JP6732056B2 - 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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- JP6732056B2 JP6732056B2 JP2019000261A JP2019000261A JP6732056B2 JP 6732056 B2 JP6732056 B2 JP 6732056B2 JP 2019000261 A JP2019000261 A JP 2019000261A JP 2019000261 A JP2019000261 A JP 2019000261A JP 6732056 B2 JP6732056 B2 JP 6732056B2
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- 230000002797 proteolythic effect 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
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 238000009877 rendering 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
- 102220104281 rs879254319 Human genes 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
- FQENQNTWSFEDLI-UHFFFAOYSA-J sodium diphosphate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]P([O-])(=O)OP([O-])([O-])=O FQENQNTWSFEDLI-UHFFFAOYSA-J 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
- 239000013589 supplement Substances 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
- 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
- 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
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000011285 therapeutic regimen Methods 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
- 150000003573 thiols Chemical class 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
- 238000001890 transfection Methods 0.000 description 1
- 150000003623 transition metal compounds Chemical class 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 239000010981 turquoise Substances 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
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
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- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- 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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- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- 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
- A61K38/37—Factors VIII
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—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
- A61K47/50—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
- A61K47/51—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
- A61K47/56—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
- A61K47/59—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
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—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
- A61K47/50—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
- A61K47/51—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
- A61K47/56—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
- A61K47/59—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
- 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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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—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
- A61K47/50—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
- A61K47/51—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
- 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
- A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
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- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F120/00—Homopolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride, ester, amide, imide or nitrile thereof
- C08F120/02—Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
- C08F120/10—Esters
- C08F120/34—Esters containing nitrogen, e.g. N,N-dimethylaminoethyl (meth)acrylate
- C08F120/36—Esters containing nitrogen, e.g. N,N-dimethylaminoethyl (meth)acrylate containing oxygen in addition to the carboxy oxygen, e.g. 2-N-morpholinoethyl (meth)acrylate or 2-isocyanatoethyl (meth)acrylate
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- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/32—Polymers modified by chemical after-treatment
- C08G65/329—Polymers modified by chemical after-treatment with organic compounds
