JP2022000043A - Il−2部分とポリマーとのコンジュゲート - Google Patents
Il−2部分とポリマーとのコンジュゲート Download PDFInfo
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- 230000000704 physical effect Effects 0.000 description 1
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- 229940001584 sodium metabisulfite Drugs 0.000 description 1
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- 239000001488 sodium phosphate Substances 0.000 description 1
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- 235000011008 sodium phosphates Nutrition 0.000 description 1
- 229940054269 sodium pyruvate Drugs 0.000 description 1
- ITQQKJGENXWHJK-UHFFFAOYSA-M sodium;hydrogen carbonate;sulfurous acid Chemical compound [Na+].OC(O)=O.OS([O-])=O ITQQKJGENXWHJK-UHFFFAOYSA-M 0.000 description 1
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- 238000004611 spectroscopical analysis Methods 0.000 description 1
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- 239000008107 starch Substances 0.000 description 1
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- 125000005017 substituted alkenyl group Chemical group 0.000 description 1
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- 239000001384 succinic acid Substances 0.000 description 1
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- 238000010189 synthetic method Methods 0.000 description 1
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- ISXSCDLOGDJUNJ-UHFFFAOYSA-N tert-butyl prop-2-enoate Chemical compound CC(C)(C)OC(=O)C=C ISXSCDLOGDJUNJ-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
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- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
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Abstract
Description
本出願は、米国特許法第119条(e)に基づき、2010年11月12日に出願された米国仮特許出願第61/413,236号明細書に対する優先権の利益を主張し、その開示は全体として参照により本明細書に援用されるものとする。
