JP6813712B2 - グルココルチコイド受容体作動薬及びそのイムノコンジュゲート - Google Patents
グルココルチコイド受容体作動薬及びそのイムノコンジュゲート Download PDFInfo
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Description
(a)配列番号3に記載の重鎖と配列番号4に記載の軽鎖とを含む抗TNFα抗体;及び(b)式:
(a)配列番号3に記載の重鎖と配列番号4に記載の軽鎖とを含む抗TNFα抗体;及び(b)式:
本開示を理解し易くするために、多数の用語と語句について以下に定義する。
本開示はグルココルチコイド受容体作動薬をタンパク質(例えば抗体)と連結したイムノコンジュゲートを提供する。ある実施形態において、前記抗体はヒト抗体、ヒト化抗体、キメラ抗体又はマウス抗体である。ある実施形態において、前記タンパク質(例えば抗体)は細胞の表面の標的と結合して内在化することができる。
グルココルチコイド受容体作動薬を含むイムノコンジュゲートも提供する。ある実施形態において、イムノコンジュゲートはFcγ受容体と結合する。ある実施形態において、イムノコンジュゲートはGRE膜貫通型TNFαレポーターアッセイにおいて活性である(本願で使用する「GRE膜貫通型TNFαレポーターアッセイ」とは下記実施例7で使用するアッセイを意味する。)。ある実施形態において、イムノコンジュゲートはこのイムノコンジュゲートにおけるタンパク質(例えば抗体)単独と比較した場合に免疫原性の低下(抗薬物免疫応答(ADA)の低下)を示す。
(SM−L−Q)n−A I−a
を有する化合物を開示し、式中、
Aは抗腫瘍壊死因子(TNF)α抗体、抗TNFαモノクローナル抗体又はアダリムマブであり;
Lはリンカーであり;
Qはヘテロ二官能基であり;又は
Qは不在であり;
nは1〜10であり;
SMは下式:
(1)式II−a:
本開示の種々のイムノコンジュゲートの一般合成法は下式III−a、III−b、III−c又はIII−dのいずれかのNH2で官能基化された低分子(SM)をリンカー部分と反応させる工程、及び得られた化合物を官能基化し、ブロモアセトアミドて官能基化された中間体とする工程を含む。その後、ブロモアセトアミドで官能基化された中間体をHS−Aと反応させる(なお、HS−Aは還元された鎖間ジスルフィド結合数の少ない抗体、例えばアダリムマブである。)。
Aはアダリムマブであり;
Lはリンカーであり;
nは1〜10であり;
SMは式III−a〜III−dのいずれか1種を有するグルココルチコステロイド基であり;
前記方法は、
a)式V:
Aがアダリムマブであり;
nが1〜10である化合物を開示する。
本願ではインビトロ又はインビボで使用することができる式I−aを有する(例えば表3に示す式を有する)コンジュゲートを提供する。従って、生理的に許容される基剤、賦形剤又は安定剤(Remington’s Pharmaceutical Sciences(1990)Mack Publishing Co.,Easton,PA)中に所望の純度を有するコンジュゲート又はグルココルチコイド受容体作動薬を含有する組成物、例えば所定のインビボ用途の医薬組成物も提供する。許容される基剤、賦形剤又は安定剤は利用される用量と濃度で被投与者に非毒性である。
本開示は1個以上の容器を含む医薬パック及びキットも包含し、1個の容器に1回分以上の用量の本願に記載する抗体薬物複合体又は組成物を収容することができる。所定の実施形態において、前記パック又はキットは1種以上の他の薬剤の存在下又は不在下で単位用量即ち規定量の組成物又は抗体薬物複合体を含む。
以下の手順の詳細、一般的な手順の説明又は実施例の表には分析データが含まれている。特に指定しない限り、全ての1H及び13C NMRデータはVarian Mercury Plus 400MHz又はBruker AVIII 300MHz機器で取得し、化学シフトは百万分率(ppm)で表す。HPLC分析データについては実験セクションに詳述するか、又は表4に示す方法を使用し、LC/MS及びHPLC条件を箇条書きする。
