JP2022025098A - 脂肪酸誘導体を用いたタンパク質結合体及びその製造方法 - Google Patents
脂肪酸誘導体を用いたタンパク質結合体及びその製造方法 Download PDFInfo
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Abstract
Description
IgG2及びIgG4サブクラスであることが好ましく、補体依存的傷害(CDC, complementdependent cytotoxicity)などのエフェクター機能(effector function)がほとんどないIgG4のFc領域であることが最も好ましい。特に、本発明のタンパク質結合体に含まれるキャリア用免疫グロブリンFc領域は、ヒトIgG4由来の非グリコシル化されたFcフラグメントであってもよい。ヒト由来のFcフラグメントは、ヒト生体において抗原として作用し、それに対する新規な抗体を生成するなどの好ましくない免疫反応を起こす非ヒト由来のFcフラグメントに比べて優れた効果を発揮することができる。
本発明の薬剤学的組成物は、生体内持続性及び安定性が天然生理活性ポリペプチドより向上した持続性製剤であってもよい。
薬剤学的に許容される担体は、経口投与の場合は、結合剤、滑沢剤、崩壊剤、賦形剤、可溶化剤、分散剤、安定化剤、懸濁化剤、色素、香料などを用いることができ、注射剤の場合は、緩衝剤、保存剤、鎮痛剤、可溶化剤、等張化剤、安定化剤などを混合して用いることができ、局所投与用の場合は、基剤、賦形剤、滑沢剤、保存剤などを用いることができる。本発明の薬剤学的組成物の剤形は、前述したような薬剤学的に許容される担体と混合して様々な形態に製造することができる。例えば、経口投与の場合は、錠剤、トローチ剤、カプセル剤、エリキシル剤、懸濁剤、シロップ剤、ウエハー剤などの形態に製造することができ、注射剤の場合は、単位投薬アンプル又は複数回投薬形態に製造することができる。その他、溶液、懸濁液、錠剤、丸薬、カプセル剤、徐放性製剤などに剤形化することができる。
テトラヒドロフラン(tetrahydrofuran; THF, 5L)に溶解した2-(2-アミノエトキシ)エタノール(150mL,1.459mol)にトリエチルアミン(229mL,1.645mol)、クロロギ酸ベンジル(211mL,1.495mol)を加え、その後12時間攪拌した。固体を濾過して酢酸エチルで洗浄し、その後濾液を濃縮した。カラムクロマトグラフィーで精製して標題化合物(202g)を得た。
1H NMR (300 MHz, CDCl3) δ 7.37-7.29(m, 5H), 5.25(br, 1H), 5.10(s, 2H), 4.13-4.11(m, 2H), 3.57-3.54(m, 4H), 3.43-3.38(m, 2H), 2.24(br, 1H).
前記工程1で得たベンジル2-(2-ヒドロキシエトキシ)エチルカルバメート(129g,0.539mol)をTHF(2L)に溶解し、その後カリウムt-ブトキシド(60.5g,0.593mol)を0℃で滴下した。30分後にt-ブチルブロモアセテートを加えて0℃で3時間攪拌し、常温で15時間さらに攪拌した。この反応溶液に水を入れて反応を終結させ、その後濃縮して酢酸エチルを入れて抽出した。有機層を無水硫酸マグネシウムで乾燥し、次いで濾過して濾液を濃縮し、その後カラムクロマトグラフィーで精製して標題化合物(87.5g)を得た。
1H NMR (300 MHz, CDCl3) δ 7.36-7.30(m, 5H), 5.38(br, 1H), 5.10(s, 2H), 4.00(s, 2H), 3.70-3.64(m, 4H), 3.60-3.56(m, 2H), 3.43-3.40(m, 2H), 1.46(s, 9H).
前記工程2で得たt-ブチル3-オキソ-1-フェニル-2,7,10-トリオキサ-4-アザドデカン-12-オエート(22.0g,62.249mmol)をジクロロメタン(138mL)に溶解し、その後トリフルオロ酢酸(138mL)を加えて常温で5時間攪拌した。この反応溶液を濾過し、濾液を濃縮して標題化合物(13.0g)を得た。
1H NMR (300 MHz, CDCl3) δ 7.36-7.31(m, 5H), 5.11(s, 2H), 4.15(s, 2H), 3.74-3.58(m, 6H), 3.42-3.40(m, 2H).
