JP2021518142A - シグナル調節タンパク質αに対する抗体及び使用方法 - Google Patents
シグナル調節タンパク質αに対する抗体及び使用方法 Download PDFInfo
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Abstract
Description
本出願は、2018年3月21日に出願された米国特許仮出願第62/646,210号の優先権を主張するものであり、その出願の全体は、参照により本明細書に援用される。
ASCIIテキストファイルでの以下の提出の内容は、その全体が参照により本明細書に援用される:757972000640SEQLIST.txt、記録日:2019年3月19日、サイズ:230KB)。
(Treffers,LW.et al.(2018),Eur.J.Immunol.48:344−354;Zhao,X.et al.(2011),PNAS.108:18342−47;van der Heijden,J.(2014).Genetic variation in human Fc gamma receptors:Functional consequences of polymorphisms and copy number variation(Doctoral dissertation))。
正常な免疫機能及び腫瘍形成におけるSIRP−α−CD47相互作用の重要性により、ヒトSIRP−αに結合する抗体の特定は、臨床候補の開発にとって極めて興味深いものである。
本明細書において引用される全ての参考文献は、特許出願、特許公報、非特許文献及びUniProtKB/Swiss−Protアクセッション番号を含め、それぞれの個々の参考文献が参照により援用されることが具体的かつ個別に示される場合と同様に、その全体が参照により本明細書に援用される。
本開示の実施形態を詳述する前に、本開示は、特定の組成物または生物系に限定されず、当然のことながら、変わり得ることを理解されたい。また、本明細書で使用される用語は、特定の実施形態を記載する目的でのみ使用され、限定を意図するものではないことが理解される。
本開示のある特定の態様は、ヒトSIRP−αポリペプチドの細胞外ドメイン(例えば、D1ドメイン)に結合する抗体に関する。いくつかの実施形態では、抗体は、ヒト化抗体である。いくつかの実施形態では、抗体は、モノクローナル抗体である。
本開示の抗体は、当該技術分野において知られている任意の手段によって産生することができる。抗体産生のための例示的な技術が以下に記載されるが、これらの例示的な技術は、例示のみを目的に提供されるものであり、限定を意図するものではない。加えて、本明細書に記載される抗体との併用が企図される例示的な抗体の特性もさらに記載される。
本開示のある特定の態様は、本明細書に記載される抗体を使用して、疾患または障害を治療することに関する。いくつかの実施形態では、疾患は、がんである。いくつかの実施形態では、疾患は、自己免疫疾患または炎症性疾患である。
方法
抗体産生
以下のタンパク質を免疫化に使用した。各々は、免疫原性を高めるために、改変したFc領域(S228P変異を含むヒンジ領域を有するヒトIgG4 Fc、またはIgG1_AAA_N297Aと記載されるL234A/L235A/G237A/N297A ヒトIgG1 Fcのいずれか)を融合させたヒトまたはマウスSIRP−αペプチドを含む。
様々なSIRPタンパク質に対する抗体クローンの結合は、表面プラズモン共鳴(SPR)検出を使用し、0.01%Tween−20(PBST)を添加したリン酸緩衝生理食塩水(PBS、pH7.4)をランニング緩衝液に用い、ProteOn XPR36機器(Bio−Rad(Hercules,CA))で測定した。分泌された抗体を含有する培地を予め濾過し、これをアッセイに直接使用した。まず、抗ヒトIgG Fc(BR−1008−39(GE Healthcare))をGLCセンサーチップ上にアミン結合させ、抗体に対する捕捉表面を作った。1フローセル当たり約4000RUの固定化抗ヒトIgG Fcが得られる。以下と同じ方法を使用して、各クローンをスクリーニングする。スクリーニングに使用したSIRPアナライトは、様々な種(ヒトv1、ヒトv2、カニクイザル、マウス129、BL6、BALBc、NOD)由来のSIRP−α、ヒトSIRP−β、及びヒトSIRP−γであり;それぞれ、配列番号5、6、11、7、9、10、8、13、及び15であった。
