JP6873184B2 - 抱合方法 - Google Patents
抱合方法 Download PDFInfo
- Publication number
- JP6873184B2 JP6873184B2 JP2019084898A JP2019084898A JP6873184B2 JP 6873184 B2 JP6873184 B2 JP 6873184B2 JP 2019084898 A JP2019084898 A JP 2019084898A JP 2019084898 A JP2019084898 A JP 2019084898A JP 6873184 B2 JP6873184 B2 JP 6873184B2
- Authority
- JP
- Japan
- Prior art keywords
- antibody
- conjugate
- linker
- maleimide
- reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Description
本発明は、2官能性リンカーを介してエフェクター基(たとえば、細胞傷害剤)又はリポーター基(たとえば、放射性標識)を抗体又はその断片のような細胞結合剤に抱合させる新規の方法に関する。さらに具体的には、本発明は、分子内又は分子間の反応のために形成される望ましくない加水分解された種又は望ましくない架橋された種の形成を結果として生じる工程を製造過程が排除するように、2官能性リンカーを介してエフェクター基(たとえば、マイタンシノイド)又はリポーター基(たとえば、放射性標識)を細胞結合剤(抗体又はその断片)に抱合させる新規の方法に関する。
された抗体の高い特異性のゆえに腫瘍特異的である。腫瘍細胞への特異的な結合の際、抗体/細胞傷害剤の抱合体は標的の癌細胞に内部移行され、分解され、それによって、たとえば、微小管動態又はDNA複製のような本質的な細胞機能を阻害する活性のある細胞傷害剤を放出し、その結果、癌細胞の殺傷を生じる。血漿における抱合体の所望の安定性を維持する一方で、内部移行の際、細胞内への剤の送達を高め、抱合体の処理を高めることを目的に、抗体を細胞傷害剤に連結するのに種々のリンカーが採用されている。これらのリンカーには、細胞内チオールによる還元動態に影響を及ぼすように様々な程度の立体障害とともに設計されるジスルフィドリンカー、バリン/シトルリン結合のような切断可能なペプチドリンカー、及びチオエーテル結合のような切断不能なリンカーが挙げられる(Widdison, W., et al., J. Med. Chem., 2006, 49, 4392-4408; Erickson, H., et al, Cancer Res., 2006, 66, 4426-4433)。
えば、チオールのような反応基を含有するエフェクター基(C)(たとえば、細胞傷害剤)のようなエフェクターと反応して抗体/エフェクターの抱合体を生成し、それは、再び追加の精製工程にて精製される(米国特許第5,208,020号、同第5,416,064号又は同第5,024,834号を参照)。従って、上記製造過程では、少なくとも2つの精製工程を必要とする。
、それらは本発明の実施において使用され得る。
スキーム及び実施例の説明に使用されている略語は以下のとおりである:
C=エフェクター基又はリポーター基(たとえば、細胞傷害剤又は放射性標識)
L=リンカー(切断可能又は切断不能なリンカー)
X=アミン反応基(たとえば、N−ヒドロキシスクシンイミドエステル(NHSエステル)、スルホ−NHSエステル、p−ニトロフェノールエステル、テトラフルオロスルホネートフェニルエステル、1−ヒドロキシ−2−ニトロ−ベンゼン−4−スルホン酸エステル)
Y=マレイミド又はハロアセトアミド(ヨードアセトアミド、ブロモアセトアミド)
Ybは、反応性の混合ジスルフィド基(たとえば、2−ピリジルジチオ、4−ピリジルジチオ、2−ニトロ−ピリジルジチオ、5−ニトロ−ピリジルジチオ、2−カルボキシ−5−ニトロ−ピリジルジチオ)である
X’=アミド結合
Y’=チオエーテル(R−S−R’)又はセレノエーテル(R−Se−R’)結合
Y’b=ジスルフィド(R−S−S−R’)結合
X−L−Y+C→X−L−Y’−C (1)
Ab+X−L−Y’−C(反応1から未精製)→Ab(X’−L−Y’−C)m (2)
は、中間体生成物X−L−Y’−Cの精製が関与しないので、抗体とそれをそのまま混合する(未精製の中間体生成物を抗体に加える、又は抗体を未精製の中間体生成物に加える)という利点を提供し、それによって繁雑な精製工程を排除するので方法が抱合に有利になる。重要なことに、従来の2工程法と精製順によって調製される抱合体で認められる鎖間タンパク質架橋又は不活化されたマレイミド残基とは対照的に、本方法によって鎖間タンパク質架橋又は不活化されたマレイミド残基を伴わない均質な抱合体が得られる。
の抗体の反応についての代替方法には、DMxとヘテロ2官能性リンカーの最初の反応混合物(DMx/リンカーの反応の完了時)を抗体と低いpH(pH約5)で混合し、次いで抱合反応のために緩衝液又は塩基を添加してpHを約6.5〜8.5に上げることが含まれる。
Y−L−Y+C→Y−L−Y’−C (3)
Ab+Y−L−Y’−C(反応3から未精製)→Ab(Y’−L−Y’−C)m (4)
は、中間体生成物Y−L−Y’−Cの精製を含まないので、抱合のために有利な方法である。
X−L−Yb+C→X−L−Yb’−C (5)
Ab+X−L−Yb’−C(反応5から未精製)→Ab−(X’−L−Yb’−C)m
(6)
(a)X−L−YとX−L−Ybのリンカーを細胞傷害剤Cに接触させて式X−L−Y’−CとX−L−Yb’−Cの中間体生成物を生成すること、(b)反応式7〜9に示すような順番で又は同時に、未精製の反応混合物を抗体と混合して、
X−L−Y+C→X−L−Y’−C (7)
X−L−Yb+C→X−L−Yb’−C (8)
Ab+X−L−Y’−C+X−L−Yb’−C(反応7〜8から未精製)→Ab−(X’−L−Y’−C)m(X’−L−Yb’−C)m’ (9)
