JP2010159255A - B細胞表面マーカーに結合するアンタゴニストを用いた自己免疫疾患の治療 - Google Patents
B細胞表面マーカーに結合するアンタゴニストを用いた自己免疫疾患の治療 Download PDFInfo
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Abstract
【解決手段】CD19又はCD20等のB細胞表面マーカーに結合する治癒的有効量のアンタゴニストを用いた、哺乳動物の自己免疫疾患を治療する方法。アンタゴニストは抗体を含む。
【選択図】なし
Description
B細胞は骨髄内で成熟し、骨髄がその細胞表面に抗原結合性抗体を発現するようにする。まず、未処置のB細胞は、その膜結合性抗体が特異的な抗原と遭遇すると、速やかに分裂し始め、その子孫が記憶B細胞及び「形質細胞」と呼ばれるエフェクター細胞に分化する。記憶B細胞はより長い寿命を持ち、最初の親細胞と同じ特異性を有する膜結合性抗体を発現し続ける。形質細胞は膜結合性抗体を産生しないが、代わりに分泌可能な形態の抗体を産生する。分泌される抗体は体液性免疫の主要なエフェクター分子である。
B細胞リンパ腫でCD20が発現すると、この抗原は、そのようなリンパ腫の「ターゲティング」のための候補薬となり得る。本質的に、このようなターゲティングは以下のように一般化される:B細胞のCD20表面抗原に特異的な抗体を患者に投与する。これらの抗CD20抗体は正常及び悪性B細胞の双方のCD20抗原(見かけ上)に特異的に結合する。さらに、腫瘍を破壊する可能性のある化学薬剤又は放射活性標識を、該薬剤が新生物B細胞に特異的に「送達」されるように、抗CD20抗体にコンジュゲートさせることができる。アプローチに関係なく、第1の目的は腫瘍を破壊することであり;特定のアプローチは利用する特定の抗CD20抗体により決定され、よってCD20抗原をターゲティングするために有用なアプローチはかなり多様である。
B細胞系列の細胞により発現した分化段階に特異的な抗原を認識する更なる抗体が同定されている。これらのなかには、CD21抗原に対するB2抗体;CD22抗原に対するB3抗体;及びCD10抗原に対するJ5抗体(CALLAとも称される)がある。1997年1月21日に発行された米国特許第5,595,721号を参照。
さらなる態様において、本発明は、容器と該容器に収容される組成物を含んでなる製造品に関し、ここで組成物はB細胞表面マーカーに結合するアンタゴニストを含有し、また組成物が自己免疫疾患を患っているか、又はその素因を有している患者を治療することを使用者に指示するための包装挿入物をさらに含む製造品に関する。
I.定義
ここで「B細胞表面マーカー」とは、そこに結合するアンタゴニストにより標的にされ得るB細胞の表面で発現する抗原である。B細胞表面マーカーの例には、CD10、CD19、CD20、CD21、CD22、CD23、CD24、CD37、CD53、CD72、CD73、CD74、CDw75、CDw76、CD77、CDw78、CD79a、CD79b、CD80、CD81、CD82、CD83、CDw84、CD85及びCD86白血球表面マーカーが含まれる。特に関心あるB細胞表面マーカーは哺乳動物の他の非B細胞組織と比較してB細胞で優先的に発現しており、前駆体B細胞及び成熟B細胞の双方で発現し得る。一実施態様では、マーカーは、CD20又はCD19のように、幹細胞段階から形質細胞への末端分化の直前までの系列の分化の間の全体にわたってB細胞に見出されるものである。ここで好ましいB細胞表面マーカーはCD19及びCD20である。
「CD20」抗原は、末梢血又はリンパ系器官の90%以上のB細胞の表面で見出される〜35kDaの非グルコシル化リンタンパク質である。CD20は初期のプレB細胞発育中に発現し、形質細胞分化まで残る。CD20は正常なB細胞及び悪性のB細胞の双方に存在する。文献でのCD20の他の名称には「Bリンパ球制限抗原」及び「Bp35」が含まれる。CD20抗原は、例えばClarkら, PNAS(USA)82:1766(1985)に記載されている。
「CD19」抗原とは、例えばHD237-CD19又はB4抗体により同定される〜90kDaの抗原を意味する(Kieselら, Leukemia Research II, 12:1119(1987))。CD20と同様、CD19は幹細胞段階から形質細胞への末端分化の直前までの系列の分化の間の全体にわたって細胞に見出されるものである。CD19にアンタゴニストが結合することで、CD19抗原の内部移行が引き起こされる。
「ヒトエフェクター細胞」とは、一又は複数のFcRsを発現し、エフェクター機能を実行する白血球のことである。その細胞が少なくともFcγRIIIを発現し、ADCCエフェクター機能を実行することが望ましい。ADCCを媒介するヒト白血球の例として、末梢血単核細胞(PBMC)、ナチュラルキラー(NK)細胞、単球、細胞障害性T細胞及び好中球が含まれるが、PBMCsとNK細胞が好適である。
「成長阻害」アンタゴニストは、アンタゴニストが結合する抗原を発現する細胞の増殖を防止又は低減するものである。例えば、アンタゴニストはインビトロ及び/又はインビボでB細胞の増殖を防止又は低減可能である。
「アポトーシスを誘発する」アンタゴニストは、アネキシンVの結合、DNAの断片化、細胞収縮、小胞体の拡張、細胞断片化、及び/又は膜小胞の形成(アポトーシス体と呼ばれる)等の標準的なアポトーシスアッセイにより決定される、例えばB細胞の、プログラム細胞死を誘発するものである。
「抗体断片」は無傷の抗体の一部、好ましくはその抗原結合又は可変領域を含む。抗体断片の例には、Fab、Fab'、F(ab')2及びFv断片;ダイアボディー;線形抗体;単鎖抗体分子;及び抗体断片から形成される多重特異性抗体が含まれる。
抗体のパパイン消化により、各々が単一の抗原結合部位を有する「Fab」断片と呼ばれる2つの同一の抗原結合断片と、その名称が容易に結晶化する能力を表す、残りの「Fc」断片が産生される。ペプシン処理により、2つの抗原結合部位を有し、更に抗原を架橋させ得るF(ab')2断片が生じる。
またFab断片は、軽鎖の定常ドメインと重鎖の第一定常領域(CH1)を有する。Fab'断片は、抗体ヒンジ領域からの一又は複数のシステインを含む重鎖CH1ドメインのカルボキシ末端に数個の残基が付加している点でFab断片とは異なる。Fab'-SHは、定常ドメインのシステイン残基が少なくとも1つのフリーのチオール基を担持しているFab'に対するここでの命名である。F(ab')2抗体断片は、間にヒンジシステインを有するFab'断片の対として生産された。抗体断片の他の化学カップリング法も知られている。
