JP2011508754A - 慢性疲労症候群の治療用の抗cd20抗体又はその断片などのb細胞除去剤 - Google Patents
慢性疲労症候群の治療用の抗cd20抗体又はその断片などのb細胞除去剤 Download PDFInfo
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Abstract
Description
慢性疲労症候群(CFS)は、連続して少なくとも6ヶ月存続して、職業、社会、又は個人的な活動の従前レベルの実質的な低下を伴う、説明不能で重篤な疲労を特徴とする。また、これらの患者は、短期記憶又は集中の障害、筋肉痛、関節炎の証拠がない関節痛、頭痛、睡眠障害、及び運動後の消耗といった持続性又は再発性の症状をしばしば体験する(Fukuda K, et al., 1994, Ann Intern Med 121 :953-9et al 1994)。多くの研究が血液検査や放射医学上の検討において微妙な変化を示してきたが、バイオマーカーも診断検査法も存在していない。
CFSの病因は、依然として不明である。様々な仮説には、免疫学、ウイルス学、神経内分泌学、及び心理学上の機序が含まれる。CFSの病理発生は多因子性であり、宿主と環境の両方の要因が関与すると推察されている(Devanur & Kerr 2006)。
Whistler T, et al., 2003, J Transl Med 1 :10)。この遺伝子発現データは、決定的ではないものの、CFSには様々な細胞機能を表徴する遺伝子発現障害があることを示唆して、この疾患には種々雑多な病理発生があることを示す可能性がある。
正確な病理発生に関する知識の不足と原因機序が知られていないために、CFSに対する現行の標準的な特定治療法はない。系統的な概説は、進取的な筋肉リハビリテーションを行動及び認知の治療と組み合わせることを重視した「生物心理社会モデル」とCFSを結び付けるべきであると結論付けた(Maquet et al, 2006, Ann Readapt Med Phys 49:337-47, 418-27)
生物学的な仮説に基づいた療法を評価する研究がほとんど実施されてこなかった理由は、CFSの病因が知られていないためであろう。
リツキシマブ(Mabthera[マブセラ]、RITUXAN(登録商標))は、膜貫通分子、CD20の細胞外部分中のエピトープに対して指向されたモノクローナル抗体である。この抗体は、断片抗原結合(Fab)部分がマウスであり、Fc部分がヒトである、ヒト−マウスのキメラ抗体である。CD20タンパク質は、Bリンパ球で発現されるが、幹細胞や成熟形質細胞では発現されない。CD20はまた、大多数のB細胞リンパ腫で発現される。CD20は、膜貫通カルシウム伝導と細胞周期進行の調節に関与している可能性があるが、正確な機能は知られていない(Janas et al 2005, Biochem Soc Symp:165-75)。リツキシマブのCD20への結合時には、そのFc部分への補体の結合と補体カスケードの活性化を介して、そしてまた抗体依存性細胞傷害活性(ADCC)の活性化を介して、免疫学的な細胞殺傷が媒介される(Glennie et al 2007, MoI Immunol 44:3823-37)。
B細胞リンパ腫の治療におけるリツキシマブの役割は、にわかに注目されている。無痛性リンパ腫において、化学療法と組み合せてリツキシマブを使用する免疫化学療法、又はリツキシマブ単独療法は、今や現行の標準治療法であり、最も一般的なタイプの侵襲性B細胞リンパ腫(び慢性大細胞性B細胞リンパ腫)において、高齢者(Coiffier et al 2002, N Engl J Med 346:235-42)と若年患者(Pfreundschuh et al 2006, Lancet Oncol 7:379-91)の両方で、そしてまた最も一般的な無痛性リンパ腫(濾胞性リンパ腫)(Marcus et al 2005, Blood 105:1417-23)において全体生存率を改善してきた。濾胞性リンパ腫の選択された患者において、リツキシマブはまた、導入療法後の維持治療として3ヶ月ごとに2年間の注入で使用されて、全体生存率の改善を示している(van Oers et al 2006, Blood 108:3295-301)。
B細胞リンパ腫の治療におけるリツキシマブの安全性プロフィールはよく知られていて、370,000名の患者のデータベースからの経験に基づく(Kavanaugh 2006, J Rheumatol Suppl 77:18-23)。リンパ腫の治療では、主に最初の腫瘍負荷が高い患者において、サイトカイン放出によって引き起こされる、最初の注入の間の軽度〜中等度の反応が最も一般的な副作用である(Solal-Celigny 2006, Leuk Res 30 Suppl 1 :S16-21)。この注入の間には、リツキシマブ分子のタンパク質の性質により、アレルギー反応が見られる場合がある。
