JP2015529656A - 抗etbr抗体および免疫複合体 - Google Patents
抗etbr抗体および免疫複合体 Download PDFInfo
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- JP2015529656A JP2015529656A JP2015525601A JP2015525601A JP2015529656A JP 2015529656 A JP2015529656 A JP 2015529656A JP 2015525601 A JP2015525601 A JP 2015525601A JP 2015525601 A JP2015525601 A JP 2015525601A JP 2015529656 A JP2015529656 A JP 2015529656A
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Abstract
Description
から選択される式を有し、Abは、(i)配列番号12のアミノ酸配列を含むHVR−H1、(ii)配列番号13のアミノ酸配列を含むHVR−H2、(iii)配列番号14のアミノ酸配列を含むHVR−H3、(iv)配列番号15のアミノ酸配列を含むHVR−L1、(v)配列番号16のアミノ酸配列を含むHVR−L2、および(vi)配列番号17のアミノ酸配列を含むHVR−L3を含む、抗体であり、pは、1〜8、または1〜7、または1〜6、または1〜5、または1〜4、または1〜3の範囲である。いくつかのかかる実施形態において、本抗体は、配列番号8のVH配列および配列番号7のVL配列を含む。いくつかの実施形態において、本抗体は、配列番号6の重鎖および配列番号5の軽鎖を含む。
を有するPBD二量体を含み、式中、波線は、リンカーへの結合を示す。いくつかの実施形態において、第2の免疫複合体は、MC−val−cit−PABを含むリンカーを含む。前述の実施形態のうちのいずれかにおいて、ETBR陽性がんは、黒色腫であり得る。いくつかの実施形態において、ETBR陽性がんはまた、PMEL17陽性でもある。
本明細書における目的のために、「アクセプターヒトフレームワーク」は、下に定義される、ヒト免役グロブリンフレームワークまたはヒトコンセンサスフレームワークに由来する、軽鎖可変ドメイン(VL)フレームワークまたは重鎖可変ドメイン(VH)フレームワークのアミノ酸配列を含むフレームワークである。ヒト免役グロブリンフレームワークまたはヒトコンセンサスフレームワーク「に由来する」アクセプターヒトフレームワークは、その同じアミノ酸配列を含んでもよく、またはそれは、アミノ酸配列変化を含有し得る。いくつかの実施形態において、アミノ酸変化の数は、10以下、9以下、8以下、7以下、6以下、5以下、4以下、3以下、または2以下である。いくつかの実施形態において、VLアクセプターヒトフレームワークは、配列において、VLヒト免役グロブリンフレームワーク配列またはヒトコンセンサスフレームワーク配列と同一である。
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および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よう。特に別途定めのない限り、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。
に示されるオルト、メタ、またはパラ配置にあり得、そのフェニル基は、置換されていないか、または−C1〜C8アルキル、−O−(C1〜C8アルキル)、−アリール、−C(O)R’、−OC(O)R’、−C(O)OR’、−C(O)NH2、−C(O)NHR’、−C(O)N(R’)2−NHC(O)R’、−S(O)2R’、−S(O)R’、−OH、−ハロゲン、−N3、−NH2、−NH(R’)、−N(R’)2、および−CNを含むが、これらに限定されない最大4個の基で置換されている可能性があり、式中、各R’は独立して、H、−C1〜C8アルキル、およびアリールから選択される。
一態様において、本発明は、部分的に、ETBRに結合する抗体およびかかる抗体を含む免疫複合体に基づく。本発明の抗体および免疫複合体は、例えば、ETBR陽性がんの診断または治療に有用である。
いくつかの実施形態において、ETBRに結合する単離抗体が提供される。ETBRは、メラニン細胞内で発現されるGタンパク質共役受容体である。
抗ETBR抗体が「配列番号10のアミノ酸64〜101内のエピトープに結合する」かどうかを決定するために、N末端およびC末端欠失を伴うETBRポリペプチドを、哺乳類細胞(CHO細胞または293細胞等)内で発現させ、切頭型ポリペプチドへの抗体の結合をFACSによって試験する。細胞内で発現される完全長ETBRへの結合と比べた、切頭型ポリペプチドへの抗体の結合の実質的な低減(70%以上の低減)または排除は、抗体がその切頭型ポリペプチドに結合しないことを示す。代替的に、いくつかの実施形態において、抗ETBR抗体が「配列番号10のアミノ酸64〜101内のエピトープに結合する」かどうかは、ELISAアッセイを使用して決定される。細胞外ドメイン等の、ETBRのより長い部分への結合と比べた、切頭型ポリペプチドへの抗体の結合の実質的な低減(70%以上の低減)または排除は、抗体がその切頭型ポリペプチドに結合しないことを示す。
