JP2020503260A - 抗cd20/抗cd3二重特異性抗体による処置のための投与 - Google Patents
抗cd20/抗cd3二重特異性抗体による処置のための投与 Download PDFInfo
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Abstract
Description
本出願には、ASCII形式にて電子的に提出され、その全体が参照することにより本明細書に組み込まれる配列表を含む。2017年11月13日に作成された該ASCIIコピーは、50474−150WO3_Sequence_Listing_11.13.17_ST25と称され、21,101バイトのサイズである。
本明細書で使用される「約」という用語は、当業者に容易に知られているそれぞれの値の通常の誤差範囲を指す。本明細書における「約」値またはパラメータへの言及は、その値またはパラメータ自体を対象とする実施形態を含む(かつ説明する)。
(a)アミノ酸残基26〜32(L1)、50〜52(L2)、91〜96(L3)、26〜32(H1)、53〜55(H2)、及び96〜101(H3)で生じる超可変ループ(Chothia and Lesk,J.Mol.Biol.196:901−917(1987))、
(b)アミノ酸残基24〜34(L1)、50〜56(L2)、89〜97(L3)、31〜35b(H1)、50〜65(H2)、及び95〜102(H3)で生じるCDR(Kabat et al.,Sequences of Proteins of Immunological Interest,5th Ed.Public Health Service,National Institutes of Health,Bethesda,MD(1991))、
(c)アミノ酸残基27c〜36(L1)、46〜55(L2)、89〜96(L3)、30〜35b(H1)、47〜58(H2)、及び93〜101(H3)で生じる抗原接触体(MacCallum et al.J.Mol.Biol.262:732−745(1996))、ならびに
(d)HVRアミノ酸残基46〜56(L2)、47〜56(L2)、48〜56(L2)、49〜56(L2)、26〜35(H1)、26〜35b(H1)、49〜65(H2)、93〜102(H3)、及び94〜102(H3)を含む、(a)、(b)、及び/または(c)の組み合わせ、を含む。
100×分数X/Y
のように計算され、式中、Xは、配列整列プログラムALIGN−2によって、そのプログラムのAとBとの整列において完全な一致としてスコア化されたアミノ酸残基の数であり、Yは、Bにおけるアミノ酸残基の総数である。アミノ酸配列Aの長さがアミノ酸配列Bの長さと等しくない場合、AのBへのアミノ酸配列同一性%は、BのAへのアミノ酸配列同一性%とは等しくないことが理解されるだろう。別段具体的に述べられない限り、本明細書で使用される全てのアミノ酸配列同一性%値は、直前の段落に記載されるようにALIGN−2コンピュータプログラムを使用して得られる。
本発明は、抗表面抗原分類20(CD20)/抗表面抗原分類3(CD3)の二重特異性抗体による分画用量漸増投与計画を使用して、がん(たとえば、B細胞増殖性疾患)を有する被検体を治療する方法に部分的に基づく。方法は、サイトカイン駆動毒性(たとえば、サイトカイン放出症候群(CRS))、輸液関連反応(IRR)、マクロファージ活性化症候群(MAS)、神経毒性、重症の腫瘍崩壊症候群(TLS)、好中球減少症、血小板減少症、肝酵素上昇、及び/または中枢神経系(CNS)毒性を含む、望まれない治療効果を低下させる、または阻害すると予想される。したがって、これらの方法は、より好ましいベネフィット−リスクプロファイルを達成しながら被検体を処置するために有用である。
本明細書に記載されるこれらの方法は、がん(たとえば、B細胞増殖性疾患、たとえば、非ホジキンリンパ腫(NHL)、たとえば、びまん性大細胞型B細胞性リンパ腫(DLBCL)たとえば、再発性または難治性DLBCL)を有する被検体へCD20及びCD3(すなわち、抗CD20/抗CD3抗体)に結合する二重特異性抗体を投与することを備える。
