JP2019518068A - グリコシル化免疫チェックポイントタンパク質に特異的に結合する抗体を選択する方法 - Google Patents
グリコシル化免疫チェックポイントタンパク質に特異的に結合する抗体を選択する方法 Download PDFInfo
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Abstract
Description
本出願は、ASCIIフォーマットで電子提出され、参照により全体が本明細書に組み込まれる配列表を含む。2017年3月23日に作製された前記ASCIIのコピーは、名称が24258_105006PCT_SL.txtであり、大きさは31,652バイトである。
本明細書において使用される用語「1つの(a)」または「1つの(an)」は、1つまたは複数を意味しうる。
MRIFAVFIFM TYWHLLNAFT VTVPKDLYVV EYGSNMTIEC KFPVEKQLDL AALIVYWEME DKNIIQFVHG EEDLKVQHSS YRQRARLLKD QLSLGNAALQ ITDVKLQDAG VYRCMISYGG ADYKRITVKV NAPYNKINQR ILVVDPVTSE HELTCQAEGY PKAEVIWTSS DHQVLSGKTT TTNSKREEKL FNVTSTLRIN TTTNEIFYCT FRRLDPEENH TAELVIPELP LAHPPNERTH LVILGAILLC LGVALTFIFR LRKGRMMDVK KCGIQDTNSK KQSDTHLEET(配列番号1)。配列番号1において、アミノ末端のアミノ酸1〜18は、ヒトPD−L1タンパク質のシグナル配列を構成する。したがって、成熟ヒトPD−L1タンパク質は、配列番号1のアミノ酸19〜290からなる。
MQIPQAPWPV VWAVLQLGWR PGWFLDSPDR PWNPPTFSPA LLVVTEGDNA TFTCSFSNTS ESFVLNWYRM SPSNQTDKLA AFPEDRSQPG QDCRFRVTQL PNGRDFHMSV VRARRNDSGT YLCGAISLAP KAQIKESLRA ELRVTERRAE VPTAHPSPSP RPAGQFQTLV VGVVGGLLGS LVLLVWVLAV ICSRAARGTI GARRTGQPLK EDPSAVPVFS VDYGELDFQW REKTPEPPVP CVPEQTEYAT IVFPSGMGTS SPARRGSADG PRSAQPLRPE DGHCSWPL(配列番号2)。配列番号2において、グリコシル化アミノ酸残基を下線および太字で示す。同様に配列番号2において、アミノ末端アミノ酸1〜20位は、ヒトPD−1タンパク質のシグナル配列を構成する。したがって、成熟ヒトPD−1タンパク質は、配列番号2のアミノ酸21〜288位からなる。
抗体産生に関して、レシピエント動物に、グリコシル化ICPまたはペプチドなどの抗原を接種して、免疫応答を生成し、グリコシル化ICPまたはペプチド、例えばPD−L1に対して特異的な抗体を産生する。免疫応答を増強するために、しばしば、抗原を別の分子に結合またはコンジュゲートさせる。本明細書において使用されるように、コンジュゲートは、動物において免疫応答を誘発するために使用される、抗原に結合する任意のペプチド、ポリペプチド、タンパク質、または非タンパク質様物質である。抗原の接種に応答して動物において産生される抗体は、多様な個々の抗体産生Bリンパ球によって作製される多様な非同一の分子(ポリクローナル抗体)を含む。ポリクローナル抗体は、そのそれぞれが、同じ抗原上の異なるエピトープを認識しうる抗体種の混合集団である。動物におけるポリクローナル抗体産生に対する正確な条件を考慮すると、動物の血清中の抗体のほとんどは、動物が免疫されている抗原性化合物上の集合的エピトープを認識する。この特異性を親和性精製によってさらに増強して、目的の抗原またはエピトープを認識するそれらの抗体のみを選択する。
グリコシル化ICPに優先的かつ特異的に結合する抗体を同定および単離した後、それらを、例えば治療としてより適切にするためにさらに操作してもよい。非ヒトモノクローナル抗体の場合、抗体を「キメラ」または「ヒト化」にすべきである。モノクローナル抗体の軽鎖および重鎖定常ドメインを、外来抗体の可変領域をインタクトにしたままで、ヒト起源の類似のドメインで置き換える方法が開発されている。齧歯類とヒトアミノ酸配列の両方を有する抗体可変ドメインを組み換えにより構築することによって、モノクローナル抗体の可変ドメインをよりヒト形態に変換する方法も同様に開発されている。「ヒト化」モノクローナル抗体では、超可変CDRのみが非ヒト(例えば、マウス、ラット、ニワトリ、ラマ等)モノクローナル抗体に由来して、フレームワーク領域は、ヒト抗体アミノ酸配列に由来する。齧歯類の特徴である抗体中のアミノ酸配列を、ヒト抗体の対応する位置に見出されるアミノ酸配列に置き換えると、ヒトにおいて治療的に使用する際の外来タンパク質に対する有害な免疫反応の可能性を低減させる。ハイブリドーマまたは他の抗体産生細胞を同様に、ハイブリドーマによって産生される抗体の結合特異性を変更しうるまたは変更しない遺伝子変異または他の変化に供してもよい。