本明細書に使用されるように、「B細胞除去」又は「B細胞除去活性」という用語は、被検者の循環B細胞レベルを低下させる、化学的実体又は生物学的実体(例、抗体)のいずれかの実体の能力を意味する。B細胞除去は、例えば、細胞死を誘導するか又は増殖を抑制することによって達成してよい。
より広義の意味において、本発明は、抗体又はその断片のCFSの治療への使用だけでなく、B細胞除去活性を有するCD20分子アンタゴニスト全般のCFSの治療への使用にも関する。
「CD20結合抗体断片」は、その抗原結合領域を含む、インタクト抗体の一部を含む。抗体断片の例には、Fab、Fab’、F(ab’)2、及びFv断片;ダイアボディ;直鎖(linear)抗体;単鎖抗体分子;及び、抗体断片より形成される多重特異性抗体が含まれる。本発明の目的では、「インタクト抗体」は、重鎖及び軽鎖の可変ドメイン、並びにFc領域を含んでなる抗体である。
ポリクローナル抗体は、好ましくは、関連抗原及びアジュバントの多数の皮下(sc)又は腹腔内(ip)注射によって動物において産生する。二機能性又は誘導化の薬剤、例えば、マレイミドベンゾイルスルホスクシンイミドエステル(システイン残基を介した共役)、N−ヒドロキシスクシンイミド(リジン残基を介する)、グルタルアルデヒド、無水コハク酸、SOCl2、又はR1N=C=NR(ここでRとR1は異なるアルキル基である)を使用して、免疫化される種において免疫原性であるタンパク質(例、アオガイヘモシアニン、血清アルブミン、ウシチログロブリン、又は大豆トリプシン阻害剤)へ関連抗原を共役させることが有用であり得る。
モノクローナル抗体は、実質的に均質な抗体の集団より得られる。即ち、この集団を含んでなる個別の抗体は、そのモノクローナル抗体の産生の間に生じる可能な変異体(このような変異体は、概して微量に存在する)を除けば、同一である、及び/又は同じエピトープへ結合する。このように、「モノクローナル」という修飾語は、別種の抗体又はポリクローナル抗体の混合物ではないという抗体の特徴を示す。例えば、モノクローナル抗体は、Kohler et al, Nature, 256: 495 (1975) によって初めて記載されたハイブリドーマ法を使用して作製しても、組換えDNA法(米国特許第4,816,567号)によって作製してもよい。
当該技術分野では、非ヒト抗体をヒト化する方法について記載されてきた。好ましくは、ヒト化抗体は、非ヒトである供給源よりそれへ導入された1以上のアミノ酸残基を有する。これらの非ヒトアミノ酸残基は、典型的には「インポート」可変ドメインより取られる「インポート」残基としばしば呼ばれる。ヒト化は、本質的には、Winter と共同研究者の方法(Jones et al, Nature, 321 :522-525 (1986); Riechmann et al, Nature, 332:323-327 (1988); Verhoeyen et al., Science, 239:1534-1536 (1988))に従って、超可変領域配列をヒト抗体の対応配列で置換することによって実施することができる。従って、そのような「ヒト化」抗体はキメラ抗体であり(米国特許第4,816,567号)、ここではインタクトなヒト可変ドメインより実質的に少ない部分が非ヒト種由来の対応配列によって置換されていて、実際には、ヒト化抗体は、典型的には、いくつかの超可変領域残基とおそらくはいくつかのFR残基が齧歯動物の抗体中の類似部位からの残基によって置換されているヒト抗体である。ヒト化抗体を作製するときに使用すべき重鎖と軽鎖の両方のヒト可変ドメインの選択は、抗原性を抑えるのにきわめて重要である。いわゆる「ベストフィット」法によって、齧歯動物の抗体の可変ドメイン配列を既知のヒト可変ドメイン配列の全体ライブラリーに対してスクリーニングする。次いで、齧歯動物の配列に最も近いヒト配列をヒト化抗体のヒトフレームワーク領域(FR)として受容する(Sims et al, J. Immunol, 151 :2296 (1993); Chothia et al, J. MoI. Biol, 196:901 (1987))。別の方法は、軽鎖又は重鎖の可変領域の特別な亜群のすべてのヒト抗体のコンセンサス配列に由来する特別なフレームワーク領域を使用する。同じフレームワークをいくつかの異なるヒト化抗体に使用してよい(Carter et al, Proc. Natl Acad. ScL USA, 89:4285 (1992); Presta et al, J. Immunol, 151 :2623 (1993))。抗原への高い親和性と他の好ましい生物学的特質を保持して抗体をヒト化することがさらに重要である。