ある一定の実施形態において、本明細書に提供される二重特異性抗体は、CD20、CD3、または両方に関して、≦1μM、≦100nM、≦10nM、≦1nM、≦0.1nM、≦0.01nM、または≦0.001nM(たとえば、10−8M以下、たとえば、10−8Mから10−13M、たとえば、10−9Mから10−13M)の解離定数(Kd)を有する。
ある一定の実施形態において、抗CD20/抗CD3二重特異性抗体は、たとえば、CD20及びCD3に結合する抗体フラグメントなどの、抗体フラグメントである。抗体フラグメントには、Fab、Fab’、Fab’−SH、F(ab’)2、Fv、及びscFvフラグメント、ならびに以下に記載される他のフラグメントが含まれるが、これらに限定されない。ある特定の抗体フラグメントの概説については、Hudson et al.Nat.Med.9:129−134(2003)に記載される。scFvフラグメントの概説については、例えば、Pluckthun,in The Pharmacology of Monoclonal Antibodies,vol.113,Rosenburg and Moore eds.,(Springer−Verlag,New York),pp.269−315(1994)を参照されたく、また、WO93/16185、ならびに米国特許第5,571,894号及び同第5,587,458号も参照のこと。サルベージ受容体結合エピトープ残基を含み、インビボ半減期が増加したFab及びF(ab’)2フラグメントの考察については、米国特許第5,869,046号を参照されたい。
ある一定の実施形態において、本明細書に記載される方法に従って使用するための抗CD20/抗CD3抗体は、キメラ抗体である。ある一定のキメラ抗体は、たとえば、米国特許第4,816,567号、及びMorrison et al.Proc.Natl.Acad.Sci.USA,81:6851−6855(1984))に記載される。一例では、キメラ抗体は、非ヒト可変領域(例えば、マウス、ラット、ハムスター、ウサギ、または非ヒト霊長類、例えばサルに由来する可変領域)及びヒト定常領域を含む。さらなる例では、キメラ抗体は、クラスまたはサブクラスが親抗体のクラスまたはサブクラスから変化した「クラススイッチ」抗体である。キメラ抗体には、その抗原結合フラグメントが含まれる。
抗CD20/抗CD3二重特異性抗体は、抗体全長または抗体フラグメントとして調製されることができる。二重特異性抗体を作製するための技法としては、異なる特異性を有する2つの免疫グロブリン重鎖−軽鎖対の組換え共発現(Milstein and Cuello,Nature 305:537(1983))、WO93/08829、及びTraunecker et al.,EMBO J.10:3655(1991)を参照する)、ならびに「ノブインホール」工学的設計(たとえば、米国特許第5,731,168号を参照する)が挙げられるが、これらに限定されない。二重特異性抗体の「ノブインホール」工学的設計を利用して、ノブを含む第一アーム、及び第一アームのノブが結合することができるホールを含む第二アームを生成することができる。二重特異性抗体のノブは、1つの実施形態において、抗CD3アーム上にあることができる。代替に、本発明の二重特異性抗体のノブは、抗CD20アーム上にあることができる。本発明の二重特異性抗体のホールは、1つの実施形態において、抗CD3アーム上にあることができる。代替に、本発明の二重特異性抗体のホールは、抗CD20アーム上にあることができる。いくつかの例において、ノブインホール技術を使用して産生される抗CD20/抗CD3二重特異性抗体は、1箇所以上の重鎖定常ドメインを含むことができ、1箇所以上の重鎖定常ドメインは、第一CH1(CH11)ドメイン、第一CH2(CH21)ドメイン、第一CH3(CH31)ドメイン、第二CH1(CH12)ドメイン、第二CH2(CH22)ドメイン、及び第二CH3(CH32)ドメインから選択される。いくつかの例において、1箇所以上の重鎖定常ドメインのうちの少なくとも1箇所は、別の重鎖定常ドメインと対合される。いくつかの例において、CH31及びCH32ドメインは、突起または空洞を各含み、CH31ドメイン内の突起または空洞は、それぞれ、CH32ドメイン内の空洞または突起中に配置可能である。いくつかの例において、CH31及びCH32ドメインは、突起と空洞との間の境界面において会合する。いくつかの例において、CH21及びCH22ドメインは、突起または空洞を各含み、CH21ドメイン内の突起または空洞は、それぞれ、CH22ドメイン内の空洞または突起中に配置可能である。いくつかの例において、CH21及びCH22ドメインは、突起と空洞との間の境界面において会合する。