特定の実施形態において、非グリコシル化PD−L1と比較してグリコシル化ICPタンパク質、PD−L1(例えば、特異的N−グリカン構造を有するPD−L1タンパク質;PD−L1の特異的グリコペプチド)またはグリコシル化PD−L1ペプチドに特異的に結合し、グリコシル化PD−L1/PD−1相互作用(抗glyPD−L1抗体)の免疫抑制機能を阻害する抗体を単離および同定する方法が提供される。そのような抗glycPD−L1抗体は、疾患、特にがんの処置において有用である。抗glycPD−L1抗体は、IgG、IgM、IgA、IgD、およびIgE Igクラスの抗体、ならびに抗原結合活性を保持する抗体CDRドメインを含むポリペプチドでありうる。実例として、抗glycPD−L1抗体は、キメラ、親和性成熟、ヒト化、またはヒト抗体でありうる。好ましい実施形態において、抗glycPD−L1抗体は、モノクローナル抗体である。別の好ましい実施形態において、モノクローナル抗glycPD−L1抗体は、ヒト化またはヒト抗体である。公知の手段によって、および本明細書において記述されるように、そのような抗原またはエピトープが、天然起源から単離されるか、または天然の化合物の合成誘導体もしくは変種であるかによらず、グリコシル化PD−L1抗原、そのそれぞれのエピトープの1つもしくは複数、または前述のいずれか1つのコンジュゲートに対して特異的な、ポリクローナル抗体またはモノクローナル抗体、抗体断片、結合ドメイン、およびCDR(前述のいずれかの改変形態を含む)を作製してもよい。抗体は二重特異性またはバイパラトピックでありうる。
ある特定の態様において、記述される方法によって得た抗体またはその抗原結合断片(例えば、PD−L1などのグリコシル化ICPに特異的に結合する抗体)を、がんを処置するために処置方法に使用して投与してもよい。したがって、本明細書において、がんを処置するために、少なくとも1つの抗グリコシル化ICP抗体またはその結合断片、例えば抗glycPD−L1抗体の治療有効量を、必要とする対象に投与することによって、がんを処置する方法が提供される。本明細書において記載されるように、処置または治療的処置は、がん細胞の成長、増殖、遊走等を低減、防止、阻害、または遮断することを伴う。方法は、T細胞、特にキラーまたは細胞傷害性T細胞などの免疫エフェクター細胞の細胞表面上に発現する同起源のICリガンドと結合/相互作用することができるICP細胞表面タンパク質を発現する対象の腫瘍細胞について、処置を受けている対象、例えばヒト患者に利益をもたらす。これらの対象を、抗グリコシル化ICP抗体の少なくとも1つの有効量で処置することによって、腫瘍細胞上のグリコシル化ICPへの抗体の結合、ならびにICP発現腫瘍細胞と、同起源のIDPリガンドを発現するT細胞との相互作用の防止、遮断、または阻害が起こり、それによってT細胞活性の免疫抑制を防止または回避して、PD−L1などのICPを発現する腫瘍細胞を殺滅するようにT細胞を活性化することができる。したがって、記述の方法によって産生されて得られた抗グリコシル化ICP抗体を使用する方法は、本発明の方法の実践によって達成される抗がん結果の利益を必要とする、利益を受けることができる、または利益を受けることが望ましい対象にとって有利である。対象が、少なくとも1つの抗グリコシル化ICP抗体またはその結合断片、例えば抗glycPD−L1抗体またはその結合断片の治療有効量の投与を伴う方法の治療上の利益を求めることは、当技術分野に対して利点を提供する。加えて、本発明の方法は、他の処置および処置モダリティと比較して、副作用、有害な転帰、禁忌等をなくすもしくは回避する、またはそのような問題が起こるリスクまたは可能性を低減させるさらなる利点を提供する。
ある特定の実施形態において、組成物および方法は、グリコシル化ICPタンパク質、例えばPD−L1に特異的かつ優先的に結合する抗グリコシル化ICP抗体またはその結合部分、例えば抗glycPD−L1抗体の単独投与、または第2のもしくは追加の薬物もしくは治療との併用投与を伴う。そのような薬物または治療は、そのリガンドと相互作用するヒトグリコシル化ICPに関連する、例えばヒトPD−L1もしくはグリコシル化ヒトPD−L1とヒトPD−1との相互作用に関連する任意の疾患の処置に適用されうる。例えば、疾患はがんでありうる。特定のおよび例示的な実施形態において、グリコシル化PD−L1タンパク質またはその結合部分に結合する少なくとも1つの抗PD−L1抗体を含む組成物および方法は、がんまたは他の疾患の処置において、特にPD−1/PD−L1相互作用を防止、低減、遮断、または阻害して、それによって治療効果および処置を提供することによって、治療効果または保護効果を有する。
A/B/A B/A/B B/B/A A/A/B A/B/B B/A/A A/B/B/B B/A/B/B
B/B/B/A B/B/A/B A/A/B/B A/B/A/B A/B/B/A B/B/A/A
