JP2023029851A - 第viii因子両性イオンポリマーコンジュゲート - Google Patents
第viii因子両性イオンポリマーコンジュゲート Download PDFInfo
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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 230000012846 protein folding Effects 0.000 description 1
- 230000020978 protein processing Effects 0.000 description 1
- 230000030788 protein refolding Effects 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- VJSSTIHJOHSMPR-UHFFFAOYSA-N purin-4-ol Chemical compound C1=NC=NC2(O)C1=NC=N2 VJSSTIHJOHSMPR-UHFFFAOYSA-N 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 1
- 229920013730 reactive polymer Polymers 0.000 description 1
- 101150079601 recA gene Proteins 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 210000003705 ribosome Anatomy 0.000 description 1
- 108091092562 ribozyme Proteins 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 238000005464 sample preparation method Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 229960001153 serine Drugs 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 238000001542 size-exclusion chromatography Methods 0.000 description 1
- IFGCUJZIWBUILZ-UHFFFAOYSA-N sodium 2-[[2-[[hydroxy-(3,4,5-trihydroxy-6-methyloxan-2-yl)oxyphosphoryl]amino]-4-methylpentanoyl]amino]-3-(1H-indol-3-yl)propanoic acid Chemical compound [Na+].C=1NC2=CC=CC=C2C=1CC(C(O)=O)NC(=O)C(CC(C)C)NP(O)(=O)OC1OC(C)C(O)C(O)C1O IFGCUJZIWBUILZ-UHFFFAOYSA-N 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 125000003011 styrenyl group Chemical class [H]\C(*)=C(/[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- WPLOVIFNBMNBPD-ATHMIXSHSA-N subtilin Chemical compound CC1SCC(NC2=O)C(=O)NC(CC(N)=O)C(=O)NC(C(=O)NC(CCCCN)C(=O)NC(C(C)CC)C(=O)NC(=C)C(=O)NC(CCCCN)C(O)=O)CSC(C)C2NC(=O)C(CC(C)C)NC(=O)C1NC(=O)C(CCC(N)=O)NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C1NC(=O)C(=C/C)/NC(=O)C(CCC(N)=O)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)CNC(=O)C(NC(=O)C(NC(=O)C2NC(=O)CNC(=O)C3CCCN3C(=O)C(NC(=O)C3NC(=O)C(CC(C)C)NC(=O)C(=C)NC(=O)C(CCC(O)=O)NC(=O)C(NC(=O)C(CCCCN)NC(=O)C(N)CC=4C5=CC=CC=C5NC=4)CSC3)C(C)SC2)C(C)C)C(C)SC1)CC1=CC=CC=C1 WPLOVIFNBMNBPD-ATHMIXSHSA-N 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- XCAQIUOFDMREBA-UHFFFAOYSA-N tert-butyl n-[(2-methylpropan-2-yl)oxycarbonyl]carbamate Chemical compound CC(C)(C)OC(=O)NC(=O)OC(C)(C)C XCAQIUOFDMREBA-UHFFFAOYSA-N 0.000 description 1