例えば、本発明は、以下の項目を提供する。
(項目1)
水溶性ポリマーに共有結合したIL−2部分の残基を含むコンジュゲート。
(項目2)
前記水溶性ポリマーに共有結合した前記IL−2部分が、放出可能な連結を介して共有結合している、項目1に記載のコンジュゲート。
(項目3)
前記水溶性ポリマーに共有結合した前記IL−2部分が、安定な連結を介して共有結合している、項目1に記載のコンジュゲート。
(項目4)
前記水溶性ポリマーが分枝鎖状水溶性ポリマーである、項目1〜3のいずれか一項に記載のコンジュゲート。
(項目5)
前記水溶性ポリマーが、ポリ(アルキレンオキシド)、ポリ(ビニルピロリドン)、ポリ(ビニルアルコール)、ポリオキサゾリン、及びポリ(アクリロイルモルホリン)からなる群から選択されるポリマーである、項目1〜4のいずれか一項に記載のコンジュゲート。
(項目6)
前記水溶性ポリマーがポリ(アルキレンオキシド)である、項目5に記載のコンジュゲート。
(項目7)
前記ポリ(アルキレンオキシド)がポリ(エチレングリコール)である、項目6に記載のコンジュゲート。
(項目8)
前記ポリ(エチレングリコール)が、ヒドロキシ、アルコキシ、置換アルコキシ、アルケノキシ、置換アルケノキシ、アルキノキシ、置換アルキノキシ、アリールオキシ及び置換アリールオキシからなる群から選択されるエンドキャップ部分で末端がキャップされている、項目7に記載のコンジュゲート。
(項目9)
前記水溶性ポリマーが、約500ダルトン〜約100,000ダルトンの範囲の重量平均分子量を有する、項目1〜7のいずれか一項に記載のコンジュゲート。
(項目10)
前記コンジュゲートが、前記IL−2部分の残基のアミン基に共有結合している、項目1〜10のいずれか一項に記載のコンジュゲート。
(項目11)
1個、2個、3個又は4個の水溶性ポリマーが前記IL−2部分の残基に結合している、項目1〜10のいずれか一項に記載のコンジュゲート。
(項目12)
1個、2個又は3個の水溶性ポリマーが前記IL−2部分の残基に結合している、項目1〜10のいずれか一項に記載のコンジュゲート。
(項目13)
1個又は水溶性ポリマーが前記IL−2部分の残基に結合している、項目1〜10のいずれか一項に記載のコンジュゲート。
(項目14)
1個の水溶性ポリマーが前記IL−2部分の残基に結合している、項目1〜10のいずれか一項に記載のコンジュゲート。
(項目15)
水溶性ポリマーに共有結合したIL−2部分の残基を含むコンジュゲートであって、前記水溶性ポリマーが、共有結合する前には、N−ヒドロキシスクシンイミジル基を有するポリマー試薬である、コンジュゲート。
(項目16)
項目1〜15のいずれか一項に記載のコンジュゲートと、薬学的に許容可能な賦形剤とを含む医薬組成物。
(項目17)
項目16に記載の医薬組成物を個人に投与するステップを含む方法。
(項目18)
コンジュゲート形成条件下で、IL−2部分をポリマー試薬と接触させるステップを含むコンジュゲートの作製方法。
(項目19)
IL−2部分をコードする単離核酸分子であって、配列番号5に示される配列と少なくとも95%の配列同一性を有する配列を含む核酸分子。
(項目20)
DNAである、項目19に記載の核酸分子。
(項目21)
項目19に記載の核酸分子を含む発現ベクター。
(項目22)
プラスミドである、項目21に記載の発現ベクター。
(項目23)
項目22に記載のベクターを含むインビトロ宿主細胞。
(項目24)
タンパク質を、前記タンパク質のサイズより小さい孔径を有する透析バッグ内に入れてタンパク質が入った透析バッグを形成するステップと、前記タンパク質が入った透析バッグをタンパク質変性剤不含溶液に供するステップとを含む方法。
(項目25)
IL−2部分と、5〜15mM酢酸ナトリウムと、2〜7%トレハロースとを含む組成物。
