JP2012502919A - 進行型多発性硬化症の治療方法 - Google Patents
進行型多発性硬化症の治療方法 Download PDFInfo
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Abstract
Description
この出願は、その全体が出典明示によりここに援用される2008年9月16日出願の合衆国仮出願第61/097464号の優先権を主張する。
(発明の分野)
本発明は、患者における進行型多発性硬化症(MS)を治療するための方法と、そのような使用の指示書を含む製造品に関する。
多発性硬化症(MS)はヒト中枢神経系(CNS)の炎症性及び脱随性変性疾患である。それは合衆国においておよそ300000人の人々が罹患している世界的な疾患である;それは、若年成人の疾患であり、70%−80%が20歳から40歳の間で発症する(Anderson等 Ann Neurology 31(3):333-6 (1992);Noonan等 Neurology 58:136-8 (2002))。MSは、臨床経過、磁気共鳴画像法(MRI)スキャン評価、及びバイオプシー及びオートプシー材料の病理分析に基づく不均一な疾患である(Lucchinetti等 Ann Neurol 47:707-17 (2000))。該疾患は、脊髄、脳幹、脳神経、小脳性、大脳性、及び認知症候群を含む欠陥の多数の可能な組み合わせに顕在化する。進行性能力障害は、特に25年の見方を含めると、MSの殆どの患者の運命である。MS患者の半分は、疾患発症から15年以内に歩くのに杖を必要とする。MSは若年及び中年成人に神経性能力障害の主要な原因であり、過去十年まで、有益な治療法は知られていなかった。MSは、MRIスキャン、誘発電位、及び脳脊髄液(CSF)研究からなる幾つかの先進技術を含む高度に構造化された診断基準の開発に至る非特異的な臨床所見のために診断が難しい。全ての診断基準は、異なった時点で生じる中枢白質中に病変が散在し、感染、血管障害、又は自己免疫疾患のような他の病因によって説明されない一般原理に依存する(McDonald等 Ann Neurol 50:121-7 (2001))。MSは、4つの疾患パターンを有している:再発寛解型MS(RRMS;発症症例の80%−85%)、一次性進行型MS(PPMS;発症の10%−15%)、進行性再発型MS(PRMS;発症の5%);及び二次性進行型MSSPMS)(Kremenchutzky等 Brain 122 (Pt 10):1941-50 (1999); Confavreux等 N Engl J Med 343(20):1430-8 (2000))。RRMSの患者の推定50%が10年でSPMSを発症し、RRMS患者の90%までが最終的にSPMSを発症する(Weinshenker等 Brain 112(Pt 1):133-46 (1989))。
リンパ球は、造血過程の間に骨髄において生産される多くのタイプの白血球のうちの1つである。リンパ球の2つの主な集団がある:Bリンパ球(B細胞)とTリンパ球(T細胞)である。ここで特に対象とするリンパ球はB細胞である。
6/0067930号及び国際公開第2006/31370号(Lowman等); 国際公開第2006/29224号(Ashkenazi, A.);米国特許出願公開第2006/0110387号及び国際公開第2006/41680号(Brunetta, P.);米国特許出願公開第2006/0134111号及び国際公開第2006/066086号(Agarwal, S.);国際公開第2006/069403号(Ernst及びYansura);米国特許出願公開第2006/0188495号及び国際公開第2006/076651号(Dummer, W.);国際公開第2006/084264号(Lowman, H.);国際公開第2006/093923号(Quan及びSewell); 国際公開第2006/106959号(Numazaki等);国際公開第2006/126069号(Morawala); 国際公開第2006/130458号 (Gazit-Bornstein等);米国特許出願公開第2006/0275284号(Hanna, G.);米国特許出願公開第2007/0014785号 (Golay等);米国特許出願公開第2007/0014720号 (Gazit-Bornstein等);及び米国特許出願公開第2007/0020259号 (Hansen等);米国特許出願公開第2007/0020265号 (Goldenberg及びHansen);米国特許出願公開第2007/0014797号 (Hitraya);米国特許出願公開第2007/0224189号(Lazar等);国際公開第2007/014238号(Bruge及びBruger);及び国際公開第2008/003319号(Parren及びBaadsgaard)を参照のこと。これらのあるものは、とりわけ、多発性硬化症の治療を含んでいる。
「B細胞」は、骨髄内で成熟するリンパ球であり、ナイーブB細胞、メモリーB細胞、又はエフェクターB細胞(プラズマ細胞)を含む。ここでのB細胞は正常な又は非悪性のB細胞でありうる。
MSの「症状」は、被験者によって経験され、MSを示している構造、機能、又は感覚における任意の病的現象又は正常からの逸脱である。
「ラベル」はここではバイアルのような容器及びパッケージ挿入物を含む薬学的製剤の商業的パッケージ、並びに他のタイプのパッケージに常套的に含められる情報を指すためにここで使用される。
ここで使用される場合及び添付の特許請求の範囲では、単数形「a」、「又は(or)」及び「その(the)」は、文脈が明らかに他の意味を示していない限り、複数の参照対象を含む。ここに記載された発明の態様及び変形例は、態様及び変形例「からなる」及び/又は「から本質的になる」ことを含む。
本発明は、患者における進行型多発性硬化症を治療する方法であって、有効量の抗CD20抗体を患者に投与することを含む方法を提供する。