実施例6の生成物はN−(2−((((9H−フルオレン−9−イル)メトキシ)カルボニル)アミノ)エチル)−N−(tert−ブトキシカルボニル)−L−アラニル−L−アラニン(下記工程S1及びS2の生成物)を実施例2のアミノ生成物とカップリングした後に工程S4〜S6:(1)Fmoc脱保護、(2)2−ブロモ酢酸とのカップリング、及び(3)Boc脱保護を行うことにより合成することができる。Fmoc=フルオレニルメチルオキシカルボニル;Boc=tert−ブトキシカルボニル。
PBS緩衝液(pH6〜7.4)で目的とする抗体の約5〜20mg/mL溶液を調製した。TCEP等の選択した還元剤をH2O、DMSO、DMA又はDMF等の溶媒で希釈又は溶解し、濃度範囲1〜25mMの溶液とした。還元剤約2〜3.5当量を加えて短時間混合し、0〜4℃で一晩インキュベートすることにより抗体(抗hTNF hIgG1(D2E7)又は抗mTNF mIgG2a(8C11;McRae BL et al.J Crohns Colitis 10(1):69−76(2016))を部分的に還元した。次にトリス緩衝液(pH8〜8.5)(20〜50mM)を加えた後、リンカー−薬物のDMSO又はDMA溶液(合計15%未満)を加え、混合液を室温で2〜3時間インキュベートした。次に、過剰のリンカー−薬物と有機溶媒を精製により除去した。その後、精製したADC試料をSEC、HIC及び還元条件下の質量分析法により分析した。
アニオン交換クロマトグラフィー(AEC)又は疎水性相互作用クロマトグラフィー(HIC)によりADCをプロファイリングし、ADCの連結度と純度を求めた。
アダリムマブのジスルフィド還元後にブロモアセトアミドグリシン−グルタミン酸ステロイド(実施例4)でアルキル化(連結)する2段階化学反応プロセスにより、集合体DARが4.0であるアダリムマブとBrAc−Gly−Glu−ステロイド−PO4のADCを作製した。
親細胞株を作製するために、完全増殖培地(RPMI,10%FBS,1%L−グルタミン,1%ピルビン酸Na及び1%MEM NEAA)2mLを加えた6ウェルプレート(Costar:3516)にK562細胞をウェル当たり500,000個の割合で37℃、5%CO2下に24時間播種した。翌日、pGL4.36[Luc2P/MMTV/Hygro](Promega:E316)1.5μgと、pGl4.75[hRLuc/CMV](Promega:E639A)1.5μgと、PLUS試薬(Invitrogen:10964−021)3μLをOpti−MEM(Gibco:31985−070)244μLで希釈し、室温で15分間インキュベートした。pGL4.36[luc2P/MMTV/Hygro]ベクターはグルココルチコイド受容体やアンドロゲン受容体等の数種の核内受容体の活性化に応答してルシフェラーゼレポーター遺伝子luc2Pの転写を誘導するMMTV LTR(Mammary Tumor Virus Long Terminal Repeat:マウス乳がんウイルス末端反復配列)を含む。pGL4.75[hRluc/CMV]ベクターはルシフェラーゼレポーター遺伝子hRluc(Renilla reniformis)をコードし、発現性が高く且つ異常転写が少なくなるように設計されている。