いくつかの例において、上述される抗CD20/抗CD3二重特異性抗体のアミノ酸配列変異体を予想する。例えば、二重特異性抗体の結合親和性及び/または他の生物学的特性を改善することが望ましい場合がある。抗体のアミノ酸配列変異体は、抗体を符号化するヌクレオチド配列中に適切な修飾を導入することによるか、またはペプチド合成により調製され得る。かかる修飾には、例えば、抗体のアミノ酸配列内における、残基からの欠失、及び/または残基への挿入、及び/または残基の置換が含まれる。最終構築物に到達するように、欠失、挿入、及び置換を任意に組み合わせることができるが、但し、その最終構築物が、所望の特徴、例えば、抗原結合性を有することを条件とする。
ある特定の実施形態では、1つ以上のアミノ酸置換を有する抗体変異体を提供する。置換変異原性のために対象となる部位は、HVR及びFRを含む。保存的置換は、表2の「好ましい置換」という見出しの下に示される。より実質的な変化は、表2の「例示的な置換」という見出しの下に示され、アミノ酸側鎖クラスを参照して以下にさらに記載される。アミノ酸置換は、目的の抗体中に導入され得、その産物は、所望の活性、例えば、保持/改善された抗原結合、減少した免疫原性、または改善されたADCC若しくはCDCについてスクリーニングされ得る。
アミノ酸は、一般的な側鎖特性に従って群分けされ得る:
(1)疎水性:ノルロイシン、Met、Ala、Val、Leu、Ile、
(2)中性親水性:Cys、Ser、Thr、Asn、Gln、
(3)酸性:Asp、Glu、
(4)塩基性:His、Lys、Arg、
(5)鎖配向に影響を及ぼす残基:Gly、Pro、
(6)芳香族:Trp、Tyr、Phe。
いくつかの例において、本発明の方法は、二重特異性抗体をグリコシル化する程度まで増加させる、または減少させるように、修飾されている抗CD20/抗CD3二重特異性抗体の変異体を分画用量漸増投与計画に照らして被検体へ投与することを備える。本発明の抗CD20/抗CD3抗体へのグリコシル化部位の付加または欠失は、1つ以上のグリコシル化部位を作り出すかまたは除去するように、アミノ酸配列を変化させることによって、簡便に達成されることができる。
いくつかの例において、抗CD20/抗CD3二重特異性抗体変異体は、二重特異性抗体のFc領域(すなわち、Fc領域変異体(たとえば、US2012/0251531を参照する))に導入される1つ以上のアミノ酸修飾を有し、本発明の方法に従い、がん(たとえば、B細胞増殖性疾患)を有する被検体へ投与されることができる。Fc領域変異型は、1つ以上のアミノ酸位置にアミノ酸修飾(例えば、置換)を含むヒトFc領域配列(例えば、ヒトIgG1、IgG2、IgG3、またはIgG4 Fc領域)を含み得る。
ある特定の実施形態において、二重特異性抗体の1つ以上の残基がシステイン残基で置換されているシステイン工学的に設計された抗CD20/抗CD3二重特異性抗体、たとえば、「thioMAb」を作製することが望ましい場合がある。特定の実施形態において、置換された残基は、抗体の利用しやすい部位で生じる。それらの残基をシステインで置換することにより、反応性チオール基が二重特異性抗体のアクセス可能な部位に位置付けられ、それを使用して、抗体を他の部分(薬物部分またはリンカー−薬物部分など)にコンジュゲートして、免疫コンジュゲートを作製することができる。ある一定の実施形態において、以下の残基、軽鎖のV205(Kabat番号付け)、重鎖のA118(EU番号付け)、及び重鎖Fc領域のS400(EU番号付け)のいずれか1つ以上が、システインで置換され得る。システイン工学的に設計された抗体は、例えば、米国特許第7,521,541号に記載されているように産生され得る。