- C08G65/333—Polymers modified by chemical after-treatment with organic compounds containing nitrogen
- C08G65/3332—Polymers modified by chemical after-treatment with organic compounds containing nitrogen containing carboxamide group
- C08G65/33324—Polymers modified by chemical after-treatment with organic compounds containing nitrogen containing carboxamide group acyclic
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- General Health & Medical Sciences (AREA)
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- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
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- Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Graft Or Block Polymers (AREA)
- Other Resins Obtained By Reactions Not Involving Carbon-To-Carbon Unsaturated Bonds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
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。
されないが、本明細書に開示されるものを含む多数の治療用タンパク質が知られている。
を指す。ホスホリルコリンは、両性イオン基であり、塩(分子内塩など)ならびにそのプロトン化および脱プロトン化型を含む。
れば、分子中の追加の反応基または保護基の存在によって変化する。適当な保護基には、Greeneら、「Protective Groups In Organic Synthesis」、第3版、John Wiley and Sons,Inc.ニューヨーク、1999による論文中に見出されるものが含まれる。
基、すなわち、二価炭化水素基を指す。アルキニレンと連結した2つの部分は、アルキニレンの同じ原子と連結していても異なる原子と連結していてもよい。アルキニレン基には、それだけに限らないが、エチニレン、プロピニレン、ブチニレン、sec−ブチニレン、ペンチニレンおよびヘキシニレンが含まれる。
は二置換されたフェニル、特にフェニルである。
置換基R’は、水素または未置換(C1〜C6)アルキルから選択される。
」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:
薬学的に許容される賦形剤の非限定的な例としては、水、NaCl、生理食塩水、乳酸リンゲル液、規定ショ糖、規定ブドウ糖などが挙げられる。
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。
70〜330kDaの単鎖前駆体として合成される。血漿から精製される場合(例えば、「血漿由来」または「血漿性」)、FVIIIは重鎖(A1−A2−B)および軽鎖(A3−C1−C2)で構成される。軽鎖の分子質量は80kDaであるが、Bドメイン内のタンパク質分解のために、重鎖は90〜220kDaの範囲にある。ドメインは配列番号1中以下の通り描写されるA1、残基Ala1〜Arg372;A2、残基Ser373〜Arg740;B、残基Ser741〜Arg1648;A3、残基Ser1690〜Ile2032;C1、残基Arg2033〜Asn2172;およびC2、残基Ser2173〜Tyr2332。残りの配列、残基Glu1649〜Arg1689は通常、第VIII因子軽鎖活性化ペプチドと呼ばれる。第VIII因子は、フォン・ヴィルブランド因子からこれを解離し、凝血原機能を有する第VIIIa因子を形成するトロンビンまたは第Xa因子によってタンパク質分解的に活性化される。第VIIIa因子の生物学的機能は、第X因子活性化に対して第IXa因子の触媒効率を数桁増加させることである。トロンビン活性化第VIIIa因子は160kDa A1/A2/A3−C1−C2である。
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。
は微量注入による組換えDNAの原核または真核細胞への導入、(iii)前記形質転換細胞の培養、(iv)例えば、構成的または誘導でのrFVIIIの発現、および(vi)精製rFVIIIを得るための、(v)例えば、培養培地から、または形質転換細胞を回収することによる、前記rFVIIIの単離のための当技術分野で既知の任意の方法を含む。
てもよい。あるいは、十分な活性が保持される限り、本発明のポリマーとFVIIIのカップリングのために、FVIIIのいずれの適当なアミンまたは炭水化物部分を使用してもよい。
傷Bドメインの2個の最もC末端のシステインに整列させた部分のC末端システインである)。rFVIIIの任意の所与の分子中の単一システインを介した分岐ポリマーの結合が、rFVIII活性のいずれかがある場合に、実質的な減損なしに、rFVIIIをポリマーと両性イオン電荷で囲むのに有利である。ポリマーをコンジュゲートする単一システインは、rFVIIIの異なる分子で同じであっても異なっていてもよい。機構の理解は本発明の実施に要求されないが、rFVIIIを囲むポリマー上の両性イオン電荷が、結果としてrFVIIIとタンデムに移動してrFVIIIをインビボでの分解過程から保護する水分子の層を実質的に固定すると考えられる。
頻度で、例えば、毎週間隔以下での投与で投与することができる。いくつかの予防体制では、コンジュゲートを毎週〜毎月の間、例えば、毎週、隔週または毎月の頻度で投与する。減少した投与頻度にもかかわらず、コンジュゲートを受けている対象は、現在の方法と比べて増加したFVIIIのトラフレベルを有することができる。現在の方法では、予防体制の対象は、血友病でない対照の対象における平均レベルの1%未満のレベルのFVIII活性のトラフレベルで、約18時間/週を過ごす。1%未満のレベルは、対象を急性出血の高いリスクにさらす。本方法を用いると、対象を、少なくとも1週間、1か月、1年または無期限の期間、血友病でない対照の対象におけるFVIII活性の平均レベルの約1%、3%または5%超のトラフレベルで維持することができる。活性は、Bドメインの処理によるFVIIIの活性化を含むインビトロ発色アッセイで評価することができる。
、コンジュゲートが9本のアームを有する。
コンジュゲートすることが望まれる場合、より長いリンカー配列をポリマーにスナッピングすることができる。対照的に、より小さな機能的物質は比較的短いリンカー配列を必要とする可能性がある。
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。
を有する構造を含む。
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。
あるいは、R4、R5およびR6はそれぞれ
さらに他の好ましい実施形態では、R4、R5およびR6がそれぞれ
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。
るために、使用することができる賦形剤には、例えば、水、ポリオールおよび糖が含まれる。懸濁剤を調製するために、油(例えば、植物油)を使用して水中油型または油中水型懸濁剤を得ることができる。
めに反応性にしてもよい。したがって、各システイン架橋は、理論的には、2個の反応性チオール求核剤を形成する。遊離システインの場合、1個のチオール求核剤が還元によって形成される。使用する条件に応じて、TCEPまたはDTTによる還元は、付随する活性の損失を伴う適当なタンパク質の折り畳みの損失をもたらす可能性がある。しかしながら、適当な条件下でタンパク質の再折り畳みを可能にすることによって、活性を回復させることができる。
実施例1 3−アーム「スナッピング」開始剤の調製
以下の構造を有するTFA/アミン塩開始剤(化合物B)を以下の通り合成した。
量%、0.16mL、0.26mmol、1.2当量)を1分間にわたって添加した。反応物を室温に加温し、1.5時間攪拌した。反応物を、水を添加してクエンチし、次いで、水と酢酸エチルを用いて分配した。有機層を分離し、水層を酢酸エチルで抽出した。合わせた有機層を水、飽和重炭酸ナトリウム水溶液、水、0.5Mクエン酸水溶液、水で洗浄し、次いで、乾燥させ(硫酸ナトリウム)、濾過し、真空下で濃縮した。残渣をシリカゲルカラム(60mL)に加え、70%酢酸エチルと30%ヘキサンで溶出した。生成物を含む管をプールし、真空下で濃縮すると、化合物A150mg(0.17mmol、77%)が得られた。
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.
