察到體重減輕。
實例
46
抗
MSLN ADC
之異種移植模型
(
卵巢癌
)
此研究之目的為評估DCBPR2002-4(DBCO-vc-MMAE)及DCBPR2002-4(DBCO-vc-seco-DUBA)在雌性NOD SCID小鼠OVCAR-3人類卵巢癌異種移植模型中之活體內抗腫瘤功效。
藉由用25 mM檸檬酸鈉緩衝液(pH 6.5)稀釋儲備液來調配分別包含測試物DCBPR2002-4(DBCO-vc-MMAE)、測試物DCBPR2002-4(DBCO-vc-seco-DUBA)及相應媒劑之調配物。靜脈內(IV)投與各調配物,每週一次,持續三週。
將OVCAR-3細胞作為單層培養物在37℃下5% CO
2之空氣氛圍中,在補充有20%胎牛血清之RPMI-1640培養基中活體外維持。腫瘤細胞每週藉由胰蛋白酶-EDTA處理常規繼代培養兩次。收穫生長在指數生長期之細胞且計數用於腫瘤接種。
6-7週齡之雌性NOD SCID小鼠係購自BioLasco Taiwan Co., LTD.且隔離一週。各籠中圈養五隻小鼠。所有動物均安置於19-25℃下12小時光/12小時暗循環之動物設施中。動物自由隨意獲取嚙齒動物顆粒狀食物及水。
將OVCAR-3細胞皮下(SC)植入雌性NOD SCID小鼠之右側腹中(含1 × 10
7個細胞之1:1 PBS/基質膠混合物,每隻小鼠0.2 mL)。當平均腫瘤體積達到300 mm
3時,將小鼠隨機分為4組(每組N = 6)。靜脈內投與媒劑、DCBPR2002-4(DBCO-vc-MMAE) (15及30 mg/kg)及DCBPR2002-4(DBCO-vc-seco-DUBA) (15 mg/kg)中之每一者,每週一次,持續3週。
腫瘤體積每週使用測徑規量測三次且使用下式估算:腫瘤體積= (
w 2×
l)/2,其中
w=腫瘤之寬度且
l=腫瘤之直徑長度(mm)。腫瘤生長抑制(TGI)百分比使用下式計算:TGI% = [1 - (T/C)] × 100%,其中T及C分別表示處理組及對照組之平均腫瘤體積。TGI (%)值≥58%視為顯著的抗腫瘤活性。應用單向ANOVA隨後進行鄧尼特檢驗來比較媒劑及測試物處理組。在*P<0.05下,認為差異顯著。動物每週稱重三次,直至研究完成。
圖15展示OVCAR-3植入之雌性NOD SCID小鼠的腫瘤生長曲線。靜脈內投與測試物DCBPR2002-4(DBCO-vc-MMAE) (15及30 mg/kg)及DCBPR2002-4(DBCO-vc-seco-DUBA) (15 mg/kg)中之每一者,每週一次,持續3週。與媒劑組相比,腫瘤生長抑制(TGI) ≥ 58%視為顯著的抗腫瘤活性(#)。應用單向ANOVA隨後進行鄧尼特檢驗來比較媒劑及測試物處理組。在*P<0.05下,認為差異顯著。DCBPR2002-4(DBCO-vc-MMAE) (15及30 mg/kg)及DCBPR2002-4(DBCO-vc-seco-DUBA)(15 mg/kg)顯著降低OVCAR-3腫瘤生長,TGI (%)值分別> 90%。
圖16展示OVCAR-3植入之雌性NOD SCID小鼠的體重變化。靜脈內投與測試物DCBPR2002-4(DBCO-vc-MMAE) (15及30 mg/kg)及DCBPR2002-4(DBCO-vc-seco-DUBA) (15 mg/kg)中之每一者,每週一次,持續3週。在處理組中未觀察到體重減輕。
實例
47
抗
MSLN ADC
之異種移植模型
(
卵巢癌
)
此研究之目的為評估DCBPR2002-4(DBCO-vc-MMAE)及DCBPR2002-TM在雌性NOD SCID小鼠OVCAR-3人類卵巢癌異種移植模型中之活體內抗腫瘤功效。
藉由用25 mM檸檬酸鈉緩衝液(pH 6.5)稀釋儲備液來調配分別包含測試物DCBPR2002-4(DBCO-vc-MMAE)、測試物DCBPR2002-TM及相應媒劑之調配物。靜脈內(IV)投與各調配物,每週一次,持續三週。
將OVCAR-3細胞作為單層培養物在37℃下5% CO
2之空氣氛圍中,在補充有20%胎牛血清之RPMI-1640培養基中活體外維持。腫瘤細胞每週藉由胰蛋白酶-EDTA處理常規繼代培養兩次。收穫生長在指數生長期之細胞且計數用於腫瘤接種。
6-7週齡之雌性NOD SCID小鼠係購自BioLasco Taiwan Co., LTD.且隔離一週。各籠中圈養五隻小鼠。所有動物均安置於19-25℃下12小時光/12小時暗循環之動物設施中。動物自由隨意獲取嚙齒動物顆粒狀食物及水。
將OVCAR-3細胞皮下(SC)植入雌性NOD SCID小鼠之右側腹中(含1 × 10
7個細胞之1:1 PBS/基質膠混合物,每隻小鼠0.2 mL)。當平均腫瘤體積達到300 mm
3時,將小鼠隨機分為4組(每組N=5)。靜脈內投與媒劑、DCBPR2002-4(DBCO-vc-MMAE) (5及15 mg/kg)及DCBPR2002-TM (15 mg/kg)中之每一者,每週一次,持續3週。