いくつかの例において、抗CD20/抗CD3二重特異性抗体は、本明細書に記述される方法に従い、当該技術分野において知られており、被検体へ容易に利用可能であり、投与される追加の非タンパク質性部分を含有するように修飾されることができる。抗体の誘導体化に好適な部分には、水溶性ポリマーが含まれるが、これらに限定されない。水溶性ポリマーの非限定的な例としては、ポリエチレングリコール(PEG)、エチレングリコール/プロピレングリコールのコポリマー、カルボキシメチルセルロース、デキストラン、ポリビニルアルコール、ポリビニルピロリドン、ポリ−1,3−ジオキソラン、ポリ−1,3,6−トリオキサン、エチレン/無水マレイン酸コポリマー、ポリアミノ酸(ホモポリマーまたはランダムコポリマーのいずれか)、及びデキストランまたはポリ(n−ビニルピロリドン)ポリエチレングリコール、プロプロピレングリコールホモポリマー、プロリプロピレンオキシド/エチレンオキシドコポリマー、ポリオキシエチル化ポリオール(例えば、グリセロール)、ポリビニルアルコール、ならびにこれらの混合物が含まれるが、これらに限定されない。ポリエチレングリコールプロピオンアルデヒドは、水中でのその安定性のため、製造時に有利であり得る。ポリマーは、いずれの分子量のものであってもよく、分岐状であっても非分岐状であってもよい。抗体に付着したポリマーの数は異なり得、1つ超のポリマーが付着している場合、それらは同じ分子であることも異なる分子であることもできる。一般に、誘導体化に使用されるポリマーの数及び/または種類は、改善される抗体の特定の特性または機能、抗体誘導体が定義された条件下である療法に使用されるかなどを含むが、これらに限定されない、考慮すべき事項に基づいて決定され得る。
抗CD20/抗CD3二重特異性抗体の薬学的組成物及び製剤は、所望の程度の純度を有するこれらのような抗体を、1つ以上の任意選択の薬学的に許容可能な担体(Remington’s Pharmaceutical Sciences 16th edition,Osol,A.Ed.(1980))と混合することによって、凍結乾燥製剤または水溶液の形態で調製されることが可能である。薬学的に許容される担体は一般に、レシピエントに対し、用いられる投薬量及び濃度で無毒であり、緩衝液(リン酸、クエン酸、及び他の有機酸など)、アスコルビン酸及びメチオニンを含む酸化防止剤、保存剤(オクタデシルジメチルベンジル塩化アンモニウム、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、若しくはベンジルアルコール、アルキルパラベン(メチル若しくはプロピルパラベンなど)、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、タンパク質(血清アルブミン、ゼラチン、若しくは免疫グロブリンなど)、親水性ポリマー(ポリビニルピロリドンなど)、アミノ酸(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、若しくはリジンなど)、単糖類、二糖類、及び他の炭水化物(グルコース、マンノース、若しくはデキストリンを含む)、キレート剤(EDTAなど)、糖類(スクロース、マンニトール、トレハロース、若しくはソルビトールなど)、塩形成対イオン(ナトリウムなど)、金属錯体(例えば、Zn−タンパク質錯体)、及び/または非イオン性界面活性剤(ポリエチレングリコール(PEG)など)を含むが、これらに限定されない。本明細書における例示的な薬学的に許容される担体は、可溶性の中性活性ヒアルロニダーゼ糖タンパク質(sHASEGP)、例えば、rHuPH20(HYLENEX(登録商標)、Baxter International,Inc.)等のヒト可溶性PH−20ヒアルロニダーゼ糖タンパク質等の介在性薬物分散剤をさらに含む。rHuPH20を含むある特定の例示のsHASEGP及び使用方法は、米国特許公開第2005/0260186号及び同第2006/0104968号に記載されている。一態様では、sHASEGPは、コンドロイチナーゼ等の1つ以上の追加のグリコサミノグリカナーゼと組み合わせられる。