先述のとおり、一般的にこのコンジュゲートは、水溶性ポリマーと直接、又はスペーサー部分を介して共有結合したIL−2部分の残基を含む。本明細書で使用されるとき、用語「IL−2部分」は、コンジュゲート形成前のIL−2部分、並びに非ペプチド性水溶性ポリマーと結合した後のIL−2部分を指すものとする。しかしながら、本来のIL−2部分が非ペプチド性水溶性ポリマーと結合すると、ポリマーとの連結に伴い1つ又は複数の共有結合が存在するため、IL−2部分は僅かに変化することが理解されるであろう。多くの場合に、この別の分子と結合して僅かに変化した形態のIL−2部分は、IL−2部分の「残基」と称される。
先に考察したとおり、各コンジュゲートは水溶性ポリマーと結合したIL−2部分を含む。水溶性ポリマーに関して、水溶性ポリマーは非ペプチド性で、非毒性であり、天然には存在せず、且つ生体適合性である。生体適合性に関して、物質は、生体組織に関連して物質を単独で、又は別の物質(例えば、IL−2部分などの活性薬剤)と共に使用すること(例えば、患者への投与)に伴う有益な作用が、臨床医、例えば医師が評価するとき、いかなる有害な作用にも勝る場合に、生体適合性であると見なされる。非免疫原性に関して、物質は、生体内での物質の意図される使用によって望ましくない免疫反応(例えば、抗体の形成)が生じることがない場合か、又は、免疫反応が生じる場合にも、かかる反応が、臨床医の評価で臨床的に有意、又は重要とは見なされない場合に、非免疫原性であると見なされる。非ペプチド性水溶性ポリマーは、生体適合性且つ非免疫原性であることが特に好ましい。
HO−CH2CH2O−(CH2CH2O)n−CH2CH2−OHであり、式中、(n)は典型的には0〜約4,000の範囲である。
−CH2CH2O−(CH2CH2O)n−CH2CH2−
式中、(n)は上記に定義されるとおりである。
CH3O−CH2CH2O−(CH2CH2O)n−CH2CH2−OH
式中、(n)は上記のとおりである。
polya及びpolybは、メトキシポリ(エチレングリコール)などのPEG骨格であり(いずれも同じか、又は異なる);
R”は、H、メチル又はPEG骨格などの非反応性部分であり;及び
P及びQは、非反応性の連結である。好ましい実施形態において、分枝鎖状PEGポリマーはメトキシポリ(エチレングリコール)二置換リジンである。使用される具体的なIL−2部分によっては、二置換リジンの反応性エステル官能基がさらに修飾され、IL−2部分内の標的基との反応に好適な官能基を形成してもよい。
式中:Xは、1個又は複数の原子のスペーサー部分であり、各Zは、一定長の原子鎖によってCHと連結された活性化末端基である。国際公開第99/45964号パンフレットは、本発明の1つ又は複数の実施形態に用いることが可能な様々なフォーク型PEG構造を開示している。Z官能基を分枝鎖状炭素原子と連結する原子鎖はテザー基として働き、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。
−PEG−CO2−PEG−+H2O→−PEG−CO2H+HO−PEG−
式中:
(n)は、2〜4000の値を有する整数であり;
Xは、スペーサー部分であり;
R1は、有機ラジカルであり;及び
IL−2は、IL−2部分の残基である。
式中:
各(n)は、独立して2〜4000の値を有する整数であり;
Xはスペーサー部分であり;
(b)は、2〜6の値を有する整数であり;
(c)は、2〜6の値を有する整数であり;
R2は、存在するごとに、独立してH又は低級アルキルであり;及び
IL−2は、IL−2部分の残基である。
式中:
各(n)は、独立して2〜4000の値を有する整数であり;
(a)は、0又は1のいずれかであり;
Xは、存在するとき、1つ又は複数の原子を含むスペーサー部分であり;
(b’)は、0又は1〜10の値を有する整数であり;
(c)は、1〜10の値を有する整数であり;
R2は、存在するごとに、独立してH又は有機ラジカルであり;
R3は、存在するごとに、独立してH又は有機ラジカルであり;及び
IL−2は、IL−2部分の残基である。
式中:
POLY1は、第1の水溶性ポリマーであり;
POLY2は、第2の水溶性ポリマーであり;
X1は、第1のスペーサー部分であり;
X2は、第2のスペーサー部分であり;
Hαは、イオン化水素原子であり;
R1は、H又は有機ラジカルであり;
R2は、H又は有機ラジカルであり;
(a)は、0又は1のいずれかであり;
