JP6802158B2 - 抗CD79b抗体及び使用方法 - Google Patents
抗CD79b抗体及び使用方法 Download PDFInfo
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- JP6802158B2 JP6802158B2 JP2017528910A JP2017528910A JP6802158B2 JP 6802158 B2 JP6802158 B2 JP 6802158B2 JP 2017528910 A JP2017528910 A JP 2017528910A JP 2017528910 A JP2017528910 A JP 2017528910A JP 6802158 B2 JP6802158 B2 JP 6802158B2
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Description
本出願は、2014年12月5日に出願された米国仮出願第62/088487号に対する優先権の利益を主張するものであり、その全ての内容は参照により本明細書に組み込まれる。
本出願は、ASCII形式で電子的に提出された配列表を含み、その全ての内容は参照により本明細書に組み込まれる。2015年12月2日に作成された該ASCIIの複写は、P32464WO_PCTSequenceListing.txtという名称であり、43,470バイトの大きさである。
「CD79b」という用語は、本明細書で用いる場合、別途指示されない限り、霊長動物(例えば、ヒト、カニクイザル(cynomologus monkey)(cyno))、及び齧歯動物(例えば、マウス及びラット)等の哺乳動物を含む、任意の脊椎動物源由来の任意の天然CD79bを指す。ヒトCD79bは、本明細書で「Igβ」、「B29」、「DNA225786」、または「PRO36249」とも称される。シグナル配列を含む例示的なCD79b配列が、配列番号1に示される。シグナル配列を含まない例示的なCD79b配列が、配列番号2に示される。「CD79b」という用語は、「完全長」のプロセシングされていないCD79b、ならびに細胞内のプロセシングから得られるCD79bの任意の形態を包含する。この用語は、CD79bの自然発生変異体、例えば、スプライス変異体、対立遺伝子変異体、及びアイソフォームも包含する。本明細書に記載されるCD79bポリペプチドは、ヒト組織型から、若しくは別の源から等、多様な源から単離され得るか、または組み換え法または合成法によって調製され得る。「天然配列CD79bポリペプチド」は、自然界に由来する対応CD79bポリペプチドと同じアミノ酸配列を有するポリペプチドを含む。このような天然配列CD79bポリペプチドは、自然界から単離され得るか、または組み換え手法若しくは合成手法によって産生され得る。「天然配列CD79bポリペプチド」という用語は、具体的には、特定のCD79bポリペプチド(例えば、細胞外ドメイン配列)の自然発生切頭型若しくは分泌型、自然発生変異形態(例えば、オルタナティブスプライシング型)、及びポリペプチドの自然発生対立遺伝子変異体を包含する。
(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)で発生する超可変ループ(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)で発生する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)で発生する抗原接触体(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
式中、Xは、配列アライメントプログラムALIGN−2によって、そのプログラムのA及びBのアライメント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中の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、Bに対するAのアミノ酸配列同一性%は、Aに対するBのアミノ酸配列同一性%と等しくはならないことが理解されるだろう。別途具体的に記されない限り、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。
トロキサシタビン(1,3−ジオキソランヌクレオシドシトシン類似体);アンチセンスオリゴヌクレオチド、具体的には、例えば、PKC−アルファ、Raf、H−Ras、及び上皮成長因子受容体(EGF−R)等の異常な細胞増殖に関係しているシグナル経路において遺伝子の発現を阻害するもの;THERATOPE(登録商標)ワクチン及び遺伝子療法ワクチン等のワクチン、例えば、ALLOVECTIN(登録商標)ワクチン、LEUVECTIN(登録商標)ワクチン、及びVAXID(登録商標)ワクチン;トポイソメラーゼ 1 阻害剤(例えば、LURTOTECAN(登録商標));rmRH(例えば、ABARELIX(登録商標));BAY439006(ソラフェニブ;Bayer);SU−11248(スニチニブ、SUTENT(登録商標)、Pfizer);ペリホシン、COX−2阻害剤(例えば、セレコキシブまたはエトリコキシブ)、プロテオソーム阻害剤(例えば、PS341);ボルテゾミブ(VELCADE(登録商標));CCI−779;チピファルニブ(R11577);オラフェニブ(orafenib)、ABT510;オブリメルセンナトリウム(GENASENSE(登録商標))等のBcl−2阻害剤;ピクサントロン;EGFR阻害剤(定義は以下を参照されたい);チロシンキナーゼ阻害剤;ラパマイシン(シロリムス、RAPAMUNE(登録商標))等のセリン−スレオニンキナーゼ阻害剤;ロナファルニブ(SCH 6636、SARASARTM)等のファルネシルトランスフェラーゼ阻害剤;ならびに上述のもののいずれかの薬学的に許容される塩、酸、または誘導体;ならびにCHOP(シクロホスファミド、ドキソルビシン、ビンクリスチン、及びプレドニゾロンの組み合わせ療法に対する略語である)等の上述のもののうちの2つ以上の組み合わせ;及びFOLFOX(5−FU及びロイコボリンと組み合わせたオキサリプラチン(ELOXATINTM)を用いる治療レジメンに対する略語である)が挙げられる。