- OCUICOFGFQENAS-UHFFFAOYSA-N tert-butyl n-[2-[2-(2-aminoethoxy)ethoxy]ethyl]carbamate Chemical compound CC(C)(C)OC(=O)NCCOCCOCCN OCUICOFGFQENAS-UHFFFAOYSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003507 tetrahydrothiofenyl group Chemical group 0.000 description 1
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- XSROQCDVUIHRSI-UHFFFAOYSA-N thietane Chemical compound C1CSC1 XSROQCDVUIHRSI-UHFFFAOYSA-N 0.000 description 1
- 125000004001 thioalkyl group Chemical group 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- CNHYKKNIIGEXAY-UHFFFAOYSA-N thiolan-2-imine Chemical compound N=C1CCCS1 CNHYKKNIIGEXAY-UHFFFAOYSA-N 0.000 description 1
- ATGUDZODTABURZ-UHFFFAOYSA-N thiolan-2-ylideneazanium;chloride Chemical compound Cl.N=C1CCCS1 ATGUDZODTABURZ-UHFFFAOYSA-N 0.000 description 1
- 229960002898 threonine Drugs 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000759 toxicological effect Toxicity 0.000 description 1
- 150000003623 transition metal compounds Chemical class 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 229960004441 tyrosine Drugs 0.000 description 1
- 238000005199 ultracentrifugation Methods 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 229920001567 vinyl ester resin Polymers 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 238000000196 viscometry Methods 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
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- 229930003231 vitamin Natural products 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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- 239000001993 wax Substances 0.000 description 1
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Images
Classifications
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- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/36—Blood coagulation or fibrinolysis factors
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- A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
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- A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