重鎖の定常ドメインのアミノ酸配列に応じて、抗体を異なるクラスに割り当てることができる。無傷の抗体には5つの主要なクラス:IgA、IgD、IgE、IgG及びIgMがあり、それらのいくつかは更にサブクラス(アイソタイプ)、例えばIgG1、IgG2、IgG3、IgG4、IgA及びIgA2に分けられる。異なるクラスの抗体に対応する重鎖定常ドメインは、それぞれα、σ、ε、γ及びμと呼ばれる。異なるクラスの免疫グロブリンのサブユニット構造及び3次元構造はよく知られている。
「ダイアボディ(diabodies)」なる用語は、二つの抗原結合部位を持つ小型の抗体断片を指し、その断片は同じポリペプチド鎖(VH−VL)内で軽鎖可変ドメイン(VL)に結合した重鎖可変ドメイン(VH)を含む。同じ鎖の二つのドメイン間に対形成するには短すぎるリンカーを用いることにより、ドメインは強制的に他の鎖の相補的ドメインと対形成して二つの抗原結合部位を生成する。ダイアボディは、例えば、EP 404,097; WO 93/11161; 及びHollinger等, Proc. Natl. Acad. Sci. USA, 90: 6444-6448 (1993)においてより詳細に記載されている。
CD20抗原に結合するアンタゴニストの例には、「リツキシマブ」(「リツキサン(登録商標)」)と称される「C2B8」(出典明示によって明示的にここに取り込まれる米国特許第5,736,137号)、「Y2B8」と呼称されるイッテリウム-[90]-ラベル2B8マウス抗体(出典明示によって明示的にここに取り込まれる米国特許第5,736,137号);131Iでラベルされて「131I-B1」抗体を生じるマウスIgG2a「B1」(BEXXARTM)(出典明示によって明示的にここに取り込まれる米国特許第5,595,721号);マウスモノクローナル抗体「1F5」(Pressら, Blood 69(2):584-591(1987));「キメラ2H7」抗体(出典明示によって明示的にここに取り込まれる米国特許第5,677,180号);及びインターナショナル・ロイコサイト・タイピング・ワークショップから入手可能なモノクローナル抗体L27、G28-2、93-1B3、B-C1又はNU-B2(Valentineら, In:Leukocyte Typing III(McMichael, Ed, p.440, Oxford University Press)(1987))が含まれる。
ここで、「リツキシマブ」又は「リツキサン(登録商標)」なる用語は、ここに出典明示によって明示的に取り込まれる米国特許第5,736,137号において「C2B8」と命名された遺伝子操作されたCD20抗原に対するキメラマウス/ヒトモノクローナル抗体を指す。抗体はマウス軽鎖及び重鎖可変領域配列、ヒト定常領域配列を含むIgG1カッパ免疫グロブリンである。リツキシマブは約8.0nMのCD20抗原対する結合親和性を有する。
「治療」は、治癒的処置、予防的及び防止的療法の両方を意味する。治療が必要なものとは、既に疾患又は疾病に罹っているもの、並びに疾患又は疾病が防止されるべきものを含む。よって、哺乳動物は疾患又は疾病を患っていると診断されているか、又は疾患にかかりやすいか、又はこれの影響を受けやすいと診断されている。
「治療的有効量」なる表現は、当該問題の自己免疫疾患を防止、改良又は治療するのに有効なアンタゴニストの量を意味する。
「パッケージ挿入物」という用語は効能、用法、用量、投与方法、禁忌及び/又はかかる治療製品の使用に関する警告についての情報を含む、治療製品の市販用パッケージに通常含まれるインストラクションを指すために使用される。
本発明の方法及び製造品は、B細胞表面マーカーに結合するアンタゴニストを使用するか、これを導入したものである。従って、このようなアンタゴニストを生産するための方法を以下に記載する。
アンタゴニスト(類)の製造又はスクリーニングに使用されるB細胞表面マーカーは、例えば所望のエピトープを含む抗原又はそれらの一部の可溶形態のものであってよい。あるいは、又は付加的に、アンタゴニスト(類)を生産又はスクリーニングするために、その細胞表面にB細胞表面マーカーを発現する細胞を使用することもできる。アンタゴニストの生産に有用な他の形態のB細胞表面マーカーは当業者には明らかであろう。好ましくは、B細胞表面マーカーはCD19又はCD20抗原である。
好ましいアンタゴニストは抗体であるが、ここでは抗体以外のアンタゴニストを考慮することとする。例えば、アンタゴニストには細胞障害剤(例えば上述したもの)と融合又はコンジュゲートしてもよい小分子アンタゴニストが含まれ得る。小分子のライブラリーは、抗原に結合する小分子を同定するために、ここで対象B細胞表面マーカーに対してスクリーニングされる。さらに小分子は、その拮抗特性がスクリーニングされ、及び/又は細胞障害剤とコンジュゲートされる。
また、アンタゴニストは、理論的設計又はファージディスプレイ(例えば、1998年8月13日に公開された国際公開第98/35036号)により生産されるペプチドであってもよい。一実施態様において、分子は「CDR模倣物」又は抗体のCDRに基づいて設計された抗体類似物が選択されてもよい。このようなペプチドはそれ自体で拮抗作用を示すが、ペプチドの拮抗特性を高める又は添加するために、細胞障害剤とペプチドを融合させてもよい。
以下に、本発明で使用される抗体アンタゴニストの生産のための例示的技術を示す。
ポリクローナル抗体は、好ましくは、関連する抗原とアジュバントを複数回皮下(sc)又は腹腔内(ip)注射することにより動物に産生される。免疫化される種において免疫原性であるタンパク質、例えばキーホールリンペットヘモシアニン、血清アルブミン、ウシサイログロブリン、又は大豆トリプシンインヒビターに関連抗原を、二官能性又は誘導体形成剤、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(システイン残基によるコンジュゲート)、N-ヒドロキシスクシンイミド(リジン残基による)、グルタルアルデヒド、無水コハク酸、SOCl2、又はRとR1が異なったアルキル基であるR1N=C=NRによりコンジュゲートさせることが有用である。