ここに記載された方法又は製造品の何れかの幾つかの実施態様によれば、該方法又は指示書は、有効量の抗CD20抗体を多発性硬化症患者に投与することを含み、約0.3から約4グラム(好ましくは約0.3から約1.5グラム、例えば約0.6グラム又は約1.0グラム)の初期の抗体暴露と、続く約0.3から約4グラム(好ましくは約0.3から約1.5グラム、例えば約0.6グラム又は約1.0グラム)の第二の抗体暴露をもたらし、該第二の抗体暴露が、初期の抗体暴露から約16から約60週までにはもたらされない。本発明の目的に対して、第二の抗体暴露は、最初の抗体暴露後の抗CD20抗体で患者を治療する次の機会であり、最初の暴露と第二の暴露との間に介在する抗CD20抗体治療又は暴露はない。幾つかの実施態様では、初期の抗体暴露及び/又は第二抗体暴露は、約0.3グラム、0.4グラム、0.5グラム、0.6グラム、0.7グラム、0.8グラム、0.9グラム、又は1.0グラムの何れかである。
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抗体、特にCD20に結合するものを使用し又は導入する。従って、そのような抗体を産生する方法をここに記載する。
抗体の生産又はそのスクリーニングに使用されるB細胞表面マーカーは、マーカー又は例えば所望のエピトープを含むその部分の可溶型でありうる。あるいは、又は加えて、その細胞表面にマーカーを発現する細胞を、抗体を産生し、又はスクリーニングするために使用することができる。抗体を産生させるのに有用なB細胞表面マーカーの他の形態は当業者には明らかであろう。
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おいて産生される。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結合)、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により結合させることが有用でありうる。
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、すなわち、その集団を構成する個々の抗体が、モノクローナル抗体の生産中に生じ、一般には少量で存在する可能な変異体を除いて、同一であり、及び/又は同じエピトープに結合する。よって、「モノクローナル」との修飾語は、離散した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性質を示す。
モノクローナル抗体の結合親和性は、例えばMunson等, Anal. Biochem., 107:220 (1980)のスキャッチャード解析によって決定されうる。
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。幾つかの実施態様では、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、本質的にはヒト抗体の該当する高頻度可変領域配列を置換することによりウィンターと共同研究者の方法(Jones等, Nature, 321:522-525 (1986);Riechmann等, Nature, 332:323-327 (1988);Verhoeyen等, Science, 239:1534-1536(1988))を使用して実施することができる。従って、このような「ヒト化」抗体は、完全な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対応する配列で置換されたキメラ抗体(米国特許第4816567号)である。実際には、ヒト化抗体は、典型的には幾らかの高頻度可変領域残基及び場合によっては幾らかの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。
CDR L1配列RASSSVSYXH、ここでXはM又はLであり(配列番号18)、例えば配列番号:4(図1A)、
配列番号:5のCDR L2配列(図1A)、
CDR L3配列QQWXFNPPT、ここでXはS又はAであり(配列番号19)、例えば配列番号:6(図1A)、
配列番号:10のCDR H1配列(図1B)、
CDR H2配列AIYPGNGXTSYNQKFKG、ここでXはD又はAであり(配列番号20)、例えば配列番号:11(図1B)、及び
CDR H3配列VVYYSXXYWYFDV、ここで6位のXはN、A、Y、W又はDであり、7位のXはS又はRであり(配列番号21)、例えば配列番号:12(図1B)。
DIQMTQSPSSLSASVGDRVTITCRASSSVSYMHWYQQKPGKAPKPLIYAPSNLASGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQWSFNPPTFGQGTKVEIKR(配列番号:2);
及び可変重鎖配列:
EVQLVESGGGLVQPGGSLRLSCAASGYTFTSYNMHWVRQAPGKGLEWVGAIYPGNGDTSYNQKFKGRFTISVDKSKNTLYLQMNSLRAEDTAVYYCARVVYYSNSYWYFDVWGQGTLVTVSS(配列番号:8)
を含むインタクトな抗体又は抗体断片である。
DIQMTQSPSSLSASVGDRVTITCRASSSVSYMHWYQQKPGKAPKPLIYAPSNLASGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQWSFNPPTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(配列番号:13);
及び重鎖アミノ酸配列:
EVQLVESGGGLVQPGGSLRLSCAASGYTFTSYNMHWVRQAPGKGLEWVGAIYPGNGDTSYNQKFKGRFTISVDKSKNTLYLQMNSLRAEDTAVYYCARVVYYSNSYWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(配列番号:14)
又は重鎖アミノ酸配列:
EVQLVESGGGLVQPGGSLRLSCAASGYTFTSYNMHWVRQAPGKGLEWVGAIYPGNGDTSYNQKFKGRFTISVDKSKNTLYLQMNSLRAEDTAVYYCARVVYYSNSYWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNATYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIAATISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(配列番号:15)