抗SIRPα抗体と、様々な種(ヒトv1、ヒトv2、カニクイザル、マウス129、BL6、BALBc、NOD)に由来するSIPRα、SIRPβ及びSIRPγとの相互作用について、抗体の直接固定化(GLCチップによる)またはビオチン化プロテインAを介した捕捉(NLCチップによる)による2つの方法を次のプロトコルに従って使用して分析した。実験は全て、GLCまたはNLCセンサーチップを備えるSPR系ProteOn XPR36バイオセンサー(BioRad,Inc(Hercules,CA))を使用して25℃で実施した。FreeStyle(商標)293−FS細胞(Thermo Fisher)を使用して抗体を発現させた。標準的なプロテインAアフィニティーカラムクロマトグラフィーにより精製を行い、溶出した抗体をPBS緩衝液中に保存した。
選択されたマウスSIRP−αタンパク質に対する様々な抗体クローンの結合反応速度を決定した。試験したマウスタンパク質には、BALBc(配列番号10)、BL6(配列番号9)、NOD(配列番号8)及びm129(配列番号7)のSIRP−αタンパク質が含まれる。結果を以下の表B〜Eにまとめる。AB21及びAB25の可変ドメイン配列を表J1に示す。
先の実施例は、抗SIRP−α抗体の特定及び特性評価について記載している。次に、これらの抗体を、動物モデルで試験し、腫瘍成長に対するSIRP−αの生物学的効果を調査した。
インビボにおける抗腫瘍活性
MC38同系マウス結腸癌モデルの場合、MC38細胞をC57BL/6マウスに皮下移植し、複数群(8〜10匹/群)に無作為化した。処置群には、ビヒクル(PBS)、AB25b、AB25c、及びAB27bを含めた。全ての抗SIRPα抗体は、マウスIgG2aを有するAB25cを除き、N297Aの変異を有するマウスIgG1 Fc領域を有した。処置は、移植後7日目に、腫瘍が平均60〜65mm3になったときに開始した。マウスに抗SIRPαを10mg/kgで週2回、3週間にわたって腹腔内(IP)投与した。腫瘍が約2000mm3の体積に達したら、動物を屠殺した。
様々な抗SIRP−α抗体のインビボ抗腫瘍作用を同系マウス結腸癌モデルでアッセイした。MC38同系マウス結腸癌モデルにおいて、遮断抗SIRP−α抗体AB25b、AB25c及びAB27bの抗腫瘍活性を試験して、それぞれの単剤活性を評価した。遮断抗SIRP−α抗体AB25b、AB25c、及びAB27bは、MC38同系マウスモデルにおいて、ビヒクル単独と比較して10mg/kgで腫瘍形成を遅らせた(図1)。25日目に、抗SIRPα抗体で処置した群では、600mm3未満のマウスがAB25bで3匹、600mm3未満のマウスがAB25cで4匹、600mm3未満のマウスがAB27bで3匹であったのに対し、ビヒクル処置群では、600mm3未満のマウスは2匹のみであった。
上記の実施例は、完全ヒト重鎖及びニワトリ軽鎖を有する抗SIRP−α抗体の作製及び特徴付けについて記載している。ニワトリ由来の軽鎖をヒト化するために、これらの抗体のニワトリHVRを様々なヒトλ軽鎖フレームワーク上にグラフト化した。
ヒト化
標準的な技術を使用して抗体をヒト化した。生産収率を測定するために、抗SIRPα抗体を発現する、同量のExpi293培養液をプロテインAアフィニティークロマトグラフィーによって精製した。緩衝液をPBSに交換した後、A280によりタンパク質濃度を決定し、mg/mLで示した。
ヒト化軽鎖を設計するために、IgBLAST(NCBI)により、各ニワトリ軽鎖配列と、最も近いヒト生殖細胞系列フレームワークとのアライメントを行った。この解析を使用すると、ニワトリλ軽鎖フレームワークに最も近いものは、ヒトIGLV3である(配列番号27〜30参照)。
次に、様々な抗SIRP−α抗体を食作用及び樹状細胞活性化アッセイで調べた。
腫瘍細胞株の培養
DLD−1(ヒト大腸腺癌)細胞及びOE19(ヒト食道癌)細胞を、10%非働化ウシ胎児血清(Gibco)、1%ペニシリン/ストレプトマイシン(Gibco)及び1%Glutamax(Gibco)を添加したRPMI(Gibco)からなる成長培地中に維持した。