いくつかの実施形態において、本発明は、(a)配列番号12のアミノ酸配列を含むHVR−H1、(b)配列番号13のアミノ酸配列を含むHVR−H2、(c)配列番号14のアミノ酸配列を含むHVR−H3、(d)配列番号15のアミノ酸配列を含むHVR−L1、(e)配列番号16のアミノ酸配列を含むHVR−L2、および(f)配列番号17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、抗ETBR抗体または免疫複合体を提供する。
ある特定の実施形態において、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以下の、および任意に、10−13M以上である、解離定数(Kd)を有する。(例えば、10−8M以下、例えば、10−8M〜10−13M、例えば、10−9M〜10−13M)。
ある特定の実施形態において、本明細書に提供される抗体は、抗体断片である。抗体断片には、Fab、Fab’、Fab’−SH、F(ab’)2、Fv、およびscFv断片、ならびに下に記載される他の断片が含まれるが、これらに限定されない。ある特定の抗体断片の概説については、Hudson et al.Nat.Med.9:129−134(2003)に記載される。scFv断片の概説については、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、国際公開第93/16185号、ならびに米国特許第5,571,894号および同第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、増加した体内半減期を有する、FabおよびF(ab’)2断片の考察については、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において、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は、例えば、米国特許第4,816,567号、およびMorrison et al.,Proc.Natl.Acad.Sci.USA,81:6851−6855(1984))に記載される。一例において、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類に由来する可変領域)およびヒト定常領域を含む。さらなる実施例において、キメラ抗体は、クラスまたはサブクラスが親抗体のそれから変更された、「クラススイッチされた」抗体である。キメラ抗体には、それらの抗原結合断片が含まれる。
ある特定の実施形態において、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、一般に、van Dijk and van de Winkel,Curr.Opin.Pharmacol.5:368−74(2001)およびLonberg,Curr.Opin.Immunol.20:450−459(2008)に記載される。
本発明の抗体は、コンビナトリアルライブラリを、所望の活性(単数または複数)を有する抗体についてスクリーニングすることによって、単離されてもよい。例えば、ファージディスプレイライブラリを生成し、かかるライブラリを、所望の結合特性を保有する抗体について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知られている。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、またさらに、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)、およびLee et al.,J.Immunol.Methods 284(1−2):119−132(2004)に記載される。
ある特定の実施形態において、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において、結合特異性のうちの一方は、ETBR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において、二重特異性抗体は、ETBRの2つの異なるエピトープに結合し得る。二重特異性抗体をまた使用して、細胞傷害性薬剤を、ETBRを発現する細胞に限局させてもよい。二重特異性抗体は、完全長抗体または抗体断片として調製することができる。