K562親GRE(pGL4.36[luc2P/MMTV/Hygro])細胞と、K562mFL−TNF−a又はhTNFΔ1−12GRE(pGL4.36[luc2P/MMTV/Hygro])細胞を組織培養処理済み96ウェル白プレート(Costar:3917)でアッセイ培地(RPMI,1%CSFBS,1%L−グルタミン,1%ピルビン酸Na及び1%MEAA)50μLにウェル当たり50,000個の割合で播種した。細胞をアッセイ培地で3倍ずつ段階希釈したマウス若しくはヒト抗TNFa抗体薬物複合体、ステロイド化合物又は培地単独25μLで処理し、37℃、5%CO2下に48時間インキュベートした。48時間インキュベーション後に細胞をDual−Gloルシフェラーゼアッセイシステム(Promega−E2920)75μLで10分間処理し、Microbeta(PerkinElmer)を使用して発光を測定した。4パラメータ曲線当てはめを使用してデータを解析し、EC50値を推定した。100nMデキサメタゾンを基準にして最大活性化率%を正規化した。マウスTNFα細胞株を使用した結果を下表9に示し、ヒトTNFα細胞株を使用した結果を下表10に示す。下表9中、ADCにおける抗体は抗マウスTNFα抗体8C11である。下表10中、ADCにおける抗体は抗ヒトTNFα抗体アダリムマブである。モノマー百分率(%)は上述したようにSECにより求めた(ADC分析手順参照)。
ヒト初代末梢血単核細胞(PBMC)をBiological Specialty Corporation(カタログ番号214−00−10)から購入し、PBS50mLで洗浄し、5%DMSOを添加したFBSに再懸濁し、分取し、使用時まで液体窒素で凍結保存した。PBMCを解凍し、2%FBSと1%ペニシリン−ストレプトマイシンを添加したRPMI培地に再懸濁し、細胞アッセイプレート(Costar #3799)に播種した。次に種々の濃度の抗TNF ADCを加えて37℃、5%CO2下に4時間インキュベートした。その後、LPS100ng/mLで細胞を一晩刺激した。翌日、プレートを1000rpmで5分間遠心し、上清培地100μLを別の96ウェルプレートに直接移し、IL−6(MSD,#K151AKB)とIL−1β(MSD,#K151AGB)の濃度を測定した。非線形回帰を使用して用量反応データをシグモイド曲線に当てはめ、GraphPad 5.0(GraphPad Software,Inc.)によりIC50値を計算した。表11に示す結果から明らかなように、抗TNF ADCは活性化させた初代免疫細胞からの炎症性サイトカインIL−6及びIL−1βの放出を抑制する強力な活性をもつ。
感作物質(フルオレセインイソチオシアネート(FITC))の塗布により(T細胞により誘導される)遅延型過敏(DTH)反応を使用して急性皮膚炎症を誘発する急性接触過敏モデルで抗TNFαステロイドADCを評価した。耳介腫脹抑制能により抗TNFaステロイドADCの効力を測定した。ステロイドバイオマーカーであるコルチコステロンと1型プロコラーゲンN末端プロペプチド(P1NP)も読み取りデータに加え、夫々視床下部−下垂体−副腎(HPA)軸と骨代謝に及ぼす抗TNFaステロイドADC投与の推定影響を評価した。
0日目にマウスに全身麻酔し、腹部を剃毛した。マイクロピペッターを使用し、FITC溶液(1.5%1:1アセトン:DBP溶液)400μLを腹部に皮膚塗布することによりマウスを感作した。6日後に、FITCによる耳介チャレンジの1時間前にマウスに溶媒又は治療剤を投与した。耳介チャレンジでは、マウスに全身麻酔し、FITC20μLを右耳介に塗布してチャレンジした。チャレンジから24時間後にマウスに全身麻酔し、その耳介厚をキャリパーで測定した。チャレンジした耳介とチャレンジしていない耳介の差を計算した。耳介チャレンジから72時間後に、マウスにACTHを1mpkの用量でIP注射し、ACTHの30分後に放血致死させた。血漿を採取し、P1NP、コルチコステロン、遊離ステロイド及び大分子の濃度を測定した。
最終濃度が8種類の異なる濃度値で0.03nM〜0.1μMとなるようにマウス血漿でステロイドの較正曲線を作成した。PBS緩衝液で調液した70mg/mLウシ血清アルブミン溶液で最終コルチコステロン濃度が0.3nM〜1μMとなるようにコルチコステロン較正曲線を作成した。0.1%ギ酸を添加したMeCN溶液160μLを試験血漿試料又は較正標準40μLに加えた。上清を蒸留水で希釈し、最終試料溶液30μLをLC/MS分析用に注入した。