前記工程1で得たベンジル2-(2-ヒドロキシエトキシ)エチルカルバメート(15.0g,62.691mmol)をTHF(240mL)に溶解し、その後カリウムt-ブトキシド(7.0g,62.691mmol)を0℃で滴下した。30分後にエチルブロモアセテートを加えて0℃で3時間攪拌し、常温で15時間さらに攪拌した。この反応溶液に水を入れて反応を終結させ、その後濃縮して酢酸エチルを入れて抽出した。有機層を無水硫酸マグネシウムで乾燥し、次いで濾過して濾液を濃縮し、その後カラムクロマトグラフィーで精製して標題化合物(8.6g)を得た。
1H NMR (300 MHz, CDCl3) δ 7.36-7.30(m, 5H), 5.32(br, 1H), 5.10(s, 2H), 4.19(q, 2H), 4.12(s, 2H), 3.72-3.65(m, 4H), 3.59-3.56(m, 2H), 3.41-3.38(m, 2H), 1.26(t, 3H).
前記工程4で得たエチル3-オキソ-1-フェニル-2,7,10-トリオキサ-4-アザドデカン-12-オエート(5.0g,15.368mmol)を無水THF(30mL)に溶解し、アルゴン雰囲気下、-78℃で水素化ジイソブチルアルミニウム(diisobutylaluminium hydride; DIBAL-H,23.0mL,23.051mmol)を徐々に滴下し、その後0℃で1時間攪拌した。この反応溶液に10%塩酸を加えて0℃で30分間攪拌し、その後酢酸エチルを入れて抽出した。有機層を無水硫酸マグネシウムで乾燥し、次いで濾過して濾液を濃縮した。生成物をアルゴン雰囲気下でメタノール(18mL)に溶解し、オルトギ酸トリメチル(13.4mL,122.941mmol)、p-トルエンスルホン酸(146mg,0.768mmol)を入れて常温で2時間攪拌した。酢酸エチルを入れて抽出し、次いで有機層を無水硫酸マグネシウムで乾燥し、その後濾過して濾液を濃縮し、カラムクロマトグラフィーで精製した。生成物を再びメタノール(10mL)に溶解し、10%Pd/C(76mg,0.4wt%)を入れて水素雰囲気下、常温で3時間攪拌した。反応溶液を濾過して濾液を濃縮し、その後減圧乾燥して標題化合物(673mg)を得た。
1H NMR (300 MHz, CDCl3) δ 4.53(t, 1H), 3.68-3.62(m, 6H), 3.56-3.50(m, 2H), 3.40(s, 6H), 2.87(t, 2H).
前記工程3で得た3-オキソ-1-フェニル-2,7,10-トリオキサ-4-アザドデカン-12-オイック酸(952mg,3.204mmol)をアセトニトリル(30mL)に溶解し、BOP((benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate, 1.6g,3.522mmol)、N,N-ジイソプロピルエチルアミン(N,N-diisopropylethylamine; DIPEA, 1.7mL,9.606mmol)を入れ、その後常温で30分間攪拌した。この反応溶液に工程5で得た2-(2-(2,2-ジメトキシエトキシ)エトキシ)エタン-1-アミン(650mg,3.364mmol)を入れて常温で3時間攪拌した。反応終了後、酢酸エチルを添加して重曹(炭酸水素ナトリウム)で洗浄した。その後、無水硫酸マグネシウムで乾燥し、濾過して濾液を濃縮し、カラムクロマトグラフィーで精製した。生成物を再びメタノール(8mL)に溶解し、10%Pd/C(104mg,0.4wt%)を入れて水素雰囲気下、常温で3時間攪拌した。反応溶液を濾過して濾液を濃縮し、その後減圧乾燥して中間体1(173mg)を得た。
1H NMR (300 MHz, MeOD) δ 4.52(t, 1H), 4.03(s, 2H), 3.71-3.32(m, 22H), 2.97(t, 2H).
トルエン(3.7L)にオクタデカン二酸(octadecandioic acid, 100g,318mmol)、p-トルエンスルホン酸(756mg,3.975mmol)、ベンジルアルコール(26.4mL,254.4mol)を加えて蒸留した。この反応溶液にセライトを入れ、40℃に冷却して1時間攪拌し、その後シリカゲルで濾過した。濾液を減圧濃縮し、50℃でヘプタンを加えた。固体を濾過してヘプタンで洗浄し、その後乾燥して標題化合物(67.9g)を得た。
1H NMR (300 MHz, CDCl3) δ 7.36-7.34(m, 5H), 5.11(s, 2H), 2.35(t, 4H), 1.64(t, 4H), 1.25(s, 24H).