この目標を達成するには、好ましい方法に従って、親配列とヒト化配列の三次元モデルを使用する、親配列と様々な概念上のヒト化産物の解析の方法によってヒト化抗体を製造する。三次元の免疫グロブリンモデルは、普通に入手可能であって、当業者に馴染みがある。選択される候補免疫グロブリン配列のあり得る三次元コンホメーション構造を図解及び図示するコンピュータプログラムが利用可能である。これらディスプレイの視察によって、候補免疫グロブリン配列の機能における該残基のあり得る役割の分析、即ち、その抗原へ結合する候補免疫グロブリンの能力に影響を及ぼす残基の分析が可能になる。このようにして、標的抗原(複数)への親和性の増加といった所望の抗体特性が達成されるように、レシピエント及びインポート配列よりFR残基を選択して組み合わせることができる。一般に、超可変領域残基は、抗原結合に影響を及ぼすことに直接的かつ最も実質的に関与する。
ヒト化に代わる方法として、ヒト抗体を産生することができる。例えば、免疫化のときに、内因性の免疫グロブリン産生の非存在下で、ヒト抗体の完全レパートリーを産生することが可能となるトランスジェニック動物(例、マウス)を産出することが今や可能である。例えば、キメラ及び生殖細胞系列の突然変異マウスにおける抗体重鎖連結領域(J11)遺伝子のホモ接合性欠失は、内因性の抗体産生の完全な阻害をもたらす。ヒト生殖細胞系列免疫グロブリン遺伝子アレイをそのような生殖細胞系列突然変異マウスに移すと、抗原チャレンジ時にヒト抗体の産生をもたらすものである。例えば、Jakobovits et al, Proc. Natl. Acad. ScL USA, 90: 2551(1993); Jakobovits et al, Nature, 362: 255-258 (1993);Bruggermann et al, Year in Immuno., 7:33 (1993);及び、米国特許第5,591,669号、5,589,369号、及び5,545,807号を参照のこと。あるいは、ファージディスプレイ技術(McCafferty et al, Nature 348:552-553 (1990))を使用して、非免疫化ドナー由来の免疫グロブリン可変(V)ドメイン遺伝子レパートリーよりヒト抗体及び抗体断片を in vitro で産生することができる。この技術に従って、抗体Vドメイン遺伝子を、MI3又はfdのような繊維状バクテリオファージのメジャー又はマイナーいずれかのコートタンパク質遺伝子へインフレームでクローニングして、このファージ粒子の表面に機能性の抗体断片として提示する。この繊維状粒子は、ファージゲノムの一本鎖DNAコピーを含有するので、抗体の機能特性に基づいた選択はまた、この特性を明示する抗体をコードする遺伝子の選択をもたらす。このように、このファージは、B細胞の特性のいくつかを模倣する。ファージディスプレイは、多様なフォーマットにおいて実施することができるが、その概説については、例えば、Johnson, Kevin S. and Chiswell, David J., Current Opinion in Structural Biology 3:564-571 (1993) を参照のこと。ファージディスプレイには、V遺伝子セグメントのいくつかの供給源を使用することができる。Clackson et al, Nature, 352:624-628 (1991) は、免疫化マウスの脾臓に由来するV遺伝子の小さなランダムコンビナトリアルライブラリーより抗オキサゾロン抗体の多様なアレイを単離した。Marks et al., J. MoI. Biol. 222:581-597 (1991), 又は Griffith et al, EMBOJ. 12:725-734 (1993) に記載の技術に本質的に従って、非免疫化ヒトドナーよりV遺伝子のレパートリーを構築して、多様なアレイの抗原(自己抗原が含まれる)に対する抗体を単離することができる。また、米国特許第5,565,332号及び5,573,905号を参照のこと。ヒト抗体はまた、in vitro 活性化B細胞によって産生してよい(米国特許第5,567,610号及び5,229,275号を参照のこと)。