B/A/B/A B/A/A/B A/A/A/B B/A/A/A A/B/A/A A/A/B/A
方法のいくつかの実施形態において、抗glycICP抗体の投与と併用して、または投与と共に、免疫療法を使用してもよい。がんの処置の文脈において、免疫療法は一般的に、がん細胞を標的として破壊するために、免疫エフェクター細胞および分子の使用に依存する。リツキシマブ(RITUXAN(登録商標))は、そのような一例である。チェックポイント阻害剤、例えばイピリムマブは、別のそのような例である。免疫エフェクターは、例えば、腫瘍細胞の表面上のマーカー(細胞表面タンパク質または受容体)に対して特異的な抗体でありうる。抗体単独は、治療のエフェクターとしての役割を果たしてもよく、または細胞殺滅を実際に行うために他の細胞を動員してもよい。抗体はまた、薬物または毒素(化学療法剤、放射性核種、リシンA鎖、コレラ毒素、百日咳毒素など)にコンジュゲートしてもよく、単に標的化剤としての役割を果たしてもよい。あるいは、エフェクターは、腫瘍細胞標的と直接または間接的に相互作用する表面分子、例えばT細胞上のPD−1/腫瘍細胞上のPD−L1相互作用を有するリンパ球でありうる。様々なエフェクター細胞には、細胞傷害性T細胞およびNK細胞が挙げられる。
抗グリコシル化ICP抗体を含むタンパク質の精製技術は、当業者に周知である。これらの技術は、1つのレベルで細胞、組織、または臓器のホモジナイゼーション、ならびにポリペプチドおよび非ポリペプチド分画への簡易分画を伴う。目的のタンパク質またはポリペプチドを、特に示していなければ部分精製または十分な精製(または均一になるまで精製)を達成するためにクロマトグラフィーおよび電気泳動技術を使用してさらに精製してもよい。純粋なタンパク質またはペプチドの調製に特に適した分析方法は、イオン交換クロマトグラフィー、サイズ排除クロマトグラフィー、逆相クロマトグラフィー、ヒドロキシアパタイトクロマトグラフィー、ポリアクリルアミドゲル電気泳動、アフィニティークロマトグラフィー、イムノアフィニティークロマトグラフィー、および等電点電気泳動である。ペプチドの特に効率的な精製方法は、中圧液体クロマトグラフィー(FPLC)または高速液体クロマトグラフィー(HPLC)である。一般的に当技術分野で公知であるように、様々な精製ステップを実施する順序を変化させてもよく、および/またはある特定のステップを省略してもよく、それでもなお実質的に精製されたポリペプチドの適した調製方法が得られうる。
一実施形態において、記述の少なくとも1つの抗グリコシル化ICP抗体の使用を伴う方法が提供される。そのような方法は、がんまたは腫瘍を有する対象から得た腫瘍細胞またはがん細胞のバイオマーカー評価において有用でありうる。がんを有する対象が、ICPを有する腫瘍細胞またはがん細胞のバイオマーカーとしてグリコシル化ICP、特にそのような細胞の細胞表面上にグリコシル化PD−L1の検出可能なレベルを発現するがんまたは腫瘍を有するか否かを決定する方法が提供される。例えば、対象のがんまたは腫瘍細胞を試験して、細胞表面上にグリコシル化ICP、例えばPD−L1を発現すると決定されれば、対象を、記述の抗グリコシル化ICP抗体、例えば抗glycPD−L1抗体の単独、または例えば別の抗がん剤との併用によって処置すると、処置によって利益が得られる可能性が高くなる。そのような方法は、がんまたは腫瘍を有する対象から試料を得ること、当技術分野において公知で使用される、または上記の結合方法を使用して、対象のがんまたは腫瘍に由来する細胞上のグリコシル化ICP、例えばPD−L1の存在について試料を試験すること、ならびに対象のがんまたは腫瘍がグリコシル化ICP、例えばPD−L1タンパク質の細胞表面発現について陽性であることが見出されれば、対象に、抗グリコシル化ICP抗体、例えば抗glycPD−L1抗体の有効量を単独でまたは別の抗がん剤と併用して投与することを含む。処置前に対象が、グリコシル化ICP、例えばPD−L1を発現するがんまたは腫瘍を有すると診断されれば、投与された抗グリコシル化ICP抗体、例えば抗glycPD−L1抗体が、対象のグリコシル化ICP、例えばglycPD−L1発現がんまたは腫瘍細胞と、対象のICP発現T細胞、例えばPD−1発現T細胞との相互作用を遮断または阻害する可能性がより高く、それによってT細胞活性の免疫抑制を防止して、活性化T細胞殺滅により腫瘍細胞またはがん細胞の殺滅を促進することから、より有効な処置が得られ、対象にとって利益が得られる。一実施形態において、方法は、そのがんまたは腫瘍が、発現されたグリコシル化ICP、例えばPD−L1タンパク質の存在に対する試験に感受性がありうる対象を最初に選択することを伴いうる。