動物を、例えばタンパク質又はコンジュゲート100μg又は5μg(それぞれウサギ又はマウスの場合)を完全フロイントアジュバント3容量と併せ、この溶液を複数部位に皮内注射することによって、抗原、免疫原性コンジュゲート、又は誘導体に対して免疫化する。1ヶ月後、該動物を、完全フロイントアジュバントに入れた初回量の1/5ないし1/10のペプチド又はコンジュゲートを用いて複数部位に皮下注射することにより、追加免疫する。7日ないし14日後に動物を採血し、抗体価について血清を検定する。動物は、力価がプラトーに達するまで追加免疫する。好ましくは、動物は、同じ抗原のコンジュゲートであるが、異なったタンパク質にコンジュゲートさせた、及び/又は異なった架橋剤によってコンジュゲートさせたコンジュゲートで追加免疫する。コンジュゲートはまたタンパク融合として組換え細胞培養中で調製することもできる。また、ミョウバンのような凝集化剤が、免疫反応の増強のために好適に使用される。
モノクローナル抗体は実質的に均一な抗体の集団から得られる抗体を意味する、すなわち、集団に含まれる個々の抗体が、少量存在しうる自然に生じる可能な突然変異を除いて同一である。よって、「モノクローナル」との修飾詞は、別個の抗体の混合物ではなく、抗体の特性を示すものである。
例えば、モノクローナル抗体は、Kohlerら, Nature, 256:495 (1975)により最初に記載されたハイブリドーマ法を用いて作製でき、又は組換えDNA法(米国特許第4,816,567号)によって作製することができる。
ハイブリドーマ法においては、マウス又はその他の適当な宿主動物、例えばハムスターを上記したようにして免疫し、免疫化に用いられるタンパク質と特異的に結合する抗体を生産するか又は生産することのできるリンパ球を導き出す。別法として、リンパ球をインビトロで免疫することもできる。次に、リンパ球を、ポリエチレングリコールのような適当な融剤を用いて骨髄腫細胞と融合させ、ハイブリドーマ細胞を形成する(Goding, Monoclonal Antibodies: Principles and Practice,pp.59-103(Academic Press, 1986))。
このようにして調製されたハイブリドーマ細胞を、融合していない親の骨髄腫細胞の増殖または生存を阻害する一又は複数の物質を好ましくは含む適当な培地に蒔き、増殖させる。例えば、親の骨髄腫細胞が酵素ヒポキサンチングアニジンホスホリボシルトランスフェラーゼ(HGPRT又はHPRT)を欠失するならば、ハイブリドーマのための培地は、典型的には、HGPRT欠失細胞の増殖を妨げる物質であるヒポキサンチン、アミノプテリン及びチミジンを含有するであろう(HAT培地)。
モノクローナル抗体の結合親和性は、例えばMunsonほか, Anal. Biochem., 107:220 (1980)のスキャッチャード分析法によって測定することができる。
所望の特異性、親和性、及び/又は活性の抗体を産生するハイブリドーマ細胞が同定された後、該クローンを限界希釈法によりサブクローニングし、標準的な方法により増殖させることができる(Goding, Monoclonal Antibodies: Principles and Practice, pp.59-103(Academic Press, 1986))。この目的に対して好適な培地には、例えば、D-MEM又はRPMI-1640培地が包含される。加えて、該ハイブリドーマ細胞は、動物において腹水腫瘍としてインビボで増殖させることができる。
典型的には、このような非免疫グロブリンポリペプチドは、抗体の定常ドメインに置換され、又は抗体の1つの抗原結合部位の可変ドメインに置換されて、抗原に対する特異性を有する1つの抗原結合部位と異なる抗原に対する特異性を有するもう一つの抗原結合部位とを含むキメラ二価抗体を作り出す。
非ヒト抗体をヒト化する方法は従来からよく知られている。好ましくは、ヒト化抗体には非ヒト由来の一又は複数のアミノ酸残基が導入されている。これら非ヒトアミノ酸残基は、しばしば、典型的には「移入」可変ドメインから得られる「移入」残基と呼ばれる。ヒト化は、ヒト抗体の該当する配列を高度可変領域配列で置換することによりウィンターと共同研究者の方法(Jonesほか, Nature, 321:522-525 (1986)、Riechmannほか, Nature, 332:323-327 (1988)、Verhoeyenほか, Science, 239:1534-1536(1988))に本質的に従って実施することができる。よって、このような「ヒト化」抗体は、無傷のヒト可変ドメインより実質的に少ない分が非ヒト種由来の該当する配列で置換されたキメラ抗体(米国特許第4,816,567号)である。実際には、ヒト化抗体は、典型的にはいくらかの高度可変領域残基及び場合によってはいくらかのFR残基が齧歯類抗体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。
ヒト化のための別法により、ヒト抗体を生産することができる。例えば、内因性の免疫グロブリン産生がなくともヒト抗体の全レパートリーを免疫化することで産生することのできるトランスジェニック動物(例えば、マウス)を作ることが今は可能である。例えば、キメラ及び生殖系列突然変異体マウスにおける抗体重鎖結合領域(JH)遺伝子の同型接合除去が内因性抗体産生の完全な阻害をもたらすことが記載されている。このような生殖系列突然変異体マウスにおけるヒト生殖系列免疫グロブリン遺伝子列の転移は、抗原投与時にヒト抗体の産生をもたらす。Jakobovitsら, Proc.Natl.Acad.Sci.USA, 90:2551 (1993);Jakobovitsら, Nature 362:255-258 (1993); Bruggermanら, Year in Immuno., 7:33 (1993);米国特許第5,591,669号、同5,589,369号及び同5,545,807号を参照されたい。
また、ヒト抗体は、活性化B細胞によりインビトロで生産してもよい(例えば米国特許第5,567,610号及び同5,229,275号を参照)。