(b)は、0又は1のいずれかであり;
Re1は、存在するとき、第1の電子改変基であり;
Re2は、存在するとき、第2の電子改変基であり;及び
(FG)は、活性薬剤のアミノ基と反応してカルバメート連結などの放出可能な連結を形成することが可能な官能基である。この式中、さらに確定的な構造を有するポリマー試薬が企図される:
式中、POLY1、POLY2、X1、X2、R1、R2、Hα及び(FG)の各々は、先に定義したとおりであり、及びRe1は第1の電子改変基であり;及びRe2は第2の電子改変基である。
式中:
POLY1は、第1の水溶性ポリマーであり;
POLY2は、第2の水溶性ポリマーであり;
X1は、第1のスペーサー部分であり;
X2は、第2のスペーサー部分であり;
Hαは、イオン化水素原子であり;
R1は、H又は有機ラジカルであり;
R2は、H又は有機ラジカルであり;
(a)は、0又は1のいずれかであり;
(b)は、0又は1のいずれかであり;
Re1は、存在するとき、第1の電子改変基であり;
Re2は、存在するとき、第2の電子改変基であり;
Y1は、O又はSであり;
Y2は、O又はSであり;及び
(IL−2)は、IL−2部分の残基である。
式中、(IL−2)及び隣接するカルボニル基は、カルボキシル含有IL−2部分に対応し、Xは連結鎖、好ましくはO、N(H)、及びSから選択されるヘテロ原子であり、POLYは、場合により末端にエンドキャップ部分を有する、PEGなどの水溶性ポリマーである。
POLY−L0,1−C(O)Z−Y−S−S−(IL−2)
式中、POLYは水溶性ポリマーであり、Lは任意選択のリンカーであり、Zは、O、NH、及びSからなる群から選択されるヘテロ原子であり、Yは、C2〜10アルキル、C2〜10置換アルキル、アリール、及び置換アリールからなる群から選択され、(IL−2)はIL−2部分である。IL−2部分と反応することができ、結果としてこのタイプのコンジュゲートをもたらすポリマー試薬は、米国特許出願公開第2005/0014903号明細書に記載されている。
これにより、以下の構造を有するコンジュゲートが形成される:
式中:
(各構造について)各(n)は、独立して2〜4000の値を有する整数であり;及び
IL−2は、IL−2部分の残基である。
これにより、以下の構造を有するコンジュゲートが形成される:
式中:
(各構造について)(n)は、独立して2〜4000の値を有する整数であり;及び
IL−2は、IL−2部分の残基である。
コンジュゲートは、典型的には組成物の一部である。概して、組成物は複数のコンジュゲートを含み、必須ではないが、好ましくは各コンジュゲートは同じIL−2部分を含む(すなわち、組成物全体のなかに、ただ1つのタイプのIL−2部分が存在する)。加えて、組成物は、任意の所与のコンジュゲートが2つ以上の異なるIL−2部分からなる群から選択されるある部分を含む複数のコンジュゲートを含み得る(すなわち、組成物全体のなかに、2つ以上の異なるIL−2部分が存在する)。しかしながら、最適には、組成物中の実質的に全てのコンジュゲート(例えば、組成物中の複数のコンジュゲートのうちの85%以上)が、各々、同じIL−2部分を含む。
Laboratories Inc.,San Diego CAから入手可能)では、IL−2は、ドデシル硫酸ナトリウム(「SDS」)と組み合わせて提供される。対照的に、本発明の組成物は、有利にはSDSが不要であってよく、SDS並びに一般的に界面活性剤(例えばTween 20及びTween 80)を含まない(又は実質的に含まない)。結果的に、本発明の組成物及びコンジュゲートは、SDS、Tween 20、及びTween 80を添加するステップを実施することなく調製することができる。加えて、本発明の組成物及びコンジュゲートは、界面活性剤又は他の賦形剤を添加するステップを実施することなく調製することができる。