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- C07K14/745—Blood coagulation or fibrinolysis factors
- C07K14/755—Factors VIII, e.g. factor VIII C (AHF), factor VIII Ag (VWF)
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- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
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- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
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Abstract
Description
により、ポリマーが3本以上のアームを有する。場合により、ポリマーが3、4、5、6、7、8、9、10、11または12本のアームを有する。場合により、ポリマーが3、6または9本のアームを有し、好ましくはポリマーが9本のアームを有する。
本発明は、ホスホリルコリンなどの、親水基または両性イオンを有する高分子量(MW)ポリマーを提供する。本発明によると、高MWポリマーを作製するための方法および新規な出発材料も提供される。本発明によると、高MWポリマーと、機能的物質(本明細書で定義される)とのコンジュゲートも提供される。国際特許出願番号PCT/US2011/032768号パンフレットおよびPCT/US2007/005372号パンフレットが、全ての目的のために参照により本明細書に組み込まれる。
「ポリマー」は、結びついている一連のモノマー群を指す。高MWポリマーは、それだけに限らないが、アクリレート、メタクリレート、アクリルアミド、メタクリルアミド、スチレン、ビニル-ピリジン、ビニル-ピロリドンおよびビニルエステル(酢酸ビニルなど)を含むモノマーから調製される。さらなるモノマーが本発明の高MWポリマーに有用である。2つの異なるモノマーを使用する場合、2つのモノマーを「コモノマー」と呼び、異なるモノマーを共重合して単一ポリマーを形成することを意味する。ポリマーは直鎖であっても分岐であってもよい。ポリマーが分岐である場合、各ポリマー鎖を「ポリマーアーム」と呼ぶ。開始剤部分と連結したポリマーアームの末端が近位端であり、ポリマーアームの成長鎖末端が遠心端である。ポリマーアームの成長鎖末端上では、ポリマーアーム末端基がラジカルスカベンジャーであっても別の基であってもよい。
mediated polymerization)(NMP)であってもよい。重合は、退行移動などの、「偽」制御重合であってもよい。開始剤がATRPに適している場合、これはホモリシス開裂して、ラジカル重合を開始することができるラジカルである開始剤断片、I、および成長ポリマー鎖のラジカルと反応して重合を可逆的に停止するラジカルスカベンジャー、I’を形成することができる不安定な結合を含む。ラジカルスカベンジャーI’は、典型的にはハロゲンであるが、ニトリルなどの有機部分であってもよい。
」は元のスルフヒドリル保有基の残りとチオールの硫黄原子の付着点を示す)
を有する-S-マレイミド基を形成する構造:
凝固第VIII因子(FVIII)は、極めて低濃度で血漿中を循環しており、フォン・ヴィルブランド因子(VWF)と非共有結合的に結合している。止血中、FVIIIはVWFから分離し、カルシウムおよびリン脂質または細胞膜の存在下で活性化の速度を増強することによって活性化第IX因子(FIXa)媒介第X因子(FX)活性化の補因子として作用する。
thrombin potential)分析等などの当技術分野で周知の技術(例えば、Chandlerら、上記)によってインビトロで評価することができる。本発明による第VIII因子分子は、野生型ヒトFVIIIの活性の少なくとも約10%、少なくとも20%、少なくとも30%、少なくとも40%、少なくとも50%、少なくとも60%、少なくとも70%、少なくとも80%、少なくとも90%および100%または100%超のFVIII活性さえ有する。
を有する。
を有する。R1は、好ましくはNH2-、OH-およびSHからなる群から選択される。より好ましくは、R1がNH2-である。
からなる群から選択される}
を有する。好ましくは、XがBrである。
からなる群から選択される。好ましくは、両性イオンがホスホリルコリンである。
R9は
からなる群から選択される}
を有する活性化エステルである。
を有する。好ましくは、ZがBrであり、Xが4、8または12であり、Yが1~10である。より好ましくは、Yが4である。
を有する。
より好ましくは、Yが4であり、Xが4、8または12であり、モノマーがHEMA-pcである。
を有する化合物が提供される。好ましくは、ZがBrであり、Xが4、8または12であり、Yが1~10である。より好ましくは、Yが4である。