タンパク質トリプシン消化に基づくLCMSプラットフォームで血漿中P1NPの定量を行った。血漿試料を部分的に沈降させ、MeCN/0.1M重炭酸アンモニウム/DTT混合液を加えることにより完全に還元させた。上清を採取し、ヨード酢酸を加えることによりアルキル化した。アルキル化したタンパク質をトリプシンにより消化し、得られたトリプシンペプチドをLCMSにより分析した。ウマ血清(非干渉性代替マトリックス)にスパイクした合成トリプシンペプチドを使用することにより較正曲線を作成した。MeCN/DTTタンパク質沈降混合液に加える内部標準として、安定同位体で標識したフランキングペプチド(トリプシンペプチドの両末端の3〜6アミノ酸延長部分)を使用し、消化効率とLCMS注入量を正規化した。
結果を下表12に示す。
抗mTNFaステロイドADC(ADC1)が疾患に作用する能力をコラーゲン誘発性関節炎(CIA)の関節炎モデルで評価した。
マレイミド系リンカーのインビボ安定性を高めるために加水分解が利用されているが、一般に塩基性pHに暴露する必要があるため、抗体の変性(例えば脱アミド化)、不均一性増加、収率低下等に繋がる恐れがある(Shen et al.,Nature Biotechnology 30:184-189(2012)(マレイミドを加水分解して薬物の早期放出と薬物全身暴露を避ける);Strop et al.,Chemistry & Biology 20(2):161−167(2013)(同様の報告);Tumey et al.,Bioconjugate Chem 25(10):1871−1880(2014)(塩基性条件下の環加水分解を可能にするために近位PEG鎖を使用する);Lyon et al.,Nature Biotechnology 32:1059−1062(2014)(スクシンイミド加水分解物の生成を助長する方法);Christie et al.,J Control Release 220(PtB):660−70(28 Dec 2015)(塩基性条件下のスクシンイミド環加水分解を助長するためにN−アリールマレイミドを使用する);Dovgan et al.,Scientific Reports 6:1(2016)(長期間にわたって弱塩基性条件下の環加水分解を助長するために2−(マレイミドメチル)−1,3−ジオキサンを使用する);及びJ Pharm Sci 2013:102(6)1712−1723(アスパラギンの脱アミド化は緩衝液種、pH及び温度に依存する))。一方、マレイミド(連結とその後の塩基性pHでの環加水分解)では数日間を要するが、ブロモアセトアミドを使用した典型的な連結条件は数時間以内で完了する。更に、システインとブロモアセトアミドの反応中に形成される2−メルカプトアセトアミドは逆マイケル反応を生じにくく、下表13でADC4について実証するように、リンカーと抗体の安定した結合が得られる。
長期安定性を評価するために、バイオ医薬品で加速ストレス試験を実施した。この試験のプロトコールは40℃の15mMヒスチジン中で100mg/mLのバイオ医薬品を21日間保温する。ADC4でこの試験を行った処、凝集増加率は<5%であったが、これに対して米国特許出願公開第2018/0126000号(公開日2018年5月10日)のADC203の凝集増加率は18%であった(表14)。これは、Gly−Gluリンカーとペイロードのリン酸プロドラッグによりADC4の性質が改善されたことを実証するものである。米国特許出願公開第2018/0126000号のADC203は以下の通りである。
特許及び出願公開を含めて発明の詳細な説明で引用した全刊行物はその開示内容全体を本願に援用する。
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