抗体断片を生産するために様々な技術が開発されている。伝統的には、これらの断片は、無傷の抗体のタンパク分解性消化を介して誘導されていた(例えば、Morimotoら, Journal of Biochemical and Biophysical Methods 24:107-117 (1992)及びBrennanら, Science, 229:81(1985)を参照されたい)。しかし、これらの断片は現在は組換え宿主細胞により直接生産することができる。例えば、抗体断片は上述において検討した抗体ファージライブラリーから分離することができる。別法として、Fab'-SH断片は大腸菌から直接回収することができ、化学的に結合してF(ab')2断片を形成することができる(Carterら, Bio/Technology 10:163-167(1992))。他のアプローチ法では、F(ab')2断片を組換え宿主細胞培養から直接分離することができる。抗体断片の生産のための他の方法は当業者には明らかであろう。他の実施態様では、選択抗体は単鎖Fv断片(scFV)である。国際公開第93/16185号;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。また、抗体断片は、例えば米国特許第5,641,870号に記載されているような「直鎖状抗体」であってもよい。このような直鎖状抗体断片は単一特異性又は二重特異性であってよい。
二重特異性抗体は、少なくとも2つの異なるエピトープに対して結合特異性を有する抗体である。例示的な二重特異性抗体は、B細胞表面マーカーの2つの異なるエピトープに結合しうる。他のこのような抗体は第1のB細胞表面マーカーに結合し、さらに第2のB細胞表面マーカーに結合する。あるいは、抗B細胞表面マーカー結合アームは、B細胞に細胞防御メカニズムを集中させるように、FcγRI(CD64)、FcγRII(CD32)及びFcγRIII(CD16)等のIgG(FcγR)に対するFcレセプター、又はT細胞レセプター分子(例えばCD2又はCD3)等の白血球上のトリガー分子に結合するアームと結合しうる。また、二重特異性抗体はB細胞に細胞障害剤を局在化するためにも使用されうる。これらの抗体はB細胞表面マーカー結合アーム及び細胞障害剤(例えば、サポリン(saporin)、抗インターフェロン-α、ビンカアルカロイド、リシンA鎖、メトトレキセート又は放射性同位体ハプテン)と結合するアームを有する。二重特異性抗体は全長抗体又は抗体断片(例えばF(ab')2二重特異性抗体)として調製することができる。
米国特許第5,731,168号に記載された他のアプローチ法によれば、一対の抗体分子間の界面を操作して組換え細胞培養から回収されるヘテロダイマーのパーセントを最大にすることができる。好適な界面は抗体定常ドメインのCH3ドメインの少なくとも一部を含む。この方法では、第1抗体分子の界面からの一又は複数の小さいアミノ酸側鎖がより大きな側鎖(例えばチロシン又はトリプトファン)と置き換えられる。大きな側鎖と同じ又は類似のサイズの相補的「キャビティ」を、大きなアミノ酸側鎖を小さいもの(例えばアラニン又はスレオニン)と置き換えることにより第2の抗体分子の界面に作り出す。これにより、ホモダイマーのような不要の他の最終産物に対してヘテロダイマーの収量を増大させるメカニズムが提供される。
最近の進歩により、大腸菌からのFab'-SH断片の直接の回収が容易になり、これは化学的に結合して二重特異性抗体を形成することができる。Shalabyら,J.Exp.Med., 175:217-225 (1992)は完全にヒト化された二重特異性抗体F(ab')2分子の製造を記述している。各Fab'断片は大腸菌から別個に分泌され、インビトロで定方向化学共役を受けて二重特異性抗体を形成する。このようにして形成された二重特異性抗体は、正常なヒトT細胞及びErbB2レセプターを過剰発現する細胞に結合可能で、ヒト乳房腫瘍標的に対するヒト細胞障害性リンパ球の細胞溶解活性の誘因となる。
二価より多い抗体も考えられる。例えば、三重特異性抗体を調製することができる。Tuttら J.Immunol. 147:60(1991)。
ここでの方法に使用され、製造品に包含されるアンタゴニストは、通常細胞障害剤とコンジュゲートされる。
このようなアンタゴニスト-細胞障害剤コンジュゲートの生成に有用な化学療法剤は上述したものである。
また、ここではカリチーマイシン(calicheamicin)、メイタンシン(maytansine)(米国特許第5,208,020号)、トリコセン(trichothene)、及びCC1065等の、一又は複数の小分子毒素とアンタゴニストとのコンジュゲートが考えられる。本発明の一実施態様において、アンタゴニストは一又は複数のメイタンシン分子(例えば、アンタゴニスト1分子当たり、メイタンシン1〜10分子)とコンジュゲートされる。例えば、メイタンシンはMay-SH3に還元され、修飾されたアンタゴニストと反応するMay-SS-Meに転化され(Chariら, Cancer Research, 52:127-131(1992))、メイタンシノイド-アンタゴニストコンジュゲートを生産する。
本発明では、ヌクレオサイティック活性を有する化合物(例えば、リボヌクレアーゼ又はDNAエンドヌクレアーゼ、例えばデオキシリボヌクレアーゼ;DNase)とコンジュゲートしたアンタゴニストをさらに考慮する。
種々の放射活性同位体も放射性コンジュゲートアンタゴニストの生成に利用できる。具体例にはAt211、I131、I125、Y90、Re186、Re188、Sm153、Bi212、P32及びLuの放射性同位体が含まれる。
別法として、アンタゴニスト及び細胞障害剤を含有する融合タンパク質は、例えば組換え技術又はペプチド合成により作製される。
このようなコンジュゲートの酵素成分には、より活性な細胞障害形態に転化するように、プロドラッグに作用し得る任意の酵素が含まれる。
限定するものではないが、この発明の方法に有用な酵素には、ホスファート含有プロドラッグを遊離の薬剤に転化するのに有用なアルカリ性ホスファターゼ;スルファート含有プロドラッグを遊離の薬剤に転化するのに有用なアリールスルファターゼ;非毒性5-フルオロシトシンを抗癌剤5-フルオロウラシルに転化するのに有用なシトシンデアミナーゼ;プロテアーゼ、例えばセラチアプロテアーゼ、サーモリシン、サブチリシン、カルボキシペプチダーゼ及びカテプシン(例えば、カテプシンB及びL)で、ペプチド含有プロドラッグを遊離の薬剤に転化するのに有用なもの;D-アミノ酸置換基を含有するプロドラッグの転化に有用なD-アラニルカルボキシペプチダーゼ;炭水化物切断酵素、例えばグリコシル化プロドラッグを遊離の薬剤に転化するのに有用なノイラミニダーゼ及びβガラクトシダーゼ;βラクタムで誘導体化された薬剤を遊離の薬剤に転化させるのに有用なβラクタマーゼ;及びペニシリンアミダーゼ、例えばそれぞれフェノキシアセチル又はフェニルアセチル基で、それらのアミン性窒素において誘導体化された薬剤を遊離の薬剤に転化するのに有用なペニシリンVアミダーゼ又はペニシリンGアミダーゼが含まれる。あるいは、「アブザイム」としてもまた公知の酵素活性を有する抗体を、遊離の活性薬剤に本発明のプロドラッグを転化させるために使用することもできる(例えば、Massey, Nature 328:457-458(1987)を参照)。アンタゴニスト-アブザイムコンジュゲートは、ここで記載されているようにして、腫瘍細胞個体群にアブザイムを送達するために調製することができる。