腫瘤體積每週使用測徑規量測三次且使用下式估算:腫瘤體積= (
w 2×
l)/2,其中
w=腫瘤之寬度且
l=腫瘤之直徑長度(mm)。腫瘤生長抑制(TGI)百分比使用下式計算:TGI% = [1 - (T/C)] × 100%,其中T及C分別表示處理組及對照組之平均腫瘤體積。TGI (%)值≥58%視為顯著的抗腫瘤活性。應用單向ANOVA隨後進行鄧尼特檢驗來比較媒劑及測試物處理組。在*P<0.05下,認為差異顯著。動物每週稱重三次,直至研究完成。
圖17展示OVCAR-3植入之雌性NOD SCID小鼠的腫瘤生長曲線。靜脈內投與測試物DCBPR2002-4(DBCO-vc-MMAE) (5及15 mg/kg)及DCBPR2002-TM (15 mg/kg)中之每一者,每週一次,持續3週。與媒劑組相比,腫瘤生長抑制(TGI) ≥ 58%視為顯著的抗腫瘤活性(#)。應用單向ANOVA隨後進行鄧尼特檢驗來比較媒劑及測試物處理組。在*P<0.05下,認為差異顯著。DCBPR2002-4(DBCO-vc-MMAE) (5及15 mg/kg)顯著降低OVCAR-3腫瘤生長。15 mg/kg之DCBPR2002-TM未顯示出抗腫瘤活性。
圖18展示OVCAR-3植入之雌性NOD SCID小鼠的體重變化。靜脈內投與測試物DCBPR2002-4(DBCO-vc-MMAE) (5及15 mg/kg)及DCBPR2002-TM (15 mg/kg)中之每一者,每週一次,持續3週。在處理組中未觀察到體重減輕。
實例
48
抗
MSLN ADC
之異種移植模型
(
卵巢癌
)
此研究之目的為評估DCBPR2002-4(DBCO-vc-MMAE)在雌性NOD SCID小鼠OVCAR-3人類卵巢癌異種移植模型中之活體內抗腫瘤功效。
藉由用25 mM檸檬酸鈉緩衝液(pH 6.5)稀釋儲備液來調配分別包含測試物DCBPR2002-4(DBCO-vc-MMAE)及相應媒劑之調配物。靜脈內(IV)投與各調配物,每週一次,持續三週。
將OVCAR-3細胞作為單層培養物在37℃下5% CO
2之空氣氛圍中,在補充有20%胎牛血清之RPMI-1640培養基中活體外維持。腫瘤細胞每週藉由胰蛋白酶-EDTA處理常規繼代培養兩次。收穫生長在指數生長期之細胞且計數用於腫瘤接種。
6-7週齡之雌性NOD SCID小鼠係購自BioLasco Taiwan Co., LTD.且隔離一週。各籠中圈養五隻小鼠。所有動物均安置於19-25℃下12小時光/12小時暗循環之動物設施中。動物自由隨意獲取嚙齒動物顆粒狀食物及水。
將OVCAR-3細胞皮下(SC)植入雌性NOD SCID小鼠之右側腹中(含1 × 10
7個細胞之1:1 PBS/基質膠混合物,每隻小鼠0.2 mL)。當平均腫瘤體積達到300 mm
3時,將小鼠隨機分為4組(每組N=5)。靜脈內投與媒劑及DCBPR2002-4(DBCO-vc-MMAE) (5、10及15 mg/kg)中之每一者,每週一次,持續3週。
腫瘤體積每週使用測徑規量測三次且使用下式估算:腫瘤體積= (
w 2×
l)/2,其中
w=腫瘤之寬度且
l=腫瘤之直徑長度(mm)。腫瘤生長抑制(TGI)百分比使用下式計算:TGI% = [1 - (T/C)] × 100%,其中T及C分別表示處理組及對照組之平均腫瘤體積。TGI (%)值≥58%視為顯著的抗腫瘤活性。應用單向ANOVA隨後進行鄧尼特檢驗來比較媒劑及測試物處理組。在*P<0.05下,認為差異顯著。動物每週稱重三次,直至研究完成。
圖19展示OVCAR-3植入之雌性NOD SCID小鼠的腫瘤生長曲線。靜脈內投與測試物DCBPR2002-4(DBCO-vc-MMAE) (5、10及15 mg/kg)中之每一者,每週一次,持續3週。與媒劑組相比,腫瘤生長抑制(TGI) ≥ 58%視為顯著的抗腫瘤活性(#)。應用單向ANOVA隨後進行鄧尼特檢驗來比較媒劑及測試物處理組。在*P<0.05下,認為差異顯著。DCBPR2002-4(DBCO-vc-MMAE) (5、10及15 mg/kg)以劑量依賴性方式顯著降低OVCAR-3腫瘤生長。
圖20展示OVCAR-3植入之雌性NOD SCID小鼠的體重變化。靜脈內投與測試物DCBPR2002-4(DBCO-vc-MMAE) (5、10及15 mg/kg)中之每一者,每週一次,持續3週。在處理組中未觀察到體重減輕。
以上實例清楚地說明用於獲得及表徵本發明ADC之各種方法,以及本發明ADC在治療癌症方面之有效性。即使本發明之實施例藉由有限數目個實例加以說明,但熟習此項技術者應瞭解,在不脫離本發明之範疇的情況下,其他變化及修改係可能的。因此,本發明之保護範疇應僅受所附申請專利範圍限制。
圖1A及1B展示抗間皮素抗體之序列比對。
圖2展示表現小鼠可變區、IMGT及4D5可變區之人源化版本的載體構築體。
圖3展示間皮素對抗體之親和力。
圖4展示使用BIAcore之SS1及HuSS1抗體之動力學分析。
圖5展示所偵測之ADC的ELISA結合親和力。