一態様では、本発明は、部分的に抗CD79b抗体に基づく。ある特定の実施形態では、CD79b結合ドメイン及びCD3結合ドメインを含む抗CD79b抗体が提供される。ある特定の実施形態では、抗CD79b抗体は、抗CD79bT細胞依存性二重特異性(TDB)抗体である。本発明の抗体は、例えば、B細胞増殖性疾患の診断または治療に有用である。
一態様では、本発明は、CD79bに結合する単離された抗体を提供する。抗CD79b抗体のうちのいずれかのいくつかの実施形態では、CD79b結合ドメインは、配列番号63に結合する。
一態様では、本発明は、(a)配列番号5のアミノ酸配列を含むHVR−H1、(b)配列番号8のアミノ酸配列を含むHVR−H2、(c)配列番号9のアミノ酸配列を含むHVR−H3、(d)配列番号10のアミノ酸配列を含むHVR−L1、(e)配列番号11のアミノ酸配列を含むHVR−L2、及び(f)配列番号12のアミノ酸配列を含むHVR−L3から選択される、少なくとも1、2、3、4、5、または6つのHVRを含むCD79b結合ドメインを含む、抗CD79b抗体を提供する。いくつかの実施形態では、HVR−H1は、配列番号3のアミノ酸配列を含む。いくつかの実施形態では、HVR−H1は、配列番号4のアミノ酸配列を含む。いくつかの実施形態では、HVR−H2は、配列番号6のアミノ酸配列を含む。いくつかの実施形態では、HVR−H2は、配列番号7のアミノ酸配列を含む。
一態様では、本発明は、(a)配列番号31のアミノ酸配列を含むHVR−H1、(b)配列番号32のアミノ酸配列を含むHVR−H2、(c)配列番号33のアミノ酸配列を含むHVR−H3、(d)配列番号34のアミノ酸配列を含むHVR−L1、(e)配列番号35のアミノ酸配列を含むHVR−L2、及び(f)配列番号36のアミノ酸配列を含むHVR−L3から選択される、少なくとも1、2、3、4、5、または6つのHVRを含むCD79b結合ドメインを含む、抗CD79b抗体を提供する。
ある特定の実施形態では、本明細書に提供される抗体は、1μM以下、100nM以下、10nM以下、1nM以下、0.1nM以下、0.01nM以下、または0.001nM以下(例えば、10−8M以下、例えば、10−8M〜10−13M、例えば、10−9M〜10−13M)の解離定数(Kd)を有する。
ある特定の実施形態では、本明細書に提供される抗体は、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を含むが、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)を参照されたい。scFvフラグメントの概説については、例えば、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号も参照されたい。サルベージ受容体結合エピトープ残基を含み、上昇したインビボ半減期を有する、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。
ある特定の実施形態では、本明細書に提供される抗体は、キメラ抗体である。ある特定のキメラ抗体が、例えば、米国特許第4,816,567号、及びMorrison et al.,Proc.Natl.Acad.Sci.USA,81:6851−6855(1984))に記載されている。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、またはサル等の非ヒト霊長動物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ものから変化している、「クラススイッチ」抗体である。キメラ抗体は、それらの抗原結合フラグメントを含む。
ある特定の実施形態では、本明細書に提供される抗体は、ヒト抗体である。ヒト抗体は、当該技術分野で既知の種々の技法を使用して産生することができる。ヒト抗体は概して、van Dijk and van de Winkel,Curr.Opin.Pharmacol.5:368−74(2001)及びLonberg,Curr.Opin.Immunol.20:450−459(2008)に記載されている。
本発明の抗体は、所望の活性(複数可)を有する抗体についてコンビナトリアルライブラリをスクリーニングすることによって単離され得る。例えば、ファージディスプレイライブラリを生成し、所望の結合特性を保有する抗体についてかかるライブラリをスクリーニングするための多様な方法が、当該技術分野で既知である。かかる方法は、例えば、Hoogenboom et al.in Methods in Molecular Biology 178:1−37(O’Brien et al.,ed.,Human Press,Totowa,NJ,2001)に概説され、例えば、McCafferty et al.,Nature 348:552−554、Clackson et al.,Nature 352: 624−628(1991)、Marks et al.,J.Mol.Biol.222:581−597(1992)、Marks and Bradbury,in Methods in Molecular Biology 248:161−175(Lo,ed.,Human Press,Totowa,NJ,2003)、Sidhu et al.,J.Mol.Biol.338(2):299−310(2004)、Lee et al.,J.Mol.Biol.340(5):1073−1093(2004)、Fellouse,Proc.Natl.Acad.Sci.USA 101(34):12467−12472(2004)、及びLee et al.,J.Immunol.Methods 284(1−2):119−132(2004)にさらに記載されている。
