JP2019532019A - オキシム含有リンケージを有する第viii因子部分のコンジュゲート - Google Patents
オキシム含有リンケージを有する第viii因子部分のコンジュゲート Download PDFInfo
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- JP2019532019A JP2019532019A JP2019502676A JP2019502676A JP2019532019A JP 2019532019 A JP2019532019 A JP 2019532019A JP 2019502676 A JP2019502676 A JP 2019502676A JP 2019502676 A JP2019502676 A JP 2019502676A JP 2019532019 A JP2019532019 A JP 2019532019A
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- factor viii
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- 230000002797 proteolythic effect Effects 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 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
- 230000002285 radioactive effect Effects 0.000 description 1
- MUPFEKGTMRGPLJ-ZQSKZDJDSA-N raffinose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO[C@@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O2)O)O1 MUPFEKGTMRGPLJ-ZQSKZDJDSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
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- 230000004044 response Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
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- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 229910000077 silane Inorganic materials 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 235000011083 sodium citrates Nutrition 0.000 description 1
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- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 description 1
- 235000019254 sodium formate Nutrition 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 235000011008 sodium phosphates Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
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- 239000008117 stearic acid Substances 0.000 description 1
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- 210000002784 stomach Anatomy 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 125000005017 substituted alkenyl group Chemical group 0.000 description 1
- 125000004426 substituted alkynyl group Chemical group 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
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- 239000006188 syrup Substances 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 229920001897 terpolymer Polymers 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