アンタゴニストの他の修飾をここで考察する。例えば、アンタゴニストは種々の非タンパク質様ポリマー、例えばポリエチレングリコール、ポリプロピレングリコール、又はポリオキシアルキレン、又はポリエチレングリコールとポリプロピレングリコールのコポリマーに結合してもよい。
特に有用なリポソームは、ホスファチジルコリン、コレステロール及びPEG-誘導ホスファチジルエタノールアミン(PEG-PE)を含む脂質組成物での逆相蒸発法によって生成される。リポソームは、所定サイズのフィルターを通して押し出され、所望の径を有するリポソームが生成される。本発明の抗体のFab’断片は、Martin等, J. Biol. Chem. 257: 286-288 (1982)に記載されているように、ジスルフィド交換反応を介してリポソームにコンジュゲートされ得る。化学療法剤は、場合によってはリポソーム内に包含される。Gabizon等, J. National Cancer Inst. 81(19) 1484 (1989)参照。
(1)疎水性:norleucine, met, ala, val, leu, ile;
(2)中性の親水性:cys, ser, thr;
(3)酸性:asp, glu;
(4)塩基性:asn, gln, his, lys, arg;
(5)鎖配向に影響する残基:gly, pro; 及び
(6)芳香族:trp, tyr, phe。
非保存的置換は、これらの分類の一つのメンバーを他の分類のものに交換することが必要であろう。アンタゴニストの適切な配置の維持に含まれない任意のシステイン残基は、一般的にセリンで置換し、分子の酸化的安定性を向上させて異常な架橋を防止する。逆に、アンタゴニストにシステイン結合を付加して、その安定性を向上させてもよい(特に、アンタゴニストがFv断片などの抗体断片である場合)。
ポリペプチドのグリコシル化は、典型的には、N-結合又はO-結合の何れかである。N-結合とは、アスパラギン残基の側鎖への炭水化物部分の結合を意味する。アスパラギン-X-セリン及びアスパラギン-X-スレオニン(ここでXはプロリンを除く任意のアミノ酸)というトリペプチド配列は、アスパラギン側鎖への炭水化物部分の酵素的結合のための認識配列である。したがって、ポリペプチド中にこれらのトリペプチド配列の何れかが存在すると、潜在的なグリコシル化部位が作出される。O-結合グリコシル化は、ヒドロキシアミノ酸、最も一般的にはセリン又はスレオニンに、糖類N-アセチルガラクトサミン、ガラクトース、又はキシロースの一つが結合することを意味するが、5-ヒドロキシプロリン又は5-ヒドロキシリジンもまた用いられる。
アンタゴニストのアミノ酸配列変異体をコードする核酸分子は、この分野で知られた種々の方法によって調製される。これらの方法は、これらに限られないが、天然源からの単離(自然に生じるアミノ酸配列変異体の場合)又はオリゴヌクレオチド媒介(又は部位指向性)突然変異誘発、PCR突然変異誘発、及びカセット突然変異誘発による初期調製された変異体又はアンタゴニストの非変異体の調製を含む。
アンタゴニストの血清半減期を増加させるために、例えば米国特許第5,739,277号に記載されているようにして、アンタゴニスト(特に抗体断片)にサルベージレセプター結合エピトープを導入してもよい。ここで用いられる場合、用語「サルベージレセプター結合エピトープ」は、IgG分子のインビボ血清半減期を向上させる原因となるIgG分子(例えば、IgG1、IgG2、IgG3、又はIgG4)のFc領域のエピトープを意味する。
本発明で使用されるアンタゴニストの治療用調製物は、所望される程度の純度を持つアンタゴニストを、凍結乾燥調製物又は水性溶液の形態で、任意の製薬上許容される担体、賦形剤又は安定化剤と混合することにより調製され保存される(Remington's Pharmaceutical Science 16th edition, Osol, A. Ed. (1980))。許容される担体、賦形剤、又は安定化剤は、用いられる用量及び濃度で受容者に非毒性であり、リン酸、クエン酸、及び他の有機酸などのバッファー;アスコルビン酸及びメチオニンを含む酸化防止剤;防腐剤(オクタデシルジメチルベンジルアンモニウムクロライド;ヘキサメトニウムクロライド;ベンズアルコニウムクロライド;ベンズエトニウムクロライド;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等のアルキルパラベン;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-クレゾールなど);低分子量(約10残基未満)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等のタンパク質;ポリビニルピロリドン等の親水性ポリマー;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、又はリシン等のアミノ酸;グルコース、マンノース、又はデキストリンを含む単糖類、二糖類、及び他の炭水化物;EDTA等のキレート剤;スクロース、マンニトール、トレハロース又はソルビトールなどの糖;ナトリウムなどの塩形成対イオン;金属錯体(例えば、Zn-タンパク質錯体);及び/又はトゥイーン(TWEEN)TM、プルロニクス(PLURONICS)TM、又はポリエチレングリコール(PEG)等の非イオン性界面活性剤を含む。
皮下投与に適した凍結乾燥調製物は、国際公開第97/04801号に記載されている。このような凍結乾燥調製物は適切な希釈剤で高濃度タンパク質に再構成され、再構成された調製物はここで治療される哺乳動物に皮下的に投与される。