本発明の別の態様では、上述の疾患の治療、予防、及び/または診断に有用な材料を含有する製品が提供される。製品は、容器、及び容器上の、または容器と関連したラベルまたは添付文書を含む。好適な容器には、例えば、ボトル、バイアル、シリンジ、IV溶液バッグ等が含まれる。容器は、ガラスまたはプラスチック等の多様な材料から形成され得る。容器は、それ自体で、または別の組成物との組み合わせで、病態の治療、予防、及び/または診断に有効である組成物を保持し、滅菌アクセスポートを有し得る(例えば、容器は、静脈注射用溶液バッグまたは皮下注射針によって穿孔可能な栓を有するバイアルであり得る)。本組成物中の少なくとも1つの活性剤は、本明細書に記載される抗CD20/抗CD3二重特異性抗体である。ラベルまたは添付文書は、組成物を使用して選択状態(たとえば、B細胞増殖性疾患、たとえば、非ホジキンリンパ腫(NHL)、たとえば、びまん性大細胞型B細胞性リンパ腫(DLBCL)、たとえば、再発性または難治性DLBCL)を処置し、さらに本明細書に記載される投与計画の少なくとも1つに関する情報を含むことを示す。さらに、製品は、(a)本明細書に記載される抗CD20/抗CD3二重特異性抗体を含む組成物をその中に収容した第一容器、及び(b)さらなる細胞傷害性薬剤、またはその他の治療剤を含む組成物をその中に収容した第二容器を含み得る。あるいは、または加えて、本製品は、注射用静菌水(BWFI)、リン酸緩衝生理食塩水、リンガー溶液、及びデキストロース溶液等の薬学的に許容される緩衝液を含む第2(または第3)の容器をさらに含み得る。それは、他の緩衝液、希釈剤、フィルター、針、及びシリンジを含む、商業的及びユーザの立場から望ましい他の材料をさらに含んでもよい。
以下は、本発明の方法の例である。上述の概要を考慮すると、様々な他の実施形態が実施され得ることを理解する。
「ノブインホール」工学的設計を使用して、CD20及びCD3の両方を結合するIgG1二重特異性抗体全長を産生した(たとえば、米国特許第5,731,168号参照)。安全性及び薬力学(PD)は、その提案された作用機序とカニクイザルの毒物学研究において一致した。抗CD20/抗CD3二重特異性抗体による処置と関連する毒性は、サイトカインレベル、及び活性化されたT細胞数におけるPD変化によって明らかなように、T細胞の刺激により主に駆動された。抗CD20/抗CD3二重特異性抗体による、カニクイザルの反復投与毒性試験において、サイトカインレベル、T細胞活性化、及び急性投与後観察の向上は、第一投与量に主に限定され、次の後の投与量を減少させた、または無視できた。したがって、臨床計画は、代替の投与計画を通してT細胞刺激の程度を制御するように設計された。
実施例1に記載された二段階分画用量漸増投与計画に照らして抗CD20/抗CD3二重特異性抗体を投与する患者のCRSを観察する事象において、観察されたCRSは、適切に管理される。
前述の発明は、明確な理解のために例証及び例によっていくらか詳細に記載されているが、説明及び例は、本発明の範囲を限定するものと解釈されるべきではない。本明細書で引用される全ての特許及び科学文献の開示は、参照によりそれらの全体が明示的に組み込まれる。
Claims (69)
- B細胞増殖性疾患を有する被検体を処置する方法であって、少なくとも第一投与サイクル及び第二投与サイクルを有する投与計画においてCD20及びCD3に結合する二重特異性抗体を前記被検体へ投与することを備え、
(a)前記第一投与サイクルは前記二重特異性抗体の第一投与量(C1D1)、第二投与量(C1D2)、及び第三投与量(C1D3)を有し、前記C1D1及び前記C1D2は前記C1D3より各多くなく、前記C1D1は約0.02mgから約4.0mgの間にあり、前記C1D2は約0.05mgから約20.0mgの間にあり、前記C1D3は約0.2mgから約20.0mgの間にあり、
(b)前記第二投与サイクルは前記二重特異性抗体の単回投与量(C2D1)を有し、前記C2D1は前記C1D3以上であり、約0.2mgから約20mgの間にある、
前記方法。 - (a)前記C1D1は、約0.4mgから約4.0mgの間にあり、前記C1D2は、約1.0mgから約20.0mgの間にあり、前記C1D3は、約3.0mgから約20.0mgの間にあり、
(b)前記C2D1は、約3.0mgから約20.0mgの間にある、
請求項1に記載の前記方法。 - (a)前記C1D1は、約0.8mgから約3.0mgの間にあり、前記C1D2は、約1.0mgから約6.0mgの間にあり、前記C1D3は、約3.0mgから約6.0mgの間にあり、
(b)前記C2D1は、約3.0mgから約6.0mgの間にある、
請求項2に記載の前記方法。 - (a)前記C1D1は、約0.8mgであり、前記C1D2は、約2.0mgであり、前記C1D3は、約4.2mgであり、前記C2D1は、約4.2mgである、または
(b)前記C1D1は、約1.0mgであり、前記C1D2は、約1.0mgであり、前記C1D3は、約3.0mgであり、前記C2D1は、約3.0mgである、または