圖6展示ADC內化之結果。
圖7展示ADC DCBPR2002-4(DBCO-vc-MMAE)之質量分析。
圖8展示ADC DCBPR2002-4(DBCO-vc-MMAE)之藥物動力學概況的結果。
圖9展示KLM-1植入之雄性NOD SCID小鼠的腫瘤生長曲線。
圖10展示KLM-1植入之雄性NOD SCID小鼠的體重變化。
圖11展示KLM-1植入之雄性NOD SCID小鼠的腫瘤生長曲線。
圖12展示KLM-1植入之雄性NOD SCID小鼠的體重變化。
圖13展示KLM-1植入之雄性NOD SCID小鼠的腫瘤生長曲線。
圖14展示KLM-1植入之雄性NOD SCID小鼠的體重變化。
圖15展示OVCAR-3植入之雌性NOD SCID小鼠的腫瘤生長曲線。
圖16展示OVCAR-3植入之雌性NOD SCID小鼠的體重變化。
圖17展示OVCAR-3植入之雌性NOD SCID小鼠的腫瘤生長曲線。
圖18展示OVCAR-3植入之雌性NOD SCID小鼠的體重變化。
圖19展示OVCAR-3植入之雌性NOD SCID小鼠的腫瘤生長曲線。
圖20展示OVCAR-3植入之雌性NOD SCID小鼠的體重變化。
圖21A至21T展示免疫共軛物之製備。A:DCBPR2002-2Az之製備。B:DCBPR2002-4Az之製備。C:DCBPR2002-4(DBCO-vc-MMAE)之製備。D:DCBPR2002-4(DBCO-S-DM1)之製備。E:DCBPR2002-4(DBCO-vc-seco DUBA)之製備。F:DCBPR2002-4(DBCO-PEG4-vc-PAB-MMAF)。G:DCBPR2002-4(DBCO-DTPA)之製備。H:DCBPR2002-4(DBCO-PEG3-vc-依昔替康)之製備。I:DCBPR2002-4(DBCO-PEG3-GGFG-依昔替康)之製備。J:DCBPR2002-4(DBCO-PEG12-GGFG-依昔替康)之製備。K:DCBPR2002-4(DBCO-PEG3-GGFG-DXd2)之製備。L:DCBPR2002-4(DBCO-PEG12-GGFG-DXd2)之製備。M:DCBPR2002-4(BCN-PEG3-VC-PAB-MMAE)之製備。N:DCBPR2002-4(BCN-PEG12-GGFG-依昔替康)之製備。O:DCBPR2002-4(BCN-PEG3-GGFG-依昔替康)之製備。P:DCBPR2002-4(BCN-PEG12-GGFG-DXd2)之製備。Q:DCBPR2002-4(DBCO-PEG3-2(PEG3-VC-PAB-MMAE))之製備。R:DCBPR2002-2(DBCO-vc-MMAE)-2(DBCO-vc-seco DUBA)之製備。S:DCBPR2002-2(DBCO-vc-MMAE)-2(DBCO-S-DM1)之製備。T:DCBPR2002-2(DBCO-vc-seco DUBA)-2(DBCO-S-DM1)之製備。
<![CDATA[<110> 財團法人生物技術開發中心]]> <![CDATA[<120> 含有抗間皮素抗體的抗體-藥物共軛物及其用途]]> <![CDATA[<130> 無]]> <![CDATA[<140> 110120509]]> <![CDATA[<141> 2021-06-04]]> <![CDATA[<150> 63/035,175]]> <![CDATA[<151> 2020-06-05]]> <![CDATA[<160> 12 ]]> <![CDATA[<170> PatentIn version 3.5]]> <![CDATA[<210> 1]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 小鼠]]> <![CDATA[<400> 1]]> Gly Tyr Ser Phe Thr Gly Tyr Thr Met Asn 1 5 10 <![CDATA[<210> 2]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 小鼠]]> <![CDATA[<400> 2]]> Leu Ile Thr Pro Tyr Asn Gly Ala Ser Ser Tyr Asn Gln Lys Phe Arg 1 5 10 15 Gly <![CDATA[<210> 3]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 小鼠]]> <![CDATA[<400> 3]]> Gly Gly Tyr Asp Gly Arg Gly Phe Asp Tyr 1 5 10 <![CDATA[<210> 4]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 小鼠]]> <![CDATA[<400> 4]]> Ser Ala Ser Ser Ser Val Ser