ある特定の実施形態において、本明細書に提供される抗体のアミノ酸配列変異形が企図される。例えば、抗体の結合親和性および/または他の生物学的特性を改善することが望ましいことがある。抗体のアミノ酸配列変異形は、適切な修飾を、抗体をコードするヌクレオチド配列中に導入することによって、またはペプチド合成によって、調製されてもよい。かかる修飾には、例えば、抗体のアミノ酸配列からの残基の欠失、および/またはそこへ残基の挿入、および/またはその内の残基の置換が含まれる。欠失、挿入、および置換の任意の組み合わせを作製して、最終構築物に到達することができるが、但し、その最終構築物が、所望の特性、例えば、抗原結合性を保有することを条件とする。
ある特定の実施形態において、1つ以上のアミノ酸置換を有する抗体変異形が提供される。置換型突然変異生成に対する目的の部位には、HVRおよびFRが含まれる。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、「例となる置換」の見出しの下に提供され、またアミノ酸側鎖クラスを参照して下にさらに記載される。アミノ酸置換が目的の抗体中に導入され、産物が、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もしくはCDCについて、スクリーニングされてもよい。
(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において、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変化させられる。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り出されるか、または除去されるように、アミノ酸配列を変化させることによって、好都合に遂行されてもよい。
ある特定の実施形態において、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領域変異形を生成してもよい。Fc領域変異形は、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)を含んでもよい。
ある特定の実施形態において、抗体の1個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Mab」を作り出すことが望ましい場合がある。特に実施形態において、置換残基は、抗体の利用しやすい部位において生じる。そ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はそれによって、抗体の利用しやすい部位に位置付けられ、それを使用して、抗体を、薬物部分またはリンカー−薬物部分等の他の部分に複合して、本明細書にさらに記載される、免疫複合体を作り出してもよい。ある特定の実施形態において、次の残基のうちの任意の1個以上が、システインで置換されてもよい:軽鎖のV205(Kabat付番)、重鎖のA118(EU付番)、および重鎖Fc領域のS400(EU付番)。非限定的な例となるシステイン操作された抗ETBR抗体の重鎖および軽鎖は、配列番号18、19、および20に示される。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てもよい。
ある特定の実施形態において、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、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)、およ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起因して、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、分岐していても非分岐であってもよい。抗体に結合したポリマーの数は、様々であってもよく、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。一般に、誘導体化に使用されるポリマーの数および/または種類は、改善対象の抗体の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、決定することができる。