(c)前記C1D1は、約1.0mgであり、前記C1D2は、約2.0mgであり、前記C1D3は、約6.0mgであり、前記C2D1は、約6.0mgである、または
(d)前記C1D1は、約0.8mgであり、前記C1D2は、約2.0mgであり、前記C1D3は、約6.0mgであり、前記C2D1は、約6.0mgである、
請求項1から3のいずれか1項に記載の前記方法。 - 前記第一投与サイクルの長さは、21日である、請求項1から4のいずれか1項に記載の前記方法。
- 前記方法は、前記被検体へ前記C1D1、前記C1D2、及び前記C1D3を前記第一投与サイクルの、それぞれ1日目、8日目、及び15日目に、または約1日目、約8日目、及び約15日目に投与することを備える、請求項5に記載の前記方法。
- 前記第二投与サイクルの長さは、21日である、請求項1から6のいずれか1項に記載の前記方法。
- 前記方法は、前記被検体へ前記C2D1を前記第二投与サイクルの1日目に投与することを備える、請求項7に記載の前記方法。
- 前記投与計画は、1回以上の追加の投与サイクルを含む、請求項1から8のいずれか1項に記載の前記方法。
- 前記投与計画は、1回から6回の追加の投与サイクルを含む、請求項9に記載の前記方法。
- 前記1回以上の追加の投与サイクルのそれぞれの長さは、21日である、請求項9または10に記載の前記方法。
- 前記1回以上の追加の投与サイクルのそれぞれは、前記二重特異性抗体の単回投与量を含む、請求項9から11のいずれか1項に記載の前記方法。
- 前記方法は、前記被検体へ前記1回以上の追加の投与サイクルの前記単回投与量を前記1回以上の追加の投与サイクルの1日目に投与することを備える、請求項12に記載の前記方法。
- 前記二重特異性抗体は、以下の6箇所の超可変領域(HVR)を含む第一結合ドメインを含む抗CD20アームを備え、
前記6箇所の超可変領域は、
(a)前記アミノ酸配列のGYTFTSYNMH(配列番号1)を含むHVR−H1、
(b)前記アミノ酸配列のAIYPGNGDTSYNQKFKG(配列番号2)を含むHVR−H2、
(c)前記アミノ酸配列のVVYYSNSYWYFDV(配列番号3)を含むHVR−H3、
(d)前記アミノ酸配列のRASSSVSYMH(配列番号4)を含むHVR−L1、
(e)前記アミノ酸配列のAPSNLAS(配列番号5)を含むHVR−L2、及び
(f)前記アミノ酸配列のQQWSFNPPT(配列番号6)を含むHVR−L3、を備える、請求項1から13のいずれか1項に記載の前記方法。 - 前記二重特異性抗体は、
(a)前記アミノ酸配列の配列番号7に少なくとも95%の配列同一性を有するアミノ酸配列を含む重鎖可変(VH)ドメイン、
(b)前記アミノ酸配列の配列番号8に少なくとも95%の配列同一性を有するアミノ酸配列を含む軽鎖可変(VL)ドメイン、または
(c)(a)にあるようなVHドメイン、及び(b)にあるようなVLドメイン、
を含む第一結合ドメインを含む抗CD20アームを備える、請求項1から14のいずれか1項に記載の前記方法。 - 前記第一結合ドメインは、アミノ酸配列の配列番号7を含むVHドメイン、及びアミノ酸配列の配列番号8を含むVLドメインを含む、請求項15に記載の前記方法。
- 前記二重特異性抗体は、以下の6箇所のHVRを含む第二結合ドメインを含む抗CD3アームを備え、
前記6箇所のHVRは、
(a)前記アミノ酸配列のNYYIH(配列番号9)を含むHVR−H1、
(b)前記アミノ酸配列のWIYPGDGNTKYNEKFKG(配列番号10)を含むHVR−H2、
(c)前記アミノ酸配列のDSYSNYYFDY(配列番号11)を含むHVR−H3、
(d)前記アミノ酸配列のKSSQSLLNSRTRKNYLA(配列番号12)を含むHVR−L1、
(e)前記アミノ酸配列のWASTRES(配列番号13)を含むHVR−L2、及び
(f)前記アミノ酸配列のTQSFILRT(配列番号14)を含むHVR−L3、を含む、請求項1から16のいずれか1項に記載の前記方法。 - 前記二重特異性抗体は、
(a)前記アミノ酸配列の配列番号15に少なくとも95%の配列同一性を有するアミノ酸配列を含むVHドメイン、
(b)前記アミノ酸配列の配列番号16に少なくとも95%の配列同一性を有するアミノ酸配列を含むVLドメイン、または