ある特定の実施形態では、本明細書に提供される抗体は、多重特異性抗体、例えば、二重特異性抗体である。多重特異性抗体は、少なくとも2つの異なる部位に対する結合特異性を有するモノクローナル抗体である。ある特定の実施形態では、結合特異性のうちの一方は、CD79bに対するものであり、他方は、任意の他の抗原に対するものである。ある特定の実施形態では、二重特異性抗体は、CD79bの2つの異なるエピトープに結合することができる。二重特異性抗体を使用して、細胞傷害性薬剤を、CD79bを発現する細胞に限局することもできる。二重特異性抗体は、完全長抗体または抗体フラグメントとして調製することができる。
ある特定の実施形態では、本明細書に提供される抗体のアミノ酸配列変異体が企図される。例えば、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、抗体をコード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って、またはペプチド合成によって調製することができる。かかる修飾には、例えば、抗体のアミノ酸配列内の残基からの欠失、及び/またはそこへの挿入、及び/またはその置換が挙げられる。最終構築物に到達ために欠失、挿入、及び置換の任意の組み合わせを行うことができるが、最終構築物が所望の特性、例えば、抗原結合を保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が提供される。置換変異導入のための目的とする部位には、HVR及びFRを含む。保存的置換は、表1において「好ましい置換」の見出しの下に示される。より実質的な変化は、表1において「例示的置換」の見出しの下に提供され、アミノ酸側鎖クラスを参照してさらに後述される。アミノ酸置換が目的とする抗体に導入され、その産物が、所望の活性、例えば、抗原結合の保持/改善、免疫原性の低下、またはADCCまたはCDCの改善に対してスクリーニングされ得る。
(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。
ある特定の実施形態では、本明細書に提供される抗体は、抗体がグリコシル化される程度を増加または減少させるように改変される。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が作製されるか、または除去されるようにアミノ酸配列を改変することによって、好都合に達成され得る。
ある特定の実施形態では、1つ以上のアミノ酸修飾が、本明細書に提供される抗体のFc領域に導入され、それによってFc領域変異体を生成することができる。Fc領域変異体は、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IgG4Fc領域)を含み得る。
ある特定の実施形態では、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、システイン操作された抗体、例えば、「チオマブ(thioMAb)」を作製することが望ましい場合がある。特定の実施形態では、置換された残基は、抗体の接触可能部位で発生する。これらの残基をシステインで置換することによって、反応性のチオール基がそれにより抗体の接触可能部位に位置付けられ、それを使用して、薬物部分またはリンカー−薬物部分等の他の部分に抗体を複合体化して、本明細書にさらに記載される免疫複合体を作製することができる。ある特定の実施形態では、次の残基のうちの任意の1つ以上が、システインで置換され得る: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)。システイン操作された抗体は、例えば、米国特許第7,521,541号に記載されるように生成され得る。
ある特定の実施形態では、本明細書に提供される抗体は、当該技術分野で既知であり、かつ容易に入手可能な、追加の非タンパク質性部分を含有するようにさらに修飾されてもよい。抗体の誘導体化に好適な部分には、水溶性ポリマーを含むが、これに限定されない。水溶性ポリマーの非限定的な例には、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(propropylene)グリコールホモポリマー、プロリプロピレン(prolypropylene)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、ならびにそれらの混合物が挙げられるが、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により、製造における利点を有し得る。ポリマーは、任意の分子量のものであってもよく、分岐であっても、または非分岐であってもよい。抗体に結合したポリマーの数は可変であり、1つを超えるポリマーが結合される場合、それらは、同じ分子または異なる分子であり得る。一般的に、誘導体化に使用されるポリマーの数及び/またはタイプは、抗体の改善されるべき特定の特性または機能、抗体誘導体が規定の条件下で療法において使用されるかどうか等を含むが、これらに限定されない考慮に基づいて決定され得る。