- DRDVJQOGFWAVLH-UHFFFAOYSA-N tert-butyl n-hydroxycarbamate Chemical compound CC(C)(C)OC(=O)NO DRDVJQOGFWAVLH-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 125000005063 tetradecenyl group Chemical group C(=CCCCCCCCCCCCC)* 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 150000004992 toluidines Chemical class 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 238000005199 ultracentrifugation Methods 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 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
- 210000005253 yeast cell Anatomy 0.000 description 1
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Abstract
Description
本願は、全体が参照により本明細書に組み込まれる2016年7月22日に出願された米国仮特許出願第62/365,836号に対する優先権による利益を主張する。
出血性疾患の分野では、タンパク質(例えば、第VIII因子等の)が患者に投与されて、出血性疾患に対処し又は出血性疾患を寛解し得る。(中でも)非コンジュゲート化対応物と比較して長い半減期の利点を有する、第VIII因子のPEG化のための様々な手法が記載されている。第VIII因子のコンジュゲーションは、成功してはいるが、(例えば)第VIII因子の更なるコンジュゲートを提供することによって、以前の成功が改善される可能性があり得る。従って、本開示は、この必要性及び他の必要性の解決を模索する。
CH3O−CH2CH2O−(CH2CH2O)m’−CH2CH2−O−NH=CH−(FVIII)
を有し、式中、(m’)は、0〜約4,000の範囲であり、FVIIIは、第VIII因子部分であり、〜CH−(FVIII)は、第VIII因子部分の酸化炭水化物のカルボニル基の残基である。
から選択される構造を有し、式中、上記の分枝状構造の各々に関する(m’)又は(n)は、独立して約1〜約4,000の範囲であり、Xは、実例的な実施形態の任意の1つ以上において前述した通りである。前述の分枝状構造に関するいくつかの実施形態において、(m’)又は(n)の各々は、約227である。
を有する高分子オキシアミン試薬を提供し、式中、Xは1つ以上の原子を含むスペーサーであり、各(n)は、約1〜約4,000の範囲である。
第VIII因子等の血液因子のランダムPEG化は、以前に記載されており、治療的に有益な生成物をもたらすことができる。例えば、米国特許第7,199,223号明細書を参照されたい。しかしながら、第VIII因子等のタンパク質における非常に多数のリシンに起因して、ランダムPEG化は、例えばコンジュゲート混合物の再現可能な調製、生成物の特徴付け、及び生成物が治療的に有用であるように十分な生理活性を維持する、該生成物の形成、において困難が存在し得る。
例示的コンジュゲートの記載に先立って、水溶性ポリマーの特徴を下記に詳解する。水溶性ポリマーの様々な実施形態は、各々、本開示の対象である反応性水溶性ポリマー、コンジュゲート、組成物、関連方法等に適用される。
HO−CH2CH2O−(CH2CH2O)m’−CH2CH2−OH
式中、(m’)は、典型的には0〜約4,000、好ましくは約20〜約1,000の範囲である。前述のPEGは、PEGジオールとも称され、第VIII因子部分、例えば第VIII因子部分のカルボキシル基との反応に好適な、PEG反応関与体を提供するための出発物質として使用され得る。いくつかの場合、ポリエチレングリコールポリマーにおける反復単位の数は、本明細書に(m’)ではなく(n)により指定され得る。そのような場合、本明細書に提供する(m’)の実例的な値及び範囲は、(n)にも適用される。上記した前述のポリマー、α−,ω−ジヒドロキシポリ(エチレングリコール)は、HO−PEG−OHとして短縮形で表すことができ、−PEG−記号は、以下の構造単位:
−CH2CH2O−(CH2CH2O)m’−CH2CH2−
(式中、(m’)は、上記に定義した通りである)を表すことができることが理解される。
CH3O−CH2CH2O−(CH2CH2O)m’−CH2CH2−
(式中、(m’)は、上述した通りである。)
を有し得る。
(式中:
polya及びpolybは、メトキシポリ(エチレングリコール)等のPEGs(同じ又は異なる)であり;
R’’は、H、メチル又はPEGバックボーン等の非反応性部分であり;
P及びQは、非反応性リンケージである。好ましい実施形態において、分枝状PEGポリマーは、メトキシポリ(エチレングリコール)二置換リシンであり、第VIII因子部分との反応後、オキシム含有リンケージを有するコンジュゲートを形成する。)
により表す。式中:Xは、スペーサー部分であり、各Zは、規定長さの原子の鎖によってCHに結合したオキシアミンである。Z官能基を分枝炭素原子に結合する原子の鎖は、連結基の役割を果たし、例えばアルキル鎖、エーテル鎖、エステル鎖、アミド鎖及びそれらの組み合わせを含み得る。米国特許第6,362,254号明細書は、本明細書に開示した第VIII因子部分コンジュゲートを提供するのに使用可能な様々な分岐状PEG構造を開示している。
式中、各(m’)は、独立して、2〜4000、又は約1〜約3,000、又は1〜約2,000、好ましくは約20〜約1,000の値を有する整数である。
PEG−X−O−NH2