さらに、本発明の組成物は、SDS、Tween20、及びTween80などの界面活性剤を含まない又は実質的に含まない(例えば、約20%未満、より好ましくは約15%未満、さらにより好ましくは約10%未満、さらになおより好ましくは約9%未満、さらになおより好ましくは約8%未満、さらになおより好ましくは約7%未満、さらになおより好ましくは約6%未満、さらになおより好ましくは約5%未満、さらになおより好ましくは約4%未満、さらになおより好ましくは約3%未満、さらになおより好ましくは約2%未満、さらになおより好ましくは約1%未満、さらになおより好ましくは約0.5%未満であり、0.001%未満が最も好ましい)。加えて、本発明の組成物及びコンジュゲートは、SDS、Tween 20、及びTween 80などの界面活性剤を(例えば限外ろ過により)除去するステップを実施することなく調製することができる。さらに、本発明の組成物及びコンジュゲートは、界面活性剤を(例えば限外ろ過により)除去するステップを実施することなく調製することができる。
Pharmaceutical Excipients」、第3版、American
Pharmaceutical Association、Washington,D.C.、2000年に記載されている。
試料は、Invitrogen NuPAGEシステム及びNovex 4〜10%ビス−トリスプレキャストゲル(Invitrogen,Carlsbad,CA)を使用して、ドデシル硫酸ナトリウム−ポリアクリルアミドゲル電気泳動(SDS−PAGE)により分析した。製造者が記載するとおり試料を調製し、ゲルに負荷し、電気泳動法を実施した。
ベッドボリュームが約100mlのSP−HP Sepharose(GE Healthcare)陽イオン交換カラム(canion exchange column)を、標準方法を用いて調製した。カラムをGE Healthcare(Chalfont St.Giles,UK)AKTA Explorer100に接続し、調製したPEG−rIL−2コンジュゲートを精製した。精製過程の詳細は以下に記載する。
Agilent(Santa Clara,CA)1100 HPLCシステムで逆相クロマトグラフィー(RP−HPLC)分析を実施した。試料は、Silverton(日本)Intrada WP−RPカラム(3um粒度、2.1×150mm)を使用して分析した。カラムの流量は0.5ml/分であった。移動相は水中0.09%TFA(溶媒A)及びアセトニトリル中0.04%TFA(溶媒B)であった。
IL−2遺伝子のクローニング及びrIL−2の発現
ヒトIL−2 cDNA配列は、生物ごとにコドン使用頻度が大きく異なるため、大腸菌(E.coli)などの原核生物では最適に発現しないこともある。既存のヒト由来cDNA配列に対して点突然変異を多数行って大腸菌(E.coli)コドン使用頻度を最大化する代わりに、PCR技法を用いて遺伝子を完全に合成した。
NaCl、pH8.0の緩衝液を使用して、3段階で洗浄した。洗浄後、粗IL−2封入体が得られた。
mPEG2−C2−fmoc−20K−NHSによるrIL−2のペグ化
mPEG2−C2−fomc−20K−N−ヒドロキシスクシンイミド誘導体、20kDa(「mPEG2−C2−fmoc−20K−NHS」)
アルゴン下に−80℃で保存したmPEG2−C2−fmoc−20K−NHSを、窒素パージ下で周囲温度に加温した。mPEG2−C2−fmoc−20K−NHSのストック溶液(200mG/mL)を2mMのHCl中に調製し、mPEG2−C2−fmoc−20K−NHSを、mPEG2−C2−fmoc−20K−NHS対rIL−2のモル比が100:1に達するのに十分な量でrIL−2に添加した。混合物中のrIL−2の最終濃度は0.5mG/mL(0.035mM)であった。重炭酸ナトリウム緩衝液(1M、pH9.0)を混合物に添加して最終濃度を20mMとし、コンジュゲート形成を30分間進行させると、[mPEG2−C2−fmoc−20K]−[rIL−2]コンジュゲートが提供された。30分後、反応混合物に1Mグリシン(pH6.0)を添加することによりクエンチングを達成し、最終濃度を100mMとした。次にクエンチした反応混合物を、0.5mS/cm(25℃)未満の伝導度となるようにH2Oで希釈した。氷酢酸を使用してpHを4.0に調整した後、カラムクロマトグラフィー精製した。
mPEG2−CAC−fmoc−20K−NHSによるrIL−2のペグ化