前記工程1で得た18-(ベンジルオキシ)-18-オキソオクタデカン酸(20.0g,49.43mmol)をN-ヒドロキシスクシンイミド(6.8g,59.319mmol)、DIC(N,N’-diisopropylcarbodiimide, 12.24g,59.312mmol)をNMP(N-methyl-2-pyrrolidone, 200mL)に溶解し、その後60℃で2.
5時間攪拌した。反応終了後、反応溶液を常温に冷却して固体を濾過した。濾液に水を加え、生成された固体を濾過して水で洗浄した。固体をイソプロピルアルコールで再結晶して標題化合物(21.6g)を得た。
1H NMR (300 MHz, CDCl3) δ 7.37-7.31(m, 5H), 5.11(s, 2H), 2.83(s, 2H), 2.60(t, 2H), 2.35(t, 2H), 1.77-1.53(m, 6H), 1.25(s, 24H).
前記工程2で得た1-ベンジル18-(2,5-ジオキソピロリジン-1-イル)オクタデカノエート(10.0g,19.934mmol)、L-グルタミン酸5-t-ブチルエステル(4.3g,20.931mmol)をNMP(80mL)に入れて50℃で4時間攪拌した。反応終了後、反応溶液を常温に冷却し、水(230mL)、0.5M硫酸水素カリウム(34mL)、酢酸エチルを添加して抽出した。有機層を無水硫酸マグネシウムで乾燥し、濾過して濾液を濃縮した。生成物をNMP(75mL)に溶解し、次いでN-ヒドロキシスクシンイミド(3.7g,31.894mmol)、DCC(N,N’-dicyclohexylcarbodiimide, 5.4g,25.914mmol)を加え、その後常温で16時間攪拌した。固体を濾過して濾液を水で洗浄し、その後有機層を無水硫酸マグネシウムで乾燥し、濾過して濾液を濃縮した。カラムクロマトグラフィーで精製して標題化合物(7.1g)を得た。
1H NMR (300 MHz, CDCl3) δ 7.36-7.31(m, 5H), 6.19(d, 1H), 5.11(s, 2H), 4.64-4.57(m, 1H), 2.83(s, 4H), 2.73-2.62(m, 2H), 2.35(t, 2H), 2.24-2.17(m, 2H), 1.66-1.55(m, 4H), 1.48(s, 9H), 1.24(s, 26H).
前記工程3で得た(S)-1-t-ブチル5-(2,5-ジオキソピロリジン-1-イル)2-(18-(ベンジルオキシ)-18-オキソオクタデカンアミド)ペンタンジオエート(329mg,0.478mmol)、作製例1で準備した中間体1(170mg,0.502mmol)、トリエチルアミン(0.2mL,1.435mmol)をアセトニトリル(8mL)に入れて常温で16時間攪拌した。反応終了後、反応溶液を濃縮してカラムクロマトグラフィーで精製した。生成物をメタノール(10mL)に溶解し、10%Pd/C(140mg,0.4wt%)を入れて水素雰囲気下、常温で3時間攪拌した。反応溶液を濾過し、その後濾液を濃縮し、減圧乾燥して中間体2(300mg)を得た。
1H NMR (300 MHz, CDCl3) δ 6.87(br, 1H), 6.63(d, 1H), 4.52(t, 1H), 4.41(m, 1H), 4.04(s, 2H), 3.70-3.47(m, 18H), 3.41(s, 6H), 2.35-2.2.20(m, 7H), 1.93-1.86(m, 1H), 1.63-1.53(m, 4H), 1.46(s, 9H), 1.26(s, 24H).