抱合体Ab−(X’−L−Y’−C)m(X’−L−Yb’−C)mを提供すること(式中、X、L、Y’、C、Yb’及びmは上記のとおりであり、m’は1〜20の整数である)、及び(c)接線流濾過、透析又はクロマトグラフィ(たとえば、ゲル濾過、イオン交換クロマトグラフィ、疎水性相互作用クロマトグラフィ)又はそれらの組み合わせによって抱合体を精製すること。これら2つのリンカーエフェクター中間体(X−L−Y’−C及びX−L−Yb’−C)は、種々の比率で異なった順にて(先ずX−L−Y’−C、次いでX−L−Yb’−C又は先ずX−L−Yb’−C、次いでX−L−Y’−C)精製せずに抗体と混合される。
時)を抗体と低いpH(pH約5)で混合し、次いで抱合反応のために緩衝液又は塩基を添加してpHを約6.5〜8.5に上げることが含まれる。
エフェクター基
ァ、シタラビン、ジデオキシウリジン、ドキシフルリジン、エノシタビン、フルオクスウリジン、5−FU;アンドロゲン、たとえば、カルステロン、プロピオン酸ドロモスタノロン、エピチオスタノール、メピチオスタン、テストラクトン;抗副腎薬、たとえば、アミノグルテチミド、ミトタン、トリロスタン;葉酸補充薬、たとえば、フォリン酸;アセグラトン;アルドホスファミドグリコシド;アミノレブリン酸;アムサクリン;ベストラブシル;ビサントレン;エダトレキセート;デフォファミド;ジアジクオン;エルフォミチン;酢酸エリプチニウム;エポチロン;エトグルシド;硝酸ガリウム;ヒドロキシ尿素;レンチナン;ロニダミン;マイタンシノイド類、たとえば、マイタンシン及びアンサミトシン;ミトグアゾン;ミトキサントロン;モピダモール;ニトラクリン;ペントスタチン;フェナメット;ピラルビシン;ポドフィリン酸;2−エチルヒドラジン;プロカルバジン;PSK(登録商標);ラゾキサン;リゾキシン;シゾフィラン;スピロゲルマニウム;テヌアゾン酸;トリアジクオン;2、2’、2”−トリクロロトリエチルアミン;トリクロテセン(特にT−2毒素、ベラクリンA、ロリジンA、及びアングイジン);ウレタン;ビンデシン;ダカルバジン;マンノムスチン;ミトブロニトール;ミトラクトール;ピポブロマン;ガシトシン;アラビノシド(「Ara−C」);サイクロホスファミド;チオテパ;タキソイド類、たとえば、パクリタキセル(TAXOL(登録商標)、ニュージャージー州、プリンストンのブリストルマイヤーズスクイブオンコロジー)及びドキセタキセル(TAXOTERE(登録商標)、フランス、アントニーのローヌプーラン);クロラムブシル;ゲムシタビン;6−チオグアニン;メルカプトプリン;メソトレキセート;白金類似体、たとえば、シスプラチン及びカルボプラチン;ビンブラスチン;白金;エトポシド(VP−16);イフォスファミド;マイトマイシンC;ミトキサントロン;ビンクリスチン;ビノレビン;ナベルビン;ノバントロン;テニポシド;ダウノマイシン;アミノプテリン;キセロダ;イバンドロネート;CPT−11;トポイソメラーゼ阻害剤RFS2000;ジフルオロメチロミチン(DMFO);レチノイン酸;カペシタビン;並びに上記の薬学上許容可能な塩、酸、又は誘導体が挙げられる。この定義で挙げられるのはまた、腫瘍におけるホルモンの作用を調節する又は阻害するように作用する抗ホルモン剤、たとえば、タモキシフェン、ラロキシフェン、アロマターゼ阻害の4(5)−イミダゾール、4−ヒドロキシタモキシフェン、トリキシフェン、ケオキシフェン、LY117018、オナプリストン及びトレミフェン(Fareston)を含む抗エストロゲン、並びにフルタミド、ニルタミド、ビカルタミド、レウプロリド及びゴセレリンのような抗アンドロゲン;siRNA並びに上記の薬学上許容可能な塩、酸、又は誘導体である。本発明と共に使用することができるそのほかの化学療法剤は、その全体が参照によって本明細書に組み入れられる米国特許公開第20080171040号及び同第20080305044号に開示されている。
胞の生存率を低下させる任意の化合物であってもよく、各細胞傷害剤はチオール部分を含む。
マイタンシノイド
(1)C−19のデクロロ(米国特許第4,256,746号)(アンサミトシンP2のLAH還元によって調製される);
(2)C−20ヒドロキシ(又はC−20デメチル)+/−C−19デクロロ(米国特許第4,361,650号及び同第4,307,016号)(Streptomyces若しくはActinomycesを用いた脱メチル化又はLAHを用いた脱塩素化によって調製される);
(3)C−20デメトキシ、C−20アシルオキシ(−OCOR)+/−デクロロ(米国特許第4,294,757号)(塩化アシルを用いたアシル化によって調製される);
が挙げられる。
(1)C−9SH(米国特許第4,424,219号)(H2S又はP2S5とのマイタンシノールの反応によって調製される);
(2)C−14アルコキシメチル(デメトキシ/CH2OR)(米国特許第4,331,598号);
(3)C−14ヒドロキシメチル又はアシルオキシメチル(CH2OH又はCH2OAc)(米国特許第4,450,254)(ノカルジアから調製される);
(4)C−15ヒドロキシ/アシルオキシ(米国特許第4,364,866号)(Str
eptomycesによるマイタンシノールの変換によって調製される);
(5)C−15メトキシ(米国特許第4,313,946号)(Trewia nudifloraから単離される);
(6)C−18N−デメチル(米国特許第4,362,663号及び同第4,322,348号)(Streptomycesによるマイタンシノールの脱メチル化によって調製される);
(7)4,5−デオキシ(米国特許第4,371,533号)(マイタンシノールの三塩化チタン・LAH還元によって調製される)が挙げられる。
mは0、1、2、又は3であり;
Mayはマイタンシノイドである。
Mayはマイタンシノイドである。
Y0はCl又はHであり;
X3はH又はCH3である。
R1、R2、R3、R4は、H、CH3又はCH2CH3であり、同一であっても異なっていてもよく;
mは0、1、2、又は3であり;
Mayはマイタンシノイドである。
0は、1、2又は3であり;
pは、0〜10の整数であり;
Mayはマイタンシノイドである。
0は、1、2又は3であり;
pは、0〜10の整数であり;
Y0はCl又はHであり;
X3はH又はCH3である。
タキサン類
CC−1065類似体
ダウノルビシン/ドキソルビシン類似体
Molecular Cancer Therapeutics,vol.3,No.