(式中、Xは、上記に一般に記載されているスペーサーである)を有するものを含む。
CH3O−CH2CH2O−(CH2CH2O)m’−CH2CH2−O−NH2
式中、(m’)は、典型的には0〜約4,000、又は約0〜約3,000、又は約0〜約2,000、好ましくは約20〜約1,000の範囲である。上記に示した構造を有する特定の実例的線状PEGオキシアミンは、例えば、約5,000ダルトン、約10,000ダルトン、約20,000ダルトン、又は約30,000ダルトンの分子量を有するであろう。前述の線状PEGオキシアミンは、スペーサーを含まず;このPEG試薬では、ポリエチレングリコールはオキシアミン基に共有結合している。この式に包含される高分子試薬は、文献に記載されている手法に従って合成することができ、また商業的に(例えば、JenKem Technology USA,Plano,TXから)得ることができる。例えば、PEGオキシアミンは、S.Albrecht,et al,Synthesis,2006,1635−1638に記載されているように、tert−ブチルN−ヒドロキシカルバメートをPEG−O−メタンスルホネートによりOーアルキル化した後、酸性N−脱保護することにより、メトキシ−PEG(即ち、末端ヒドロキシル基の変換)から調製することができる。そのような高分子試薬を用いて調製される代表的な第VIII因子部分コンジュゲートは、支持実施例に記載されている。
式中、本明細書に提供する各構造の(m’)又は(n)は、典型的には約1〜約4,000、又は約1〜約3,000、又は1〜約2,000、好ましくは約20〜約1,000の範囲である。この分枝状PEG試薬は、本明細書で時にはRU−PEG2−オキシアミンと称される。上記の構造を有する特定の分枝状PEGsは、各々が約10,000ダルトンの分子量を有する2つのPEG「アーム」を有し、従って各PEGアームにおいて(m’)が約227である。前述の構造による追加の実例的分枝状PEGオキシアミンは、各々が約5,000ダルトン、又は10,000ダルトン(前述のように)、又は20,000ダルトン等の分子量を有する2つのPEG「アーム」又は分枝を有する。上記の分枝状構造において、2つのPEGアーム、CH3−(OCH2CH2O)m’〜は、2−(4−((2−(2−(アミノオキシ)アセトアミド)エチル)アミノ)−4−オキソブトキシ)プロパン−1,3−ジイルジカルバメートである有機コアから延びる。上記に示す分枝状構造において、分枝状PEGとオキシアミン基との間に介在するセグメント又はスペーサーは、〜(CH2)3C(O)NH(CH2)2NHC(O)CH2〜であるが、上述したような任意の好適なスペーサーを使用することができる。
のものを含み、式中、PEGは、任意のPEG部分、特に本明細書に記載されるものを包含し、Xは、上記に詳細に記載した、任意のスペーサー部分である。オキシム含有リンケージを介して第VIII因子部分に結合したPEG部分に関する好適な及び例示的な分子量値は、上記に記載されている。例えば、1つの実例的第VIII因子部分コンジュゲートは、概して以下に記載され、スペーサーXは一般式に存在しない:
CH3O−CH2CH2O−(CH2CH2O)m’−CH2CH2−O−NH=CH−(FVIII)
式中、(m’)は、典型的には0〜約4,000の範囲であり、F8は、カルボニル含有第VIII因子部分の残基である。即ち、オキシムの「CH」は、PEG−オキシアミン試薬との反応前の第VIII因子部分のカルボニル基の炭素原子を表す。
が挙げられ、式中、上記の各分枝状構造の(m’)又は(n)は、典型的には約1〜約4,000、又は約1〜約3,000、又は1〜約2,000、好ましくは約20〜約1,000の範囲である。いくつかの実施形態において、各PEG「アーム」は、約10,000ダルトンの分子量を有し、従って(m’)は各PEGアーム内で約227である。
次いで、例えば、t−Boc保護基の場合、トリフルオロ酢酸を用いて保護基を除去して、所望の生成物を提供する。生成物は、典型的には上述したようにアルコール、例えばイソプロピルアルコールを用いた沈殿により回収され、以下の構造(その塩形態を含む)を有する:
逆ウレタン(RU)−PEG2−アミン、20kDの調製
エチレンジアミン(1.20g、0.0200モル)及びトリエチルアミン(1.01g、0.0200モル)の無水ジクロロメタン(200mL)溶液に、固体逆ウレタンPEG2−NHS 20K(反応スキームの一番左、20.0g、0.0020モル)を30分間加え、この混合物を窒素雰囲気下で一晩撹拌した。次に、混合物を濾過し、減圧下で濃縮し、600mLのイソプロピルアルコールに加えた。沈殿生成物を濾去し、真空下で乾燥した。収率19.2g。
t−Boc保護逆ウレタンPEG2−オキシミン(Oxymine)、20kDの調製
RU−PEG2−アミン20K(19.2g、0.0019モル)の無水ジクロロメタン(500mL)溶液に、2−(tert−ブトキシカルボニルアミノオキシ)酢酸(0.367g、0.0019モル)を加えた後、N−(3−ジメチルアミノプロピル)−N’−エチルカルボジイミド塩酸塩(0.368g、0.0019モル)及びN,N−ジメチルピリジン(0.059g、0.0048モル)を加えた。この混合物を窒素雰囲気下で一晩撹拌し、次にこれをろ過し、減圧下で濃縮し、500mLのイソプロピルアルコールに加えた。沈殿生成物を濾去し、真空下で乾燥した。収率19.2g。
逆ウレタンPEG2−オキシアミン、20kDの調製
t−Boc保護逆ウレタンPEG2−オキシミン(Oxymine)20K(19.2g、0.0019モル)の無水ジクロロメタン(100mL)及びトリフルオロ酢酸(100mL)の混合物中の溶液を、室温で一晩撹拌した。次に、溶液を減圧下で濃縮し、500mLのイソプロピルアルコールに加えた。沈殿生成物を濾去し、真空下で一晩乾燥した。収率19.2g。(白色粉末、Mn=21946、多分散度1.004)。