抗体は、例えば、米国特許第4,816,567号に記載される、組み換え法および組成物を使用して産生されてもよい。一実施形態において、本明細書に記載される抗ETBR抗体をコードする単離核酸が提供される。かかる核酸は、抗体のVLを含むアミノ酸配列および/またはVHを含むアミノ酸配列(例えば、抗体の軽鎖および/または重鎖)をコードし得る。さらなる実施形態において、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。さらなる実施形態において、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において、宿主細胞は、(1)抗体のVLを含むアミノ酸配列および抗体の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、および抗体の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)。一実施形態において、宿主細胞は、真核性、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。一実施形態において、抗ETBR抗体を作製する方法が提供され、本方法は、上に提供される抗体をコードする核酸を含む宿主細胞を、抗体の発現に好適な条件下で培養することと、任意に、抗体を宿主細胞(または宿主細胞培養培地)から回収することとを含む。
本明細書に提供される抗ETBR抗体は、それらの物理/化学特性および/または生物活性について、当該技術分野で既知の種々のアッセイによって、特定され、スクリーニングされ、または特徴付けられてもよい。
本発明はまた、本明細書において、化学療法剤もしくは化学療法薬、成長阻害性薬剤、毒素(例えば、タンパク質毒素、細菌、真菌、植物、もしくは動物起源の酵素活性毒素、またはそれらの断片)、または放射性同位体(すなわち、放射性物質複合体(radioconjugate))等の、1つ以上の細胞傷害性薬剤に複合される抗ETBR抗体を含む、免疫複合体も提供する。
抗体−薬物複合体(ADC)化合物の例となる実施形態は、腫瘍細胞を標的とする抗体(Ab)、薬物部分(D)、およびAbをDに結合するリンカー部分(L)を含む。いくつかの実施形態において、本抗体は、リジンおよび/またはシステイン等の1個以上のアミノ酸残基を通じて、リンカー部分(L)に結合される。
Ab−(L−D)pI
を有し、式中、pは、1〜約20である。いくつかの実施形態において、抗体に複合され得る薬物部分の数は、遊離システイン残基の数によって限定される。いくつかの実施形態において、遊離システイン残基は、本明細書に記載される方法によって抗体アミノ酸配列中に導入される。式Iの例となるADCには、1、2、3、または4個の操作されたシステインアミノ酸を有する抗体が含まれるが、これらに限定されない(Lyon,R.et al(2012)Methods in Enzym.502:123−138)。いくつかの実施形態において、1個以上の遊離システイン残基が、操作を使用することなく、抗体においてすでに存在しており、その場合、既存の遊離システイン残基を使用して、抗体を薬物に複合してもよい。いくつかの実施形態において、本抗体は、1個以上の遊離システイン残基を生成するために、抗体の複合前に還元条件に曝露される。
「リンカー」(L)は、1個以上の薬物部分(D)を抗体(Ab)に連結して、式Iの抗体−薬物複合体(ADC)を形成するために使用することができる、二機能性または多機能性部分である。いくつかの実施形態において、抗体−薬物複合体(ADC)は、薬物におよび抗体に共有結合するための反応性官能基を有するリンカーを使用して、調製することができる。例えば、いくつかの実施形態において、抗体の(Ab)システインチオールは、リンカーの反応性官能基または薬物−リンカー中間体との結合を形成して、ADCを作製することができる。
を有し、式中、Aは、「ストレッチャー(stretcher)単位」であり、aは、0〜1の整数であり、Wは、「アミノ酸単位」であり、wは、0〜12の整数であり、Yは、「スペーサ単位」であり、yは、0、1、または2である。式IIのリンカーを含むADCは、式I(A)、すなわちAb−(Aa−Ww−Yy−D)pを有し、式中、Ab、D、およびpは、式Iについて上にあるように定義される。かかるリンカーの例となる実施形態は、米国特許第7,498,298号に記載され、それは参照により本明細書に明示的に組み込まれる。
を有し、式中、Qは、−C1〜C8アルキル、−O−(C1〜C8アルキル)、−ハロゲン、−ニトロ、または−シアノであり、mは、0〜4範囲の整数であり、Xは、1つ以上の追加のスペーサ単位であり得るか、または不在であり得、pは、1〜約20の範囲である。いくつかの実施形態において、pは、1〜10、1〜7、1〜5、または1〜4の範囲である。非限定的な例となるXスペーサ単位には、
式中、R1およびR2は独立して、HおよびC1〜C6アルキルから選択される。いくつかの実施形態において、R1およびR2は各々、−CH3である。
(式中、R1およびR2は独立して、HおよびC1〜C6アルキルから選択される。いくつかの実施形態において、R1およびR2は各々、−CH3である。
(式中、nは、0〜12である)。いくつかの実施形態において、nは、2〜10である。いくつかの実施形態において、nは、4〜8である。