ここでの調製物は、特に治療的指示に必要な1以上の活性化合物、好ましくは互いに悪影響を及ぼさない補足的活性を有するものをさらに含有する。例えば、細胞障害剤、化学療法剤、サイトカイン又は免疫抑制剤(例えば、T細胞に作用するもの、例えばシクロスポリン、又はT細胞に結合する抗体、例えばLFA-1に結合するもの)をさらに提供することが望ましい。このような他の薬剤の有効量は、調製物中に存在するアンタゴニストの量、疾患又は疾病又は治療の種類、及び上述した他の要因に依存する。これらは一般的に、同じ用量、上において使用したような投与経路、又は上において使用した用量の1〜99%で使用される。
インビボ投与に使用される調製物は滅菌されなくてはならない。これは滅菌濾過膜を通した濾過により容易に達成される。
B細胞表面抗原に結合するアンタゴニストを含有する組成物は、良好な医療実務に合致する方式で調製され、調薬され、そして投与される。このときに考慮する因子は、治療される特定の疾患又は疾病、治療される特定の哺乳動物、個々の患者の臨床的状態、疾患又は疾病の原因、薬剤の送達部位、投与方法、投与の日程計画、及び医療実務者に知られた他の因子を含む。投与されるアンタゴニストの治療的有効量は、そのような考察によって決定される。
一般的な提案として、腸管外投与される調薬当たりのアンタゴニストの治療的有効量は、患者体重1kg当たり1日に約0.1〜20mgであり、用いられるアンタゴニストの典型的な初期範囲は約2〜10mg/kgの範囲である。
さらに、抗体を一又は複数回初期投与し、続いて一又は複数回二次投与してもよく、ここで、二次投与の抗体のmg/m2用量は、初期投与の抗体のmg/m2用量を越える。例えば、初期投与は約20mg/m2〜約250mg/m2(例えば約50mg/m2〜約200mg/m2)の範囲であってよく、二次投与は約250mg/m2〜約1000mg/m2の範囲であってよい。
タンパク質アンタゴニストの患者への投与の他に、本出願は遺伝子治療によるアンタゴニストの投与が考えられる。アンタゴニストをコードする核酸の投与は「アンタゴニストを治療的有効量で投与する」という表現に含まれる。例えば、遺伝子治療を用いた細胞内抗体の生産に関する、1996年3月14日に公開された国際公開第96/07321号を参照のこと。
本発明の他の実施態様では、上記の疾患又は疾病の治療に有用な物質を含む製造品が提供される。この製造品は容器とラベル又は容器内に挿入されるか添付されるパッケージ挿入物を含んでなる。好適な容器は、例えば、ビン、バイアル、シリンジ等を含む。容器は、ガラス又はプラスチックなどの多様な材料から形成されてよい。容器は、疾患又は疾病の治療に有効な組成物を収容し、無菌のアクセスポートを有し得る(例えば、容器は皮下注射針で貫通可能なストッパーを有する静脈内溶液バッグ又はバイアルであってよい)。組成物中の少なくとも1つの活性剤は通常、B細胞表面マーカーに結合するアンタゴニストである。ラベル又はパッケージ挿入物は、組成物がここで列挙されたような自己免疫疾患を患っているか、又はかかりやすい患者の治療のために使用されることを示す。製造品はさらに、製薬的に許容可能な希釈バッファー、例えば注射用の静菌水、リン酸緩衝塩水、リンガー液及びデキストロース溶液を含む第2の容器を具備してもよい。さらに、他のバッファー、希釈剤、フィルター、針及びシリンジを含む商業的及び使用者の見地から望ましい他の材料を含んでもよい。
本発明のさらなる詳細を、以下の非限定的実施例により例証する。本明細書における全ての引用文の開示は、出典明示によって明示的にここに取り込まれる。
慢性関節リウマチ(RA)と臨床診断された患者をリツキシマブ(リツキサン(登録商標))抗体を用いて治療する。治療された患者はB細胞悪性腫瘍を有してはいない。さらに患者は場合によっては、RAの治療に使用される一又は複数の薬剤、例えばサリチラート;非ステロイド性炎症剤、例えばインドメタシン、フェニルブタゾン、フェニル酢酸誘導体(例えばイブプロフェン及びフェノプロフェン)、ナフタレン酸(ナプロクサン)、ピロールアルカン酸(トメチン(tometin))、インドール酢酸(スリンダク)、ハロゲン化アントラニル酸(メクロフェナミン酸ナトリウム(meclofenamate sodium))、ピロキシカム、ゾメピラック(zomepirac)及びジフルニーサル;抗マラリア剤、例えばクロロキン;金塩;ペニシラミン;又は免疫抑制剤、例えばメトトレキサート又はコルチコステロイドを、このような薬剤の既知の用量又はそれよりも少ない用量でさらに治療する。しかしながら好ましくは、患者はリツキサン(登録商標)のみで治療される。
(A) 1日に50mg/m2IV
8、15及び22日に150mg/m2IV
(B) 1日に150mg/m2IV
8、15及び22日に375mg/m2IV
(C) 1、8、15及び22日に375mg/m2IV
一次反応をポールインデックス(Paulus index)(Paulusら, Athritis Rheum. 33:477-484(1990))、すなわち朝のこわばり、痛みがあり炎症を起こした関節の数、赤血球沈降速度(ESR)の改善と、患者及び医師により評価される、5ポイントの疾患重度性における少なくとも2ポイントの改善とによって決定される。リツキサン(登録商標)の投与により、上述のようにして治療された患者のRAの一又は複数の徴候が緩和されるであろう。
自己免疫性溶血性貧血(AIHA)、例えばクリオグロブリン血症又はクームズ陽性貧血と診断された患者をリツキサン(登録商標)抗体で治療する。AIHAは、自己抗体が患者の赤血球と反応する後天性溶血性貧血である。治療された患者はB細胞悪性腫瘍を有してはいない。
リツキサン(登録商標)は任意の次の投与スケジュールに従い、患者に静脈内(IV)に投与される:
(A) 1日に50mg/m2IV
8、15及び22日に150mg/m2IV
(B) 1日に150mg/m2IV
8、15及び22日に375mg/m2IV
(C) 1、8、15及び22日に375mg/m2IV
全反応速度は、血球数の改善、輸血の必要性減少、ヘモグロビンレベルの改善、及び/又は通常の化学的パラメータにより決定される溶血現象の形跡の低減に基づいて決定される。リツキサン(登録商標)の投与により、上述のようにして治療された患者の溶血性貧血の一又は複数の徴候が改善されるであろう。例えば、上述のようにして治療された患者は、少なくとも1g/dlまでヘモグロビンが増加し、溶血性の化学的パラメータが50%まで改善するか、又は血清乳酸デヒドロゲナーゼ、ビリルビンにより正常まで回復するであろう。