mPEG2−CAC−fmoc−20K−N−ヒドロキシスクシンイミド誘導体、20kDa(「mPEG2−CAC−fmoc−20K−NHS」)
アルゴン下に−80℃で保存したmPEG2−CAC−fmoc−20K−NHSを、窒素パージ下で周囲温度に加温した。mPEG2−CAC−fmoc−20K−NHSのストック溶液(200mG/mL)を2mMのHCl中に調製し、mPEG2−CAC−fmoc−20K−NHSを、mPEG2−CAC−fmoc−20K−NHS対rIL−2のモル比が100:1に達するのに十分な量でrIL−2に添加した。混合物中のrIL−2の最終濃度は0.5mG/mL(0.035mM)であった。重炭酸ナトリウム緩衝液(1M、pH9.0)を混合物に添加して最終濃度を20mMとし、コンジュゲート形成を30分間進行させると、[mPEG2−CAC−fmoc−20K]−[rIL−2]コンジュゲートが提供された。30分後、反応混合物に1Mグリシン(pH6.0)を添加することによりクエンチングを達成し、最終濃度を100mMとした。次にクエンチした反応混合物を、0.5mS/cm(25℃)未満の伝導度となるようにH2Oで希釈した。氷酢酸を使用してpHを4.0に調整した後、カラムクロマトグラフィー精製した。
分枝鎖状mPEG−N−ヒドロキシスクシンイミジル誘導体、20kDaによるrIL−2のペグ化
mPEG2−ru−20K−N−ヒドロキシスクシンイミジル(Hydroxylsuccinimidyl)誘導体、20kDa(「mPEG2−ru−20K−NHS」)
アルゴン下に−80℃で保存したmPEG2−ru−20K−NHSを、窒素パージ下で周囲温度に加温した。mPEG2−ru−20K−NHSのストック溶液(200mG/mL)を2mMのHCl中に調製し、mPEG2−ru−20K−NHSを、mPEG2−ru−20K−NHS対rIL−2のモル比が100:1に達するのに十分な量でrIL−2に添加した。混合物中のrIL−2の最終濃度は0.5mG/mL(0.035mM)であった。重炭酸ナトリウム緩衝液(1M、pH9.0)を混合物に添加して最終濃度を20mMとし、コンジュゲート形成を30進行させると、[mPEG2−ru−20K]−[rIL−2]コンジュゲートが提供された。30分後、反応混合物に1Mグリシン(pH6.0)を添加することによりクエンチングを達成し、最終濃度を100mMとした。次にクエンチした反応混合物を、0.5mS/cm(25℃)未満の伝導度となるようにH2Oで希釈した。氷酢酸を使用してpHを4.0に調整した後、カラムクロマトグラフィー精製した。
分枝鎖状mPEG−N−ヒドロキシスクシンイミジル誘導体、40kDaによるrIL−2のペグ化
mPEG2−ru−40K−N−ヒドロキシスクシンイミジル(Hydroxylsuccinimidyl)誘導体、40kDa(「mPEG2−ru−40K−NHS」)
アルゴン下に−80℃で保存したmPEG2−ru−40K−NHSを、窒素パージ下で周囲温度に加温した。mPEG2−ru−40K−NHSのストック溶液(200mG/mL)を2mMのHCl中に調製し、mPEG2−ru−40K−NHSを、mPEG2−ru−40K−NHS対rIL−2のモル比が100:1に達するのに十分な量でrIL−2に添加した。混合物中のrIL−2の最終濃度は0.5mG/mL(0.035mM)であった。重炭酸ナトリウム緩衝液(1M、pH9.0)を混合物に添加して最終濃度を20mMとし、コンジュゲート形成を30分間進行させると、[mPEG2−ru−40K]−[rIL−2]コンジュゲートが提供された。30分後、反応混合物に1M
グリシン(pH4.0)を添加することによりクエンチングを達成し、最終濃度を100mMとした。次にクエンチした反応混合物を、0.5mS/cm(25℃)未満の伝導度となるようにH2Oで希釈した。氷酢酸を使用してpHを4.0に調整した後、カラムクロマトグラフィー精製した。
分枝鎖状mPEG−N−ヒドロキシスクシンイミジル誘導体、4kDaによるrIL−2のペグ化
mPEG2−ru−20K−N−ヒドロキシスクシンイミジル(Hydroxylsuccinimidyl)誘導体、4kDa(「mPEG2−ru−4K−NHS」)