を含む。
DIQMTQSPSSLSASVGDRVTITCRASSSVSYLHWYQQKPGKAPKPLIYAPSNLASGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQWAFNPPTFGQGTKVEIKR(配列番号:23)
及び2H7.v511可変重鎖ドメイン配列:
EVQLVESGGGLVQPGGSLRLSCAASGYTFTSYNMHWVRQAPGKGLEWVGAIYPGNGATSYNQKFKGRFTISVDKSKNTLYLQMNSLRAEDTAVYYCARVVYYSYRYWYFDVWGQGTLVTVSS(配列番号:24)
を含む。
DIQMTQSPSSLSASVGDRVTITCRASSSVSYLHWYQQKPGKAPKPLIYAPSNLASGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQWAFNPPTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(配列番号:16)
及び配列番号17又は:
EVQLVESGGGLVQPGGSLRLSCAASGYTFTSYNMHWVRQAPGKGLEWVGAIYPGNGATSYNQKFKGRFTISVDKSKNTLYLQMNSLRAEDTAVYYCARVVYYSYRYWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNATYRVVSVLTVLHQDWLNGKEYKCKVSNAALPAPIAATISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG(配列番号:25)
の重鎖アミノ酸配列を含みうる。
ヒト化のための別法として、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時に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)を作製す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等, Proc.Natl.Acad.Sci.USA, 90:2551 (1993);Jakobovits等, Nature 362:255-258 (1993);Bruggerman等, Year in Immuno., 7:33 (1993);及び米国特許第5591669号、同第5589369号及び同第5545807号を参照のこと。
ヒト抗体はまたインビトロ活性化B細胞によって産生させることもできる(米国特許第5567610号及び同第5229275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、インタクトな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等, Journal of Biochemical and Biophysical Methods 24:107-117 (1992)及びBrennan等, Science, 229:81(1985)を参照のこと)。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、抗体断片は上で検討した抗体ファージライブラリーから単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、化学的に結合させてF(ab')2断片を形成することができる(Carter等, Bio/Technology 10:163-167(1992))。他のアプローチ法によれば、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技術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5571894号;及び米国特許第5587458号を参照のこと。また、抗体断片は、例えば米国特許第5641870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りうる。
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B細胞表面マーカーに結合し得、更に第二の異なったB細胞表面マーカーに結合しうる。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組み合わされうる。また、二重特異性抗体はB細胞に細胞傷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傷害剤(例えば、サポリン、抗インターフェロン-a、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。二重特異性抗体は完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。
ここでの方法に用いられ又は製造品に含められる抗体は場合によっては細胞傷害剤にコンジュゲートされる。例えば、抗体は、国際公開第2004/032828号に記載されるように薬剤にコンジュゲートされうる。
そのような抗体-細胞傷害剤コンジュゲートの生産に有用な化学療法剤は前述している。
様々な放射性同位元素が放射性コンジュゲート抗体の生産に利用できる。例にはAt211、I131、I125、Y90、Re186、Sm153、Bi212、P32及びLuの放射線同位元素が含まれる。
更に他の実施態様では、腫瘍の事前ターゲティングに利用するために、「レセプター」(例えばストレプトアビジン)に抗体をコンジュゲートすることができ、ここで、抗体-レセプターコンジュゲートを患者に投与し、続いて清澄化剤を使用し、循環から未結合コンジュゲートを除去し、細胞傷害剤(例えば放射性ヌクレオチド)にコンジュゲートする「リガンド」(例えばアビジン)を投与する。
そのようなコンジュゲートの酵素成分には、より活性な細胞毒形態にそれを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。
(1)無極性:Ala(A),Val(V),Leu(L),Ile(I),Pro(P),Phe(F),Trp(W),Met(M);