抗体は、例えば、米国特許第4,816,567号に記載される組み換え法及び組成物を使用して産生され得る。一実施形態では、本明細書に記載される抗CD79b抗体をコードする単離された核酸が提供される。かかる核酸は、抗体のVLを含むアミノ酸配列及び/または抗体のVHを含むアミノ酸配列(例えば、抗体の軽鎖及び/または重鎖)をコードし得る。さらなる実施形態では、かかる核酸を含む1つ以上のベクター(例えば、発現ベクター)が提供される。さらなる実施形態では、かかる核酸を含む宿主細胞が提供される。1つのかかる実施形態では、宿主細胞は、(1)抗体のVLを含むアミノ酸配列及び抗体のVHを含むアミノ酸配列をコードする核酸を含むベクター、または(2)抗体のVLを含むアミノ酸配列をコードする核酸を含む第1のベクター、及び抗体のVHを含むアミノ酸配列をコードする核酸を含む第2のベクターを含む(例えば、それらで形質転換されている)。一実施形態では、宿主細胞は、真核生物のもの、例えば、チャイニーズハムスター卵巣(CHO)細胞またはリンパ系細胞(例えば、Y0、NS0、Sp20細胞)である。一実施形態では、抗CD79b抗体の作製方法が提供され、該方法は、上に提供されるように、抗体の発現に適した条件下で、抗体をコードする核酸を含む宿主細胞を培養することと、及び任意に、宿主細胞(または宿主細胞培養培地)から抗体を回収することと、を含む。
本明細書に提供される抗CD79b抗体は、当該技術分野で既知の種々のアッセイによって、それらの物理/化学特性及び/または生物活性について、特定されるか、スクリーニングされるか、または特徴付けられてもよい。
一態様では、本発明の抗体は、例えば、ELISA、ウエスタンブロット等の既知の方法によってその抗原結合活性について試験される。
一態様では、アッセイは、生物活性を有する抗CD79b抗体(例えば、抗CD79b/CD3 TDB抗体)を特定するために提供される。生物活性には、例えば、細胞成長または増殖(例えば、「細胞死滅」活性)を阻害する能力、プログラム細胞死(アポトーシス)を含む細胞死を誘発する能力、または抗原結合活性が挙げられる。インビボ及び/またはインビトロにおいてかかる生物活性を有する抗体も提供される。
本発明は、本明細書において、化学治療剤若しくは薬物、成長阻害剤、毒素(例えば、タンパク質毒素、細菌、真菌、植物、若しくは動物起源の酵素活性毒素、またはそれらのフラグメント)、または放射性同位体等の1つ以上の細胞傷害性薬剤に複合体化される抗CD79b抗体を含む、免疫複合体も提供する。
一態様では、本発明の抗CD79b抗体は、生体試料中のCD79bの存在の検出に有用である。「検出すること」という用語は、本明細書で用いる場合、定量または定性検出を包含する。ある特定の実施形態では、生体試料は、細胞または組織を含む。ある特定の実施形態では、かかる組織は、正常組織、ならびに/または他の組織、例えば、B細胞及び/若しくはB細胞関連組織と比べて、高水準でCD79bを発現する癌性組織を含む。
本明細書に記載される抗CD79b抗体の薬学的製剤が、所望の程度の純度を有するかかる抗体を、1つ以上の任意の薬学的に許容される担体(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。薬学的に許容される担体は一般に、用いられる投薬量及び濃度でレシピエントに対して非毒性であり、リン酸塩、クエン酸塩、及び他の有機酸等の緩衝剤、アスコルビン酸及びメチオニンを含む抗酸化物質、防腐剤(塩化オクタデシルジメチルベンジルアンモニウム、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、メチル若しく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−クレゾール等)、低分子量(約10残基未満)のポリペプチド、血清アルブミン、ゼラチン、若しく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、若しくはリジン等のアミノ酸、単糖類、二糖類、及びグルコース、マンノース、若しくはデキストリンを含む他の炭水化物、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、若しくはソルビトール等の糖類、ナトリウム等の塩形成対イオン、金属複合体(例えば、Zn−タンパク質複合体)、ならびに/また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的なsHASEGP及びその使用方法は、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される。
本明細書に提供される抗CD79b抗体(例えば、抗CD79b/CD3 TDB抗体)のうちのいずれかが、治療法において使用され得る。
本発明の別の態様では、上述の障害の治療、予防、及び/または診断に有用な材料を含有する製造品が提供される。製造品は、容器と、容器上の、または容器と関連するラベル若しくは添付文書とを含む。好適な容器には、例えば、ボトル、バイアル瓶、シリンジ、IV溶液バッグ等が挙げられる。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、それ自体によって、または別の組成物と組み合わせて、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てもよい(例えば、容器は、静脈注射溶液バッグまたは皮下注射針によって貫通可能な栓を有するバイアル瓶であり得る)。組成物中の少なくとも1つの活性薬剤は、本発明の抗体である。ラベルまたは添付文書は、組成物が、選定した病態を治療するために使用されることを示す。さらに、製造品は、(a)本発明の抗体を含む組成物をその中に収容した第1の容器、及び(b)さらなる細胞傷害性薬剤、さもなければ治療剤を含む組成物をその中に収容した第2の容器を含み得る。本発明のこの実施形態の製造品は、組成物を使用して特定の病態を治療することができることを示す添付文書をさらに含み得る。あるいは、または加えて、製造品は、注射用静菌水(BWFI)、リン酸緩衝食塩水、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剤を含む第2の(または第3の)容器をさらに含み得る。それは、他の緩衝剤、希釈剤、フィルター、針、及びシリンジを含む、商業的観点及びユーザの観点から望ましい他の材料をさらに含んでもよい。