いくつかの実施形態において、ADCは、アントラサイクリンを含む。アントラサイクリンは、細胞傷害性活性を示す抗生物質化合物である。いかなる特定の理論にも拘束されることを意図するものではないが、研究は、アントラサイクリンが、1)細胞のDNA中への薬物分子のインターカレーションによって、DNA依存性核酸合成を阻害すること、2)薬物により遊離ラジカルが産生され、それが次いで細胞巨大分子と反応して、細胞への損傷を引き起こすこと、および/または3)薬物分子の細胞膜との相互作用を含む、いくつかの異なる機構によって、細胞を死滅させるように作動し得ることを示してきた(例えば、C.Peterson et al.,“Transport And Storage Of Anthracycline In Experimental Systems And Human Leukemia” in Anthracycline Antibiotics In Cancer Therapy;N.R.Bachur,“Free Radical Damage” id.at pp.97−102を参照されたい)。それらの細胞傷害性の可能性のために、アントラサイクリンは、白血病、乳がん、肺がん腫、卵巣腺がん、および肉腫等の多数のがんの治療において使用されてきた(例えば、P.H− Wiernik,in Anthracycline:Current Status And New Developments p 11を参照されたい)。
に示され、式中、R1は、水素原子、ヒドロキシ、またはメトキシ基であり、R2は、C1−C5アルコキシ基であるか、またはその薬学的に許容される塩であり、
L1およびZは共に、本明細書に記載されるリンカー(L)であり、
Tは、本明細書に記載される抗体(Ab)であり、
mは、1〜約20である。いくつかの実施形態において、mは、1〜10、1〜7、1〜5、または1〜4である。
に示され、式中、R1は、水素原子、ヒドロキシ、またはメトキシ基であり、R2は、C1−C5アルコキシ基であるか、またはその薬学的に許容される塩であり、
L2およびZは共に、本明細書に記載されるリンカー(L)であり、
Tは、本明細書に記載される抗体(Ab)であり、
mは、1〜約20である。いくつかの実施形態において、mは、1〜10、1〜7、1〜5、または1〜4である。
(式中、波線は、リンカー(L)への結合を示す)。
薬物負荷は、式Iの分子における1抗体当たりの薬物部分の平均数である、pによって表される。薬物負荷は、1抗体当たり1〜20個の薬物部分(D)の範囲であり得る。式IのADCは、1〜20個の範囲の薬物部分と共に複合された抗体の集団を含む。複合反応からのADCの調製における、1抗体当たりの薬物部分の平均数は、質量分析法、ELISAアッセイ、およびHPLC等の従来の手段によって特徴付けられてもよい。pの単位でのADCの定量分布がまた決定されてもよい。いくつかの事例において、pがある特定の値である同種のADCの、他の薬物負荷を有するADCからの分離、精製、および特性評価は、逆相HPLCまたは電気泳動等の手段によって達成されてもよい。
式IのADCは、(1)抗体の求核基を二価リンカー試薬と反応させて、共有結合を介してAb−Lを形成し、続いて薬物部分Dと反応させることと、(2)薬物部分の求核基を二価リンカー試薬と反応させて、共有結合を介してD−Lを形成し、続いて抗体の求核基と反応させることとを含む、いくつかの経路によって、当業者に既知の有機化学反応、条件、および試薬を用いて調製されてもよい。後者の経路を介して式IのADCを調製するための例となる方法は、米国公開特許第7498298号に記載され、それは参照により本明細書に明示的に組み込まれる。
ある特定の実施形態において、本明細書に提供される抗ETBR抗体のいずれも、生体試料中のETBRの存在を検出するために有用である。本明細書で使用される「検出すること」という用語は、定量または定性検出を包含する。「生体試料」は、例えば、細胞または組織(例えば、黒色腫を有するかまたはそれを有することが疑われる対象からの組織を含む、癌性のまたは癌性の可能性がある皮膚組織を含む、生検材料)を含む。
本明細書に記載されるETBR抗体または免疫複合体の医薬製剤抗は、所望の程度の純度を有するかかる抗体または免疫複合体を、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、用いられる投薬量および濃度で、受容者に対して非毒性であり、リン酸塩、クエン酸塩、および他の有機酸等の緩衝液;アスコルビン酸およびメチオニンを含む酸化防止剤;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等;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、もしくはベンジルアルコール;メチルも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;およびm−クレゾール等);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、もしくは免役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、もしくはリジン等のアミノ酸;単糖類、二糖類、およびグルコース、マンノース、もしくはデキストリンを含む他の炭水化物;EDTA等のキレート薬剤;ショ糖、マンニトール、トレハロース、も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が含まれるが、これらに限定されない。