(2)無電荷極性:Gly(G),Ser(S),Thr(T),Cys(C),Tyr(Y),Asn(N),Gln(Q);
(3)酸性:Asp(D),Glu(E);
(4)塩基性:Lys(K),Arg(R),His(H)。
(1)疎水性:ノルロイシン、Met、Ala、Val、Leu、Ile;
(2)中性の親水性:Cys、Ser、Thr、Asn、Gln;
(3)酸性:Asp、Glu;
(4)塩基性:His、Lys、Arg;
(5)鎖配向に影響する残基:Gly、Pro;
(6)芳香族:Trp、Tyr、Phe。
抗体の適切な高次構造の維持に関与しない任意のシステイン残基も、一般的には、セリンと置換して、分子の酸化的安定性を改善して、異常な架橋を防ぐことができる。逆に、システイン結合を抗体に付加して、その安定性を改善してもよい(特に抗体が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)のトリペプチド配列は、アスパラギン側鎖への糖鎖部分の酵素的結合のための認識配列である。従って、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。
抗体がFc領域を含有する場合、それに接着する炭水化物を変更してもよい。例えば、抗体のFc領域に接着するフコースを欠損する成熟炭水化物構造の抗体は、米国特許出願公開第2003/0157108A1号(Presta, L.)に記載されている;CD20抗体組成物に関する米国特許出願公開第2004/0093621A1号(Kyowa Hakko Kogyo Co., Ltd.)も参照のこと。抗体のFc領域に結合した糖鎖内のN-アセチルグルコサミン(GlcNAc)を二分する抗体は、国際公開第03/011878号, Jean-Mairet等、及び米国特許第6602684号, Umana等が参照される。抗体のFc領域に結合するオリゴサッカライド内の少なくとも一のガラクトース残基を有する抗体は、国際公開第97/30087号, Patel 等に報告されている;また、そのFc領域に結合した改変糖鎖を有する抗体については、国際公開第98/58964号(Raju, S.)及び国際公開第99/22764号(Raju, S.)も参照のこと。
改変されたC1q結合及び/又は補体依存性細胞傷害性(CDC)を有する抗体は、国際公開第99/51642号、米国特許第6194551B1号、米国特許第6242195B1号、米国特許第6528624B1号及び米国特許第6538124号 (Idusogie 等)に記載される。抗体は、そのFc領域のアミノ酸位置270、322、326、327、329、313、333及び/又は334の一又は複数にアミノ酸置換を含む。
3又はそれ以上(好ましくは4)の機能的抗原結合部位を有する操作された抗体もまた考えられる(米国特許出願公開第2002/0004587A1号, Miller等)。
本発明に従って使用される抗体の治療用製剤は、所望の純度を有する抗体を任意の薬学的に許容可能な担体、賦形剤又は安定剤と混合することによって凍結乾燥製剤又は水溶液の形態で、貯蔵のために調製される(Remington's Pharmaceutical Sciences 16版, Osol, A.編(1980))。許容可能な担体、賦形剤、又は安定化剤は、用いられる用量及び濃度でレシピエントに非毒性であり、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抗酸化剤;保存料(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;ベンゼ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、又はリジン等のアミノ酸;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)又はTWEENTM、PLURONICSTM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。
抗体又は抗体の結晶化形態もまた考慮される。例えば米国特許出願公開第2002/0136719A1号(Shenoy等)を参照のこと。
インビボ投与に使用される製剤は無菌でなければならない。これは、滅菌濾過膜を通す濾過によって容易に達成される。
本発明は、(a)オクレリズマブを収容する容器;及び(b)患者における多発性硬化症を治療するための指示書を含むパッケージ挿入物を含む製造品であって、該指示書が、約0.3から約0.6グラムの間の初期のオクレリズマブ暴露と、続く約0.3から約0.6グラムの間の第二のオクレリズマブ暴露をもたらすのに有効であるオクレリズマブの量が患者に投与されることを示し(つまり、指示し)、第二の暴露が、初期の暴露から約16から60週までにはもたらされず、オクレリズマブの各暴露は、オクレリズマブの一又は二の用量として患者にもたらされる製造品を提供する。幾つかの実施態様では、初期のオクレリズマブ暴露は約0.6グラムである。幾つかの実施態様では、第二のオクレリズマブ暴露は約0.6グラムである。幾つかの実施態様では、第二の暴露は、最初の暴露から約24週後から投与される。幾つかの実施態様では、一又は複数回のオクレリズマブ暴露がオクレリズマブの一用量として患者にもたらされる。幾つかの実施態様では、一又は複数回のオクレリズマブ暴露がオクレリズマブの二用量として患者にもたらされる。幾つかの実施態様では、オクレリズマブの二用量は約0.3グラムのオクレリズマブを含む。
製造品の何れかの幾つかの実施態様では、患者の年齢は約51未満である。
製造品の何れかの幾つかの実施態様では、治療は、確認された無増悪期間を減少させる。幾つかの実施態様では、確認された疾患進行は、12週間保持されるEDSSの増加である。幾つかの実施態様では、確認された疾患進行は、24週間保持されるEDSSの増加である。
本発明の他の実施態様では、ここに記載の進行型多発性硬化症の治療に有用な材料を含む製造方法が提供される。幾つかの実施態様では、抗CD20抗体又はその薬学的組成物を製造するための方法は、抗CD20抗体又は薬学的組成物及び抗CD20抗体又は薬学的組成物が進行型多発性硬化症の患者の治療に効能があることを示すラベルをパッケージ中に組み合わせることを含み、ここで、患者は、(a)約55歳未満の年齢、(b)一又は複数のガドリニウム染色病変、及び(c)治療開始前の2年にわたる総合障害度評価尺度(EDSS)において少なくとも約1ポイントの増加、及び(d)約5ポイントより大きい多発性硬化症重症度スコア(MSSS)からなる群から選択される一又は複数の特性を有する。