成人性免疫血小板減少性紫斑病(ITP)は最も一般的な免疫媒介性血小板減少症を構成する比較的希少な血液疾患である。この疾患は、典型的には、骨髄における正常な又は増加した巨大核細胞の存在下で、急性出血に関連したある種の血小板減少性紫斑病である。ITPを患っている多くの患者は、血小板膜の外面において標的抗原を直接指向するIgG抗体を有し、結果として脾臓において血小板が腐敗し、血小板の細網内皮系破壊が促進させる。(Bussell, J.B.Hematol. Oncol. Clin. North Am.(4):179(1990))。いくつかの治療的干渉がITPの治療に有効であることが示されている。ステロイドは第一線級の治療であると考えられており、多くの患者が静脈免疫グロブリン(IVIG)の候補薬、脾臓摘出、ビンクリスチン又は免疫抑制/細胞障害剤を含む他の医学的治療を受ける。当初、ITPを患っている患者の80%までがステロイドに反応していたが、完全で持続性のある鎮静を得たものはごく僅かである。脾臓摘出はステロイド性機能不全のための標準的な第二線級治療として推奨されており、ほぼ60%のケースにおいて鎮静の長期化に至っているが、感染に対する免疫性が低減する結果となっている。脾臓摘出は主要な外科的手法であり、実質的罹患率(15%)及び死亡率(2%)である。IVIGは第二線級医学的治療として使用されているが、ITPを患っている成人患者の少集団しか鎮静を達成できない。
コルチコステロイド及び/又は脾臓摘出により生じる罹患に係ることなくB細胞を活性化することにより自己抗体の生産に干渉する治療的意見が、ITPを患っている患者集団への重要な治療的アプローチを提供している。
リツキサン(登録商標)は任意の次の投与スケジュールに従い、ITP患者に静脈内(IV)に投与される:
(A) 1日に50mg/m2IV
8、15及び22日に150mg/m2IV
(B) 1日に150mg/m2IV
8、15及び22日に375mg/m2IV
(C) 1、8、15及び22日に375mg/m2IV
1. B細胞表面マーカーに結合する治療的有効量のアンタゴニストを哺乳動物に投与することを含む、哺乳動物の自己免疫疾患を治療する方法。
2. B細胞表面マーカーがCD10、CD19、CD20、CD21、CD22、CD23、CD24、CD37、CD53、CD72、CD73、CD74、CDw75、CDw76、CD77、CDw78、CD79a、CD79b、CD80、CD81、CD82、CD83、CDw84、CD85及びCD86からなる群から選択される実施態様1に記載の方法。
3. アンタゴニストが抗体を含む実施態様1に記載の方法。
4. 抗体がCD20に結合する実施態様3に記載の方法。
5. 抗体がCD19に結合する実施態様3に記載の方法。
6. 自己免疫疾患が、乾癬;皮膚炎;全身性強皮症及び硬化症;炎症性腸疾患に関連した反応;クローン病;潰瘍性大腸炎;呼吸困難症候群;成人性呼吸困難症候群(ARDS);皮膚炎;髄膜炎;脳炎;ブドウ膜炎;大腸炎;糸球体腎炎;アレルギーによる病状;湿疹;喘息;T細胞の浸潤に関連した病状及び慢性炎症反応;アテローム性動脈硬化症;白血球付着欠損症;リウマチ様関節炎;全身性エリテマトーデス(SLE);真性糖尿病;多発性硬化症;レノー症候群;自己免疫甲状腺炎;アレルギー性脳脊髄炎;ショルゲン(Sjorgen)症候群;若年発症糖尿病;Tリンパ球及びサイトカインにより媒介される急性及び遅延高血圧に関連した免疫反応;結核;サルコイドーシス;多発性筋炎;肉芽種症;血管炎;悪性貧血(アジソン病);白血球血管外遊出に関連した疾患;中枢神経系(CNS)炎症疾病;多臓器傷害症候群;溶血性貧血;重症筋無力症;抗原-抗体複合体媒介性疾患;抗糸球体基底膜疾患;抗リン脂質症候群;アレルギー性神経炎;クレーブス病;ランベルト-イートン筋無力症症候群;類天疱瘡;天疱瘡;自己免疫多腺性内分泌障害;ライター病;stiff-man症候群;ベーチット疾患;巨細胞動脈炎;免疫複合体腎炎;IgA腎症;IgM多発性神経障害;免疫血小板減少性紫斑病(ITP)又は自己免疫血小板減少病からなる群から選択される実施態様1に記載の方法。
7. 哺乳動物がヒトである実施態様1に記載の方法。
8. 抗体が細胞障害剤とコンジュゲートしていない実施態様3に記載の方法。
9. 抗体がリツキシマブ(リツキサン(登録商標))を含んでなる実施態様4に記載の方法。
10. 抗体が細胞障害剤とコンジュゲートした実施態様3に記載の方法。
11. 細胞障害剤が放射活性化合物である実施態様10に記載の方法。
12. 抗体がY2B8又は131I-B1(BEXXARTM)を含んでなる実施態様11に記載の方法。
13. アンタゴニストを静脈内投与することを含む実施態様1に記載の方法。
14. アンタゴニストを皮下投与することを含む実施態様1に記載の方法。
15. 哺乳動物に実質的に375mg/m2未満の用量で投与することを含む実施態様3に記載の方法。
16. 用量が約20mg/m2〜約250mg/m2の範囲である実施態様15に記載の方法。
17. 用量が約50mg/m2〜約200mg/m2の範囲である実施態様15に記載の方法。
18. 抗体を初期投与し、続いて二次投与することを含んでなり、二次投与における抗体のmg/m2用量が初期投与における抗体のmg/m2用量を越える実施態様3に記載の方法。
19. 自己免疫疾患が免疫血小板減少性紫斑病(ITP)である実施態様6に記載の方法。
20. 自己免疫疾患がリウマチ様関節炎である実施態様6に記載の方法。
21. 自己免疫疾患が溶血性貧血である実施態様6に記載の方法。
22. 溶血性貧血がクリオグロブリン血症又はクームズ陽性貧血である実施態様21に記載の方法。
23. 自己免疫疾患が血管炎である実施態様6に記載の方法。
24. 哺乳動物にアンタゴニストを投与することから本質的になる実施態様1に記載の方法。
25. 容器と該容器に収容される組成物を含んでなる製造品において、組成物がB細胞表面マーカーに結合するアンタゴニストを含有し、自己免疫疾患を患っているか、又はその素因を有している患者を治療することを使用者に指示するための包装挿入物をさらに含む製造品。