本明細書における例となる薬学的に許容される担体には、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(insterstitial)薬物分散剤がさらに含まれる。rHuPH20を含む、ある特定の例となるsHASEGPおよび使用方法は、米国特許公開第2005/0260186号および同第2006/0104968号に記載される。一態様において、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ETBR抗体または免疫複合体のいずれも、方法、例えば、治療方法において使用され得る。
を有するPBD二量体が含まれ、式中、波線は、リンカー(L)への結合を示す。例えば、国際公開第2009/016516号、米国公開特許第2009/304710号、米国公開特許第2010/047257号、米国公開特許第2009/036431号、米国公開特許第2011/0256157号、および国際公開第2011/130598号を参照されたい。PBD含有免疫複合体のリンカー部分は、いくつかの実施形態において、本明細書に記載されるリンカーであってもよい。いくつかの実施形態において、リンカーは、例えば、次の構造におけるような、MC−val−cit−PABを含む:
本発明の別の態様において、上述の障害の治療、予防、および/または診断に有用な物質を含有する製品が提供される。製品は、容器、およ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、組成物を、それ自体で、または障害を治療する、予防する、および/もしくは診断するのに有効な別の組成物と組み合わせて保有し、また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貫通可能な栓を有するバイアルであり得る)。組成物中の少なくとも1つの活性な薬剤は、本発明の抗体または免疫複合体である。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表示する。さらに、製品は、(a)組成物がその中に含有された第1の容器(この組成物は本発明の抗体または免疫複合体を含む)、および(b)組成物がその中に含有された第2の容器(この組成物はさらなる細胞傷害性薬剤または治療剤を含む)を含んでもよい。本発明のこの実施形態の製品は、組成物が特定の病態を治療するために使用され得ることを表示する、添付文書をさらに含んでもよい。代替的に、または追加的に、製品は、注射用静菌水(BWFI)、リン酸緩衝食塩水、リンゲル液または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の(または第3の)容器をさらに含んでもよい。それは、他の緩衝液、希釈剤、フィルター、針、およびシリンジを含む、商業的およ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、本発明の方法および組成物の実施例である。上に提供される一般的説明を考慮すると、種々の他の実施形態が実施され得ることが理解される。
抗ETBR抗体−薬物複合体(ADC)を、hu5E9.v1(配列番号5および6)またはch5E9(配列番号27および28)を、本明細書に描写される薬物−リンカー部分MC−vc−PAB−MMAEに複合することによって産生した。便宜上、薬物−リンカー部分MC−vc−PAB−MMAEはときに、これらの実施例においておよび図において、「vcMMAE」または「VCE」と称される。
抗ETBR−vc−MMAEに対して耐性を発達した黒色腫における、ネモルビシン誘導体を含む抗ETBR免疫複合体の有効性を決定するために、抗ETBR−vc−MMAE(抗EDNRB−vc−MMAE、抗ETBR−MC−val−cit−PAB−MMAE等とも称される;例えば、米国公開第US 2011/0206702号を参照されたい)に対して耐性であるUACC−257X2.2黒色腫細胞を体内および体外で発達させた。
Claims (56)
- 細胞傷害性薬剤に共有結合されたETBRに結合する抗体を含む、免疫複合体であって、前記抗体は、配列番号10のアミノ酸64〜101内のエピトープに結合し、前記細胞傷害性薬剤は、ネモルビシン誘導体である、免疫複合体。
- 前記抗体は、(i)配列番号14のアミノ酸配列を含むHVR−H3、(ii)配列番号17のアミノ酸配列を含むHVR−L3、および(iii)配列番号13のアミノ酸配列を含むHVR−H2を含む、請求項1に記載の免疫複合体。