抗体断片の産生には、様々な技術が開発されてきた。伝統的には、インタクト抗体のタンパク分解的な消化を介してこれらの断片を導いた(例えば、Morimoto et al, Journal of Biochemical and Biophysical Methods 24:107-117 (1992) 及び Brennan et al, Science, 229:81 (1985) を参照のこと)。しかしながら、これらの断片は、今日では、組換え宿主細胞より直接産生することができる。例えば、抗体断片は、上記に考察した抗体ファージライブラリーより単離することができる。あるいは、Fab’−SH断片を大腸菌(E. coli)より直接回収して、化学的にカップリングさせて、F(ab’)2断片を生成することができる(Carter et al, Bio/Technology 10:163-167 (1992))。別のアプローチによれば、組換え宿主培養物よりF(ab’)2断片を直接単離することができる。当業者には、抗体断片の産生のための他の技術が明らかであろう。他の態様において、選択される抗体は、単鎖Fv断片(scFv)である。WO93/16185;米国特許第5,571,894号;及び、米国特許第5,587,458号を参照のこと。抗体断片は、例えば、米国特許第5,641,870号に記載されるような「線状抗体」であってもよい。そのような線状抗体断片は、単特異性又は二重特異性であってよい。
本発明に拠って使用する抗体又は他のアンタゴニストのようなB細胞除去剤の治療用製剤は、所望の度合いの純度を有する抗体又はその断片を任意選択の医薬的に許容される担体、賦形剤、又は安定化剤と混合することによって、凍結乾燥製剤又は水溶液剤の形態で保存用に調製する(「Remington's Pharmaceutical Sciences(レミントン製薬科学)」第16版、Osol, A. 監修(1980))。許容される担体、賦形剤、又は安定化剤は、利用される投与量及び濃度でレシピエントに対して無毒であり、リン酸塩、クエン酸塩、及び他の有機酸のような緩衝剤;アスコルビン酸及びメチオニンが含まれる抗酸化剤;保存剤(塩化アンモニウムオクタデシルジメチルベンジル;塩化ヘキサメトニウム;塩化ベンザルコニウム、塩化ベンゼトニウム;フェノール、ブチル、又はベンジルアルコール;メチル又はプロピルパラベンのようなアルキルパラベン;カテコール;レゾルシノール;シクロヘキサノール;3−ペンタノール;及びm−クレゾールのような);低分子量(約10未満の残基)ポリペプチド;血清アルブミン、ゼラチン、又は免疫グロブリンのようなタンパク質;ポリビニルピロリドンのような親水性ポリマー;グリシン、グルタミン、アスパラギン、ヒスチジン、アルギニン、又はリジンのようなアミノ酸;単糖、二糖、及び、グルコース、マンノース、又はデキストリンが含まれる他の炭水化物;EDTAのようなキレート形成剤;ショ糖、マンニトール、トレハロース、又はソルビトールのような糖;ナトリウムのような塩形成性の対イオン;金属錯体(例、Zn−タンパク質錯体);及び/又は、TWEENTM、PLURONICSTM、又はポリエチレングリコール(PEG)のような非イオン性界面活性剤が含まれる。
第一のパイロット患者として、上記の女性は、この手技の実験的な性質とそれに伴うリスクについて知らされた後で、リツキシマブ500mg/m2を単回注入として受けた。治療前、彼女は、顕著な疲労がある安定したCFSを有して、戸外で働くことも家事をすることもできなかった。彼女は、外出には電動車椅子を使用した。注入後5週目と6週目の間に始まって、彼女は、疲労の著しい減少、筋肉痛の減少、皮膚の灼熱痛の減少、及び頭痛の低下、それに伴うオピオイド鎮痛薬の必要性の漸減といった、顕著な症状改善を体験した。疲労の低下により、彼女は長時間の散歩が可能になり、自らの趣味を再開して、家事をして子供たちの世話をすることができた。彼女はまた、集中する能力を維持する、認知機能の顕著な改善を報告して、再び読書をすることができて、例えばコンピュータ作業もできた。この一回目の注入後の効果は、リツキシマブ注入後14週間まで続いてから低下して、CFS症状が徐々に、完全にではないが再発した。
彼は42歳の男性であり、8年前のエプシュタイン・バー感染後にCFSを発症した。彼には顕著な疲労があって、このことに遭遇して以来、どんな仕事もすることができなかった。彼は1日の大半を肘掛け椅子に座るように束縛された。軽い運動の後で、彼は、消耗、筋肉痛及び頭痛の増加という大問題を抱えた。彼にはまた、発熱感、発汗、及び下痢があった。彼には重篤な認知障害があった。かつては熟練したコンピュータ技師であったが、彼はコンピュータを使うことも、本の1〜2頁以上を文脈に沿って読むこともできなかった。
彼女は22歳の学生であり、7年前の単球増加症の後でCFSを発症している。当初、彼女には、頭痛が含まれる疼痛、認知障害、及び自律神経症状を伴う、顕著な疲労がある発病段階の臨床像があった。しかしながら、この4年間、彼女はいくらかの改善を体験したが、依然として顕著な疲労、過度の睡眠要求、及び軟便が残った。彼女には、中等度の認知障害と中等度の筋肉痛があった。
Claims (13)
- 慢性疲労症候群及び筋痛性脳脊髄炎の治療のためのB細胞除去剤。
- B細胞除去性抗CD20抗体又はそのCD20結合抗体断片である、請求項1に記載のB細胞除去剤。
- モノクローナル抗体又はそのCD20結合抗体断片である、請求項2に記載のB細胞除去性抗CD20抗体又はCD20結合抗体断片。