8,pp.921−932(2004); 米国特許公開第11/134826号、米国特許公開第20060074008号、同第2006022925号に記載されている。
類似体及び誘導体
ことを容易に理解するであろう。当業者はまた、これらの化合物の多くが本明細書で記載される細胞傷害剤の代わりに使用され得ることも理解するであろう。従って。本発明の細胞傷害剤は、本明細書で記載される化合物の類似体及び誘導体を含む。
リポーター基
リンカー
HOOC−Xl−Yn−Zm−COOH
式中、Xは2〜20の炭素原子を有する直鎖又は分枝鎖のアルキル基、アルケニル基又はアルキニル基であり、Yは3〜10の炭素原子を有するシクロアルキル基又はシクロアルケニル基であり、Zは6〜10の炭素原子を有する置換若しくは非置換の芳香族基、又は置換若しくは非置換の複素環基であり、ヘテロ原子はN、O、又はSから選択され、l、m及びnが同時にすべてゼロではないという条件で、l、m及びnはそれぞれ0又は1である。
細胞結合剤
再表面化する抗体(米国特許第5,639,641号);
ヒト化抗体又は完全にヒトの抗体(ヒト化抗体又は完全にヒトの抗体は、huMy9−6、huB4、huC242、huN901、DS6、CD38、IGF−IR、CNTO95、B−B4、トラスツズマブ、ビバツズマブ、シブロツズマブ及びリツキシマブから選択されるが、これらに限定されない)(たとえば、米国特許第5,639,641号、同第5,665,357号及び同第7,342,110号、国際特許出願WO02/16,401号、米国特許公開第20060045877号、同第20060127407号、同第20050118183号、Pedersen et al, (1994) J. MoI. Biol. 235, 959-973, Roguska et al., (1994) Proceedings of the National Academy of Sciences, VoI
91, 969-973, Colomer et al., Cancer Invest., 19: 49-56 (2001), Heider et al, Eur. J. Cancer, 3 IA: 2385-2391 (1995), Welt et al., ./. Clin. Oncol, 12: 1193-1203 (1994), and Maloney et al., Blood, 90: 2188-2195 (1997)を参照);並びに
優先的に標的細胞に結合するsFv、Fab、Fab’及びF(ab’)2のような抗体断片(Parham, J. Immunol. 131 :2895-2902 (1983); Spring et al, J. Immunol. 113:470-478 (1974); Nisonoff et al, Λrc/z. Biochem. Biophys. 89:230-244 (I960))
を含む抗体が挙げられる。
アンキリン反復タンパク質(ARPins; Zahnd et al., J. Biol. Chem., 281, 46, 35167
-35175, (2006); Binz, H.K., Amstutz, P. & Pluckthun, A. (2005) Nature Biotechnology, 23, 1257-1268)又はたとえば、米国特許公開第20070238667号、米国
特許第7,101,675号、WO/2007/147213,WO/2007/062466に記載されたアンキリン様反復タンパク質又は合成ペプチド;
インターフェロン(たとえば、α、β、γ);
リンホカイン、たとえば、IL−2、IL−3、IL−4、IL−6;
ホルモン、たとえば、インスリン、TRH(甲状腺刺激ホルモン放出ホルモン)、MSH(色素形成細胞刺激ホルモン)、アンドロゲン及びエストロゲンのようなステロイドホルモン、並びに
増殖因子及びコロニー刺激因子、たとえば、EGF、TGF−α、IGF−I、G−CSF、M−CSF及びGM−CSF (Burgess, Immunology Today 5:155-158 (1984))によって例示されるが、これらに限定されないそのほかの細胞結合タンパク質及びポリペプチドが挙げられる。
PA)のようなプラスミノーゲンアクチベータ;トロンビン;造血増殖因子:腫瘍壊死因子α及びβ;エンケファリナーゼ;RANTES(発現された及び分泌された正常T細胞の活性化を調節する);ヒトマクロファージ炎症タンパク質(MIP−1α);たとえば、ヒト血清アルブミンのような血清アルブミン;ミュラー管阻害物質;レラキシンA鎖;レラキシンB鎖;プロレラキシン;マウス性腺刺激関連ペプチド;たとえば、β−ラクタマーゼのような微生物タンパク質;DNA分解酵素;IgE;たとえば、CTLA−4のような細胞傷害性Tリンパ球関連抗原(CTLA);インヒビン;アクチビン;血管内皮増殖因子(VEGF);ホルモン又は増殖因子のための受容体;プロテインA又はD;リウマチ因子;たとえば、骨由来の神経栄養因子(BDNF)、ニューロトロピン−3、−4、−5又は−6(NT3、NT4、NT5又はNT6)のような神経栄養因子、又はNGF−βのような神経成長因子;血小板由来増殖因子(PDGF);たとえば、FGF及びbFGFのような線維芽細胞増殖因子;上皮増殖因子(EGF);たとえば、TGFβ1、TGF−β2、TGF−β3、TGF−β4、又はTGF−β5を含むTGFα及びTGFβのような形質転換増殖因子;インスリン様増殖因子−I及びII(IGF−I及びIGF−II);デス(1〜3)−IGF−I(脳IGF−I),インスリン様増殖因子結合タンパク質;たとえば、CD3、CD4、CD8、CD19、CD20及びCD40のようなCDタンパク質;エリスロポイエチン;骨誘導因子;免疫毒素;骨形成タンパク質(BMP);たとえば、インターフェロンα、β及びγのようなインターフェロン;たとえば、M−CSF、GM−CSF、及びG−CSFのようなコロニー刺激因子(CSF);たとえば、IL−1〜IL−10のようなインターロイキン;スーパーオキシドジスムターゼ;T細胞受容体;表面膜タンパク質;分解促進因子;たとえば、HIVエンベロープの一部のようなウイルス抗原;輸送タンパク質;ホーミング受容体;アドレシン;調節性タンパク質;たとえば、CD11a、CD11b、CD11c、CD18、ICAM、VLA−4及びVCAM、ヘテロ二量体ヒトインテグリン受容体のαVサブユニットのようなインテグリン;たとえば、HER2、HER3又はHER4受容体のような腫瘍関連抗原;並びに上記に列記されたポリペプチドの断片が挙げられる。
tent no. 5,885,793; McCafferty et al, WO 92/01047; Liming et al, WO 99/0
6587を参照)のファージライブラリの使用である。
)、たとえば、標的細胞が、非ホジキンリンパ腫又は慢性リンパ性白血病でこの抗原を発現するB細胞又は冒された細胞である場合使用することができるマウスIgG1である。同様に、抗体N901は、小細胞肺癌細胞及び神経内分泌起源のそのほかの腫瘍の細胞で見つかったCD56に結合するマウスのモノクローナルIgG1抗体であり(Roy et al.
J Nat. Cancer Inst. 88:1136-1145 (1996))、hu242抗体はCanA抗原に結合し、トラスツズマブはHER2/neuに結合し、抗EGF受容体抗体は、EGF受容体に結合する。
精製方法
反応性マレイミド残基又はハロアセトアミド残基とのヘテロ2官能性リンカーによるタンパク質の最初の反応を採用する従来の抱合方法は2つの主な欠点に悩まされている:(i)エフェクター分子又はリポーター分子との反応の前に、抗体に取り込まれたリンカーの水性不活性化のために抱合体生成物が加水分解されたリンカーから成る可能性がある;及び(ii)タンパク質又はペプチドにおける天然のヒスチジン、リジン、チロシン又はシステインとのマレイミド(又はハロアセトアミド)の反応のために、抱合体の鎖間又は鎖内の架橋(A. Papini et al., Int. J. Pept. Protein Res., 1992, 39, 348-355; T. Ueda et al., Biochemistry, 1985, 24, 6316-6322)。抗体におけるそのような鎖間架橋は結果的に、重鎖と軽鎖の間又は重鎖間に非還元性の共有結合を生じ、それらは、予想される重鎖及び軽鎖のバンドよりも高い分子量のバンドとして還元型SDS−PAGEで明らかになる。抗体におけるそのような鎖間又は鎖内の架橋はまた、予想される抗体プラス連結されたリポーター基又はエフェクター基の質量とは異なった異常な質量のピークとしてMSによって明らかになる。従来の抱合方法とは異なって、本出願に記載される方法は、鎖間架橋又は加水分解されたリンカーを実質的に伴わない高い均質性で抱合体を生じる。
30〜60mMの濃度でN,N−ジメチルアセトアミド(DMA)にてDMxチオール及びマレイミド−スルホ−NHS−ヘテロ2官能性リンカーのストック溶液を作製した。40%v/vまでの200mMのコハク酸緩衝液、2mMのEDTA、pH5.0を含有するDMAにてリンカーとDMxチオールを一緒に混合して1.6のDMxとリンカーの比率と15mMに等しいDMxの最終濃度を得た。混合した後、反応物を1〜4時間放置し、次いで反応混合物のアリコートを10倍に希釈して、反応の完了とマレイミドの非存在を評価するために302〜320nmで吸収を測定した(302nmと252nmでモニターする吸収によって、反応混合物の凍結アリコートの追加の逆相HPLC解析を後で行って、抗体に反応混合物を添加した時点でのリンカーマレイミドの完全な消失と所望のリンカー/DMx試薬の形成を検証した)。UVによってさらなるマレイミドが存在しなかった場合、4mg/mLのAb、90%のリン酸緩衝液/10%DMA、pH7.5という最終抱合条件下にてリン酸緩衝液(pH7.5)における抗体の混合物に、反応混合物のアリコートを加えた。抱合反応を常温にて2時間進めた。pH7.5のリン酸緩衝液
で平衡化したG25ゲル濾過カラムを用いて、又は接線流濾過によって過剰な未反応のDMx及び非抱合のリンカー生成物からAb−DMxの抱合体を精製した。pH7.5の緩衝液で抱合混合物を4℃にて2日間保持して、非共有結合で又は不安定な結合で抗体に結合したDMx種を解離させた。次いでpH5.5のヒスチジン/グリシン緩衝液で抱合体を一晩透析し、次いで最終保存のために0.22μmのフィルターで濾過した。252nmと280nmで抱合体の吸収を測定し、これら2つの波長でのDMxと抗体の既知の吸光係数を用いて最終的な抱合体における抗体分子(平均)当たりのDMx分子の数を測定した。
出願で記載された方法によって調製した抱合体は、従来の2工程法を用いて調製したものに比べて、鎖間架橋の欠如という点ではるかに優れている(図9)。