以下は、本発明の方法及び組成物の実施例である。上に提供される概要を仮定して、種々の他の実施形態が実践され得ることが理解される。
材料及び方法
A.モノクローナル抗体生成
ヒトCD79bのFc標的化またはHis標的化細胞外ドメイン(ECD)を発現するベクターをCHO細胞内に一過性トランスフェクションすることによって、マウスの免疫化のためのタンパク質を生成した。タンパク質Aカラム上のトランスフェクトされた細胞上清からタンパク質を精製し、タンパク質の同一性をN末端シークエンシングによって確認した。10個のBalb/cマウス(Charles River Laboratories,Hollister,Calif.)を、ヒトCD79bの組み換えFc標的化またはHis標的化ECDで過免疫化した。直接ELISAによりヒトCD79b免疫原に対して高い抗体価を示し、Ramos細胞に対して特異的に結合するマウス由来のB細胞を、以前に記載されているように(Hongo,J.S.et al.,Hybridoma,14:253−260(1995)、Kohler,G.et al.,Nature,256:495−497(1975)、Freund,Y.R.et al.,J.Immunol.,129:2826−2830(1982))、マウス骨髄腫細胞(X63.Ag8.653;American Type Culture Collection,Rockville,Md.)と融合した。10〜12日後、上清を収集し、直接ELISA、及び上述のFACSによって抗体産生及び結合に関してスクリーニングした。限界希釈による第2巡目のサブクローニング後、最も高い免疫結合を示す陽性クローンを、ヒトCD79b特異性及び交差反応を含むさらなる特性評価のために拡張及び培養した。以前に記載されているように(Hongo,J.S.et al.,Hybridoma,14:253−260(1995)、Kohler,G.et al.,Nature,256:495−497(1975)、Freund,Y.R.et al.,J.Immunol.,129:2826−2830(1982))、各ハイブリドーマ系統から収集された上清を、親和性クロマトグラフィー(Pharmacia高速タンパク質液体クロマトグラフィー(FPLC)、Pharmacia,Uppsala,Sweden)によって精製した。次いで、精製された抗体調製物を滅菌濾過して(0.2−Φm孔径;Nalgene,Rochester N.Y.)、リン酸緩衝食塩水(PBS)中で、4℃で保管した。
以前に記載されているように(Atwell et al.J.Mol.Biol.270:26−35,1997)、ヒトIgG1である、ノブ・イントゥ・ホール(knob−into−hole)形式の完全長抗体である、TDB抗体を産生した。半抗体がタンパク質A−親和性クロマトグラフィーによって精製されたE.coliまたはチャイニーズハムスター卵巣(CHO)細胞内で発現され、以前に記載されているように(Spiess et al.Nat.Biotechnol.2013)、その適切な半抗体対をインビトロでアニーリングした。CHO細胞内でTDB抗体産生を行った場合、TDB抗体が、エフェクターのない(effector−less)変異体であり、抗体依存性の細胞媒介性細胞傷害(ADCC)を始めることが不可能であるように、抗体は、例えば、残基N297(例えば、N297G)に非グリコシル化突然変異を有し得る。
BiacoreまたはFACS分析によって、CD3/CD79b TDBの各々に対する結合親和性を試験した。簡潔に述べると、Biacore結合アッセイでは、ヒトCD3γεが、Biacoreのアミンカップリングキットを使用してBiacore Series S CM5センサチップ上に固定され、抗CD79b/CD3 TDB抗体またはそのFab変異体が、通過画分中に存在した。FACS結合アッセイでは、BJAB細胞(B細胞抗原に対する)または定められる他の細胞株を、種々の濃度のTDB抗体を加えて4℃で30分間インキュベートし、次いで、細胞を洗浄し、細胞を再び洗浄してFACS分析への準備を整える前に、第2の抗体(抗huIgG−PE、BD Bioscience)を加えてさらに15分間インキュベートした。
生成された抗CD79b/CD3 TDB抗体を、B細胞死滅及び細胞傷害性T細胞の活性化を支援する、その能力に関して試験した。これらのアッセイでは、Ficoll分離によって健常ドナーの全血からPBMCを単離した。簡潔に述べると、ヘパリン処理されたシリンジ中でヒト血液を採取し、製造業によって推薦される、Leucosep(Greiner Bio−one、カタログ番号227290P)及びFicoll Paque Plus(GE Healthcare Biosciences、カタログ番号95038−168)を使用してPBMCを単離した。必要に応じて、製造業者の指示書に従ってMiltenyiキットを用いて、CD4+T及びCD8+T細胞を分離した。