Blood Centers of the Pacificからトリマ残留物を入手し、リン酸緩衝生理食塩水(PBS(Gibco))で1:4に希釈した。希釈した血液を4つのチューブに分け、20mlのFicoll−Paque Plus(GE Healthcare)の上に重ねた。試験管を400×gで30分間遠心分離にかけた。境界面からPBMCを回収し、FACS緩衝液(0.5%ウシ血清アルブミン含有PBS(Gibco))中に再懸濁した。Monocyte Isolation Kit II(Miltenyi Biotec)及びLSカラム(Miltenyi Biotec)を製造元のプロトコルに従って使用して、ネガティブ選択によりCD14+単球を精製した。
DLD−1細胞を、20mlのPBSで2回洗浄し、10mlのTrypLE Select(Gibco)中で37℃、10分間、インキュベーションすることによって、培養プレートから剥離した。細胞を遠心分離にかけ、PBSで洗浄し、培地中に再懸濁した。Celltrace CFSE Cell Proliferationキット(Thermo Fisher)を製造元の説明書に従って用いて細胞に標識し、IMDM中に再懸濁した。マクロファージを、20mlのPBSで2回洗浄し、10mlのTrypLE Select中で37℃、20分間、インキュベーションすることによって、培養プレートから剥離した。セルスクレーパー(Corning)を用いて細胞を取り出し、PBSで洗浄し、IMDM中に再懸濁した。
Balb/cマウス(n=3/群)に対し、ヒトIgG1対照、様々な抗SIRP−α抗体、マウスIgG対照、またはビヒクル(PBS)を10mg/kgで静脈内注射した。注射から5時間後、脾臓を摘出し、物理的に解離させることによって単一細胞懸濁液に処理した。CD4+脾臓樹状細胞の活性化マーカーCD86、MHCII及びCCR7のレベルをフローサイトメトリーにより測定した。
M2マクロファージによるEGFR(+)DLD−1細胞の食作用に対する、上記のヒト化抗体の作用について、抗EGFR抗体セツキシマブと組み合わせて、試験した(図3A)。全てのヒト化抗体がセツキシマブ誘導食作用を亢進することがわかった。M2マクロファージによるEGFR(+)DLD−1細胞の食作用に対する、上記の追加のヒト化抗体(Hum1またはHum9軽鎖と組み合わせた抗体25重鎖バリアント、及びHum1軽鎖と組み合わせた抗体27重鎖バリアント)の作用について、抗EGFR抗体セツキシマブと組み合わせて、試験した(図3B)。全てのヒト化抗体がセツキシマブ誘導食作用を亢進することがわかった。試験した全ての抗体は、L234A、L235A、G237A、及びN297A変異を有する完全長ヒトIgG1抗体として作製された。
方法
インビボにおける抗腫瘍活性
CT26同系マウス結腸癌モデルの場合、CT26細胞をBALB/cマウスに皮下移植し、複数群(8〜9匹/群)に無作為化した。処置群には、ビヒクル(PBS)、AB25b、抗PD−L1、及びAB25b/抗PD−L1を含めた。抗PD−L1は、アテゾリズマブのVH及びVLドメインと、N297A変異を有するマウスIgG1 Fc領域とを融合することによって作製される。抗SIRP−α抗体も全て、N297A変異を有するマウスIgG1 Fc領域を有する。処置は、移植後7または8日目に、腫瘍が平均75〜80mm3になったときに開始した。マウスに抗SIRPα抗体を3mg/kgまたは10mg/kgで週2回3週間、及び抗PD−L1を3mg/kgで、3回5日間隔で腹腔内(IP)投与した。腫瘍が約2000mm3の体積に達したら、動物を屠殺した。
CT26同系マウス結腸癌モデルにおいて、遮断AB25b抗SIRP−α抗体の抗腫瘍活性を、単独で、また抗PD−L1抗体と組み合わせて試験した。図5に示されるように、AB25b 10mg/kgを抗PD−L1 3mg/kgと組み合わせて投与すると、単剤またはビヒクル対照のそれぞれによる処置と比較して、腫瘍形成が遅延した。試験27日目に、ビヒクル、抗PD−L1単剤及び抗SIRP−α単剤の処置群における腫瘍の大きさが600mm3未満のマウスは、それぞれ2匹、2匹及び2匹であったのに比べて、併用処置群における腫瘍の大きさが600mm3未満のマウスは、6匹であった。