他の薬剤を、処置の治療有効性を改善するために、本実施形態のある特定の態様と共に使用してもよいと企図される。これらの追加の薬剤は、細胞表面受容体およびGAP接合部のアップレギュレーションに影響を及ぼす薬剤、細胞抑制および分化剤、細胞接着阻害剤、アポトーシス誘発剤に対する過増殖細胞の感受性を増加させる薬剤、または他の生物薬剤を含む。GAP接合部の数を増加させることによる細胞内シグナル伝達の増加は、隣接する過増殖細胞集団に対して抗過増殖作用を増加させうる。他の実施形態において、細胞抑制または分化剤は、処置の抗過増殖有効性を改善するために、本実施形態のある特定の態様と併用して使用されうる。細胞接着阻害剤は、本実施形態の有効性を改善すると企図される。細胞接着阻害剤の例は、接着斑キナーゼ(FAK)阻害剤およびロバスタチンである。さらに、処置の有効性を改善するために、アポトーシスに対する過増殖細胞の感受性を増加させる他の薬剤、例えば抗体c225を、本実施形態のある特定の態様において併用して使用することができると企図される。
本明細書において提供される抗グリコシル化ICP抗体はまた、他のタンパク質との融合タンパク質として発現させるか、または別の部分と化学的にコンジュゲートさせることができる。いくつかの実施形態において、抗体またはポリペプチドは、アイソタイプまたはサブクラスによって変化しうるFc部分を有し、キメラもしくはハイブリッドであってよく、および/または例えばエフェクター機能を改善するために、半減期もしくは組織アクセシビリティを制御するために、生物物理学的特徴、例えば安定性を強化するために、および産物の有効性を改善するために、改変することができ、これらはコスト低減に関連しうる。融合タンパク質の構築において有用な多くの改変、およびそれらを作製するための方法は、当技術分野で公知であり、例えば、Mueller, J.P. et al., 1997, Mol. Immun. 34(6):441-452;Swann, P.G., 2008, Curr. Opin. Immunol., 20:493-499;およびPresta, L.G., 2008, Curr. Opin. Immunol., 20:460-470に記述されている。いくつかの実施形態において、Fc領域は、抗体のネイティブIgG1、IgG2、またはIgG4 Fc領域である。いくつかの実施形態において、Fc領域はハイブリッド、例えばIgG2/IgG4 Fc定常領域を含むキメラである。Fc領域の改変には、Fcγ受容体および補体への結合を防止するために改変されるIgG4;1つまたは複数のFcγ受容体への結合を改善するために改変されるIgG1;エフェクター機能を最小限にするように改変されるIgG1(アミノ酸の変化);変更されたグリカンを有する/グリカンを有しない(典型的に、発現宿主を変化させることによって)IgG1;ならびにFcRnへのpH依存的結合が変更されたIgG1が挙げられるがこれらに限定されるわけではない。Fc領域は、全ヒンジ領域、または抗体の全ヒンジ領域より少ない部分を含みうる。
抗体−薬物コンジュゲート(ADC)は、強力な細胞傷害薬が、化学リンカー、またはカップリング剤を介して特異的標的抗原、特に腫瘍細胞またはがん細胞の表面上に発現するまたは過剰発現する標的抗原に対する抗体、典型的にモノクローナル抗体に共有結合により連結されている生物学的治療剤である。そのような「ロード」された抗体は、腫瘍細胞またはがん細胞に対して致死性の細胞傷害性の積み荷を送達するように設計される。ADCは、副作用を低減させ、全身毒性を最小限にしながら、新生物細胞にペイロード薬物を標的化する手段を提供する。ADCは、ADCの抗体成分とその標的抗原との特異的相互作用により、細胞表面発現標的抗原に結合する。標的抗原に結合後、ADCは、特に抗体が高い内在化活性を有する場合には細胞に内在化されうる。内在化機能を有する抗glycICP抗体の例は、本明細書において記述される実施形態の抗glycPD−L1抗体、例えばSTM108およびSTM073である。したがって、そのようなADCが細胞に内在化される場合、それらは細胞を殺滅するかまたは細胞内の分子を標的とするように直接作用し、それによってアポトーシスまたは細胞死が起こる。本明細書において記述される抗glycICP抗体、例えば抗glycPD−L1抗体(例えば、STM108およびSTM073)、特にモノクローナル、ヒト化、キメラ、またはヒト抗体を含むそのようなADCは、腫瘍およびがん細胞上のグリコシル化ICPへの抗体の特異的標的化を、細胞傷害薬または化合物のがん殺滅能と組み合わせ、それによって抗glycICP抗体による処置および治療のさらなる利点を提供する。ADCを調製および使用する技術は当技術分野で公知であり、本明細書において記述される抗glycPD−L1抗体に限定されないと意図される。(例えば、Valliere Douglass, J.F., et al., 2015, Mol. Pharm., 12(6):1774-1783;Leal, M. et al., 2014, Ann. N.Y. Acad. Sci., 1321:41-54;Panowski, S. et al., 2014, mAbs, 6(1):34-45;Beck, A. 2014, mAbs, 6(1):30-33;Behrens, C.R. et al., 2014, mAbs, 6(1):46-53;およびFlygare, J.A. et al., 2013, Chem. Biol. Drug Des., 81(1):113-121を参照されたい)。実施形態において、上記の部分のいくつかまたは全て、特に毒素および細胞毒素を、抗glycPD−L1抗体にコンジュゲートさせて、がんを処置するために有効なADCを産生してもよい。実施形態において、ACDの抗glycICP抗体成分は、二重特異性、多重特異性、二重パラトープ性または多重パラトープ性抗体でありうる。