う最終抱合条件下にてリン酸緩衝液(pH7.5)の抗体溶液とアリコートを混合した。常温にて2時間、抱合反応を進めた。pH7.5のリン酸緩衝液で平衡化したG25ゲル濾過を用いて過剰の小分子DM4とリンカー反応物から抗体/DM4の抱合体を精製した。pH7.5の緩衝液で抱合混合物を4℃にて2日間保持して、非共有結合で又は不安定な結合で抗体に結合したDMx種を解離させた。次いでpH5.5のヒスチジン/グリシン緩衝液で抱合体を一晩透析し、次いで最終保存のために0.22μmのフィルターで濾過した。252nmと280nmで抱合体の吸収を測定し、これら2つの波長でのDM4と抗体の既知の吸光係数を用いて最終的な抱合体における抗体分子当たりのDM4分子の平均数を測定した。4〜12%のBisTrisゲル(Invitrogen)と共にNuPage電気泳動システムを用いた非還元型SDS−PAGEによって抱合体試料を解析した。熱変性した試料を10μg/レーンで負荷した。本発明で記載された方法を用い(クエンチなしで)調製した抱合体の非還元型SDS−PAGEは、軽鎖バンド(約25kDa)と半々抗体バンド(重鎖−軽鎖;約75kDa)の証拠を示した(図18)。他方、本発明で記載された方法で調製し、4−マレイミド酪酸で処理した(過剰のDMxチオールを覆った)抱合体は、有意に低い量のこれら望ましくないバンドを有した(未修飾の抗体試料に匹敵するレベル)。4−マレイミド酪酸のようなチオールのクエンチ剤によるDMxとヘテロ2官能性リンカーの最初の反応(抗体との抱合の前)のクエンチの別の利点は、抗体の抱合反応の間、「遊離の」DMx種(DM1又はDM4)がないので、精製後の最終抱合体が「遊離の」又は非抱合のDMx種を含有しないことである。4−マレイミド酪酸(又はそのほかの極性のチオールクエンチ試薬)とのDMx付加体はDMxよりも水溶性なので、共有結合した抗体/DMxの抱合体からさらに分離し易い。
30〜60mMの濃度でDMAにて、DM1又はDM4チオール(DMx)及びスルホ−NHS基を伴ったスルホ−SMCCへテロ2官能性リンカー(Pierce Endogenから購入、図13)のストック溶液を作製した。40%v/vまでの水性200mMのコハク酸緩衝液、2mMのEDTA、pH5.0を含有するDMAにてリンカーとDM1又はDM4チオールを一緒に混合して1.6:1のDM1又はDM4(DMx)とリンカーの比率と6mMの最終濃度を得た。混合した後、反応物を常温で1〜4時間放置し、次いで反応混合物のアリコートを10倍に希釈して、マレイミドがすべて反応したかどうかを評価するために302〜320nmで吸収を測定した(302nmと252nmでモニターする吸収によって、反応混合物の凍結アリコートの追加の逆相HPLC解析を後で行って、抗体に反応混合物を添加した時点でのリンカーマレイミドの完全な消失と所望のスルホ−NHS−リンカー−Mal−DMx試薬の形成を検証した)。UVによってさらなるマレイミドが存在しなかった場合、4mg/mLのAb、90%のリン酸緩衝液/10%DMA、pH7.5という最終抱合条件下にてリン酸緩衝液(pH7.5)における抗体の水溶液に、反応物のアリコートを加えた。抱合反応を常温にて2時間進めた。pH7.5のリン酸緩衝液(水性)で平衡化したG25ゲル濾過カラムを用いて、過剰な未反応試薬と過剰なDMxからAb−DMxの抱合体を精製した。pH7.5の緩衝液で抱合体を4℃にて2日間保持して、非共有結合で又は不安定な結合で抗体に結合したDMx種を解離させた。次いでpH5.5のヒスチジン/グリシン緩衝液で抱合体を一晩透析し、次いで最終保存のために0.22μmのフィルターで濾過した。252nmと280nmで抱合体の吸収を測定し、これら2つの波長でのDMxと抗体の既知の吸光係数を用いて最終的な抱合体における抗体分子当たりのDMx分子の数を測定した。
させた後、G25クロマトグラフィを用いて、修飾した抗体を過剰な未反応リンカーから精製した。精製されたAbの回収を280nmでのUVの吸収によって測定した。少量の修飾抗体アリコートを用いて、マレイミドに対して過剰に加えられる既知の量のチオール(たとえば、2−メルカプトエタノール)を添加して修飾抗体におけるマレイミド残基と反応させ、次いでDTNBを用いたEllmanのアッセイによって残りのチオールを測定すること(412nmでのTNBチオレートの吸光係数は、14150M−1cm−1:Riddles, P. W. et al, Methods Enzymol., 1983, 91, 49-60; Singh, R., Bioconjugate Chem., 1994, 5, 348-351)によって、修飾された抗体における結合したマレイミド基の数を測定した。95%のpH6.5リン酸緩衝液/5%DMAにおける2.5mg/mLの抗体濃度にて、修飾されたAbのDM1又はDM4チオールによる抱合を行い、Abにて結合したマレイミドのモル当たり、1.7モル当量のDM1又はDM4チオールを加えた。18℃で8〜24時間放置し、G25クロマトグラフィを介して過剰で未反応のDM1(又はDM4)から抱合体を分離した。精製後、pH6.5の緩衝液にて4℃で2日間、抱合体を保持し、弱く結合したDM1/DM4種を加水分解させた。その後、ヒスチジン/グリシン緩衝液pH5.5に対して抱合体を一晩透析し、最終保存のために0.22μmのフィルターで濾過した。252nmと280nmにて抱合体の吸収を測定し、これら2つの波長でのDM1/DM4とAbについての既知の吸光係数を用いることによって最終的な抱合体におけるAb分子当たりのDM1又はDM4の分子の数を測定した。