本発明はまた抗CD20抗体又はその薬学的に許容可能な組成物を宣伝するための方法であって、聴衆に、進行型多発性硬化症の患者又は患者集団を治療するための抗CD20抗体又はその薬学的組成物の使用を促進することを含み、ここで患者又は患者集団は(a)約55歳未満の年齢、(b)一又は複数のガドリニウム染色病変、(c)治療開始前の2年にわたる総合障害度評価尺度(EDSS)において少なくとも約1ポイントの増加、及び(d)約5ポイントより大きい多発性硬化症重症度スコア(MSSS)からなる群から選択される一又は複数の特性を有する方法を提供する。
方法の何れかの幾つかの実施態様では、患者は(a)約55歳未満の年齢、(b)一又は複数のガドリニウム染色病変、及び(c)治療開始前の2年にわたる総合障害度評価尺度(EDSS)において少なくとも約1ポイントの増加からなる群から選択される一又は複数の特性を有する。
方法の何れかの幾つかの実施態様では、治療は、確認された無増悪期間を減少させる。幾つかの実施態様では、確認された疾患進行は、12週間保持されるEDSSの増加である。幾つかの実施態様では、確認された疾患進行は、24週間保持されるEDSSの増加である。
本発明はまた進行型多発性硬化症の患者が多発性硬化症を治療するために使用される薬剤での治療に応答するかどうかを分析するためのシステム及び方法を提供する。本発明は、多発性硬化症を治療するために使用される薬剤での治療に対する進行型多発性硬化症の患者の応答性を解析するためのシステムであって、(a)(i)約55歳未満の年齢、(ii)一又は複数のガドリニウム染色病変、(iii)治療開始前の2年にわたる総合障害度評価尺度(EDSS)において少なくとも約1ポイントの増加、及び(iv)約5ポイントより大きい多発性硬化症重症度スコア(MSSS)からなる群から選択される一又は複数の特性を評価すること;(b)(a)の評価を実施するためのハードウェア;及び(c)患者が上記治療に感受性又は応答性であるかどうかを決定するためにアルゴリズムを実施する計算手段を具備するシステムを提供する。
システム及び/又は方法の何れかの幾つかの実施態様では、システム又は方法は患者にアドバイスすることを更に含む。
システム及び/又は方法の何れかの幾つかの実施態様では、治療は、確認された無増悪期間を減少させる。幾つかの実施態様では、確認された疾患進行は、12週間保持されるEDSSの増加である。幾つかの実施態様では、確認された疾患進行は、24週間保持されるEDSSの増加である。
再発寛解型多発性硬化症(RRMS)の患者におけるオクレリズマブの二用量レジメンの、脳核磁気共鳴画像法(MRI)病変によって測定した効能、及び安全性を評価するために第II相の多施設無作為、平行群、部分盲検、プラセボ及びAvonex制御用量所見研究を実施する。
調査される二種のオクレリズマブ用量レジメンは次の通りである:1)オクレリズマブ1000mg用量レジメン:第1回目の治療サイクルに対する1000mgの二回注入に次の治療サイクルに対する1000mgの単一注入が続くものからなる、及び2)オクレリズマブ600mg用量レジメン:第1回目の治療サイクルに対する300mgの二回注入に次の治療サイクルに対する600mgの単一注入が続くものからなる。
適格の患者を図7に記載するように4組の治療群A、B、C又はDの一つに無作為化(1:1:1:1)する。研究デザインの概要を図7に示す。
i.v.注入(オクレリズマブ又はプラセボ)であれ、又はAvonexの最初のi.m.注射であれ、研究医薬の最初の投与が治療期間の最初(1日目)を定める。全ての患者はまた研究の1日目に100mgのメチルプレドニゾロンのi.v.注入を受け、それぞれ次に又はオクレリズマブ注入に必要な時点に従ってAvonexを受ける患者(D群)に対してはオクレリズマブ又はプラセボ注入を受ける。
改訂されたマクドナルド基準(2005)に従って再発寛解型多発性硬化症(RRMS)と診断され、以下に提供される組み入れ/除外基準に合致する18から55歳の年齢の男性及び女性が調査への登録に適格である。
患者は治験エントリーに適格であるには次の基準に合致しなければならない:
1.改訂されたマクドナルド基準(2005)に従うRRMS;
2.年齢18−55歳;
3.スクリーニング前の最近3年以内に少なくとも2回の実証された再発があり、その少なくとも1回がスクリーニング前の最後の年に起きている;
4.1.0から6.0ポイントのベースラインでの総合障害度評価尺度(EDSS);
5.以下に定義された多発性硬化症(MS)疾患負荷のエビデンス
a.局所的読み取りに基づくスクリーニング前の年になされたMRIスキャンで少なくとも6つのT2病変。MRIスキャンが最後の年に利用できないか6つ未満のT2病変を示す場合には、少なくとも6つのT2病変のスクリーニングMRIスキャンが患者が適格であるために必要とされ、又は
b.患者がスクリーニング前の年内に2回の実証された再発を有していた。
1.スクリーニング時に二次性又は一次性進行型多発性硬化症(往診1);
2.EDSS=2.0の患者における15年を越える疾患期間。
この研究における第一の目的は、プラセボと比較して12週目、16週目、20週目及び24週目に脳のMRIスキャンで観察されるガドリニウム増強T1病変の全数に対する600又は100mgの静脈内二用量レジメンとして投与されたオクレリズマブの効果(図7を参照)を調査することである。
MRIはMSにおける中枢神経系(CNS)病変をモニターするために有用なツールである。脳MRIスキャンは、幾人かの患者では(二次エンドポイントを参照)スクリーニング時にのみ、ベースラインでは全ての患者において、及びベースラインと24週目の間で4週間隔で得られる。また、患者のサブグループ(A群及びB群)では、脳MRIが96週目(往診16)及び48週後、つまり144週目に実施される。
MRIは各時点における次のスキャンの獲得を含む:T2強調MRIスキャン、T1強調MRIスキャン(ガドリニウム増強を伴わず)、及びT1強調MRIスキャン(ガドリニウム増強を伴う)。