材料および方法
細胞培養、安定なトランスフェクタント、およびトランスフェクション。細胞は全て、American Type Culture Collection(ATCC)から得た。これらの細胞は、10%ウシ胎仔血清(FBS)を補充したDMEM/F12またはRPMI 1640培地で成長させた。MDA−MB−468、BT549、および293T細胞におけるPD−L1安定トランスフェクタントを、ピューロマイシン(InvivoGen,San Diego,CA,USA)を使用して選択した。一過性のトランスフェクションに関して、細胞に、SNリポソーム(Hu, M. C. et al., 2004, Cell, 117:225-237)およびlipofectamine(商標)2000(Life Technologies,Carlsbad,CA,USA)を使用して、DNA、例えばPD−L1をコードするDNAを一過性にトランスフェクトした。
グリコシル化PD−L1結合抗体の産生およびスクリーニング
この代表的な実施例は、グリコシル化ICP、すなわちグリコシル化PD−L1に特異的に結合するモノクローナル抗体を得る説明を提供する。しかし、本明細書において記述される方法は、グリコシル化ICPとその相互作用リガンドとの会合を防止することによって、免疫抑制を阻害するために、他のグリコシル化免疫チェックポイント分子に特異的に結合する抗体を生成することに応用可能である。
特異的グリコシル化PD−L1結合抗体の結合領域の同定
グリコシル化PD−L1に結合するモノクローナル抗glycPD−L1抗体の領域を同定するために、野生型(グリコシル化)PD−L1(PD−L1 WT)およびグリコシル化変種タンパク質N35/3NQ、N192/3NQ、N200/3NQ、およびN219/3NQ(図4A〜4C)を、PD−L1ノックダウンBT549細胞において過剰発現させた。図4Cにおけるウェスタンブロットによって決定した場合に、いくつかのMAbは、他のPD−L1変異体と比較して高い結合レベルで特定のPD−L1変異体を認識し、そのようなMAbが認識されるグリコシル化に対して部位特異的であることを証明した。さらに、肝臓がん細胞溶解物を使用するウェスタンブロット分析はまた、異なる抗glycPD−L1抗体が、異なるパターンのPD−L1グリコシル化を認識することも明らかにした(図4D)。
抗glycPD−L1抗体を使用する免疫組織化学染色
これらのMAbの組織病理学的重要性を、図5に示すように免疫組織化学(IHC)染色によってさらに証明した。サイトスピン染色分析において、抗glycPD−L1モノクローナル抗体は、一貫してPD−L1タンパク質のグリコシル化タンパク質を認識して結合したが、非グリコシル化PD−L1タンパク質には結合しなかった。ヒトトリプルネガティブ乳がん患者の試料において、抗glycPD−L1モノクローナル抗体はまた、膜および細胞質染色を1:30の比率で示した。これらのデータは、抗glycPD−L1モノクローナル抗体が、バイオマーカー分析において、バイオマーカーとしてグリコシル化PD−L1の検出のために使用することができることを証明した。
結合アッセイ
本明細書において記述される抗glycPD−L1モノクローナル抗体がPD−1とPD−L1との相互作用を特異的に阻害するか否かを決定するために、以下の結合アッセイを実施した。アッセイの0日目に、血清含有培地をPD−L1発現BT549標的細胞培養物から採取して、D−PBSによって丁寧に2回すすいだ。細胞を採取して計数した。細胞浮遊液を遠心分離(1000RPM、5分間)して、細胞沈降物を細胞50,000個/mlで培養培地に浮遊させた。手動でのマルチチャンネルピペットを使用して、細胞(100μL/ウェル、すなわち、細胞5000個/ウェル)を平底マイクロプレートのあらゆるウェルに播種した。プレートを室温で30分間放置した。その後、細胞を含むプレートを、5%CO2インキュベータにおいて終夜インキュベートした。
T細胞殺滅アッセイ
T細胞殺滅活性を利用して、抗glycPD−L1モノクローナル抗体が腫瘍細胞に及ぼす細胞傷害活性を決定した。従ったプロトコールは以下のとおりである;0日目、グリコシル化野生型PD−L1(PD−L1 WT)発現BT549 RFP標的細胞培養物から血清含有培地を除去して、PBSで丁寧に2回すすいだ。細胞を回収して計数した。細胞浮遊液を遠心分離(1000RPM、4分間)して、細胞沈降物を培養培地に細胞50,000個/mlで浮遊させた。手動のマルチチャンネルピペットを使用して、細胞を平底マイクロプレートのあらゆるウェルに播種した(100μL/ウェル、すなわち、細胞5000個/ウェル)。プレートを室温で30分間放置した後、IncuCyteZOOM(登録商標)生細胞イメージング装置の中に入れて、20分間平衡にした後、初回スキャンを計画した。初回スキャンの開始直後から3時間ごとに、24時間の繰り返しスキャン(10倍対物レンズ)を計画した。細胞のコンフルエンスを、所望のコンフルエンス(例えば20%)が達成されるまで、続く18時間で(終夜)モニターした。