を有するポリマーが提供される。ポリMPCは、重合反応、例えば、ATRPで、2-(メタクリロイルオキシエチル)-2’-(トリメチルアンモニウムエチル)ホスフェートを用いて調製される。好ましくは、ポリマーの総分子量が約500,000~約1,000,000ダルトンである。より好ましくは、ポリマーの総分子量が約650,000~約850,000ダルトンである。さらにより好ましくは、ポリマーの総分子量が約750,000ダルトンである。
1H NMR(400MHz CDCl3):δ=Need to put in data 1.44(s,9H,OCCH3),1.96(s,18H,CC(CH3)2Br),3.31 (q,J=4.8Hz,2H,OCNHCH2CH2O),3.5-3.6(m,12H),3.99(s,2H,OCH2C),4.32(s,6H,CCH2OC=O),5.0(br s,1H,CH2NHC=OO),6.8(br s,1H,CH2NHC=OC),LC-MS(ES,m/z):[M+H]+ 計算値 C30H51Br3N2O12+H=871.1;実測値 871.8.
1H NMR(400MHz CDCl3):δ=1.94(s,18H,CC(CH3)2Br),3.2(br,2H,OCNHCH2CH2O),3.5-3.8(m,12H),3.99(s,2H,OCH2C),4.34(s,6H,CCH2OC=O),7.11(br t,1H,CH2NHC=O),7.99(br,3H,NH3+).
LC-MS(ES,m/z):[M+H]+ 計算値 C25H43Br3N2O10+H=771.1;実測値 771.6.
100mL丸底に、化合物D(2.96g、4.4mmol、1.0当量)、ジエチルエーテル(20mL)、引き続いて水(16mL)を添加した。氷浴を用いてフラスコを0℃に冷却した。これに、臭化水素酸溶液(水中48重量%)(1.64mL、14.5mmol、3.3当量)を添加した。反応物を0℃で1時間迅速に攪拌した。有機層を分離し、水層を0℃の反応フラスコに戻し、ここにジエチルエーテル(20mL)を添加し、攪拌を15分間続けた。有機層を再度分離し、水層を0℃の反応フラスコに戻し、ここにジエチルエーテル(20mL)を添加し、攪拌を10分間続けた。有機層を分離し、1M水酸化ナトリウム水溶液を添加して水層をpH4.5に調整した。真空下でのアセトニトリルとの共沸によって水を除去すると、化合物E2.5g(3.85mmol、87%)が白色固体として得られた。
200mL丸底フラスコに、窒素下で、ビス2,2-[(2-ブロモイソブチリル)ヒドロキシメチル]プロピオン酸(参照により本明細書に組み込まれる、米国特許出願第13/641,342号明細書の実施例7に記載されるように調製される)(2.32g、5.37mmol、3.3当量)および化合物E(1.06g、1.63mmol、1.0当量)、引き続いてジメチルホルムアミド(15mL)、次いで、ジイソプロピルエチルアミン(3.4mL、19.5mmol、12当量)を入れた。これに、プロピルホスホン酸無水物溶液(酢酸エチル中50重量%、3.7mL、5.87mmol、3.5当量)を添加した。反応物を60分間攪拌した。反応物を、水(1mL)を添加してクエンチし、予備的HPLCカラムにロードし、水中50%アセトニトリル(0.1%トリフルオロ酢酸を含む)から95%アセトニトリル(0.1%トリフルオロ酢酸を含む)で溶出した。生成物を含む管をプールし、真空下で濃縮し、凍結し、凍結乾燥機に入れた。これにより、化合物F640mg(0.39mmol、24%)が得られた。
氷浴を用いてフラスコを0℃に冷却した。これに、プロピルホスホン酸無水物溶液(酢酸エチル中50重量%、2.5mL、4.04mmol、5当量)を約6分間にわたって添加した。
以下の構造を有するTFA/アミン塩開始剤(化合物P)を以下の通り合成した:
実施例6 両性イオンポリマーの調製
開始剤を、典型的には約100mg/mLのDMF中ストック溶液として調製する。開始剤およびリガンド(2,2’-ビピリジル)をシュレンク管に導入した。得られた溶液を、ドライアイス/アセトン混合物を用いて-78℃に冷却し、真空下で10分間脱気した。管にアルゴンを充填し、触媒(特に指示しない限り、CuBr)を、アルゴン下で維持して、シュレンク管に導入した(開始剤上の原子臭素/触媒(CuBr)/リガンドのモル比を1/1/2に維持した)。溶液が直ちに濃褐色になった。シュレンク管を密閉し、短サイクルの真空/アルゴンを印加することによって直ちにパージした。窒素下で維持したグローブボックス中で調製した規定量のモノマーと200標準強度の脱気エタノールを混合することによって、HEMA-PCの溶液を調製した。モノマー溶液をシュレンク管に(カニューレを介して)滴加した(および光によって均質化した 攪拌:不要)。温度を-78℃で維持した。溶液からの起泡が止むまで、完全な真空を反応混合物に少なくとも10~15分間印加した。次いで、管にアルゴンを充填し、室温に加温した。溶液を攪拌し、重合が進行するにつれて、溶液が粘性になった。3~8時間またはちょうど一晩静置した後、Cu(I)をCu(II)に酸化するために、反応物を空気への直接暴露によってクエンチすると、混合物が青緑色になり、銅触媒を除去するためにこれをシリカカラムに通過させた。回収した溶液を回転蒸発によって濃縮し、得られた混合物をテトラヒドロフランを用いて沈殿させるかまたは水に対して透析し、引き続いて凍結乾燥させると自由流動性白色粉末が得られた。表2は本発明により作製した代表的なポリマーを示している。