50SCID.bgマウスに、HBSS中、5百万個のBJAB−luc抗CD79b−MC−vc−PAB−MMAE耐性モデルT1.1X1細胞をマウス1匹当たり0.2mLの量で(200ulを超えない)、または、HBSS中、5百万個のBJAB−luc抗CD79b−MC−vc−PAB−MMAE耐性モデルT1.1X1細胞と1千万個のPBMCとの混合物を0.2mlの量で(200ulを超えない)、右片側胸部内の皮下に接種した。これは予防研究であり、接種及び治療は0日目に施された。
抗体−薬物複合体(ADC)が生成されており(プロテアーゼ切断可能リンカーによってモノメチルオーリスタチンE(MMAE)に複合体化されたヒト化抗CD79b抗体(ヒト化SN8)等)、これは臨床においてNHLの治療に対して効果があることを示している。米国特許第8,088,378号及びMorschhauser et al.,「4457 Updated Results of a Phase II Randomized Study(ROMULUS)of Polatuzumab Vedotin or Pinatuzumab Vedotin Plus Rituximab in Patients with Relapsed/Refractory Non−Hodgkin Lymphoma」56th ASH Annual Meeting and Exposition:December 6−9,2014を参照されたい。
上述のようにモノクローナル抗体CD79b.A7をヒト化した。残基番号は、Kabat et al.,Sequences of proteins of immunological interest,5th Ed.,Public Health Service,National Institutes of Health,Bethesda,Md.(1991)に従う。
抗CD79b TDB抗体B細胞死滅の効率におけるCD3結合ドメイン対合の作用を分析した。40G5c及び38E4v1を含む異なる抗CD3抗体結合ドメインと組み合わせて、抗CD79b.A7.v14抗体を試験した。抗CD79b/CD3 TDB抗体を加えて、または加えずに200,000個のPBMCを48時間にわたってインキュベートした。図5AのB細胞死滅の割合を次のように計算した:(TDBを有しない生存B細胞数−TDBを有する生存B細胞数)/(TDBを有しない生存B細胞数)*100。図5Bに示されるように、CD8+T細胞集団中のCD69+/CD25+細胞にゲートを作成することによって、T細胞活性化を測定した。図5A及びBに示されるように、K&H CD79b.A7.v14/40G5cは、CD8+T活性化不良及び低割合の内因性B細胞死滅を示した。追加の実験(データは図示されない)では、抗CD79b/CD3 TDB抗体(CD79b.A7.v14/40G5c K&H)は、2つの異なるドナーを使用して、CD8+T活性化に対して1.1及び2.3ng/mLのEC50、ならびに内因性B細胞死滅に対して2658及び288ng/mLのEC50を示した。対照的に、図5A及びBに示されるように、抗CD79b/CD3 TDB抗体(CD79b.A7.v14/38E4v1 K&H)は、CD79b.A7.v14/40G5c K&Hと比べて、実質的に改善したCD8+T細胞活性化及び内因性B細胞死滅の割合(内因性B細胞死滅に対して15ng/mLのEC50)を示した。追加の実験(データは図示されない)では、抗CD79b/CD3 TDB抗体(CD79b.A7.v14/40G5c K&H)は、6つの異なるドナーを使用して、内因性B細胞死滅に対して401、14、1.5、10、12、及び16ng/mLのEC50を示した。
インビトロ及びインビボでの抗CD79b/CD3 TDB抗体(CD79b.A7.v14b/38E4v1)のB細胞死滅活性も、抗CD79b−MC−vc−PAB−MMAE耐性B細胞において試験した。BJAB細胞変異体(BJAB−CD79b ADC−R T1.1及びBJAB−SN8v28vcE CD79b ADC−R T1.2)は、抗CD79b−MC−vc−PAB−MMAE耐性B細胞で治療されるマウスの非応答性BJAB異種移植腫瘍に由来した。図8Aに示されるように、抗CD79b/CD3 TDB(CD79b.A7.v14b/38E4v1)は、BJABならびに抗CD79b−MC−vc−PAB−MMAE耐性BJAB細胞のインビトロでの細胞死滅において非常に有効であった。さらに、図8Bに示されるように、抗CD79b/CD3 TDB抗体(CD79b.A7.v14b/38E4v1)は、抗CD79b−MC−vc−PAB−MMAE耐性BJAB腫瘍のインビボでの成長を防ぐ。
Claims (66)
- 単離された抗CD79b抗体であって、以下の6つの超可変領域(HVR):
(a)配列番号5のアミノ酸配列を含むHVR−H1、
(b)配列番号8のアミノ酸配列を含むHVR−H2、
(c)配列番号9のアミノ酸配列を含むHVR−H3、
(d)配列番号10のアミノ酸配列を含むHVR−L1、
(e)配列番号11のアミノ酸配列を含むHVR−L2、及び
(f)配列番号12のアミノ酸配列を含むHVR−L3を含む、CD79b結合ドメインを含む、前記抗体。 - 前記CD79b結合ドメインが、以下の6つのHVR:
(a)配列番号3のアミノ酸配列を含むHVR−H1、
(b)配列番号6のアミノ酸配列を含むHVR−H2、
(c)配列番号9のアミノ酸配列を含むHVR−H3、
(d)配列番号10のアミノ酸配列を含むHVR−L1、
(e)配列番号11のアミノ酸配列を含むHVR−L2、及び
(f)配列番号12のアミノ酸配列を含むHVR−L3を含む、請求項1に記載の抗CD79b抗体。 - 前記CD79b結合ドメインが、以下の6つのHVR:
(a)配列番号4のアミノ酸配列を含むHVR−H1、
(b)配列番号7のアミノ酸配列を含むHVR−H2、
(c)配列番号9のアミノ酸配列を含むHVR−H3、
(d)配列番号10のアミノ酸配列を含むHVR−L1、