抗glycPD−L1抗体によるPD−L1の結合は、PD−L1内在化および分解を促進する
抗glyICP抗体が、その同起源のICP結合分子への結合後に内在化および分解を促進するか否かを決定するために、細胞染色アッセイを実施した。本実施例において、使用した抗glycICP抗体は、抗PD−L1 MAb STM108であった。アッセイに関して、A431細胞を、無血清培地中で一晩インキュベートした後、抗glycPD−L1抗体10μgと共に2日間インキュベートした。次に、細胞を回収し、細胞中のPD−L1をウェスタンブロットによって評価した。細胞を抗glycPD−L1 MAbと共にインキュベートすると、対照(IgG)と比較して細胞におけるPD−L1レベルの低減を示した。
総T細胞と比較した腫瘍細胞における抗glycPD−L1抗体が結合したPD−L1の内在化
抗glycPD−L1抗体を、活性化または非活性化T細胞と比較して細胞表面発現PD−L1の結合後にPD−L1陽性腫瘍細胞に内在化する能力について試験した。抗glycPD−L1抗体STM004、STM073、およびSTM108および対照としてのマウスIgGを、末梢血からの非活性化総T細胞、末梢血からの活性化総T細胞、およびPD−L1を発現するNCI−H226細胞と共にインキュベートした。T細胞の活性化に関して、総T細胞をビーズ、例えば抗CD3および抗CD28抗体(例えば、ThermoFisher Scientific,Rochester,NY)に1:1で共有結合によりカップリングさせた不活性な超常磁性ビーズと混合して、抗原提示細胞による刺激を模倣するようにT細胞を刺激した(例えば、A. Trickett et al., 2003, J. Immunol. Methods, 275, Issues 1-2:251-255を参照されたい)。全ての抗体を、pHrodo(商標)レッドによって標識し、内在化を上記のように可視化した。図9A〜9Dおよび図9E〜9Hは、試験したいずれの抗体も非活性化総T細胞または活性化総T細胞に内在化されなかったことを示す。図9I〜9Lは、STM073およびSTM108 MAbが、赤色の細胞内染色を示さなかった標識対照抗体mIgG(図9I)および標識非内在化STM004 MAb(図9J)と比較して、赤色の細胞内染色によって証明されるように、これらの細胞とのインキュベーション後にNCI−H226細胞に内在化されたことを示している。本実施例は、抗glycPD−L1抗体STM073およびSTM108が、PD−L1発現腫瘍細胞に選択的に内在化されるが、活性化または非活性化T細胞のいずれにも内在化されない抗glycICP抗体の例であることを証明している。
腫瘍細胞殺滅および腫瘍体積の低減におけるPD−L1 ADCの有効性
腫瘍の殺滅および腫瘍体積の低減における細胞毒素MMAEにカップリングさせた抗ヒトICP抗体、特に抗ヒトglycPD−L1 MAb、すなわちSTM108 MAbを含むADCの有効性を評価するために、in vitroおよびin vivo実験の両方を実施した。STM108−ADCは、MMAE細胞毒素ペイロードをPD−L1発現腫瘍細胞またはがん細胞に特異的に送達するために、本明細書において上記のようにシステインを介してMC−vc−PAB−MMAEに化学的に連結したSTM108 MAbを含む。STM108−ADC(STM108−MC−vc−PAB−MMAE)の測定された物理特性は、以下の通りである。
Claims (65)
- グリコシル化免疫チェックポイントタンパク質(ICP)抗原に優先的に結合する抗体を同定および単離する方法であって、
a)グリコシル化ICP抗原への特異的結合について抗体集団をスクリーニングするステップと、
b)前記グリコシル化ICP抗原より前記ICP抗原の非グリコシル化形態への結合が弱いことについて、前記グリコシル化ICPに特異的に結合する抗体をスクリーニングするステップと、
c)前記ICPの非グリコシル化形態より高い親和性で前記グリコシル化ICPに結合する抗体を単離するステップと
を含む方法。 - 前記抗体集団が、グリカン部分への結合によって改変された少なくとも1つのグリコシル化アスパラギン(N)アミノ酸を含むICPの少なくとも7連続アミノ酸の断片を含むグリコシル化ICP抗原またはそのペプチドによって免疫した動物から得たモノクローナル抗体である、請求項1に記載の方法。
- 前記スクリーニングステップの前に、