バイオポリマー粉末を120℃で90分間加熱した場合、熱脱保護後に、保護されたマレイミドバイオポリマーがMpをより高い値にシフトする傾向があることが認められた。これにより、Mpのアップシフトの量がバイオポリマー(Mp、構造等)に依存するので、バイオポリマー製造がより困難になる。脱保護の代替法が必要とされる。
実施例8 マレイミドコンジュゲーション可能3-アームポリマーの調製
以下の構造を有するマレイミドコンジュゲーション可能ポリマー(B3)を以下の通り調製した:
以下の構造を有するマレイミドコンジュゲーション可能6-アームポリマー(F4)を以下の通り合成した:
以下の構造を有するマレイミドコンジュゲーション可能6-アームポリマー(S)を以下の通り合成した:
以下の構造を有するマレイミドコンジュゲーション可能9-アームポリマー(Q)を以下の通り合成した:
哺乳動物発現野生型(FVIII-WT)は、マレイミドまたはヨードアセトアミドなどの反応基を含むチオール反応性ポリマーを用いて、酸化してジスルフィド架橋を形成する、またはBドメイン中に存在する遊離システインの場合には、不対遊離システインがコンジュゲーションのために利用可能となるのを防ぐ媒体からの代謝産物によって遮断(キャップ化)される全てのシステイン残基を有することが知られている。これらのキャップ化部分をTCEPまたはDTTなどの還元剤を用いて除去し、引き続いて還元剤を除去し、タンパク質を再折り畳みすることができる。
FVIII-WTのTCEP処理型中の明らかにされた遊離システインチオールを、種々のマレイミドと表4に示されるように分子量、構造およびリンカー長が異なる上記のヨード-アセトアミド官能化ポリマーとのコンジュゲーションに使用した。コンジュゲーション反応混合物は、50mM MOPS pH7、10mM CaCl2、200mM NaCl、0.01%Tween80ならびに20mM Tris pH8、200mM
NaCl、10mM CaCl2および0.01%Tween80に溶解した5~100×モル過剰量のマレイミドポリマー中、約0.5mg/mLのFVIII-WTタンパク質を含んでいた。反応を4℃で一晩進行させ、引き続いて非還元条件と還元条件の両方の下で、SDS-PAGEによりコンジュゲーション効率を分析した。結果は、単一重鎖-Bドメイン(HC-BD)バンドの消失を示したが、ドメインの切断型およびゲル上部の高分子量バンドの同時出現は示さず、新たに形成したコンジュゲートの存在を示した。各反応のコンジュゲーション効率(ポリマーを含まない対照と比べた、残りのHC-Bドメインバンドの百分率として計算)を表4に示す。
以下の表5は、表3の開始剤OまたはPからの9-分岐ヘマ-PCポリマーから形成したコンジュゲートの活性を示している。
Claims (84)
- 組換えFVIII(rFVIII)と両性イオンポリマーとを含むコンジュゲートであって、前記ポリマーは、1つまたは複数のモノマー単位を含み、そして、少なくとも1つのモノマー単位が、両性イオン基を含む、前記コンジュゲート。
- 前記両性イオン基が、ホスホリルコリンを含む、請求項1に記載のコンジュゲート。
- 前記モノマーが、2-(アクリロイルオキシエチル)-2’-(トリメチルアンモニウムエチル)ホスフェートを含む、請求項2に記載のコンジュゲート。
- 前記モノマーが、2-(メタクリロイルオキシエチル)-2’-(トリメチルアンモニウムエチル)ホスフェート(HEMA-PC)を含む、請求項2に記載のコンジュゲート。
- 前記rFVIIIが、Bドメインの一部または全部の欠失を有する、請求項4に記載のコンジュゲート。
- 前記ポリマーが、3本以上のアームを有する、請求項1~5のいずれか一項に記載のコンジュゲート。
- 前記ポリマーが、2、3、4、5、6、7、8、9、10、11または12本のアームを有する、請求項1~5のいずれか一項に記載のコンジュゲート。
- 前記ポリマーが、3、6または9本のアームを有する、請求項1~5のいずれか一項に記載のコンジュゲート。
- 前記ポリマーが、9本のアームを有する、請求項1~5のいずれか一項に記載のコンジュゲート。
- 前記コンジュゲートの前記ポリマー部分が、300,000~1,750,000ダルトンの間のピーク分子量を有する、請求項1~9のいずれか一項に記載のコンジュゲート。
- 前記コンジュゲートの前記ポリマー部分が、500,000~1,000,000ダルトンの間のピーク分子量を有する、請求項10に記載のコンジュゲート。
- 前記コンジュゲートの前記ポリマー部分が、600,000~800,000ダルトンの間のピーク分子量を有する、請求項11に記載のコンジュゲート。
- 前記ポリマーが、9本のアームを有する、請求項12に記載のコンジュゲート。