タンパク質結合体の生体適合性物質として免疫グロブリンFcフラグメントを用いた。免疫グロブリンFcフラグメントは、本発明者らが出願した特許文献10「開始メチオニン残基が除去された免疫グロブリンFc領域の大量生産方法」により製造した。
作製例2で準備した中間体2(150mg,0.183mmol)をアセトニトリル(5mL)に溶解し、HATU(1-[bis(dimethylamino)methylene]-1H-1, 2, 3-triazolo[4, 5-b]pyridinium 3-oxid hexafluorophosphate, 77mg,0.201mmol)、DIPEA(0.1mL,0.549mmol)を入れ、その後常温で20分間攪拌した。
この反応溶液にN-(2-アミノエチル)マレイミド(32mg,0.183mmol)を入れて常温で12時間攪拌した。反応終了後、酢酸エチルを添加して重曹で洗浄し、その後無水硫酸マグネシウムで乾燥した。濾過して濾液を濃縮し、カラムクロマトグラフィーで精製した。生成物をジクロロメタンに溶解し、その後トリフルオロ酢酸(0.16mL,2.123mmol)を入れて常温で16時間攪拌した。反応溶液を減圧濃縮し、その後ジエチルエーテルで再結晶して標題化合物(15mg)を得た。
1H NMR (300 MHz, CDCl3) δ 9.71(s, 1H), 7.20(br, 1H), 6.97(br, 1H), 6.73(s, 2H), 5.84(br, 1H), 4.48-4.44(m, 1H), 4.05(s, 2H), 3.72-3.45(m, 22H), 2.26-2.07(m, 8H), 1.62-1.57(m, 4H), 1.25(s, 24H);
MS (ESI+): [M+H]+ m/z 840.5.
作製例2で準備した中間体2(150mg,0.183mmol)をジクロロメタン(5mL)に溶解し、N-ヒドロキシスクシンイミド(23mg,0.201mmol)、EDC(1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, 42mg,0.219mmol)を入れ、その後常温で16時間攪拌した。反応終了後、重曹で洗浄し、無水硫酸マグネシウムで乾燥した。濾過して濾液を濃縮し、カラムクロマトグラフィーで精製した。
生成物をジクロロメタンに溶解し、その後トリフルオロ酢酸(0.17mL,2.181mmol)を入れて常温で16時間攪拌した。反応溶液を減圧濃縮し、その後ジエチルエーテルで再結晶して標題化合物(25mg)を得た。
1H NMR (300 MHz, CDCl3) δ 9.70(s, 1H), 7.21(d, 1H), 7.06(br, 1H), 4.53-4.46(m, 1H), 4.05(s, 2H), 3.76-3.49(m, 16H), 2.84(s, 4H), 2.60(t, 4H), 2.48-2.2.41(m, 2H), 2.23(t, 2H), 2.12-2.04(m, 2H), 1.78-1.72(m, 2H), 1.65-1.62(m,2H), 1.25(s, 24H);
MS (ESI+): [M+H]+ m/z 815.5.
実施例1又は2で作製した、反応基としてマレイミド基とアルデヒド基とを含む脂肪酸誘導体リンカーを生理活性ポリペプチドの一種であるGLP-1、GIP及びグルカゴン受容体の全てに活性を示す三重活性体(配列番号1)のシステイン残基に結合させるために、前記三重活性体と脂肪酸誘導体リンカーを1:1~2のモル比で混合し、4~8℃で約1~2時間反応させた。ここで、三重活性体の濃度は3~5mg/mLであり、反応は20mMトリス(Tris)、pH7.0~8.0、イソプロパノール下で行った。反応液は、クエン酸塩(pH3.0)、エタノールを含む緩衝液と塩化カリウム濃度勾配を用いたSP-HP(GE,米国)カラムを用いて、脂肪酸誘導体リンカーと1:1で結合された三重活性体を精製した。
脂肪酸骨格の炭化水素鎖を形成する炭素数1~100の脂肪酸誘導体を用いてタンパク質結合体を製造した。具体的には、炭素数4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20又は21の脂肪酸誘導体を用いてタンパク質結合体を製造した。
実施例3で製造したタンパク質結合体、具体的にはGLP-1、GIP及びグルカゴン受容体の全てに活性を示す三重活性体と免疫グロブリンFcが脂肪酸誘導体を介して連結された結合体のインビボ(in vivo)薬物動態を確認し、従来の三重活性体に比べて生体内持続性が向上したかを比較した。具体的には、正常動物モデルとして広く用いられるICRマウスを薬物動態の確認に用いた。3日間の馴化期間を経た非絶食の8週齢ICRマウスを次の2つの群に分けて試験物質を投与した。