26. 自己免疫疾患が、乾癬;皮膚炎;全身性強皮症及び硬化症;炎症性腸疾患に関連した反応;クローン病;潰瘍性大腸炎;呼吸困難症候群;成人性呼吸困難症候群(ARDS);皮膚炎;髄膜炎;脳炎;ブドウ膜炎;大腸炎;糸球体腎炎;アレルギーによる病状;湿疹;喘息;T細胞の浸潤に関連した病状及び慢性炎症反応;アテローム性動脈硬化症;白血球付着欠損症;リウマチ様関節炎;全身性エリテマトーデス(SLE);真性糖尿病;多発性硬化症;レノー症候群;自己免疫甲状腺炎;アレルギー性脳脊髄炎;ショルゲン(Sjorgen)症候群;若年発症糖尿病;Tリンパ球及びサイトカインにより媒介される急性及び遅延高血圧に関連した免疫反応;結核;サルコイドーシス;多発性筋炎;肉芽種症;血管炎;悪性貧血(アジソン病);白血球血管外遊出に関連した疾患;中枢神経系(CNS)炎症疾病;多臓器傷害症候群;溶血性貧血;重症筋無力症;抗原-抗体複合体媒介性疾患;抗糸球体基底膜疾患;抗リン脂質症候群;アレルギー性神経炎;クレーブス病;ランベルト-イートン筋無力症症候群;類天疱瘡;天疱瘡;自己免疫多腺性内分泌障害;ライター病;stiff-man症候群;ベーチット疾患;巨細胞動脈炎;免疫複合体腎炎;IgA腎症;IgM多発性神経障害;免疫血小板減少性紫斑病(ITP)又は自己免疫血小板減少病からなる群から選択される実施態様25に記載の製造品。
Claims (26)
- B細胞表面マーカーに結合する治療的有効量のアンタゴニストを哺乳動物に投与することを含む、哺乳動物の自己免疫疾患を治療する方法。
- B細胞表面マーカーがCD10、CD19、CD20、CD21、CD22、CD23、CD24、CD37、CD53、CD72、CD73、CD74、CDw75、CDw76、CD77、CDw78、CD79a、CD79b、CD80、CD81、CD82、CD83、CDw84、CD85及びCD86からなる群から選択される請求項1に記載の方法。
- アンタゴニストが抗体を含む請求項1に記載の方法。
- 抗体がCD20に結合する請求項3に記載の方法。
- 抗体がCD19に結合する請求項3に記載の方法。
- 自己免疫疾患が、乾癬;皮膚炎;全身性強皮症及び硬化症;炎症性腸疾患に関連した反応;クローン病;潰瘍性大腸炎;呼吸困難症候群;成人性呼吸困難症候群(ARDS);皮膚炎;髄膜炎;脳炎;ブドウ膜炎;大腸炎;糸球体腎炎;アレルギーによる病状;湿疹;喘息;T細胞の浸潤に関連した病状及び慢性炎症反応;アテローム性動脈硬化症;白血球付着欠損症;リウマチ様関節炎;全身性エリテマトーデス(SLE);真性糖尿病;多発性硬化症;レノー症候群;自己免疫甲状腺炎;アレルギー性脳脊髄炎;ショルゲン(Sjorgen)症候群;若年発症糖尿病;Tリンパ球及びサイトカインにより媒介される急性及び遅延高血圧に関連した免疫反応;結核;サルコイドーシス;多発性筋炎;肉芽種症;血管炎;悪性貧血(アジソン病);白血球血管外遊出に関連した疾患;中枢神経系(CNS)炎症疾病;多臓器傷害症候群;溶血性貧血;重症筋無力症;抗原-抗体複合体媒介性疾患;抗糸球体基底膜疾患;抗リン脂質症候群;アレルギー性神経炎;クレーブス病;ランベルト-イートン筋無力症症候群;類天疱瘡;天疱瘡;自己免疫多腺性内分泌障害;ライター病;stiff-man症候群;ベーチット疾患;巨細胞動脈炎;免疫複合体腎炎;IgA腎症;IgM多発性神経障害;免疫血小板減少性紫斑病(ITP)又は自己免疫血小板減少病からなる群から選択される請求項1に記載の方法。
- 哺乳動物がヒトである請求項1に記載の方法。
- 抗体が細胞障害剤とコンジュゲートしていない請求項3に記載の方法。
- 抗体がリツキシマブ(リツキサン(登録商標))を含んでなる請求項4に記載の方法。
- 抗体が細胞障害剤とコンジュゲートした請求項3に記載の方法。
- 細胞障害剤が放射活性化合物である請求項10に記載の方法。
- 抗体がY2B8又は131I-B1(BEXXARTM)を含んでなる請求項11に記載の方法。
- アンタゴニストを静脈内投与することを含む請求項1に記載の方法。
- アンタゴニストを皮下投与することを含む請求項1に記載の方法。
- 哺乳動物に実質的に375mg/m2未満の用量で投与することを含む請求項3に記載の方法。
- 用量が約20mg/m2〜約250mg/m2の範囲である請求項15に記載の方法。
- 用量が約50mg/m2〜約200mg/m2の範囲である請求項15に記載の方法。
- 抗体を初期投与し、続いて二次投与することを含んでなり、二次投与における抗体のmg/m2用量が初期投与における抗体のmg/m2用量を越える請求項3に記載の方法。
- 自己免疫疾患が免疫血小板減少性紫斑病(ITP)である請求項6に記載の方法。
- 自己免疫疾患がリウマチ様関節炎である請求項6に記載の方法。
- 自己免疫疾患が溶血性貧血である請求項6に記載の方法。
- 溶血性貧血がクリオグロブリン血症又はクームズ陽性貧血である請求項21に記載の方法。
- 自己免疫疾患が血管炎である請求項6に記載の方法。
- 哺乳動物にアンタゴニストを投与することから本質的になる請求項1に記載の方法。
- 容器と該容器に収容される組成物を含んでなる製造品において、組成物がB細胞表面マーカーに結合するアンタゴニストを含有し、自己免疫疾患を患っているか、又はその素因を有している患者を治療することを使用者に指示するための包装挿入物をさらに含む製造品。
- 自己免疫疾患が、乾癬;皮膚炎;全身性強皮症及び硬化症;炎症性腸疾患に関連した反応;クローン病;潰瘍性大腸炎;呼吸困難症候群;成人性呼吸困難症候群(ARDS);皮膚炎;髄膜炎;脳炎;ブドウ膜炎;大腸炎;糸球体腎炎;アレルギーによる病状;湿疹;喘息;T細胞の浸潤に関連した病状及び慢性炎症反応;アテローム性動脈硬化症;白血球付着欠損症;リウマチ様関節炎;全身性エリテマトーデス(SLE);真性糖尿病;多発性硬化症;レノー症候群;自己免疫甲状腺炎;アレルギー性脳脊髄炎;ショルゲン(Sjorgen)症候群;若年発症糖尿病;Tリンパ球及びサイトカインにより媒介される急性及び遅延高血圧に関連した免疫反応;結核;サルコイドーシス;多発性筋炎;肉芽種症;血管炎;悪性貧血(アジソン病);白血球血管外遊出に関連した疾患;中枢神経系(CNS)炎症疾病;多臓器傷害症候群;溶血性貧血;重症筋無力症;抗原-抗体複合体媒介性疾患;抗糸球体基底膜疾患;抗リン脂質症候群;アレルギー性神経炎;クレーブス病;ランベルト-イートン筋無力症症候群;類天疱瘡;天疱瘡;自己免疫多腺性内分泌障害;ライター病;stiff-man症候群;ベーチット疾患;巨細胞動脈炎;免疫複合体腎炎;IgA腎症;IgM多発性神経障害;免疫血小板減少性紫斑病(ITP)又は自己免疫血小板減少病からなる群から選択される請求項25に記載の製造品。
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