- 前記rFVIIIが、前記ポリマーと共有結合している、請求項4に記載のコンジュゲート。
- 前記ポリマーが、rFVIIIのアミノ基、ヒドロキシル基、スルフヒドリル基およびカルボキシル基の少なくとも1つと共有結合している、請求項14に記載のコンジュゲート。
- 前記スルフヒドリル基が、rFVIII中のシステイン残基からのものである、請求項15に記載のコンジュゲート。
- 前記システイン残基が、組換えシステイン残基である、請求項16に記載のコンジュゲート。
- 前記組換えシステイン残基が、Y81C、F129C、K377C、H378C、K422C、Q468C、L491C、L504C、K556C、K570C、D1795C、Q1796C、R1803C、K1804C、K1808C、K1810C、T1821C、K1813C、N1864C、T1911C、N2118C、Q2091C、F2093CおよびQ2284Cからなる群から選択され、前記残基が、前記組換え第VIII因子を配列番号1と最大限に整列させた場合の、配列番号1中の対応する残基から番号付けされる、請求項17に記載のコンジュゲート。
- 前記システイン残基が、rFVIII中に自然に存在する、請求項16に記載のコンジュゲート。
- 前記システイン残基が、Bドメイン中にある、請求項19に記載のコンジュゲート。
- 前記システイン残基が、1293C、1373C、1604Cおよび1636Cからなる群から選択される、請求項20に記載のコンジュゲート。
- 前記システイン残基が、1604Cおよび1636Cからなる群から選択される、請求項21に記載のコンジュゲート。
- 前記ポリマーが、3、6または9本のアームを有する、請求項22に記載のコンジュゲート。
- 前記ポリマーが、9本のアームを有する、請求項23に記載のコンジュゲート。
- 前記コンジュゲートの前記ポリマー部分が、100,000~1,500,000ダルトンの間のピーク分子量を有する、請求項24に記載のコンジュゲート。
- 前記コンジュゲートの前記ポリマー部分が、500,000~1,000,000ダルトンの間のピーク分子量を有する、請求項25に記載のコンジュゲート。
- 前記コンジュゲートの前記ポリマー部分が、600,000~850,000ダルトンの間のピーク分子量を有する、請求項26に記載のコンジュゲート。
- Bドメインの少なくとも一部を含む組換えFVIII(rFVIII)と、両性イオンポリマーとを含むコンジュゲートであって、前記ポリマーは1つまたは複数のモノマー単位を含み、少なくとも1つのモノマー単位は両性イオン基を含み、そして前記ポリマーは前記Bドメイン中のシステイン残基を介して前記rFVIIIとコンジュゲーションしており、rFVIIIの分子1個当たり1個の分岐ポリマーがコンジュゲーションしている前記コンジュゲート。
- 前記ポリマーが、場合により9個の分岐を有する、分岐ポリマーである、請求項29に記載のコンジュゲート。
- 前記ポリマーが、前記Bドメインの一部の中の2個の最もC末端のシステイン残基の1個であるシステイン残基を介してコンジュゲーションしている、請求項28または29に記載のコンジュゲート。
- 少なくとも20時間のヒト中でのインビボ半減期を有する、請求項28に記載のコンジュゲート。
- Bドメインの少なくとも一部を含む軽鎖および重鎖を含む組換えFVIII(rFVIII)と、両性イオンポリマーとを含むコンジュゲートの分子を含む組成物であって、前記ポリマーは1つまたは複数のモノマー単位を含み、少なくとも1つのモノマー単位は両性イオン基を含み、前記ポリマーは前記Bドメイン中のシステイン残基を介して前記rFVIIIとコンジュゲーションしており、そして組成物中の前記コンジュゲートの分子の少なくとも80、90、95または99%は前記Bドメインの同じ部分を有し、rFVIIIの分子1個当たり1個のポリマーがコンジュゲーションしている、前記組成物。
- 前記ポリマーが、場合により9個の分岐を有して分岐している、請求項32に記載の組成物。
- 前記重鎖が、配列番号1の少なくとも残基1~1604を含む、請求項32または33に記載の組成物。
- 前記重鎖が、配列番号1の少なくとも残基1~1636を含む、請求項32または33に記載の組成物。
- 前記重鎖が、配列番号1の少なくとも残基1~1648を含む、請求項32または33に記載の組成物。
- 前記重鎖が、配列番号1の残基1~1648からなる、請求項32または33に記載の組成物。
- 前記Bドメインの少なくとも一部が、無傷Bドメインである、請求項32または33に記載の組成物。
- 前記分岐ポリマーが、前記Bドメイン中の2個の最もC末端のシステインの1個であるシステインを介してコンジュゲーションしている、請求項31~38のいずれか一項に記載の組成物。
- 請求項1~39のいずれか一項に記載のコンジュゲートを含む医薬組成物。
- 治療上有効量の請求項1~40のいずれか一項に記載のコンジュゲートまたは組成物を血友病を患っている対象に投与するステップを含む、血友病を治療する方法。