以下の構造を有するTFA/アミン塩開始剤(化合物F1)を合成した。
100mL丸底フラスコに、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。
以下の構造を有するTFA/アミン塩開始剤(化合物L)を以下の通り合成した。
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O)を以下の通り合成した。
71mL、0.982mmol、6当量)を入れた。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%、0.205mL、0.327mmol、2当量)を約1分間にわたって添加した。反応物を室温に加温し、30分間攪拌した。反応物を、水(10mL)、飽和重炭酸ナトリウム水溶液(10mL)および酢酸エチル(40mL)を添加してクエンチした。有機層を分離し、水層を酢酸エチル(25mL)で抽出した。合わせた有機層を飽和重炭酸ナトリウム水溶液(10mL)、0.5Mクエン酸水溶液(10mL)、水(10mL)および飽和塩化ナトリウム水溶液(10mL)で洗浄し、次いで、乾燥させ(硫酸ナトリウム)、濾過し、真空下で濃縮した。さらに精製することなく使用した残渣により化合物M0.5g(0.172mmol、105%)が得られた。
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:
rpm3000)に30分間入れる。濾液を分析のための除去する一方、保持液を水(8mL)で希釈および混合する。遠心分離機手順をさらに3回繰り返し、その後、保持液を取り出し、バイアルに入れる。Amicon膜管を水(2×約2mL)ですすぎ、これを保持液と合わせ、これを凍結し、凍結乾燥機に入れた。これにより、B3 262mg(93%)が白色粉末として得られた。
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:
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(R)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。
充填した3mL樹脂にロードした。カラム流は、重力によって達成し、未結合分画を回収した。カラムを、合わせた21カラム体積(CV)の20mM NaClを含む洗浄緩衝液で追い出し、洗浄した。次いで、結合したタンパク質を、100、150、200、250および500mM NaClを含む異なるNaCl濃度を含む洗浄緩衝液で溶出した。各NaCl濃度について、少なくとも5CVの溶出液を回収した。分画をSDS−PAGE分析に供してタンパク質が溶出したNaCl濃度を決定した。予備的分析は、遊離タンパク質が150mM塩で溶出し、コンジュゲートが100mM塩で溶出することを示した。このことは、コンジュゲートおよび遊離タンパク質について単一ピークを与えたSuperose 6カラムでの分析的ゲル濾過によって確認された。コンジュゲートプールを濃縮し、0.2μm SpinX遠心分離フィルタを用いて滅菌濾過して、最終プロセス収率40%で2.16mg/mLの最終濃度(タンパク質に関するように)を得た。
Claims (11)
- 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、
前記方法が、
下記式を有する開始剤を提供するステップと:
R1は、−NH2、−OH、−SH、
R2は、アルコキシとアミドとの組み合わせであり、そして
R3は、
からなる群から選択される)である);
前記開始剤と、重合に適した1種または複数のモノマー型とを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種が両性イオンを含み、前記モノマー型が反応して重合開始剤を形成する、前記ステップと;
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含むリンカー重合開始剤を得るステップと;
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。 - 前記モノマーが、
からなる群から選択される、請求項1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1又は2に記載の方法。
- R2が、
である、請求項1〜3のいずれか一項に記載の方法。 - 両性イオンがホスホリルコリンである、請求項1〜4のいずれか一項に記載の方法。
- 前記リンカー部分が、
R9は、
である、請求項1〜5のいずれか一項に記載の方法。 - 前記開始剤が、下記式:
を有する、請求項1〜6のいずれか一項に記載の方法。 - 前記リンカー−重合開始剤が、式:
を有する、請求項7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1に記載の方法。
- 前記タンパク質が、ヒトFVIIIを含む、請求項9に記載の方法。
- 前記ポリマー−機能的物質コンジュゲートのポリマー部分の総分子量が約500,000〜約1,000,000ダルトンである、請求項1に記載の方法。
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JP2016530302A (ja) | 2016-09-29 |
ES2819217T3 (es) | 2021-04-15 |
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JP7232796B2 (ja) | 2023-03-03 |
JP2020183404A (ja) | 2020-11-12 |
EP3041513A2 (en) | 2016-07-13 |
LT3041513T (lt) | 2020-11-25 |
EP3041513B1 (en) | 2020-08-05 |
WO2015035342A3 (en) | 2015-04-30 |
WO2015035342A2 (en) | 2015-03-12 |
US11590235B2 (en) | 2023-02-28 |
US20160199501A1 (en) | 2016-07-14 |
JP2023029851A (ja) | 2023-03-07 |
HUE052447T2 (hu) | 2021-04-28 |
PT3041513T (pt) | 2020-09-07 |
JP2019081765A (ja) | 2019-05-30 |
EP3760639A1 (en) | 2021-01-06 |
US10702608B2 (en) | 2020-07-07 |
JP6463361B2 (ja) | 2019-01-30 |
PL3041513T3 (pl) | 2021-01-25 |
DK3041513T3 (da) | 2020-10-26 |
SI3041513T1 (sl) | 2020-11-30 |
US20200261590A1 (en) | 2020-08-20 |
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