a)動物において抗グリコシル化ICP特異的抗体の免疫応答を誘発するために有効な量で、グリカン部分への結合によって改変された少なくとも1つのグリコシル化アスパラギン(N)アミノ酸を含むICPの少なくとも7連続アミノ酸の断片を含むグリコシル化ICP抗原またはそのペプチドを、レシピエント動物に投与するステップと、
b)抗体集団を分泌するハイブリドーマ集団を前記動物から産生するステップと
をさらに含む、請求項1または2に記載の方法。 - 前記動物がマウスまたはラットである、請求項1から3のいずれか一項に記載の方法。
- 前記動物が、ヒト免疫グロブリンを発現する遺伝子についてトランスジェニックである、請求項2から4のいずれか一項に記載の方法。
- 前記抗体集団が、ファージディスプレイ抗体ライブラリである、請求項1に記載の方法。
- 前記ファージ抗体ライブラリが、ヒト抗体レパートリーライブラリである、請求項6に記載の方法。
- 前記抗体を、ICP抗原の非グリコシル化形態への抗体の結合によって示されるKdの半分より小さいKdでのグリコシル化ICP抗原への結合について試験する、請求項1から7のいずれか一項に記載の方法。
- 前記抗体を、ICP抗原の非グリコシル化形態への抗体の結合によって示されるKdの少なくとも5倍小さいKdでのグリコシル化ICP抗原への結合について試験する、請求項8に記載の方法。
- 前記抗体を、ICP抗原の非グリコシル化形態への抗体の結合によって示されるKdの半分より小さいKdでのグリコシル化ICP抗原への結合について試験する、請求項9に記載の方法。
- 蛍光標識によって直接または間接的に標識された前記抗体を、ICP抗原の非グリコシル化形態を発現する細胞への抗体の結合によって示される平均蛍光強度(MFI)値より少なくとも2倍から少なくとも20倍大きい、グリコシル化ICP抗原を発現する細胞への結合についてのMFI値で、グリコシル化ICP抗原への結合について試験する、請求項1から7のいずれか一項に記載の方法。
- 前記抗体を、ICP抗原の非グリコシル化形態への前記抗体の結合によって示されるMFI値より少なくとも3倍から少なくとも5倍大きい、グリコシル化ICP抗原への結合についてのMFI値で、グリコシル化ICP抗原への結合について試験する、請求項11に記載の方法。
- グリコシル化ICP抗原またはそのペプチドが腫瘍細胞またはがん細胞上に発現し、ICPリガンドが免疫細胞上に発現する、請求項1から12のいずれか一項に記載の方法。
- グリコシル化ICP抗原またはそのペプチドが免疫細胞上に発現し、ICPリガンドが腫瘍細胞またはがん細胞上に発現する、請求項1から12のいずれか一項に記載の方法。
- 前記免疫細胞がエフェクターT細胞またはナチュラルキラー細胞(NK細胞)である、請求項13または14に記載の方法。
- 前記ICPがヒトICPである、請求項1から15のいずれか一項に記載の方法。
- グリコシル化ICP抗原が、CD47、CD96、TIM−3、LAG−3、CEACAM1、BTN1A1、セマフォリン4D、ブチロフィリン様2(BTNL2)、BTLA、PD−1およびPD−L1からなる群から選択される、請求項1から16のいずれか一項に記載の方法。
- 前記グリコシル化ICPがPD−L1である、請求項17に記載の方法。
- 前記グリコシル化ICPがPD−1である、請求項17に記載の方法。
- 前記グリコシル化ICPがCD47である、請求項17に記載の方法。
- 前記グリコシル化ICPがCD96である、請求項17に記載の方法。
- 前記グリコシル化ICPがTIM−3である、請求項17に記載の方法。
- 前記グリコシル化ICPがLAG−3である、請求項17に記載の方法。
- 前記グリコシル化ICPがCEACAM1である、請求項17に記載の方法。
- 前記グリコシル化ICPがBTN1A1である、請求項17に記載の方法。
- 前記グリコシル化ICPがセマフォリン4Dである、請求項17に記載の方法。
- 前記グリコシル化ICPがBTNL2である、請求項17に記載の方法。
- 前記グリコシル化ICPがBTLAである、請求項17に記載の方法。
- ステップ(a)および/またはステップ(b)でのスクリーニングがフローサイトメトリー分析によって行われる、請求項1から28のいずれか一項に記載の方法。
- 前記ICPの、その同起源のICP結合パートナーへの結合の阻害について前記抗体を試験するステップをさらに含む、請求項1から29のいずれか一項に記載の方法。
- 前記抗体の相補性決定領域(CDR)を含むアミノ酸を同定するステップ、およびヒト化抗体を産生するためにCDR周囲のアミノ酸配列をヒト化するステップをさらに含む、請求項1から30のいずれか一項に記載の方法。
- ヒト化抗体を組み換え発現するステップをさらに含む、請求項31に記載の方法。
- 前記ヒトグリコシル化ICP抗原が、ヒトPD−L1の少なくとも7連続アミノ酸の断片を含む単離ポリペプチドであり、前記ポリペプチドが、ヒトPD−L1のN35、N192、N200、またはN219位に対応する少なくとも1つのアミノ酸を含み、PD−L1のN35、N192、N200、またはN219位に対応するアミノ酸の少なくとも1つがグリコシル化されている、請求項2から32のいずれか一項に記載の方法。