- 治療上有効量の請求項1~41のいずれか一項に記載のコンジュゲートまたは組成物を、血友病の対象に、前記対象が外部または内部出血していることを分かっていない時に投与するステップを含む血友病の対象の予防方法であって、ここで、前記コンジュゲートが、その後の出血後の凝固を促進するために血液中で持続するものとする、前記方法。
- 前記コンジュゲートまたは組成物が、1週間に1回以下の頻度で投与される、請求項42に記載の方法。
- 前記コンジュゲートまたは組成物が、毎週~毎月の間で投与される、請求項42に記載の方法。
- 前記対象が、血友病を有さない対照の対象における平均FVIII活性の1%、3%または5%超のFVIII活性のトラフレベルを有する、請求項42に記載の方法。
- 前記対象が、前記ポリマーとコンジュゲーションしていないFVIIIの以前の投与からFVIIIに対する抗体を発達させている、請求項41~45のいずれか一項に記載の方法。
- ポリマー-機能的物質コンジュゲートを合成する方法であって、前記コンジュゲートは1種または複数の機能的物質と、1本または複数のポリマーアームとを有し、各前記ポリマーアームは、1つまたは複数のモノマー型を有し、前記型の少なくとも1つは、両性イオンを含み、そして、前記方法が、
a.1つまたは複数のポリマー合成開始剤部分と第1の反応基とを含む開始剤を、重合に適した1つまたは複数のモノマー型と組み合わせるステップであって、前記モノマー型の少なくとも1つは両性イオンを含み;前記モノマー型はポリマー合成開始剤部分で反応してポリマーを形成して重合開始剤を得るステップと;
b.第2および第3の反応基を含むリンカー部分を前記重合開始剤とカップリングして未反応反応基を有するリンカー重合開始剤を得るステップと;
c.1種または複数の機能的物質を前記リンカー重合開始剤の前記未反応反応基とカップリングして前記ポリマー-機能的物質コンジュゲートを得るステップと
を含む、前記方法。 - R1が、NH2-、OH-およびSHからなる群から選択される、請求項48に記載の方法。
- R1が、NH2-である、請求項49に記載の方法。
- R2が、アルキル、置換アルキル、アルキレン、アルコキシ、カルボキシアルキル、ハロアルキル、シクロアルキル、環状アルキルエーテル、アルケニル、アルケニレン、アルキニル、アルキニレン、シクロアルキレン、ヘテロシクロアルキル、ヘテロシクロアルキレン、アリール、アリーレン、アリーレン-オキシ、ヘテロアリール、アミノ、アミドまたはこれらの任意の組み合わせである、請求項48に記載の方法。
- mが、4である、請求項52に記載の方法。
- XがBrである、請求項54に記載の方法。
- 前記モノマーが、2-(メタクリロイルオキシエチル)-2’-(トリメチルアンモニウムエチル)ホスフェート(HEMA-PC)および2-(アクリロイルオキシエチル)-2’-(トリメチルアンモニウムエチル)ホスフェートからなる群から選択される、請求項47に記載の方法。
- 前記モノマーが、2-(メタクリロイルオキシエチル)-2’-(トリメチルアンモニウムエチル)ホスフェートである、請求項60に記載の方法。
- Zが、Brである、請求項64に記載の方法。
- Xが4、8または12であり、そしてYが1~10である、請求項65に記載の方法。
- Yが4である、請求項66に記載の方法。
- 前記機能的物質が、タンパク質である、請求項64に記載の方法。
- 前記タンパク質が、ヒトFVIIIを含む、請求項68に記載の方法。
- 前記FVIIIが、組換えFVIII(rFVIII)である、請求項69に記載の方法。
- 前記rFVIIIが、哺乳動物宿主細胞から精製される、請求項70に記載の方法。
- 前記FVIIIが、前記Bドメインの一部または全部の欠失を含む、請求項70に記載の方法。
- Yが4であり、Xが4、8または12であり、そして前記モノマーがHEMA-pcである、請求項73に記載の方法。
- ZがBrである、請求項75に記載の化合物。
- Xが4、8または12であり、Yが1~10である、請求項75に記載の化合物。
- Yが4である、請求項77に記載の化合物。
- 総分子量が約500,000~約1,000,000ダルトンである、請求項79に記載のポリマー。
- 総分子量が約650,000~約850,000ダルトンである、請求項80に記載のポリマー。
- 総分子量が約750,000ダルトンである、請求項81に記載のポリマー。
- Xが4、8または12であり、Yが1~10である、請求項82に記載のポリマー。
- Yが4である、請求項83に記載のポリマー。
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EP3041513A4 (en) | 2017-04-12 |
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US10702608B2 (en) | 2020-07-07 |
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SI3041513T1 (sl) | 2020-11-30 |
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