- 前記抗体は、(i)配列番号12のアミノ酸配列を含むHVR−H1、(ii)配列番号13のアミノ酸配列を含むHVR−H2、および(iii)配列番号14のアミノ酸配列を含むHVR−H3を含む、請求項1または請求項2に記載の免疫複合体。
- 前記抗体は、(i)配列番号12のアミノ酸配列を含むHVR−H1、(ii)配列番号13のアミノ酸配列を含むHVR−H2、(iii)配列番号14のアミノ酸配列を含むHVR−H3、(iv)配列番号15のアミノ酸配列を含むHVR−L1、(v)配列番号16のアミノ酸配列を含むHVR−L2、および(vi)配列番号17のアミノ酸配列を含むHVR−L3を含む、請求項1に記載の免疫複合体。
- 前記抗体は、(i)配列番号15のアミノ酸配列を含むHVR−L1、(ii)配列番号16のアミノ酸配列を含むHVR−L2、および(iii)配列番号17のアミノ酸配列を含むHVR−L3を含む、請求項1〜3のいずれか1項に記載の免疫複合体。
- 前記抗体は、
a)配列番号8のアミノ酸配列に対して少なくとも95%の配列同一性を有するVH配列、または
b)配列番号7のアミノ酸配列に対して少なくとも95%の配列同一性を有するVL配列、または
c)(a)に記載のVH配列および(b)に記載のVL配列を含む、請求項1〜5のいずれか1項に記載の免疫複合体。 - 配列番号8または配列番号9のアミノ酸配列を有するVH配列を含む、請求項6に記載の免疫複合体。
- 配列番号7のアミノ酸配列を有するVL配列を含む、請求項6に記載の免疫複合体。
- 細胞傷害性薬剤に共有結合されたETBRに結合する抗体を含む、免疫複合体であって、前記抗体は、(a)配列番号8のアミノ酸配列を有するVH配列および配列番号7のアミノ酸配列を有するVL配列を含み、前記細胞傷害性薬剤は、ネモルビシン誘導体である、免疫複合体。
- 前記抗体は、IgG1、IgG2a、またはIgG2b抗体である、請求項1〜9のいずれか1項に記載の免疫複合体。
- 前記免疫複合体は、式Ab−(L−D)pを有し、式中、
(a)Abは、前記抗体であり、
(b)Lは、リンカーであり、
(c)Dは、前記細胞傷害性薬剤であり、
(d)pは、1〜8の範囲である、請求項1〜10のいずれか1項に記載の免疫複合体。 - Dは、ネモルビシン誘導体である、請求項11に記載の免疫複合体。
- 前記リンカーは、プロテアーゼによって切断可能である、請求項11〜13のいずれか1項に記載の免疫複合体。
- 前記リンカーは、val−citジペプチドまたはPhe−ホモLysジペプチドを含む、請求項14に記載の免疫複合体。
- 前記リンカーは、酸不安定性である、請求項11〜13のいずれか1項に記載の免疫複合体。
- 前記リンカーは、ヒドラゾンを含む、請求項16に記載の免疫複合体。
- pは、1〜3の範囲である、請求項11〜18のいずれか1項に記載の免疫複合体。
- 前記抗体は、配列番号8のVH配列および配列番号7のVL配列を含む、請求項20に記載の免疫複合体。
- 前記抗体は、配列番号6の重鎖および配列番号5の軽鎖を含む、請求項21に記載の免疫複合体。
- 前記抗体は、モノクローナル抗体である、請求項1〜22のいずれか1項に記載の免疫複合体。
- 前記抗体は、ヒト、ヒト化、またはキメラ抗体である、請求項1〜23のいずれか1項に記載の免疫複合体。
- 前記抗体は、ETBRに結合する抗体断片である、前請求項1〜24のいずれか1項に記載の免疫複合体。
- 前記抗体は、ヒトETBRに結合する、請求項1〜25のいずれか1項の請求項に記載の免疫複合体。
- ヒトETBRは、配列番号10または配列番号11の配列を有する、請求項26に記載の免疫複合体。
- 請求項1〜27のいずれか1項に記載の免疫複合体と、薬学的に許容される担体とを含む、医薬製剤。
- 追加の治療剤をさらに含む、請求項28に記載の医薬製剤。
- ETBR陽性がんを有する個体を治療する方法であって、前記方法は、前記個体に、有効量の、請求項1〜27のいずれか1項に記載の免疫複合体を投与することを含む、方法。
- 前記ETBR陽性がんは、黒色腫である、請求項30に記載の方法。
- 追加の治療剤を前記個体に投与することをさらに含む、請求項31に記載の方法。
- 前記追加の治療剤は、PMEL17に結合する抗体を含む、請求項32に記載の方法。
- 前記追加の治療剤は、細胞傷害性薬剤に共有結合されたPMEL17に結合する抗体を含む免疫複合体である、請求項33に記載の方法。
- ETBR陽性細胞の増殖を阻害する方法であって、前記方法は、前記細胞を、請求項1〜27のいずれか1項に記載の免疫複合体に、前記細胞の表面上のETBRへの前記免疫複合体の結合を許容する条件下で曝露し、それによって前記細胞の増殖を阻害することを含む、方法。
- 前記細胞は、黒色腫細胞である、請求項35に記載の方法。
- ETBR陽性がんを有する個体を治療する方法であって、前記ETBR陽性がんは、第1の治療薬に耐性であり、前記方法は、前記個体に、有効量の、請求項1〜27のいずれか1項に記載の免疫複合体を投与することを含む、方法。