上述の遮断抗SIRP−α抗体AB21及びAB25の特性により、バリアントAB21 VHドメイン(配列番号26)及びヒト化Hum1 VLドメイン(配列番号25)を含む抗体を分析用に選択した。上述のHum1ヒト化可変軽鎖ドメインを含む抗体軽鎖の配列を、潜在的な不安定性ホットスポット、例えば、脱アミドまたは糖化部位について分析した。
ペプチドマッピング分析
トリプシン消化の場合、試料を6MグアニジンHCl及び1mM EDTA中で希釈した。10mMのDTT及び10mMのヨードアセトアミドを使用して、試料をそれぞれ還元し、アルキル化した。その後、緩衝液を0.1MトリスHClに交換し、試料を4時間インキュベートして、消化させた。キモトリプシン消化の場合、試料を100mM炭酸水素アンモニウム中で希釈した。1%のProgentaアニオン酸分解性界面活性剤を加えた。10mMのDTT及び10mMのヨードアセトアミドを再び使用して、試料をそれぞれ還元し、アルキル化した。試料を一晩インキュベートした。
抗SIRPα抗体と、様々な種(ヒトv1、ヒトv2、カニクイザル、マウス129、BL6、BALBc、NOD)に由来するSIPRα、SIRPβ及びSIRPγとの相互作用について、抗体の直接固定化を用いて分析した。実験は全て、GLCセンサーチップを備えるSPR系ProteOn XPR36バイオセンサー(BioRad,Inc(Hercules,CA))を使用して25℃で実施した。FreeStyle(商標)293−FS細胞(Thermo Fisher)を使用して抗体を発現させた。標準的なプロテインAアフィニティーカラムクロマトグラフィーにより精製を行い、溶出した抗体をPBS緩衝液中に保存した。
Hum1 VLドメイン(配列番号25)及びヒトIGLC1 λ定常ドメイン(配列番号37)を有する軽鎖(配列番号47)と、AB21 MutAll VHドメイン(配列番号26)を有する重鎖(配列番号61)と、ヒトIgG2Da Fc領域を含む(A330S及びP331S変異を含む、EUに従ったアミノ酸位置ナンバリング)定常領域(配列番号34)とを含む抗SIRP−α抗体(抗体PC336)にトリプシン及びキモトリプシン消化を上述のように実施した。重鎖の全体的な配列包括度は、100%(444個のアミノ酸のうちの444個)であり、軽鎖は、98.6%(214個のアミノ酸のうちの211個)であった。全ての抗体の可変ドメイン及び完全鎖配列を表J1及びJ2に提供する。
異なるFc領域及び軽鎖定常ドメインを有する抗SIRP−α抗体を、これらの配列が抗SIRP−α抗体の生物学的特性にどのように影響を及ぼすかを理解するために、食作用に対する効果について試験した。
樹状細胞の機能的枯渇に関して、末梢血単核細胞(PBMC)を、Ficoll−Paque Plusにより健康な個体のトリマ残留物から単離した。500,000個のPBMCを、抗SIRPを10ug/mLの濃度で有するU底96ウェルプレート(corning)で、37℃にて48時間インキュベートした。フローサイトメトリーに関して、細胞をヒトFcR遮断試薬中でインキュベートし、lin−(CD3、CD14、CD16、CD19、CD56)及びHLADRに対する蛍光色素標識抗体のカクテルで染色した。固定可能な生死判別色素(Fixable viability dye)を使用して、生細胞を同定した。染色後、細胞を洗浄し、PBS中の0.5%パラホルムアルデヒドで固定した。取得前に、絶対計数ビーズを加え、Canto IIフローサイトメーターで試料を取得し、FlowJoソフトウェアを用いて分析した。
異なるFc領域を有するヒト化抗SIRP−α抗体を、抗EGFR抗体セツキシマブと組み合わせたM2マクロファージによるEGFR(+)DLD−1細胞の食作用に対する効果について試験した(図12)。全ての抗体は、配列番号55の軽鎖配列、及び配列番号26のVHドメイン配列を有した。試験したFc領域は、IgG2野生型(配列番号33の定常ドメイン配列に表されるように)、IgG2Da Fc領域(A330S及びP331S変異を含む、EUに従ったアミノ酸位置ナンバリング;配列番号34の定常ドメイン配列に表されるように)、N297A変異を含むIgG2 Fc領域(EUに従ったアミノ酸位置ナンバリング;配列番号137の定常ドメイン配列に表されるように)、及びN297A、L234A、L235A、及びG237A変異を含むIgG1 Fc領域(EUに従ったアミノ酸位置ナンバリング;配列番号32の定常ドメイン配列に表されるように)を含んだ。全ての抗体は、セツキシマブ誘発食作用の亢進におけるほぼ同等の活性を有することが分かった。