Tyr Met His 1 5 10 <![CDATA[<210> 5]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 小鼠]]> <![CDATA[<400> 5]]> Asp Thr Ser Lys Leu Ala Ser 1 5 <![CDATA[<210> 6]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 小鼠]]> <![CDATA[<400> 6]]> Gln Gln Trp Ser Lys His Pro Leu Thr 1 5 <![CDATA[<210> 7]]> <![CDATA[<211> 119]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 小鼠]]> <![CDATA[<400> 7]]> Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Glu Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile 35 40 45 Gly Leu Ile Thr Pro Tyr Asn Gly Ala Ser Ser Tyr Asn Gln Lys Phe 50 55 60 Arg Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Asp Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys 85 90 95 Ala Arg Gly Gly Tyr Asp Gly Arg Gly Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Thr Val Thr Val Ser Ser 115 <![CDATA[<210> 8]]> <![CDATA[<211> 107]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 小鼠]]> <![CDATA[<400> 8]]> Asp Ile Glu Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly 1 5 10 15 Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met 20 25 30 His Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr 35 40 45 Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Gly Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Asn Ser Tyr Ser Leu Thr Ile Ser Ser Val Glu Ala Glu 65 70 75 80 Asp Asp Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Lys His Pro Leu Thr 85 90 95 Phe Gly Ala Gly Thr Lys Leu Glu Ile Lys Arg 100 105 <![CDATA[<210> 9]]> <![CDATA[<211> 119]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工抗體]]> <![CDATA[<400> 9]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Leu Ile Thr Pro Tyr Asn Gly Ala Ser Ser Tyr Asn Gln Lys Phe 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Gly Tyr Asp Gly Arg Gly Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <![CDATA[<210> 10]]> <![CDATA[<211> 107]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工抗體]]> <![CDATA[<400> 10]]> Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met 20 25 30 His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr 35 40 45 Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu 65 70 75 80 Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Lys His Pro Leu Thr 85 90 95 Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105 <![CDATA[<210> 11]]> <![CDATA[<211> 119]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工抗體]]> <![CDATA[<400> 11]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Thr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Leu Ile Thr Pro Tyr Asn Gly Ala Ser Ser Tyr Asn Gln Lys Phe 50 55 60 Arg Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Gly Tyr Asp Gly Arg Gly Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <![CDATA[<210> 12]]> <![CDATA[<211> 107]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工抗體]]> <![CDATA[<400> 12]]> Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Ser Ala Ser Ser Ser Val Ser Tyr Met 20 25 30 His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr 35 40 45 Asp Thr Ser Lys Leu Ala Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu 65 70 75 80 Asp Phe Ala Val Tyr Tyr Cys Gln Gln Trp Ser Lys His Pro Leu Thr 85 90 95 Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105
Claims (14)
- 如請求項1之免疫共軛物,其中該抗體為單株抗體、人源化抗體、來自裂解抗體之抗體Fab片段、F(ab')2、Fv片段、scFv-Fc片段、微型抗體、雙功能抗體或scFv。
- 如請求項1之免疫共軛物,其中該抗體包含重鏈恆定區,且該N-聚醣結合域位於該重鏈恆定區中。
- 如請求項1之免疫共軛物,其中該抗體包含兩個N-聚醣。
- 如請求項1之免疫共軛物,其中該連接子係選自由以下組成之群:具有2至20個碳原子之直鏈或分支鏈烷基、環烷基、烯基、環烯基、炔基、芳香基、雜芳香基、烷氧基、醯基、烷胺基、芳胺基、醚、酯、醯胺、胺基甲酸酯、碳酸酯、式(3)至式(7)、含雙硫鍵之連接子、酸不穩定連接子、光不穩定連接子、肽酶不穩定連接子及酯酶不穩定連接子或其組合;
- 如請求項1之免疫共軛物,其中該治療劑為抗代謝物、烷基化劑、類烷基化劑、DNA小溝烷基化劑、蒽環黴素(anthracyclines)、抗生素、卡奇黴素(calicheamicins)、抗有絲分裂劑、拓樸異構酶抑制劑、蛋白酶體抑制劑、放射性同位素或同位素螯合劑。
- 如請求項1之免疫共軛物,其中該治療劑為單甲基奧瑞他汀E(monomethyl auristatin E,MMAE)、單甲基奧瑞他汀F(MMAF)、類美登素(maytansinoids)、多卡黴素-羥基苯甲醯胺氮雜吲哚(duocarmycin-hydroxy benzamide azaindole,DUBA)、二伸乙基三胺-N,N,N',N",N"-五乙酸酯(DTPA)、依昔替康(exatecan)或Dxd2。
- 如請求項1之免疫共軛物,其中該標記為螢光標記、發色標記、電子緻密標記、化學發光標記、放射性標記、酶標記或正子發射體。
- 如請求項1之免疫共軛物,其中該保護基為疊氮基。
- 一種醫藥組合物,其包含如請求項1至9中任一項之免疫共軛物及醫藥學上可接受之載劑。
- 一種如請求項1至9中任一項之免疫共軛物之用途,其係用以製備治療有需要之個體之癌症的藥物。
- 如請求項11之用途,其中該癌症為表現間皮素之癌症。
- 如請求項11之用途,其中該癌症為卵巢癌、間皮瘤、胰臟癌、非小細胞肺癌、食道癌、胃癌、膽管癌、結腸直腸癌、子宮內膜癌或乳癌。
- 如請求項11之用途,其中該癌症為卵巢癌。
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