EDSSによって測定される能力障害は、24週後に能力障害進行が評価される観察期間まで治験の全体にわたってスクリーニング時と12週毎に独立の研究者に全ての患者において評価される。
マクドナルド等(Ann Neurol 50:121-7(2001))によって定義された一次性進行型多発性硬化症(PPMS)の成人におけるリツキシマブの安全性及び効能を評価するために無作為化、二重盲検、群間、プラセボ対照多施設第II/III相治験(U2786g)を実施した。
この治験に対する主要効能解析は、リツキシマブとプラセボ間で96週の治療期間の間、確認された無増悪期間を比較した。疾患進行は、ベースラインEDSSが2.0と5.5ポイントの間(臨界値含む)ならば、ベースラインEDSSから=1.0ポイントの増加として(Kurtzke J. Neurology 33(11):1444-52 (1983))、あるいはベースラインEDSSが>5.5ポイントならば=0.5の増加として定義され、その変化は他の病因(例えば発熱、同時発生の病気、MS再発又は増悪、又は併用医薬)には起因しない。
主要エンドポイントに対するサブグループ解析は、次の個体群統計学及びベースライン疾患特性に従って確認された疾患無増悪期間を含んでいた:場所、年齢、性別、人種、先のMS療法、ベースラインEDSS、MS症状発症及びベースラインガドリニウム(Gd)病変以来の期間、及びベースライン多発性硬化症重症度スコア(MSSS)(如何に速く患者が進行したかの指標;Roxburgh等 Neurology 64; 1144-1151 (2005)を参照)。
進行型MSの成人におけるプラセボと比較した600mgのオクレリズマブの安全性及び効能を評価するために第III相、無作為化二重盲検、群間、多施設治験が実施される。
この治験に対する標的集団は、重なった再発の病歴を持つか持たない進行型MSの患者を含む。この治験に適格な進行型MSの患者は、改訂されたマクドナルド基準(2005)に従った診断と、再発の不存在下での6ヶ月以上の神経学的機能の実証された不可逆的喪失期間によって特徴付けられる。進行型MS患者での過去の臨床試験において潜在的なリスク因子として同定された基準を使用して、活動的な疾患のエビデンスとより速い能力障害進行の高いリスクを持つ患者が選択される。これらの因子は、より若い年齢、脳脊髄液(CSF)における炎症のエビデンス(オリゴクローナルバンド又は上昇したIgGインデックス)、脳MRIでの造影病変、再発に関連しない進行と重なった高い再発活動性、及び能力障害の履歴的により速い蓄積を含む。
組み入れ基準は次のものを含む:
1.改訂されたマクドナルド基準(2005)に従う多発性硬化症の診断。
2.臨床的再発に起因させることができない=6ヶ月の間、持続する神経学的機能の実証された不可逆的喪失によって特徴付けられる進行型MS。
3.年齢18−55歳;
4.3.0から6.5ポイントのスクリーニング時のEDSS。
5.より低い四肢所見による錐体路系又は歩行に対して機能系(FS)尺度で=2.0のスコア。
6.例えばIgGインデックスの上昇及び/又は等電点電気泳動により検出されるIgGオリゴクローナルバンドにより示される過去6ヶ月内に文献で実証され又はスクリーニング期間中に得られたCSF検体における次の研究室知見の一つの存在。
7.次の基準の少なくとも一つの存在:
・年齢<50
・スクリーニング時又はスクリーニング前の6ヶ月以内の脳MRIでのGd+病変
・再発に起因しない過去2年にわたるEDSSの少なくとも1.5ポイントの増加
・過去2年における2回の再発
1.スクリーニング時(往診1)における再発寛解型多発性硬化症
2.MS症状の発症からの疾患期間:スクリーニング時にEDSS>5.0の患者では15年を越えるか、又はスクリーニング時にEDSS=5.0の患者では10年を越える。
主要効能エンドポイントは確認された無増悪期間である。疾患進行は、ベースラインEDSSが2.0と5.5ポイントの間(臨界値含む)ならば、ベースラインEDSSから=1.0ポイントの増加として、あるいはベースラインEDSSが>5.5ポイントならば=0.5の増加として定義され、その変化は他の病因(例えば発熱、同時発生の病気、MS再発又は増悪、又は併用医薬)には起因しない。
患者は治験を通じて各往診時に治療している研究者によって再発について評価され、必要ならば予定外の往診時に往診の間に生じる再発が確認される。プロトコル定義再発の基準に合致するためには、再発はMSに起因する新たな又は悪化した神経性症状の出現として定義され、少なくとも30日の比較的安定な又は改善している神経性状態が直前に先行する。症状は>24時間持続しなければならず、交絡臨床因子(例えば、発熱、感染、傷害、併用医薬に対する有害反応)に起因するものであってはならない。新たな又は悪化した神経性症状には、EDSSについて少なくとも半分の段階、又は適切なFSSの一つの2ポイント、又は適切なFSSの二以上について1ポイントの増加に一致した客観的な神経性悪化症状が伴わなければならない。該変化は、選択されるFSS(つまり、錐体、歩行、小脳、脳幹、感覚、又は視覚)に影響を及ぼさなければならない。突発性攣縮、性機能不全、疲労、気分変動又は膀胱又は腸緊急性又は失禁は再発を確立するには十分ではない。
脳及び頸髄の核磁気共鳴画像診断が、ベースラインの際を含めてこの治験中の複数の時点で得られる。脳MRIは、各時点での次のスキャンの獲得を含む:T2強調MRIスキャン及びT1強調MRIスキャン(ガドリニウム増強なし)。
一次性進行型MSの成人におけるプラセボと比較したオクレリズマブの2種の用量レジメンの一つの安全性及び効能を評価するために第III相、無作為化二重盲検、群間、多施設治験が実施される。
調査される二種のオクレリズマブ用量レジメンは次の通りである:1)オクレリズマブ1000mg用量レジメン:第1回目の治療サイクルに対する1000mgの二回注入に次の治療サイクルに対する1000mgの単一注入が続くものからなる、及び2)オクレリズマブ600mg用量レジメン:第1回目の治療サイクルに対する300mgの二回注入に次の治療サイクルに対する600mgの単一注入が続くものからなる。