群1;三重活性体を49.2nmol/kgの用量で単回皮下注射
群2;実施例3の三重活性体と免疫グロブリンFcが脂肪酸誘導体を介して連結された結合体を5.5nmol/kgの用量で単回皮下注射
Claims (25)
- 生理活性ポリペプチドと生体適合性物質が脂肪酸誘導体を介して連結された、タンパク質結合体。
- 前記生理活性ポリペプチド及び前記生体適合性物質が脂肪酸誘導体とそれぞれ共有結合により連結された、請求項1に記載のタンパク質結合体。
- 前記脂肪酸誘導体は、脂肪酸骨格に直接又はリンカーを介して連結された少なくとも2つの反応基を有し、前記反応基を介して生理活性ポリペプチド及び生体適合性物質とそれぞれ連結された、請求項1に記載のタンパク質結合体。
- 前記反応基は、2,5-ジオキソピロリジニル、2,5-ジオキソピロリル、アルデヒド、アリールジスルフィド、ヘテロアリールジスルフィド、ハロアセトアミド(haloacetamide)又はC7-10アルキニルを含む、請求項3に記載のタンパク質結合体。
- 前記反応基は、マレイミド、N-ヒドロスクシンイミド、スクシンイミド、ホルムアルデヒド、アセトアルデヒド、プロピオンアルデヒド、ブチルアルデヒド、オルトピリジルジスルフィド(Orthopyridyl disulfide; OPSS)、ヨードアセトアミド、前記ヨードの代わりに臭素、フッ素、塩素又はアスタチンを含むハロアセトアミド、ジフルオロシクロオクチン(difluorocyclooctyne; DIFO)、ジベンゾシクロオクチン(dibenzocyclooctyne; DIBO)、ジベンゾ-アザ-シクロオクチン(Dibenzo-aza-cyclooctyne; DIBACもしくはDBCO)、ビアリールアザシクロオクチノン(biarylazacyclooctynones; BARAC)、テトラメチルチアシクロヘプチン(tetramethylthiacycloheptyne; TMTH)、ビシクロノニン(bicyclononyne; BCN)ソンドハイマージイン(Sondheimer diyne)、シクロオクチン(cyclooctyne; OCT)、モノフッ素化シクロオクチン(monofluorinated cyclooctyne; MOFO)、ジメトキシアザシクロオクチン(dimethoxyazacyclooctyne; DIMAC)、2,3,6,7-テトラメトキシ-ジベンゾシクロオクチン(2, 3, 6, 7-tetramethoxy-DIBO, TMDIBO)、スルホン化ジベンゾシクロオクチン(sulfonylated DIBO; S-DIBO)、カルボキシメチルモノベンゾシクロオクチン(carboxymethylmonobenzocyclooctyne; COMBO)、ピロロシクロオクチン(pyrrolocyclooctyne; PYRROC)又はアルキン(alkyne)である、請求項3に記載のタンパク質結合体。
- 前記リンカーは、C1-3アルキルアミノ、(C1-3アルコキシ)n(C1-3アルキルアミノ)鎖(ここで、nは1~3の整数)を含む、請求項3に記載のタンパク質結合体。
- 前記生体適合性物質に生理活性ポリペプチドと脂肪酸誘導体の連結体が少なくとも1つ連結された、請求項1に記載のタンパク質結合体。
- 前記生理活性ポリペプチドは、ホルモン、サイトカイン、インターロイキン、インターロイキン結合タンパク質、酵素、抗体、成長因子、転写調節因子、血液因子、ワクチン、構造タンパク質、リガンドタンパク質もしくは受容体、細胞表面抗原又は受容体拮抗物質である、請求項1に記載のタンパク質結合体。
- 前記生理活性ポリペプチドは、グルカゴン様ペプチド-1(GLP-1)、グルカゴン、GIP(Gastric inhibitory polypeptide)、オキシントモジュリン、キセニン(Xenin)、インスリン、CCK(Cholecystokinin)、アミリン(amylin)、ガストリン(gastrin)、グレリン(ghrelin)、PYY(peptide YY)などのように胃や腸で血糖と体重を調節するインクレチン類(incretins);レプチン(Leptin)、アディポネクチン(adiponectin)、アディポリン(adipolin)、アペリン(apelin)、カルトネクチン(cartonectin)のように脂肪質(adipose)から分泌されるアディポカイン類(adipokines);キスペプチン(Kisspeptin)、ネスファチン-1(Nesfatin-1)のように脳から分泌されるニューロペプチド類(neuropeptides);イリシン(Irisin)、マイオネクチン(myonectin)、デコリン(decorin)、フォリスタチン(follistatin)、マスクリン(musclin)のように筋肉(muscle)から分泌されるペプチド又はタンパク質類;血管作動性腸管ペプチド(Vasoactive