アルゴン下に−80℃で保存したmPEG2−ru−4K−NHSを、窒素パージ下で周囲温度に加温した。mPEG2−ru−4K−NHSのストック溶液(200mG/mL)を2mMのHCl中に調製し、mPEG2−ru−4K−NHSを、mPEG2−ru−4K−NHS対rIL−2のモル比が100:1に達するのに十分な量でrIL−2に添加した。混合物中のrIL−2の最終濃度は、0.015%SDSにより可溶化されて0.5mG/mL(0.035mM)であった。重炭酸ナトリウム緩衝液(1M、pH9.0)を混合物に添加して最終濃度を100mMとし、コンジュゲート形成を30分間進行させると、[mPEG2−ru−4K]−[rIL−2]コンジュゲートが提供された。30分後、反応混合物に1M グリシン(pH4.0)を添加することによりクエンチングを達成し、最終濃度を100mMとした。次にクエンチした反応混合物を、0.5mS/cm(25℃)未満の伝導度となるようにH2Oで希釈した。氷酢酸を使用してpHを4.0に調整した後、カラムクロマトグラフィー精製した。
直鎖状mPEG−ブチルアルデヒド誘導体、30kDaによるrIL−2のペグ化
直鎖状mPEG−ブチルアルデヒド誘導体、30kDa(「mPEG−ButyrALD」)
全ての反応成分及び緩衝液を添加した後、最終的なrIL−2濃度が2.5mg/mlになるように、ペグ化反応を設計する。アルゴン下に−20℃で保存したmPEG−ButyrALD、30kDaを、周囲温度に加温する。ペグ化されるrIL−2の10〜50mol当量に等しいPEG試薬の分量を秤量し、20mMリン酸ナトリウム緩衝液(pH7.5)及び1mM EDTAに溶解して、12%試薬溶液を形成する。12%PEG試薬溶液をストックrIL−2溶液のアリコートに添加し、15〜30分間撹拌する。次に、還元剤のシアノ水素化ホウ素ナトリウム(NaCNBH3)を、PEG試薬に対して10〜100モル過剰で添加し、反応液を室温で5〜18時間撹拌することによって第二級アミン連結を介したカップリングを確実にし、それによりコンジュゲート溶液を形成する。
分枝鎖状mPEG−ブチルアルデヒド誘導体、40kDaによるrIL−2のペグ化
分枝鎖状mPEG−ブチルアルデヒド誘導体、40kDa(「mPEG2−ButyrALD」)
全ての反応成分及び緩衝液を添加した後、最終的なrIL−2濃度が2.5mg/mlになるように、ペグ化反応を設計する。アルゴン下に−20℃で保存したmPEG2−ButyrALD、40kDaを、周囲温度に加温する。ペグ化されるrIL−2の10〜50mol当量に等しいPEG試薬の分量を秤量し、20mMリン酸ナトリウム緩衝液(pH7.5)及び1mM EDTAに溶解して、12%試薬溶液を形成する。12%PEG試薬溶液をストックrIL−2溶液のアリコートに添加し、15〜30分間撹拌する。次に、還元剤のシアノ水素化ホウ素ナトリウム(NaCNBH3)を、PEG試薬に対して10〜100モル過剰で添加し、反応液を室温で5〜18時間撹拌することによって第二級アミン連結を介したカップリングを確実にし、それによりコンジュゲート溶液を形成する。
直鎖状mPEG−スクシンイミジルα−メチルブタノエート誘導体、30kDaによるrIL−2のペグ化
直鎖状mPEG−スクシンイミジルα−メチルブタノエート誘導体、30kDa(「mPEG−SMB」)
全ての反応成分及び緩衝液を添加した後、最終的なrIL−2濃度が2.5mg/mlになるように、ペグ化反応を設計する。アルゴン下に−20℃で保存したmPEG−SMB、30kDaを、周囲温度に加温する。ペグ化されるrIL−2の10〜50mol当量に等しいPEG試薬の分量を秤量し、20mMリン酸ナトリウム緩衝液(pH7.5)及び1mM EDTAに溶解して、12%試薬溶液を形成する。12%PEG試薬溶液をストックrIL−2溶液のアリコートに添加し、室温で5〜18時間撹拌することによりコンジュゲート溶液を得る。コンジュゲート溶液は、最終的なリジンモル濃度がPEG試薬モル濃度の10〜100倍となるように、リジン溶液(pH7.5)でクエンチされる。
mPEG−PIP、20kDaによるrIL−2のペグ化