- 前記ETBR陽性がんは、黒色腫である、請求項37に記載の方法。
- 前記第1の治療薬は、ETBR以外の抗原に結合する第1の抗体を含む、請求項37または請求項38に記載の方法。
- 前記第1の治療薬は、ETBR以外の抗原に結合する第1の抗体と、第1の細胞傷害性薬剤とを含む、第1の免疫複合体である、請求項39に記載の方法。
- 前記第1の抗体は、PMEL17、チロシナーゼ関連タンパク質1(TYRP1)、細胞傷害性Tリンパ球抗原4(CTLA−4)、および糖タンパク質NMB(GPNMB)から選択される抗原に結合する、請求項39または請求項40に記載の方法。
- 前記第1の抗体は、PMEL17に結合する、請求項41に記載の方法。
- 前記第1の治療薬は、ETBRに結合する第1の抗体を含む、請求項37または請求項38に記載の方法。
- 前記第1の治療薬は、ETBRに結合する第1の抗体と、第1の細胞傷害性薬剤とを含む、第1の免疫複合体である、請求項43に記載の方法。
- 前記第1の細胞傷害性薬剤と請求項1〜27のいずれか1項に記載の免疫複合体の前記細胞傷害性薬剤とは、異なる、請求項40〜44のいずれか1項に記載の方法。
- 前記第1の細胞傷害性薬剤は、MMAEである、請求項45に記載の方法。
- ETBR陽性がんを有する個体を治療する方法であって、前記個体に、有効量の、請求項1〜27のいずれか1項に記載の第1の免疫複合体を、PMEL17に結合する抗体を含む第2の免疫複合体と組み合わせて投与することを含む、方法。
- PMEL17に結合する前記抗体は、配列番号21の配列を含むHVR−H1、配列番号22の配列を含むHVR−H2、配列番号23の配列を含むHVR−H3、配列番号24の配列を含むHVR−L1、配列番号25の配列を含むHVR−L2、および配列番号26の配列を含むHVR−L3を含む、請求項47に記載の方法。
- 前記第2の免疫複合体は、オーリスタチン、ピロロベンゾジアゼピン、およびネモルビシン誘導体から選択される細胞傷害性薬剤を含む、請求項47または請求項48に記載の方法。
- 前記第2の免疫複合体は、オーリスタチンまたはピロロベンゾジアゼピンを含む、請求項47〜49のいずれか1項に記載の方法。
- 前記第2の免疫複合体は、MMAEを含む、請求項47〜50のいずれか1項に記載の方法。
- 前記第2の免疫複合体は、MC−val−cit−PAB−MMAEを含むリンカー−薬物部分を含む、請求項47〜51のいずれか1項に記載の方法。
- 前記第2の免疫複合体は、MC−val−cit−PABを含むリンカーを含む、請求項47〜50および52のいずれか1項に記載の方法。
- 前記ETBR陽性がんは、黒色腫である、請求項47〜54のいずれか1項に記載の方法。
- 前記ETBR陽性がんは、さらにPMEL17陽性である、請求項47〜55のいずれか1項に記載の方法。
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2013
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- 2013-08-01 WO PCT/US2013/053250 patent/WO2014022680A1/en active Application Filing
- 2013-08-01 CN CN201380040550.XA patent/CN104797270A/zh active Pending
- 2013-08-01 CA CA2879670A patent/CA2879670A1/en active Pending
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JP2015530911A (ja) * | 2012-08-27 | 2015-10-29 | ホン インターナショナル コーポレーション | 外部デバイスと連動するダーツゲーム装置 |
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AR093227A1 (es) | 2015-05-27 |
MX2015001407A (es) | 2015-05-08 |
RU2015106946A (ru) | 2016-09-27 |
EP2879711A4 (en) | 2016-03-16 |
US20150196660A1 (en) | 2015-07-16 |
US9463251B2 (en) | 2016-10-11 |
KR20150032886A (ko) | 2015-03-30 |
EP2879711A1 (en) | 2015-06-10 |
WO2014022680A1 (en) | 2014-02-06 |
CN104797270A (zh) | 2015-07-22 |
CA2879670A1 (en) | 2014-02-06 |
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