この治験に対する標的集団は、一次性進行型MSの患者を含む。この治験に適格な一次性進行型MSの患者は、改訂されたマクドナルド基準(2005)に従った診断によって特徴付けられる。進行型MS患者での過去の臨床試験において潜在的なリスク因子として同定された基準を使用して、活動的な疾患のエビデンスとより速い能力障害進行の高いリスクを持つ患者が選択される。これらの因子は、より若い年齢、脳脊髄液(CSF)における炎症のエビデンス(オリゴクローナルバンド又は上昇したIgGインデックス)、及び能力障害の履歴的により速い蓄積を含む。
組み入れ基準は次のものを含む:
1.改訂されたマクドナルド基準(2005)に従う一次性進行型多発性硬化症の診断;
2.年齢18−55歳;
3.3.0から6.5ポイントのスクリーニング時のEDSS。
4.より低い四肢所見による錐体路系に対して機能系(FS)尺度で=2.0のスコア。
5.CSF検体においてIgGインデックスの上昇及び/又は等電点電気泳動により検出されるIgGオリゴクローナルバンドにより示される実験室所見の少なくとも一つのスクリーニング時における存在又は実証された病歴。
6.MS症状の発症からの疾患期間:スクリーニング時に>5.0のEDSSを持つ患者において15年未満、又はスクリーニング時に=5.0のEDSSの患者において10年未満。
1.スクリーニング時(往診1)における再発寛解型、二次性進行型、又は進行性再発性多発性硬化症の病歴。
主要効能エンドポイントは確認された無増悪期間である。疾患進行は、ベースラインEDSSが2.0と5.5ポイントの間(臨界値含む)ならば、ベースラインEDSSから=1.0ポイントの増加として、あるいはベースラインEDSSが>5.5ポイントならば=0.5の増加として定義され、その変化は他の病因(例えば発熱、同時発生の病気、MS再発又は増悪、又は併用医薬)には起因しない。
患者は治験を通じて各往診時に治療している研究者によって再発について評価され、必要ならば予定外の往診時に往診の間に生じる再発が確認される。プロトコル定義再発の基準に合致するためには、再発はMSに起因する新たな又は悪化した神経性症状の出現として定義され、少なくとも30日の比較的安定な又は改善している神経性状態が直前に先行する。症状は>24時間持続しなければならず、交絡臨床因子(例えば、発熱、感染、傷害、併用医薬に対する有害反応)に起因するものであってはならない。新たな又は悪化した神経性症状には、EDSSについて少なくとも半分の段階、又は適切なFSSの一つの2ポイント、又は適切なFSSの二以上について1ポイントの増加に一致した客観的な神経性悪化症状が伴わなければならない。該変化は、選択されるFSS(つまり、錐体、歩行、小脳、脳幹、感覚、又は視覚)に影響を及ぼさなければならない。突発性攣縮、性機能不全、疲労、気分変動又は膀胱又は腸緊急性又は失禁は再発を確立するには十分ではない。
脳及び頸髄の核磁気共鳴画像診断が、ベースラインの際を含めてこの治験中の複数の時点で得られる。脳MRIは、各時点での次のスキャンの獲得を含む:T2強調MRIスキャン及びT1強調MRIスキャン(ガドリニウム増強なし)。
Claims (47)
- 有効量の抗CD20抗体を患者に投与することを含む患者における進行型多発性硬化症を治療する方法であって、治療が、(a)約55歳未満の年齢、(b)一又は複数のガドリニウム染色病変、(c)治療開始前の2年にわたる総合障害度評価尺度(EDSS)において少なくとも約1ポイントの増加、及び(d)約5ポイントより大きい多発性硬化症重症度スコア(MSSS)からなる群から選択される一又は複数の特性を有する患者に基づく方法。
- 進行型多発性硬化症が一次性進行型多発性硬化症である請求項1に記載の方法。
- 進行型多発性硬化症が二次性進行型多発性硬化症である請求項1に記載の方法。
- 進行型多発性硬化症が進行性再発性多発性硬化症である請求項1に記載の方法。
- 患者が治療開始時に再発寛解型多発性硬化症と診断されていない請求項1に記載の方法。
- 患者が試料中に炎症のエビデンスを更に有している請求項1に記載の方法。
- 試料が脳脊髄液試料である請求項6に記載の方法。
- 炎症のエビデンスが、IgGインデックスの増加によって示される請求項7に記載の方法。
- 炎症のエビデンスが、等電点電気泳動によって検出されるIgGオリゴクローナルバンドによって示される請求項7に記載の方法。
- 患者が約15年未満の間、約5.0より大きいEDSSを有していた請求項1に記載の方法。
- 患者が約10年未満の間、約5.0より大きいEDSSを有していた請求項1に記載の方法。
- 治療開始前の2年にわたるEDSSの増加が再発に起因しうるものではない請求項1に記載の方法。
- EDSSの増加が、治療開始前の2年にわたるEDSSにおける少なくとも約1.5ポイントの増加である請求項1に記載の方法。
- 治療開始前の2年にわたるEDSSの増加が再発に起因しうるものではない請求項13に記載の方法。
- 患者の年齢が約51未満である請求項1に記載の方法。
- 患者が治療開始前の2年以内に二回以上の再発を更に有していた請求項1に記載の方法。
- 治療開始時のEDSSが約3.0と約6.5の間である請求項1に記載の方法。
- 治療が、確認された無増悪期間を減少させる請求項1に記載の方法。
- 確認された疾患進行が、12週間の間維持されているEDSSの増加である請求項18に記載の方法。
- 確認された疾患進行が、24週間の間維持されているEDSSの増加である請求項18に記載の方法。
- 抗CD20抗体が、a)配列番号:10、配列番号:11、及び配列番号:12を含む3つのCDR領域を含む重鎖可変領域、及びb)配列番号:4、配列番号:5、及び配列番号:6を含む3つのCDR領域を含む軽鎖可変領域を含む請求項1に記載の方法。
- 抗CD20抗体がオクレリズマブである請求項1に記載の方法。
- 抗CD20抗体がリツキシマブである請求項1に記載の方法。
- 抗CD20抗体がオファツムマブである請求項1に記載の方法。
- 抗CD20抗体がTRU−015又はSBI−087である請求項1に記載の方法。
- 抗CD20抗体がGA101である請求項1に記載の方法。
- 抗CD20抗体がhA20である請求項1に記載の方法。
- 有効量の抗CD20抗体を患者に投与して、約0.3から約4.0グラムの間の初期の抗CD20抗体暴露と、続く約0.3から約4.0グラムの間の第二の抗CD20抗体暴露をもたらす請求項1に記載の方法。
- 初期の抗CD20抗体暴露及び/又は第二の抗CD20抗体暴露が約0.3から約1.5グラムの間である請求項28に記載の方法。