(c)(a)にあるようなVHドメイン、及び(b)にあるようなVLドメイン、
を含む第二結合ドメインを含む抗CD3アームを備える、請求項1から17のいずれか1項に記載の前記方法。 - 前記第二結合ドメインは、アミノ酸配列の配列番号15を含むVHドメイン、及びアミノ酸配列の配列番号16を含むVLドメインを備える、請求項20に記載の前記方法。
- 前記二重特異性抗体は、アグリコシル化部位変異を含む、請求項1から19のいずれか1項に記載の前記方法。
- 前記アグリコシル化部位変異は、前記二重特異性抗体のエフェクター機能を低下させる、請求項20に記載の前記方法。
- 前記アグリコシル化部位変異は、置換変異である、請求項20または21に記載の前記方法。
- 前記二重特異性抗体は、エフェクター機能を低下させる前記Fc領域における置換変異を含む、請求項22に記載の前記方法。
- 前記置換変異は、アミノ酸残基N297、L234、L235、及び/またはD265(EU番号付け)におけるものである、請求項23に記載の前記方法。
- 前記置換変異は、N297G、N297A、L234A、L235A、D265A、及びP329Gからなる群から選択される、請求項24に記載の前記方法。
- 前記置換変異は、アミノ酸残基N297におけるものである、請求項24または25に記載の前記方法。
- 前記置換変異は、N297Aである、請求項26に記載の前記方法。
- 前記二重特異性抗体は、モノクローナル抗体である、請求項1から27のいずれか1項に記載の前記方法。
- 前記二重特異性抗体は、ヒト化抗体である、請求項1から28のいずれか1項に記載の前記方法。
- 前記二重特異性抗体は、キメラ抗体である、請求項1から29のいずれか1項に記載の前記方法。
- 前記二重特異性抗体は、CD20及びCD3を結合する抗体フラグメントである、請求項1から30のいずれか1項に記載の前記方法。
- 前記抗体フラグメントは、Fab、Fab’−SH、Fv、scFV、及び(Fab’)2フラグメントからなる群から選択される、請求項31に記載の前記方法。
- 前記二重特異性抗体は、抗体全長である、請求項1から30のいずれか1項に記載の前記方法。
- 前記二重特異性抗体は、IgG抗体である、請求項1から30及び33のいずれか1項に記載の前記方法。
- 前記IgG抗体は、IgG1抗体である、請求項34に記載の前記方法。
- 前記二重特異性抗体は、1箇所以上の重鎖定常ドメインを含み、前記1箇所以上の重鎖定常ドメインは、第一CH1(CH11)ドメイン、第一CH2(CH21)ドメイン、第一CH3(CH31)ドメイン、第二CH1(CH12)ドメイン、第二CH2(CH22)ドメイン、及び第二CH3(CH32)ドメインから選択される、請求項1から35のいずれか1項に記載の前記方法。
- 前記1箇所以上の重鎖定常ドメインのうちの少なくとも1箇所は、別の重鎖定常ドメインと対合される、請求項36に記載の前記方法。
- 前記CH31及びCH32ドメインは、突起または空洞を各含み、前記CH31ドメイン内の前記突起または空洞は、前記CH32ドメイン内の、それぞれ、前記空洞また突起内に配置可能である、請求項36または37に記載の前記方法。
- 前記CH31及びCH32ドメインは、前記突起と空洞との間の境界面において会合する、請求項38に記載の前記方法。
- 前記CH21及びCH22ドメインは、突起または空洞を各含み、前記CH21ドメイン内の前記突起または空洞は、前記CH22ドメイン内の、それぞれ、前記空洞または突起内に配置可能である、請求項36から39のいずれか1項に記載の前記方法。
- 前記CH21及びCH22ドメインは、前記突起と空洞との間の境界面において会合する、請求項40に記載の前記方法。
- 前記二重特異性抗体は、前記被検体へ単剤療法として投与される、請求項1から41のいずれか1項に記載の前記方法。
- 前記二重特異性抗体は、前記被検体へ併用療法として投与される、請求項1から41のいずれか1項に記載の前記方法。
- 前記二重特異性抗体は、前記被検体へ追加の治療剤と同時に投与される、請求項43に記載の前記方法。
- 前記二重特異性抗体は、追加の治療剤の前記投与前に、前記被検体へ投与される、請求項43に記載の前記方法。
- 前記追加の治療剤は、アテゾリズマブである、請求項44または45に記載の前記方法。