intestinal peptide)、ナトリウム利尿ペプチド類(natriuretic peptides)、好中球増加因子(G-CSF)、ヒト成長ホルモン(hGH)、エリスロポエチン(EPO)、成長ホルモン放出ホルモン、成長ホルモン放出ペプチド、インターフェロン、インターフェロン受容体、Gタンパク質共役受容体(G protein-coupled receptor)、インターロイキン類、インターロイキン受容体、酵素類、インターロイキン結合タンパク質、サイトカイン結合タンパク質、マクロファージ活性因子、マクロファージペプチド、B細胞因子、T細胞因子、タンパク質A、アレルギー抑制因子、細胞壊死糖タンパク質、免疫毒素、リンホトキシン、腫瘍壊死因子、腫瘍抑制因子、転移成長因子、α1-アンチトリプシン、アルブミン、α-ラクトアルブミン、アポリポタンパク質E、高グリコシル化エリスロポエチン、アンジオポエチン類、ヘモグロビン、トロンビン、トロンビン受容体活性化ペプチド、トロンボモジュリン、血液因子VII、VIIa、VIII、IX及びXIII、プラスミノーゲン活性因子、フィブリン結合ペプチド、ウロキナーゼ、ストレプトキナーゼ、ヒルジン、タンパク質C、C反応性タンパク質、レニンインヒビター、コラゲナーゼインヒビター、スーパーオキシドディスムターゼ、血小板由来成長因子、上皮細胞成長因子、表皮細胞成長因子、アンジオスタチン、アンジオテンシン、骨形成成長因子、骨形成促進タンパク質、カルシトニン、アトリオペプチン、軟骨誘導因子、エルカトニン、結合組織活性化因子、組織因子経路インヒビター、卵胞刺激ホルモン、黄体形成ホルモン、黄体形成ホルモン放出ホルモン、神経成長因子、副甲状腺ホルモン、リラキシン、セクレチン、ソマトメジン、インスリン様成長因子、副腎皮質ホルモン、コレシストキニン、膵臓ポリペプチド、ガストリン放出ペプチド、コルチコトロピン放出因子、甲状腺刺激ホルモン、オートタキシン、ラクトフェリン、ミオスタチン、細胞表面抗原、ウイルス由来ワクチン抗原、モノクローナル抗体、ポリクローナル抗体並びに抗体フラグメントからなる群から選択される、請求項1に記載のタンパク質結合体。
- 前記生理活性ポリペプチドは、少なくとも2つの受容体を同時に活性化することを特徴とする、請求項1に記載のタンパク質結合体。
- 前記生体適合性物質は、ポリエチレングリコール(polyethylene glycol, PEG)、コレステロール、アルブミン及びそのフラグメント、アルブミン結合物質、特定アミノ酸配列の繰り返し単位の重合体、抗体、抗体フラグメント、FcRn結合物質、生体内結合組織又はその誘導体、ヌクレオチド、フィブロネクチン、トランスフェリン(Transferrin)、サッカライド(saccharide)、高分子重合体並びにそれらの組み合わせからなる群から選択される、請求項1に記載のタンパク質結合体。
- 前記FcRn結合物質は、免疫グロブリンFc領域を含むポリペプチドである、請求項11に記載のタンパク質結合体。
- 前記免疫グロブリンFc領域は、非グリコシル化されている、請求項12に記載のタンパク質結合体。
- 前記免疫グロブリンFc領域は、ヒンジ(hinge)領域をさらに含む、請求項12に記載のタンパク質結合体。
- 前記免疫グロブリンFc領域は、IgG、IgA、IgD、IgE、IgM、それらの組み合わせ(combination)及びそれらのハイブリッド(hybrid)からなる群から選択される、請求項12に記載のタンパク質結合体。
- 前記免疫グロブリンFc領域は、IgG4 Fcフラグメントである、請求項12に記載のタンパク質結合体。
- 前記脂肪酸誘導体は、炭素数1~40の飽和脂肪酸又は不飽和脂肪酸の誘導体である、請求項1に記載のタンパク質結合体。