- 第二の暴露が、初期の暴露から約16から60週までにはもたらされない請求項29に記載の方法。
- 抗CD20抗体暴露が、抗CD20抗体の一又は二の用量として患者にもたらされる請求項30に記載の方法。
- (a)約55歳未満の年齢、(b)一又は複数のガドリニウム染色病変、(c)治療開始前の2年にわたる総合障害度評価尺度(EDSS)において少なくとも約1ポイントの増加、及び(d)約5ポイントより大きい多発性硬化症重症度スコア(MSSS)からなる群から選択される一又は複数の特性を有することが患者に見いだされた場合の患者における進行型多発性硬化症を治療する方法であって、治療が有効量の抗CD20抗体を患者に投与することを含む方法。
- 進行型多発性硬化症の治療方法であって、
(a)(i)約55歳未満の年齢、(ii)一又は複数のガドリニウム染色病変、(iii)治療開始前の2年にわたる総合障害度評価尺度(EDSS)において少なくとも約1ポイントの増加、及び(iv)約5ポイントより大きい多発性硬化症重症度スコア(MSSS)からなる群から選択される一又は複数の特性を有する、進行型多発性硬化症の患者を選択し;
(b)このようにして選択された患者に有効量の抗CD20抗体を投与する
ことを含む方法。 - 進行型多発性硬化症の患者が抗CD20抗体での治療に応答するかどうかを評価する方法であって、(a)約55歳未満の年齢、(b)一又は複数のガドリニウム染色病変、(c)治療開始前の2年にわたる総合障害度評価尺度(EDSS)において少なくとも約1ポイントの増加、及び(d)約5ポイントより大きい多発性硬化症重症度スコア(MSSS)からなる群から選択される一又は複数の特性を評価することを含み、患者における該特性の一又は複数が、患者が該治療に対して応答性であることを示す方法。
- 抗CD20抗体治療に応答する可能性のある進行型多発性硬化症の患者を同定する方法であって、
(a)(i)約55歳未満の年齢、(ii)一又は複数のガドリニウム染色病変、(iii)治療開始前の2年にわたる総合障害度評価尺度(EDSS)において少なくとも約1ポイントの増加、及び(iv)約5ポイントより大きい多発性硬化症重症度スコア(MSSS)からなる群から選択される一又は複数の特性を評価し;
(b)(i)約55歳未満の年齢、(ii)一又は複数のガドリニウム染色病変、(iii)治療開始前の2年にわたる総合障害度評価尺度(EDSS)において少なくとも約1ポイントの増加、及び(iv)約5ポイントより大きい多発性硬化症重症度スコア(MSSS)からなる群から選択される一又は複数の特性を有する患者を同定する
ことを含む方法。 - 進行型多発性硬化症患者亜集団における使用のために抗CD20抗体又はその薬学的に許容可能な組成物をマーケティングするための方法であって、(a)約55歳未満の年齢、(b)一又は複数のガドリニウム染色病変、(c)治療開始前の2年にわたる総合障害度評価尺度(EDSS)において少なくとも約1ポイントの増加、及び(d)約5ポイントより大きい多発性硬化症重症度スコア(MSSS)からなる群から選択される一又は複数の特性を有する該亜集団の患者によって特徴付けられる患者亜集団を治療するために抗CD20抗体を使用することをターゲットの聴衆に知らせることを含む方法。
- 抗CD20抗体と薬学的に許容可能な担体を含有する薬学的組成物と、抗CD20抗体又は薬学的組成物が、(a)約55歳未満の年齢、(b)一又は複数のガドリニウム染色病変、(c)治療開始前の2年にわたる総合障害度評価尺度(EDSS)において少なくとも約1ポイントの増加、及び(d)約5ポイントより大きい多発性硬化症重症度スコア(MSSS)からなる群から選択される一又は複数の特性を有する多発性硬化症患者を治療する効能があることを示すラベルを、併せて包装して含む、製造品。
- 進行型多発性硬化症の患者が多発性硬化症を治療するために使用される薬剤での治療に応答するかどうかを予測する方法であって、(a)約55歳未満の年齢、(b)一又は複数のガドリニウム染色病変、(c)治療開始前の2年にわたる総合障害度評価尺度(EDSS)において少なくとも約1ポイントの増加、及び(d)約5ポイントより大きい多発性硬化症重症度スコア(MSSS)からなる群から選択される一又は複数の特性を評価することを含み、年齢、ガドリニウム染色病変、治療開始前の2年にわたるEDSSの増加、MSSS、又はそれらの組み合わせが、患者が該治療に応答することを示す方法。
- 患者における多発性硬化症の治療方法において、有効量のオクレリズマブを患者に投与して、約0.3から約4.0グラムの間の初期のオクレリズマブ暴露と、続く約0.3から約4.0グラムの間の第二のオクレリズマブ暴露をもたらすことを含み、第二の暴露が、初期の暴露から約16から60週までにはもたらされず、オクレリズマブの各暴露は、オクレリズマブの一又は二の用量として患者にもたらされる方法。
- 最初のオクレリズマブ暴露がオクレリズマブの第一用量及び第二用量を含み、オクレリズマブの第一用量及び第二用量が約0.3グラムである請求項39に記載の方法。
- 第二のオクレリズマブ暴露が単一用量のオクレリズマブを含み、ここで、オクレリズマブの単一用量が0.6グラムである請求項40に記載の方法。
- 第二のオクレリズマブ暴露が最初のオクレリズマブ暴露からおよそ24週後にもたらされる請求項41に記載の方法。
- 第三のオクレリズマブ暴露をもたらすことを更に含む請求項42に記載の方法。
- 第四のオクレリズマブ暴露をもたらすことを更に含む請求項43に記載の方法。
- 第五のオクレリズマブ暴露をもたらすことを更に含む請求項44に記載の方法。
- 約1回から約3回の続くオクレリズマブ暴露をもたらすことを更に含む請求項42に記載の方法。
- (a)オクレリズマブを収容する容器;及び
(b)患者における多発性硬化症を治療するための指示書を含むパッケージ挿入物を含む製造品であって、該指示書が、約0.3から約0.6グラムの間の初期のオクレリズマブ暴露と、続く約0.3から約0.6グラムの間の第二のオクレリズマブ暴露をもたらすのに有効であるオクレリズマブの量が患者に投与されることを示し、第二の暴露が、初期の暴露から約16から60週までにはもたらされず、オクレリズマブの各暴露は、オクレリズマブの一又は二の用量として患者にもたらされる製造品。
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