(e)配列番号11のアミノ酸配列を含むHVR−L2、及び
(f)配列番号12のアミノ酸配列を含むHVR−L3を含む、請求項1に記載の抗CD79b抗体。 - (a)配列番号17、21、23、25、27、若しくは29のアミノ酸配列と少なくとも95%の配列同一性を有するVH配列、(b)配列番号18、22、24、26、28、若しくは30のアミノ酸配列と少なくとも95%の配列同一性を有するVL配列、または(c)(a)のVH配列及び(b)のVL配列を含む、請求項2に記載の抗CD79b抗体。
- 配列番号17、21、23、25、27、または29のVH配列を含む、請求項3〜4のいずれか1項に記載の抗CD79b抗体。
- 配列番号18、22、24、26、28、または30のVL配列を含む、請求項3〜5のいずれか1項に記載の抗CD79b抗体。
- (a)配列番号19のアミノ酸配列と少なくとも95%の配列同一性を有するVH配列、(b)配列番号20のアミノ酸配列と少なくとも95%の配列同一性を有するVL配列、または(c)(a)のVH配列及び(b)のVL配列を含む、請求項3に記載の抗CD79b抗体。
- 配列番号19のVH配列を含む、請求項3または7のいずれか1項に記載の抗CD79b抗体。
- 配列番号20のVL配列を含む、請求項3または7〜8のいずれか1項に記載の抗CD79b抗体。
- 前記CD79b結合ドメインが、配列番号63に結合する、請求項1〜9のいずれか1項に記載の抗CD79b抗体。
- 前記CD79b結合ドメインが、二重アームの二価IgG抗体として25nM未満のKdでヒトCD79bと結合する、請求項1〜10のいずれか1項に記載の抗CD79b抗体。
- 前記CD79b結合ドメインが、ヒトCD79bと結合し、一価形式で1.5ug/mL未満のEC50でB細胞と結合する、請求項1〜11のいずれか1項に記載の抗体。
- 前記抗CD79b抗体が、モノクローナル、ヒト化、またはキメラ抗体である、請求項1〜12のいずれか1項に記載の抗CD79b抗体。
- 前記抗CD79b抗体がIgG抗体である、請求項1〜13のいずれか1項に記載の抗CD79b抗体。
- 前記抗CD79b抗体が、CD79bと結合する抗体フラグメントである、請求項1〜14のいずれか1項に記載の抗CD79b抗体。
- 前記抗CD79b抗体フラグメントが、Fab、Fab’−SH、Fv、scFv、及び/または(Fab’)2フラグメントである、請求項15に記載の抗CD79b抗体。
- 前記抗CD79b抗体が、完全長抗体である、請求項1〜14のいずれか1項に記載の抗CD79b抗体。
- 前記抗CD79b抗体が、非グリコシル化(aglycosylation)部位突然変異を含む、請求項1〜17のいずれか1項に記載の抗CD79b抗体。
- 前記非グリコシル化部位突然変異が、置換突然変異である、請求項18に記載の抗CD79b抗体。
- 前記抗CD79b抗体が、低減したエフェクター機能を含む、請求項1〜19のいずれか1項に記載の抗CD79b抗体。
- 前記抗CD79b抗体が、EU番号付けによるアミノ酸残基N297、L234、L235、及び/またはD265における置換突然変異を含む、請求項1〜20のいずれか1項に記載の抗CD79b抗体。
- 前記置換突然変異が、EU番号付けによるN297G、N297A、L234A、L235A、及びD265Aからなる群から選択される、請求項21に記載の抗CD79b抗体。
- 前記抗体が、EU番号付けによるアミノ酸残基297におけるN297G置換突然変異を含む、請求項21に記載の抗CD79b抗体。
- 前記抗CD79b抗体が、単一特異性抗体である、請求項1〜23のいずれか1項に記載の抗CD79b抗体。
- 前記抗CD79b抗体が、多重特異性抗体である、請求項1〜23のいずれか1項に記載の抗CD79b抗体。
- 前記多重特異性抗体が、CD3結合ドメインを含む、請求項25に記載の抗CD79b抗体。
- 前記CD3結合ドメインが、ヒトCD3ポリペプチドまたはカニクイザル(cyno)CD3ポリペプチドに結合する、請求項26に記載の抗CD79b抗体。
- 前記ヒトCD3ポリペプチドまたは前記cynoCD3ポリペプチドが、それぞれ、ヒトCD3εポリペプチドまたはcynoCD3εポリペプチドである、請求項27に記載の抗CD79b抗体。
- 前記ヒトCD3ポリペプチドまたは前記cynoCD3ポリペプチドが、それぞれ、ヒトCD3γポリペプチドまたはcynoCD3γポリペプチドである、請求項27に記載の抗CD79b抗体。
- 前記CD3結合ドメインが、以下の6つのHVR:
(a)配列番号45のアミノ酸配列を含むHVR−H1、
(b)配列番号46のアミノ酸配列を含むHVR−H2、
(c)配列番号47のアミノ酸配列を含むHVR−H3、
(d)配列番号48のアミノ酸配列を含むHVR−L1、
(e)配列番号49のアミノ酸配列を含むHVR−L2、及び
(f)配列番号50のアミノ酸配列を含むHVR−L3を含む、請求項26〜29のいずれか1項に記載の抗CD79b抗体。 - 前記CD3結合ドメインが、配列番号59のVH配列を含む、請求項26〜30のいずれか1項に記載の抗CD79b抗体。
- 前記CD3結合ドメインが、配列番号60のVL配列を含む、請求項26〜31のいずれか1項に記載の抗CD79b抗体。
- 前記CD3結合ドメインが、以下の6つのHVR:
(a)配列番号39のアミノ酸配列を含むHVR−H1、
(b)配列番号40のアミノ酸配列を含むHVR−H2、
(c)配列番号41のアミノ酸配列を含むHVR−H3、
(d)配列番号42のアミノ酸配列を含むHVR−L1、
(e)配列番号43のアミノ酸配列を含むHVR−L2、及び
(f)配列番号44のアミノ酸配列を含むHVR−L3を含む、請求項26〜29のいずれか1項に記載の抗CD79b抗体。 - 前記CD3結合ドメインが、配列番号57のVH配列を含む、請求項26〜29、または33のいずれか1項に記載の抗CD79b抗体。