- 前記脂肪酸は、ギ酸(HCOOH,formic acid)、酢酸(CH3COOH)、プロピオン酸(C2H5COOH)、酪酸(C3H7COOH)、吉草酸(C4H9COOH)、カプロン酸(C5H11COOH)、エナント酸(C6H13COOH)、カプリル酸(C7H15COOH)、ペラルゴン酸(C8H17COOH)、カプリン酸(C9H19COOH)、ウンデシル酸(C10H21COOH)、ラウリン酸(C11H23COOH)、トリデシル酸(C12H25COOH)、ミリスチン酸(C13H27COOH)、ペンタデシル酸(C14H29COOH)、パルミチン酸(C15H31COOH)、マルガリン酸(C16H33COOH)、ステアリン酸(C17H35COOH)、ノナデシル酸(C18H37COOH)、アラキジン酸(C19H39COOH)、ベヘン酸(C21H43COOH)、リグノセリン酸(C23H47COOH)、セロチン酸(C25H51COOH)、ヘプタコサン酸(C26H53COOH)、モンタン酸(C28H57COOH)、メリシン酸(C29H59COOH)、ラッセル酸(C31H63COOH)、アクリル酸(CH2=CHCOOH)、クロトン酸(CH3CH=CHCOOH)、イソクロトン酸(CH3CH=CHCOOH)、ウンデシレン酸(CH2=CH(CH2)8COOH)、オレイン酸(C17H33COOH)、エライジン酸(C17H33COOH)、セトレイン酸(C21H41COOH)、エルカ酸(C21H41COOH)、ブラシジン酸(C21H41COOH)、ソルビン酸(C5H7COOH,F2)、リノール酸(C17H31COOH,F2)、リノレン酸(C17H29COOH,F3)、アラキドン酸(C19H31COOH,F4)、プロピオール酸(CH≡CCOOH)及びステアロール酸(C17H31COOH,F1)からなる群から選択される脂肪酸又はその誘導体である、請求項17に記載のタンパク質結合体。
- 前記脂肪酸は、パルミチン酸、ミリスチン酸、ステアリン酸又はオレイン酸の脂肪酸又はその誘導体である、請求項18に記載のタンパク質結合体。
- (a)少なくとも2つの反応基を有する脂肪酸誘導体を介して生理活性ペプチドと生体適合性物質を連結するステップと、
(b)前記(a)ステップの反応結果物であるタンパク質結合体を分離するステップとを含む、タンパク質結合体を製造する方法。 - 前記(a)ステップは、
(a1)脂肪酸誘導体の一方の反応基に生体適合性物質と生理活性ポリペプチドのいずれか一方を連結するステップと、
(a2)前記(a1)ステップの反応混合物から脂肪酸に生体適合性物質と生理活性ポリペプチドのいずれか一方が連結された連結体を分離するステップと、
(a3)前記(a2)ステップで分離された連結体の脂肪酸誘導体の他方の反応基に生体適合性物質と生理活性ポリペプチドの他方を連結し、脂肪酸の反応基がそれぞれ生理活性ポリペプチド及び生体適合性物質に連結されたタンパク質結合体を生成するステップとを含む、請求項20に記載のタンパク質結合体を製造する方法。 - 前記(a1)ステップ及び前記(a3)ステップは、還元剤の存在下で行われる、請求項21に記載のタンパク質結合体を製造する方法。
- 前記還元剤は、シアノ水素化ホウ素ナトリウム(NaCNBH3)、水素化ホウ素ナトリウム、ジメチルアミンホウ酸塩、ピコリンボランコンプレックス又はピリジンホウ酸塩(borane pyridine)である、請求項22に記載のタンパク質結合体を製造する方法。
- 前記(a1)ステップにおいて、生理活性ポリペプチドと脂肪酸誘導体の反応モル比は1:1~1:20であり、生体適合性物質と脂肪酸の反応モル比は1:1~1:20である、請求項21に記載のタンパク質結合体を製造する方法。
- 前記(a3)ステップにおいて、(a2)ステップで分離された連結体と生体適合性物質又は生理活性ポリペプチドの反応モル比は1:0.5~1:20である、請求項21に記載のタンパク質結合体を製造する方法。
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WO2015055801A1 (en) * | 2013-10-17 | 2015-04-23 | Zealand Pharma A/S | Acylated glucagon analogues |
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CN109069569B (zh) | 2023-02-14 |
EP3384935A1 (en) | 2018-10-10 |
EP3384935A4 (en) | 2019-08-21 |
WO2017095201A1 (ko) | 2017-06-08 |
JP6989503B2 (ja) | 2022-01-05 |
KR20170065016A (ko) | 2017-06-12 |
CN109069569A (zh) | 2018-12-21 |
JP2019501144A (ja) | 2019-01-17 |
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