ポリマー試薬の基本構造を以下に提供する:
全ての反応成分及び緩衝液を添加した後、最終的なrIL−2濃度が2.5mg/mlになるように、ペグ化反応を設計する。アルゴン下に−20℃で保存したmPEG−PIP、20kDaを、周囲温度に加温する。ペグ化されるrIL−2の10〜50mol当量に等しいPEG試薬の分量を秤量し、20mMリン酸ナトリウム緩衝液(pH7.5)及び1mM EDTAに溶解して、12%試薬溶液を形成する。12%PEG試薬溶液をストックrIL−2溶液のアリコートに添加し、15〜30分間撹拌する。次に、還元剤のシアノ水素化ホウ素ナトリウム(NaCNBH3)を、PEG試薬に対して10〜100モル過剰で添加し、反応液を室温で5〜18時間撹拌することによって第二級アミン連結を介した(第二級炭素との)カップリングを確実にし、それによりコンジュゲート溶液を形成する。コンジュゲート溶液は、最終的なリジンモル濃度がPEG試薬モル濃度の10〜100倍となるように、リジン溶液(pH7.5)でクエンチされる。
例示的(rIL−2)−PEGコンジュゲートの活性
アルデスロイキン(対照)、実施例2の[mPEG2−C2−fmoc−20K]−[rIL−2]、実施例3の[mPEG2−CAC−fmoc−20K]−[rIL−2]、及び実施例4の[mPEG2−ru−20K]−[rIL−2]の活性を、CTLL−2細胞を使用した細胞増殖アッセイで評価した。
1640培地に、5%CO2雰囲気下37℃で維持した。細胞を、2〜3×105細胞/mLの細胞密度に達するまで懸濁液中で培養した後、分割した。
例示的(rIL−2)−PEGコンジュゲートの薬物動態
アルデスロイキン(対照)、実施例2の[mPEG2−C2−fmoc−20K]−[rIL−2]、実施例3の[mPEG2−CAC−fmoc−20K]−[rIL−2]、及び実施例4の[mPEG2−ru−20K]−[rIL−2]の薬物動態プロファイルを、マウスにおける単回注射後、ELISAで評価した。
肺転移性黒色腫有効性試験
IL−2活性を有するものと意図される化合物の有効性の評価には、転移性黒色腫肺モデルが広く用いられており、C57BL/6マウスで展開される。このモデルでは、初めにマウスにB16F10メラノーマ細胞が静脈内投与され、それにより種々の数及びサイズの肺小結節を発生させる。肺小結節の数並びにそれらの病変部の全表面積は、移植された細胞濃度に応じて異なる。次にマウスの治療群に目的の試験化合物が投与され、及び別のマウス群が、未治療のままにしておくことで対照として供される。試験化合物の有効性は、治療群と未治療群との間の各肺についての肺小結節の数及びサイズ並びに全病変面積の減少率として決定することができる。
Laboratories Inc.,San Diego CA)、実施例1のIL−2部分、プールした3mer/4mer[mPEG2−CAC−fmoc−20K]−[rIL−2]、プールした3mer/4mer[mPEG2−ru−20K]−[rIL−2]、及びプールした1mer/2mer[mPEG2−ru−20K]−[rIL−2]の各々について、腫瘍小結節及びそのサイズをカウントした。
皮下B16F10黒色腫有効性試験
IL−2活性を有するものと意図される化合物の有効性の評価には、同系マウス、すなわちC57BL/6マウスにおける極めてロバストな皮下黒色腫モデルが用いられている。簡潔に言えば、100万個のB16F10細胞を5〜6週齢の各C57BL/6マウスの背中領域に皮下移植した。腫瘍を触知可能なサイズ、すなわち70〜120平方mmまで成長させた後、無作為化して、表6に示されるとおりの群に割り当てた。マウスに試験化合物、すなわち、アルデスロイキン(Prometheus Laboratories Inc.,San Diego CA)、rIL−2−ポリマーコンジュゲート又はビヒクルを、種々の用量濃度及び用量レジームで投与した。1日おきに体重及び腫瘍容積を計測した。この試験のエンドポイントは、所与の群の腫瘍容積中央値が1500平方mmに達した時点又は45日の、いずれか早い方である。
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