- 前記CD3結合ドメインが、配列番号58のVL配列を含む、請求項26〜29、33、または34のいずれか1項に記載の抗CD79b抗体。
- 前記CD3結合ドメインが、以下の6つのHVR:
(a)配列番号51のアミノ酸配列を含むHVR−H1、
(b)配列番号52のアミノ酸配列を含むHVR−H2、
(c)配列番号53のアミノ酸配列を含むHVR−H3、
(d)配列番号54のアミノ酸配列を含むHVR−L1、
(e)配列番号55のアミノ酸配列を含むHVR−L2、及び
(f)配列番号56のアミノ酸配列を含むHVR−L3を含む、請求項26〜29のいずれか1項に記載の抗CD79b抗体。 - 前記CD3結合ドメインが、配列番号61のVH配列を含む、請求項26〜29、または36のいずれか1項に記載の抗CD79b抗体。
- 前記CD3結合ドメインが、配列番号62のVL配列を含む、請求項26〜29、36、または37のいずれか1項に記載の抗CD79b抗体。
- 前記多重特異性抗体が、二重特異性抗体である、請求項25〜38のいずれか1項に記載の抗CD79b抗体。
- 前記抗CD79b抗体が、100ng/mL未満のB細胞死滅EC50を有する、請求項25〜39のいずれか1項に記載の抗CD79b抗体。
- 前記B細胞死滅が、内因性B細胞死滅または細胞株B細胞死滅である、請求項40に記載の抗CD79b抗体。
- 前記抗CD79b抗体が、50ng/mL未満のうちのいずれかである、細胞傷害性T細胞活性化EC50を有する、請求項25〜41のいずれか1項に記載の抗CD79b抗体。
- (a)前記CD3結合ドメインがFcドメインを含み、前記FcドメインがEU番号付けによるT366S、L368A、Y407V、及びN297G置換突然変異を含み、(b)前記CD79b結合ドメインがFcドメインを含み、前記FcドメインがEU番号付けによるT366W及びN297G置換突然変異を含む、請求項26〜42のいずれか1項に記載の抗CD79b抗体。
- 請求項1〜43のいずれか1項に記載の抗CD79b抗体をコードする、単離された核酸。
- 請求項44に記載の単離された核酸を含む、ベクター。
- 請求項45に記載のベクターを含む、宿主細胞。
- 請求項1〜43のいずれか1項に記載の抗CD79b抗体の産生方法であって、前記方法が、請求項46に記載の前記宿主細胞を培養培地中で培養することを含む、前記方法。
- 請求項1〜43のいずれか1項に記載の抗CD79b抗体及び細胞傷害性薬剤を含む、免疫複合体。
- 請求項1〜43のいずれか1項に記載の抗CD79b抗体を含む、薬学的組成物。
- 薬剤として使用するための、請求項1〜43のいずれか1項に記載の抗CD79b抗体。
- B細胞増殖性障害または自己免疫性障害の進行の治療または遅延を必要とする対象において、それに使用するための請求項1〜43のいずれか1項に記載の抗CD79b抗体。
- B細胞増殖性障害または自己免疫性障害を有する対象において、免疫機能の増強に使用するための請求項1〜43のいずれか1項に記載の抗CD79b抗体。
- 前記B細胞増殖性障害が癌である、請求項51または52に記載の抗CD79b抗体。
- 前記B細胞増殖性障害が、リンパ腫、非ホジキンリンパ腫(NHL)、侵襲性NHL、再発性侵襲性NHL、再発性低悪性度NHL、難治性NHL、難治性低悪性度NHL、慢性リンパ性白血病(CLL)、小リンパ球性リンパ腫、白血病、ヘアリー細胞白血病(HCL)、急性リンパ性白血病(ALL)、及び/またはマントル細胞リンパ腫である、請求項51〜53のいずれか1項に記載の抗CD79b抗体。
- 細胞増殖性障害または自己免疫性障害の進行を治療する、または遅延させるための薬剤の製造における、請求項1〜43のいずれか1項に記載の抗CD79b抗体の使用。
- 細胞増殖性障害または自己免疫性障害を有する対象において免疫機能を増強するための薬剤の製造における、請求項1〜43のいずれか1項に記載の抗CD79b抗体の使用。
- 前記細胞増殖性障害が癌である、請求項55または56に記載の使用。
- 前記B細胞増殖性障害が、リンパ腫、NHL、侵襲性NHL、再発性侵襲性NHL、再発性低悪性度NHL、難治性NHL、難治性低悪性度NHL、CLL、小リンパ球性リンパ腫、白血病、HCL、ALL、及び/またはマントル細胞リンパ腫である、請求項55〜57のいずれか1項に記載の使用。
- 細胞増殖性障害または自己免疫性障害の進行を治療または遅延することを必要とする対象における、細胞増殖性障害または自己免疫性障害の進行を治療または遅延するための医薬であって、請求項1〜43のいずれか1項に記載の抗CD79b抗体を含む医薬。
- 細胞増殖性障害または自己免疫性障害を有する対象における免疫機能を増強するための医薬であって、有効量の請求項1〜43のいずれか1項に記載の抗CD79b抗体を含む医薬。
- 前記細胞増殖性障害が癌である、請求項59または60に記載の医薬。
- 前記B細胞増殖性障害が、リンパ腫、NHL、侵襲性NHL、再発性侵襲性NHL、再発性低悪性度NHL、難治性NHL、難治性低悪性度NHL、CLL、小リンパ球性リンパ腫、白血病、HCL、ALL、及び/またはマントル細胞リンパ腫である、請求項59〜61のいずれか1項に記載の医薬。
- PD−1軸結合アンタゴニストまたは追加の治療剤がさらに投与される、請求項59〜62のいずれか1項に記載の医薬。
- グルココルチコイドがさらに投与される、請求項59〜63のいずれか1項に記載の医薬。
- 前記グルココルチコイドがデキサメタゾンである、請求項64に記載の医薬。
- リツキシマブがさらに投与される、請求項59〜65のいずれか1項に記載の医薬。
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