- 前記単離ポリペプチドが、ヒトPD−L1の少なくとも8〜20連続アミノ酸を含む、請求項13に記載の方法。
- 前記単離ポリペプチドが、そのアミノまたはカルボキシ末端で免疫原性ポリペプチドに融合またはコンジュゲートされる、請求項33または34に記載の方法。
- 前記ヒトグリコシル化ICP抗原が、ヒトPD−1の少なくとも7連続アミノ酸の断片を含む単離ポリペプチドであり、前記ポリペプチドが、ヒトPD−1のN49、N58、N74、および/またはN116位に対応する少なくとも1つのアミノ酸を含み、PD−1のN49、N58、N74、および/またはN116位に対応するアミノ酸の少なくとも1つがグリコシル化されている、請求項2から32のいずれか一項に記載の方法。
- 前記単離ポリペプチドがヒトPD−1の少なくとも8〜20連続アミノ酸を含む、請求項36に記載の方法。
- 前記単離ポリペプチドが、そのアミノまたはカルボキシ末端で免疫原性ポリペプチドに融合またはコンジュゲートされる、請求項36または37に記載の方法。
- 前記抗体のエピトープと重複しないヒトグリコシル化ICPのエピトープに結合する二次抗体の抗原結合ドメインを含むscFvを、前記抗体の重鎖および/または軽鎖のN−末端に連結するステップをさらに含む、請求項1から38のいずれか一項に記載の方法。
- 請求項1から39のいずれか一項に記載の方法に従って単離された単離抗体。
- 抗グリコシル化PD−L1抗体である、請求項40に記載の単離抗体。
- 抗グリコシル化PD−1抗体である、請求項40に記載の単離抗体。
- ヒト化またはヒト抗体である、請求項40から42のいずれか一項に記載の単離抗体。
- 組み換え抗体である、請求項40から43のいずれか一項に記載の単離抗体。
- IgM、IgG1、IgG2、IgG2a、IgG2b、IgG3、IgG4からなる群から選択されるアイソタイプである、請求項40から44のいずれか一項に記載の単離抗体。
- Fab’、F(ab’)2、F(ab’)3、一価scFv、二価scFv、二重パラトープ性またはシングルドメイン抗体である、請求項39から45のいずれか一項に記載の単離抗体。
- 二重特異性または二重パラトープ性抗体である、請求項40から46のいずれか一項に記載の単離抗体。
- 造影剤、化学療法剤、毒素、抗新生物剤、または放射性核種にコンジュゲートされる、請求項40から47のいずれか一項に記載の抗体。
- 抗新生物剤とコンジュゲートして抗体−薬物コンジュゲート(ADC)を産生する、請求項48に記載の単離抗体。
- 前記抗新生物剤が、チューブリン重合化を阻害する薬剤である、請求項49に記載の単離抗体。
- 前記薬剤がメイタンシノイドまたはアウリスタチンである、請求項50に記載の単離抗体。
- 前記メイタンシノイドが、DM1(N2’−デアセチル−N2’−(3−メルカプト−1−オキソプロピル)−メイタンシン)、またはDM4(N2’−デアセチル−n2’−(4−メルカプト−4−メチル−1−オキソペンチル)−6−メチルメイタンシンである、請求項51に記載の単離抗体。
- 前記アウリスタチンがモノメチルアウリスタチンE(MMAE)またはモノメチルアウリスタチンF(MMAF)である、請求項50に記載の単離抗体。
- 前記アウリスタチンがMMAEである、請求項53に記載の単離抗体。
- 前記抗体が、マレイミドおよびカプロン酸(MC)結合基に化学的にコンジュゲートされ、これがカテプシン切断可能リンカーに化学的にコンジュゲートされ、これがパラアミノ安息香酸(PAB)スペーサーに化学的にコンジュゲートされ、これがMMAEに化学的にコンジュゲートされ、それによってADCが形成された、請求項54に記載の単離抗体。
- 前記カテプシン切断可能リンカーがバリン−シトルリン(vc)である、請求項55に記載の単離抗体。
- 細胞に内在化される抗glycICP抗体を含むADCであって、前記抗体は細胞傷害薬に化学的にカップリングされたものである、ADC。
- 前記細胞傷害薬が、チューブリン重合化を阻害する薬剤である、請求項57に記載のADC。
- 前記薬剤がメイタンシノイドまたはアウリスタチンである、請求項58に記載のADC。
- 前記メイタンシノイドがDM1またはDM4である、請求項59に記載のADC。
- 前記アウリスタチンがMMAEまたはMMAFである、請求項59に記載のADC。
- 前記アウリスタチンがMMAEである、請求項61に記載のADC。
- 前記抗体が、MC結合基に化学的にコンジュゲートされ、これがカテプシン切断可能リンカーに化学的にコンジュゲートされ、これがPABスペーサーに化学的にコンジュゲートされ、これがMMAEに化学的にコンジュゲートされ、それによってADCが形成された、請求項57に記載のADC。
- 前記カテプシン切断可能リンカーがバリン−シトルリン(vc)である、請求項63に記載のADC。
- 切断可能リンカーを介してMMAEに化学的にカップリングされた抗glycICP抗体を含むADC。
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