(又はハロアセトアミド)残基が、チオールを持つDM1又はDM4(DMx)剤との反応工程の前にマレイミドの加水分解又は水和によって不活化され得る。従って、LC−MS分析は、本発明で記載された方法が、抗体に結合する不活化されたマレイミド又は架橋されたリンカーをほとんど含まない又は含まない均質な抱合体を産生する利点を有することを明らかに示す。
30〜60mMの濃度でDMAにて、DM1又はDM4チオール(DMx)及びヘテロ2官能性リンカー、4−(2−ピリジルジチオ)ブタン酸−N−ヒドロキシスクシンイミドエステル(SPDB)を含有するストック溶液を作製した。40%v/vまでの水性200mMのコハク酸緩衝液、2mMのEDTA、pH5.0を含有するDMAにてリンカーとDMxチオールを一緒に混合して1.6:1のDM1又はDM4(DMx)とリンカーの比率と8mMの最終濃度を得た。混合した後、反応物を常温で1時間放置し、次いで反応物のアリコートを4mg/mLのAb、90%のリン酸緩衝液(水性)/10%DMA、pH7.5という最終抱合条件下にてリン酸緩衝液(pH7.5)における抗体の水溶液に加えた。抱合反応を常温にて2時間進めた。pH7.5のリン酸緩衝液(水性)で平衡化したG25ゲル濾過カラムを用いて、過剰な未反応試薬と過剰なDMxからAb−DMxの抱合体を精製した。pH7.5の緩衝液で抱合体を4℃にて2日間保持して、非共有結合で又は不安定な結合で抗体に結合したDMx種を解離させた。次いでpH5.5のヒスチジン/グリシン緩衝液で抱合体を一晩透析し、次いで最終保存のために0.22μmのフィルターで濾過した。252nmと280nmで抱合体の吸収を測定し、これら2つの波長でのDMxと抗体の既知の吸光係数を用いて最終的な抱合体における抗体分子当たりのDMx分子の数を測定した。
30〜80mMの濃度でN,N−ジメチルアセトアミド(DMA)にてDM1又はDM4(DMx)チオール及びNHS−PEGn−マレイミドヘテロ2官能性リンカーのストック溶液を作製した。40%v/vまでの水性200mMのコハク酸緩衝液、2mMのEDTA、pH5.0を含有するDMAにてNHS−PEG4−マレイミドリンカーとDMxチオールを一緒に混合して1.6:1のDMxとリンカーのモル比と8mMに等しいDMxの最終濃度を得た。反応混合物を常温で2時間放置した。別に並行した反応で、1時間の反応時間を除いてNHS−PEG4−マレイミドの反応に用いた条件と同様に、SPDBとDMXチオールを一緒に混合した。双方の反応の終了後、精製しないで、等量のPEG4−Mal−DM4混合物とSPDB−DM4混合物を合わせた。合わせた反応混合物のアリコートを精製することなく、4mg/mLのAb、90%のリン酸緩衝液(水性)/10%DMA、pH7.5という最終抱合条件下にてリン酸緩衝液(pH7.5)における抗体の水溶液に加えた。抱合反応を常温にて2時間進めた。pH7.5のリン酸緩衝液(水性)で平衡化したG25ゲル濾過カラムを用いて、過剰な未反応試薬と過剰なDMxからAb−DMxの抱合体を精製した。pH7.5の緩衝液で抱合体を4℃にて2日間保持して、非共有結合で又は不安定な結合で抗体に結合したDMx種を解離させた。次いでpH5.5のヒスチジン/グリシン緩衝液で抱合体を一晩透析し、次いで最終保存のために0.22μmのフィルターで濾過した。252nmと280nmで抱合体の吸収を測定し、これら2つの波長でのDMxと抗体の既知の吸光係数を用いて最終的な抱合体における抗体分子当たりのDMx分子の数を測定した。
を調べ、切断不能なリンカーに対する切断可能なリンカーの取り込み比率を割り出した。DTT還元の間、反応pHを7.5に維持するために、抱合体を先ず、250mMのHEPES緩衝液、pH7.5に対して透析した。次いで37℃にて20分間、25mMのDTTと反応させることによって抱合体を還元した。DTT反応の後、250mMのHEPES緩衝液、pH7.5で平衡化したG25ゲル濾過を用いて反応混合物から、放出されたDMxとDTTを分離した。252nmと280nmで抱合体の吸収を測定し、これら2つの波長でのDMxと抗体の既知の吸光係数を用いて精製した生成物における抗体分子当たりのDMx分子の数を測定した。DTT処理した抱合体のD/AとDTT処理しなかった抱合体のD/Aの比率を用いて、切断不能な結合を介してAbに結合したDMxの比率を算出した。2つの追加の試料、Ab−SPDB−DM4抱合体とAb−PEG4−Mal−DM4抱合体をそれぞれ、陽性対照と陰性対照としてDTTで処理した。DTT処理の前と後でのD/Aを比較することによって、対照の切断不能なAb−PEG4−Mal−DM4抱合体は、ほぼすべてのリンカーが予想どおり切断不能であると思われることを示した。本発明に記載された方法によって作製された切断不能なリンカーとジスルフィドリンカーの双方を含有するAb−(混合SPDBとPEG4−Malリンカー)−DMx抱合体は、すべて切断可能なリンカーから成るAb−SPDB−DMX抱合体からのDMx喪失の量に比べて、DTT処理によって切断されるDMxが41%少なかった。