- 前記二重特異性抗体の前記C2D1と同時にアテゾリズマブの第一投与量を前記第二投与サイクルの1日目に前記被検体へ投与することをさらに備える、請求項13に記載の前記方法。
- アテゾリズマブを前記1回以上の追加の投与サイクルの前記二重特異性抗体の前記単回投与量と同時に前記1回以上の追加の投与サイクルの1日目に前記被検体へ投与することをさらに備える、請求項47に記載の前記方法。
- アテゾリズマブは、前記被検体へ前記二重特異性抗体と同時にのみ投与される、請求項48に記載の前記方法。
- アテゾリズマブの各投与量は、約1200mgである、請求項46から49のいずれか1項に記載の前記方法。
- 前記二重特異性抗体は、追加の治療剤の前記投与後に、前記被検体へ投与される、請求項43に記載の前記方法。
- 前記追加の治療剤は、オビヌツズマブ(GAZYVA(登録商標))である、請求項51に記載の前記方法。
- 前記追加の治療剤は、トシリズマブである、請求項51に記載の前記方法。
- 前記B細胞増殖性疾患は、非ホジキンリンパ腫(NHL)または慢性リンパ性白血病(CLL)である、請求項1から53のいずれか1項に記載の前記方法。
- 前記NHLは、びまん性大細胞型B細胞性リンパ腫(DLBCL)、縦隔(胸腺)原発B細胞性大細胞型リンパ腫(PMLBCL)、または濾胞性リンパ腫(FL)である、請求項54に記載の前記方法。
- 前記DLBCLは、再発性または難治性DLBCLである、請求項55に記載の前記方法。
- 前記投与は、静脈内注入によるものである、請求項1から56のいずれか1項に記載の前記方法。
- 前記投与は、皮下投与である、請求項1から56のいずれか1項に記載の前記方法。
- 前記被検体は、サイトカイン放出症候群(CRS)事象を有し、前記方法は、前記二重特異性抗体による処置を保留しながら前記CRS事象の前記症状を処置することをさらに備える、請求項1から53のいずれか1項に記載の前記方法。
- 前記方法は、前記被検体へトシリズマブの有効量を投与し、前記CRS事象を処置することをさらに備える、請求項59に記載の前記方法。
- トシリズマブは、前記被検体へ約8mg/kgの単回投与量として静脈内に投与される、請求項60に記載の前記方法。
- 前記CRS事象は、前記CRS事象の前記症状を処置してから24時間以内に回復せず、または悪化せず、前記方法は、前記被検体へ1回以上の追加の投与量のトシリズマブを投与し、前記CRS事象を管理することをさらに備える、請求項61に記載の前記方法。
- 前記1回以上の追加の投与量のトシリズマブは、前記被検体へ約8mg/kgの1回投与量で静脈内に投与される、請求項62に記載の前記方法。
- 前記被検体へコルチコステロイドの有効量を投与することをさらに備える、請求項62または63に記載の前記方法。
- 前記コルチコステロイドは、前記被検体へ静脈内に投与される、請求項64に記載の前記方法。
- 前記コルチコステロイドは、メチルプレドニゾロンである、請求項64または65に記載の前記方法。
- メチルプレドニゾロンは、1日あたり約2mg/kgの投与量で投与される、請求項66に記載の前記方法。
- 前記コルチコステロイドは、デキサメタゾンである、請求項64または65に記載の前記方法。
- デキサメタゾンは、約10mgの投与量で投与される、請求項68に記載の前記方法。
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CA3042435A1 (en) | 2018-05-24 |
KR20240029119A (ko) | 2024-03-05 |
US11466094B2 (en) | 2022-10-11 |
KR20190074300A (ko) | 2019-06-27 |
EP3541843A1 (en) | 2019-09-25 |
JP2024012313A (ja) | 2024-01-30 |
TWI791471B (zh) | 2023-02-11 |
WO2018093821A8 (en) | 2018-07-26 |
IL266496A (en) | 2019-07-31 |
TW201827075A (zh) | 2018-08-01 |
CN109923128A (zh) | 2019-06-21 |
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