線状mPEG20kD−オキシアミンを用いた完全長rFVIIIの炭水化物PEG化
例示的PEG化反応に使用した第VIII因子は、20mM HEPES、0.75M NaCl、2mM CaCl2、0.1%ツイーン80、pH7.1中3.57mg/mlの市販の完全長第VIII因子(ADVATE,Shire)であった。以後、この組成物を「FVIII溶液」と称する。実例的反応性アミノオキシ−PEGとの反応の前に第VIII因子を酸化して、炭水化物のビシナルジオールを、オキシアミンPEG試薬との反応に好適なアルデヒドに変換した。
線状MPEG5kD−オキシアミンを用いた完全長rFVIIIの炭水化物PEG化
上記の実施例4に記載したように、線状PEG−5kDオキシアミンを第VIII因子上の炭水化物と反応させて(即ち、第VIII因子の酸化、PEG化及び未反応アルデヒド官能基のキャッピング)、対応するPEG−5kD−オキシム−第VIII因子コンジュゲートを調製した。特定の反応関与体量をPEG化反応中に変動させて(例えば、第VIII因子に対するPEG試薬の比)、異なるPEG化度を有するコンジュゲートを調製した。
20kD−RU−PEG−オキシアミンを用いた完全長rFVIIIの炭水化物PEG化
第VIII因子の酸化:過ヨウ素酸塩酸化に先立って、FVIII溶液のpHを500mM MES、pH5.5溶液によりpH7.1から6.0に調整した。新たに調製した過ヨウ素酸ナトリウム溶液の0.1M溶液0.0592mLを7.9mL(3.27mg/mL)のpH6.0 FVIII溶液に移動した。反応混合物を暗所内にて室温で30分間撹拌した。過ヨウ素酸塩酸化後、酸化FVIIIサンプルを、10mL Zeba(商標)スピン脱塩カラムを用いて、製造業者の指示書に従って20mM MES、0.15M NaCl、2mM CaCl2、pH6.0緩衝液中に緩衝液交換した。要約すると、カラムを遠心分離にかけて貯蔵液体を除去した後、5mLの20mM MES、0.15M NaCl、2mM CaCl2、pH6.0緩衝液を3サイクルで添加し、遠心分離を行ってカラムを平衡化した。酸化FVIIIサンプルをスピンカラムに適用し、該カラムを再度遠心分離にかけて、酸化FVIIIを20mM MES、0.15M NaCl、2mM CaCl2、pH6.0緩衝液中に回収した。緩衝液交換後、FVIII濃度は3.17mg/mLと決定された。
Claims (20)
- オキシム含有リンケージを介して第VIII因子部分の酸化された炭水化物に共有結合した水溶性ポリマーを含むコンジュゲート。
- 構造POLY−X−O−N=CH−FVIIIを有し、式中、POLYは水溶性ポリマーであり、Xは1つ以上の原子を含む任意のスペーサーであり、FVIIIは第VIII因子部分であり、〜CH−FVIIIは、前記第VIII因子部分の酸化炭水化物のカルボニル基の残基である、請求項1に記載のコンジュゲート。
- Xが加水分解に安定である、請求項2のコンジュゲート。
- Xが、O、S及びNHから選択される少なくとも1つのヘテロ原子を含む、請求項2又は3に記載のコンジュゲート。
- Xが、約5個の原子〜約25個の原子の原子長を有する、請求項2〜4のいずれか一項に記載のコンジュゲート。
- 前記水溶性ポリマーが、ポリ(アルキレンオキシド)である、請求項1〜5のいずれか一項に記載のコンジュゲート。
- 前記水溶性ポリマーが、2,000ダルトン〜85,000ダルトンの重量平均分子量を有する、請求項1〜6のいずれか一項に記載のコンジュゲート。
- 構造:
CH3O−CH2CH2O−(CH2CH2O)m’−CH2CH2−O−NH=CH−(FVIII)
を有し、式中、(m’)は、0〜約4,000の範囲であり、FVIIIは、第VIII因子部分であり、〜CH−(FVIII)は、前記第VIII因子部分の酸化炭水化物のカルボニル基の残基である、請求項1に記載のコンジュゲート。 -
から選択される構造を有し、
式中、上記の分枝状構造の各々に関する(m’)又は(n)は、独立して、約1〜約4,000の範囲である、請求項1〜6のいずれか一項に記載のコンジュゲート。 - (m’)又は(n)が約227である、請求項9に記載のコンジュゲート。
- 前記第VIII因子部分が、ヒト組換えBドメイン削除第VIII因子である、請求項1〜10のいずれか一項に記載のコンジュゲート。
- 前記第VIII因子部分が、ヒト組換え完全長第VIII因子である、請求項1〜10のいずれか一項に記載のコンジュゲート。
- 請求項1〜12のいずれか一項に記載のコンジュゲートと、薬学的に許容され得る賦形剤とを含む組成物。
- 血友病Aの処置のための、請求項13に記載の組成物を患者に投与することを含む方法。
- 以下の構造:
(式中、Xは、1つ以上の原子を含むスペーサーであり、各(n)は、約1〜約4,000の範囲である。)を有する高分子オキシアミン試薬。 - Xが、−NH(CH2)1〜6−であり又はこれを含む、請求項15に記載の高分子オキシアミン試薬。
- Xが、−NH(CH2)2−であり又はこれを含む、請求項16に記載の高分子オキシアミン試薬。
- Xが、−NH(CH2)1〜6NHC(O)CH2−である、請求項15に記載の高分子オキシアミン試薬。
- Xが、−NH(CH2)2NHC(O)CH2−である、請求項18に記載の高分子オキシアミン試薬。
- 血友病A等の血液疾患の処置に使用するための請求項13に記載の組成物。
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