このことは、本発明に記載された方法によって作製されたAb−(混合SPDBとPEG4−Malリンカー)−DMx抱合体がほぼ40%の切断不能なリンカーと60%の切断可能なリンカーから構成されることを実証した。切断不能なリンカー試薬と切断可能なリンカー試薬の最初の比率を変えることによって、切断不能なリンカーと切断可能なリンカーの様々な比率で、マイタンシノイド又はそのほかのエフェクターとの抗体の抱合体を調製することができる。図21は、上述の脱グリコシル化抱合体の質量スペクトルを示すが、それは、ジスルフィドリンカー(SPDB)と切断不能なリンカー(PEG)の双方を介して結合した抗体分子当たり平均3.5のマイタンシノイド分子を伴った抗体で構成される。MSは、切断可能なリンカーと切断不能なリンカーの双方を持つ別々の抱合体種を示す(図21)。たとえば、D2−PEG−SPDBと名付けられた抱合体のピークは、ジスルフィド結合したマイタンシノイド分子1つと切断不能なチオエーテル結合したマイタンシノイド分子1つを持ち;D3−PEG−2SPDBと名付けられた抱合体のピークは、ジスルフィド結合したマイタンシノイド分子2つと切断不能なチオエーテル結合したマイタンシノイド分子1つを持ち;D3−2PEG−2SPDBと名付けられた抱合体のピークは、ジスルフィド結合したマイタンシノイド分子1つと切断不能なチオエーテル結合したマイタンシノイド分子2つを持つ。
30〜60mMの濃度でDMAにて、DM1チオール及びSMCCへテロ2官能性リンカー(Pierce)のストック溶液を作製した。50%v/vまでの200mMの水性コハク酸緩衝液、2mMのEDTA、pH5.0を含有するDMAにてリンカーとDM1チオールを一緒に混合して1.4:1のDM1とリンカーの比率と1〜6mMのDM1の最終濃度を得た。混合した後、反応物を常温で4時間まで放置し、次いで反応混合物のアリコートを10倍に希釈して、マレイミドがすべてチオールと反応したかどうかを評価するために302〜320nmで吸収を測定した。UVによってさらなるマレイミドが存在しなかった場合、2.5mg/mLのAb、70〜80%のリン酸緩衝液(水性)/30〜20%%DMA(v/v)という最終抱合条件下にてリン酸緩衝液(pH7.5〜8.5)における抗体の水溶液に、反応混合物のアリコートを加えた。抱合反応を常温にて3時間進めた。pH7.4のリン酸緩衝液(水性)で平衡化したG25ゲル濾過カラムを用いて、過剰な未反応又は加水分解された試薬と過剰なDM1からAb−DM1の抱合体を精製した。pH7.4のリン酸緩衝液(水性)で抱合体を一晩透析し、次いで最終保存のために0.22μmのフィルターで濾過した。252nmと280nmで抱合体の吸収を測定し、これら2つの波長でのDM1と抗体の既知の吸光係数を用いて最終的な抱合体に
おける抗体分子当たりのDM1分子の数を測定した。同様に、DM4チオール及びSMCCによる抗体の抱合体を調製することができる。SMCCリンカーを用いたDM1又はDM4による抗体の抱合体は、チオエーテルの切断不能なリンカーを含有する。
ジスルフィド含有のヘテロ2官能性リンカー、SSNPB(N−スルホスクシンイミジル−4−(5−ニトロ−2−ピリジルジチオ)ブチレート)及びSPP(N−スクシンイミジル−3−(2−ピリジルジチオ)プロピオネート)を用いて、実施例4でSPDBリンカーについて記載されたものと似た方法によって、ジスルフィド結合の抗体/マイタンシノイド抱合体を調製した。SPDBを用いて調製したジスルフィド結合の抱合体の構造(図19)はSSNPBによって調製した抱合体のそれ(図24)と同一である。SPDBを用いて調製したジスルフィド結合の抱合体のMSは、抗体に結合した様々な数のマイタンシノイド分子に相当する質量値を持つ別々のピークを示した。
実施例6でSMCCリンカーについて記載された方法に類似する、マイタンシノイドと直鎖アルキル炭素さを持つヘテロ2官能性リンカーの反応混合物を用いて、直鎖アルキル炭素鎖を持つ切断不能なリンカーを含有する抱合体を調製した。たとえば、図26に示されたようなBMPS(N−[β−マレイミドプロピルオキシ]スクシンイミドエステル)又はGMBS(N−[γ−マレイミドブチルオキシ]スクシンイミドエステル)リンカーを用いてDM1を伴ったヒト化抗体の抱合体を調製した。60%のDMA/40%(v/v)の200mMのコハク酸緩衝液、pH5におけるBMPS又はGMBS(8mM)とDM1チオール(10.4mM)を含有する最初の反応混合物は、15分で確認した場合、マレイミド部分の完全な反応(302〜320nmでのマレイミドの吸収の衰退に基づく)を示した。20%のDMA(v/v)を含有する80%の水性EPPS緩衝液、pH8.1における2.5mg/mLのヒト化抗体溶液に、この反応混合物を2回に分けて、30分間離して加え、リンカーは合計、抗体と等量の8モル加えた。4時間後、抱合体混合物をゲル精製し、2回の透析に供した。3.8及び5.1のDM1/抗体の比率を持つ抱合体は、71〜75%の回収率で、高いモノマー比(96.2〜97.6%)で調製した。GMBS又はBMPSによって調製したこれら抱合体は、HISEP HPLC解析によって抱合されなかった遊離の薬剤を示さなかった。図25に示されるようなAMAS(N−[β−マレイミドアセトキシ]スクシンイミドエステル)又はEMCS(N−[β−マレイミドカプロイルオキシ]スクシンイミドエステル)又はスルホ−H−ヒドロキシスクシンイミドエステル(スルホ−GMBS、スルホ−EMCS)を用いて直鎖アルキル鎖を持つ切断不能なリンカーを含有する類似の抱合体を調製することができる。表1は、本発明で記載された方法によって調製した精選抱合体のモノマー比率を示し、それらはすべてサイズ排除クロマトグラフィ解析によって高いモノマー比率を示した。比較のために、モノマー比率はまた、従来の2工程抱合方法(ヘテロ2官能性リンカーとの抗体の最初の反応、次いでマイタンシノイドチオールとの反応)によって調製した抱合体についても示す。