- ヒト化抗CD20抗体又はそのCD20結合抗体断片である、請求項2に記載のB細胞除去剤。
- CD20へ結合するB細胞除去性CD20抗体断片であり、好ましくは、F(ab’)2、F(ab’)、Fab、Fv、及びsFvからなる群より選択される抗原結合断片である、請求項2に記載のB細胞除去剤。
- ヒト化抗体:リツキシマブ(Rituximab)、オファツムマブ(Ofatumumab)、オクレリズマブ(Ocrelizumab)、GA101、BCX−301、ベルツズマブ(Veltuzumab)、又はDXL625より選択される、請求項1〜5のいずれか1項に記載のB細胞除去剤。
- メトトレキサート、TRU−015、又はSBI−087である、請求項1に記載のB細胞除去剤。
- 慢性疲労症候群/筋痛性脳脊髄炎の治療用の請求項1〜6のいずれか1項に記載のB細胞除去剤であって、ここでそのB細胞除去性抗CD20抗体の量は、投与量につき10mg〜5000mgの範囲にある、前記除去剤。
- B細胞除去性抗CD20抗体又はそのCD20結合抗体断片であって、50〜2000mg/m2の前記抗体の単回治療有効投与量又は50〜2000mg/m2の前記抗CD20抗体又はその抗CD20結合抗体断片の頻回治療有効投与量で被検者へ投与される、請求項1〜6のいずれか1項に記載のB細胞除去剤。
- 慢性疲労症候群及び筋痛性脳脊髄炎を治療する方法であって、請求項1〜9のいずれか1項に記載のB細胞除去剤をそれに罹患した被検者へ投与する工程を含んでなる、前記方法。
- 請求項1〜9のいずれか1項に記載のB細胞除去剤の1又は2の注入剤を2週以内に2回投与する工程を含んでなる、慢性疲労症候群及び筋痛性脳脊髄炎を治療するための方法。
- 慢性疲労症候群又は筋痛性脳脊髄炎に罹患している被検者へB細胞除去性抗CD20抗体又はそのCD20結合抗体断片のメトトレキサートとの組合せを同時的、分離的、又は連続的に投与することによる、請求項10又は11に記載の慢性疲労症候群及び筋痛性脳脊髄炎を治療する方法。
- 請求項1〜9のいずれか1項に記載のB細胞除去剤の、慢性疲労症候群又は筋痛性脳脊髄炎の治療への使用。
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JP2021523128A (ja) * | 2018-05-18 | 2021-09-02 | トリオン リサーチ ゲーエムベーハーTrion Research Gmbh | 再活性化現象に関連する疾患を伴うEpstein−Barrウイルス陽性患者の治療に使用するための医薬製剤 |
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EP2235060A1 (en) | 2010-10-06 |
AU2009203117A1 (en) | 2009-07-09 |
HUE034127T2 (en) | 2018-01-29 |
CA2706899C (en) | 2017-02-28 |
DK2235060T3 (en) | 2017-06-06 |
SI2235060T1 (sl) | 2017-09-29 |
JP5722044B2 (ja) | 2015-05-20 |
CN101910201A (zh) | 2010-12-08 |
PL2235060T3 (pl) | 2017-10-31 |
EP2077281A1 (en) | 2009-07-08 |
WO2009083602A1 (en) | 2009-07-09 |
RU2519229C2 (ru) | 2014-06-10 |
PT2235060T (pt) | 2017-05-31 |
KR101652530B1 (ko) | 2016-08-30 |
LT2235060T (lt) | 2017-07-25 |
KR20100116172A (ko) | 2010-10-29 |
RU2010132178A (ru) | 2012-02-10 |
EP2235060B1 (en) | 2017-03-29 |
CN101910201B (zh) | 2015-01-21 |
BRPI0906172A2 (pt) | 2015-06-30 |
HRP20170687T1 (hr) | 2017-09-08 |
CY1118918T1 (el) | 2018-01-10 |
AU2009203117B2 (en) | 2014-10-23 |
IL206767A0 (en) | 2010-12-30 |
ES2625728T3 (es) | 2017-07-20 |
IL206767A (en) | 2015-03-31 |
CA2706899A1 (en) | 2009-07-09 |
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