[1]溶液における精製された抱合体を調製する方法であって、前記抱合体が、細胞結合剤に連結されたエフェクター分子又はリポーター分子を含み、前記方法が、(a)エフェクター分子又はリポーター分子を2官能性リンカー試薬に接触させて該リンカーをエフェクター分子又はリポーター分子に共有結合させ、それによってそれに結合したリンカーを有するエフェクター分子又はリポーター分子を含む未精製の第1の混合物を調製することと、(b)未精製の第1の混合物を細胞結合剤と反応させることによって、それに結合したリンカーを有するエフェクター分子又はリポーター分子に細胞結合剤を抱合させて第2の混合物を調製することと、(c)第2の混合物を接線流濾過、透析、ゲル濾過、吸着クロマトグラフィ、選択的沈殿、又はこれらの組み合わせに供して精製された抱合体を調製することを含む方法。
[2]工程(b)が約4〜約9のpHでの溶液で行われる[1]の方法。
[3]工程(b)における第2の混合物が、分子内又は分子間の反応によって形成される望ましくない架橋された、加水分解された種を実質的に含まない[1]の方法。
[4]エフェクター分子が細胞傷害剤である[1]の方法。
[5]細胞傷害剤が、マイタンシノイド、タキサン、CC1065又はこれらの類似体である[4]の方法。
[6]細胞傷害剤がマイタンシノイドである[4]の方法。
[7]マイタンシノイドがチオール基を含む[6]の方法。
[8]マイタンシノイドがDM1である含む[6]の方法。
[9]マイタンシノイドがDM4である含む[6]の方法。
[10]細胞結合剤が、インターフェロン、インターロイキン2(IL−2)、インターロイキン3(IL−3)、インターロイキン4(IL−4)、インターロイキン6(IL−6)、インスリン、EGF、TGF−α、FGF、G−CSF、MCSF、GM−CSF又は抗体である[1]の方法。
[11]細胞結合剤が抗体である[10]の方法。
[12]抗体がモノクローナル抗体である[11]の方法。
[13]抗体が、ヒトモノクローナル抗体又はヒト化モノクローナル抗体である[11]の方法。
[14]抗体が、MY9、抗B4、CD3、CD4、CD11、CD19、CD20、CD22、CD33、CD37、CD38、CD40、CD44、CD56、CD138、HER2、HER3、cripto、アルファvベータ3インテグリン、アルファvベータ5インテグリン又はC242である[10]の方法。
[15]ヒト抗体又はヒト化抗体が、My9−6、B4、C242、N901、DS6、EphA2、Cd38、IGF−IR、CNTO95、B−B4、トラスツズマブ、ペルツズマブ、ビバツズマブ、シブロツズマブ又はリツキシマブである[13]の方法。
[16]リンカーが、切断可能なリンカー又は切断不能なリンカーである[1]の方法。
[17]リポーター分子が放射性同位元素である[1]の方法。
Claims (15)
- 以下の式:
X−L−Y’−C
(式中、
Xは、N−ヒドロキシスクシンイミドエステル(NHSエステル)、スルホ−NHSエステル、p−ニトロフェノールエステル、テトラフルオロスルホネートフェニルエステル、又は1−ヒドロキシ−2−ニトロベンゼン−4−スルホン酸エステルであり;
Lは、置換又は非置換の直鎖、分枝鎖又は環状の1〜10の炭素原子を持つアルキル基、アルケニル基又はアルキニル基、単純な又は置換されたアリール単位、又はポリエチレングリコール含有の単位であり;
Y’は、非還元性チオエーテル結合であり;
Yは、マレイミド又はハロアセトアミドから選択され;
Cは、チオール含有マイタンシノイドである)
で表される、溶液中の修飾されたマイタンシノイドを調製する方法であって、
以下の式:
X−L−Y
で表されるヘテロ2官能性リンカーを、水性溶媒、有機溶媒又は混合された有機/水性反応混合物中で、チオール含有マイタンシノイドと接触させることを含む、前記方法。 - Xが、N−ヒドロキシスクシンイミドエステル(NHSエステル)、またはスルホ−NHSエステルである、請求項1に記載の方法。
- Yが、マレイミド、ヨードアセトアミド、またはブロモアセトアミドから選択される、請求項1又は2に記載の方法。
- Lが、置換又は非置換の直鎖、分枝鎖又は環状のアルキル基であり、ここで当該置換基は、アルキル、アルコキシ、ハロゲン、ニトロ、フルオロ、カルボキシ、スルホネート、ホスフェート、アミノ、カルボニル、ピペリジノから選択される、請求項1〜4のいずれか1項に記載の方法。
- Lが、非置換の直鎖アルキル基または置換の直鎖アルキル基であり、ここで当該置換基は、任意で、カルボニルおよびスルホネートである、請求項5に記載の方法。
- Lが、置換の環状アルキル基であり、ここで当該置換基はカルボニルである、請求項7に記載の方法。
- Lが、ポリエチレングリコール含有の単位である、請求項1に記載の方法。
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