Claims (60)
- ヒトSIRP−αポリペプチドの細胞外ドメインに結合する単離された抗体であって、
(a)配列番号26のアミノ酸配列を含む重鎖可変(VH)ドメインを含む重鎖;及び
(b)式SYELTQPPSVSVSPGQTARITCSGGSYSSYYYAWYQQKPGQAPVTLIYSDDKRPSNIPERFSGSSSGTTVTLTISGVQAEDEADYYCGGYDQSSYTNPFGX1GTX2X3TVL(配列番号71)に従ったアミノ酸配列を含む軽鎖可変(VL)ドメインを含む軽鎖を含み、ここで、X1は、GまたはTであり;X2は、K、Q、またはRであり;及びX3は、LまたはVであり、前記VLドメインは、配列番号25の配列を含まない、前記抗体。 - 前記VLドメインが、配列番号39〜41からなる群から選択されるアミノ酸配列を含む、請求項1に記載の抗体。
- 前記軽鎖が、式GQPKANPTVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADGSPVKAGVETTKPSKQSX4X5KYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS(配列番号72)に従ったアミノ酸配列を含む軽鎖定常(CL)ドメイン配列をさらに含み、ここで、X4X5が、ND、DN、DS、またはSDである、請求項1または2に記載の抗体。
- 前記軽鎖が、配列番号43〜46からなる群から選択されるアミノ酸配列を含む軽鎖定常(CL)ドメイン配列をさらに含む、請求項1または2に記載の抗体。
- 前記軽鎖が、κ軽鎖定常(CL)ドメインをさらに含む、請求項1または2に記載の抗体。
- 前記軽鎖が、配列番号36のアミノ酸配列を含む、請求項5に記載の抗体。
- 前記軽鎖が、λ軽鎖定常(CL)ドメインをさらに含む、請求項1または2に記載の抗体。
- 前記軽鎖が、配列番号37または配列番号38のアミノ酸配列を含む、請求項7に記載の抗体。
- 前記軽鎖が、配列番号48〜57からなる群から選択されるアミノ酸配列を含む、請求項1に記載の抗体。
- 前記抗体が、scFv−Fc、単一ドメイン抗体、一本鎖重鎖抗体、または一本鎖軽鎖抗体である、請求項1〜9のいずれか1項に記載の抗体。
- 前記抗体が、モノクローナル抗体である、請求項1〜9のいずれか1項に記載の抗体。
- 前記重鎖が、Fc領域を含む重鎖定常ドメインを含む、請求項1〜9のいずれか1項に記載の抗体。
- 前記Fc領域が、IgG1 Fc領域、IgG2 Fc領域、及びIgG4 Fc領域からなる群から選択されるヒトFc領域である、請求項12に記載の抗体。
- 前記Fc領域が、ヒトIgG1 Fc領域である、請求項12に記載の抗体。
- 前記Fc領域が、EUに従ったアミノ酸位置ナンバリングである、L234A、L235A、及びG237A置換を含むヒトIgG1 Fc領域である、請求項12に記載の抗体。
- 前記Fc領域が、EUに従ったアミノ酸位置ナンバリングである、N297A置換をさらに含む、請求項15に記載の抗体。
- 前記Fc領域が、ヒトIgG2 Fc領域である、請求項12に記載の抗体。
- 前記Fc領域が、EUに従ったアミノ酸位置ナンバリングである、A330S及びP331S置換を含むヒトIgG2 Fc領域である、請求項12に記載の抗体。
- 前記Fc領域が、EUに従ったアミノ酸位置ナンバリングである、N297A置換をさらに含む、請求項17または18に記載の抗体。
- 前記Fc領域が、ヒトIgG4 Fc領域であり、前記重鎖が、EUに従ったアミノ酸位置ナンバリングである、S228P置換を含む、請求項12に記載の抗体。
- 前記重鎖定常ドメインが、配列番号31〜35からなる群から選択されるアミノ酸配列を含む、請求項12に記載の抗体。
- 前記重鎖定常ドメインが、配列番号33、34、及び137からなる群から選択されるアミノ酸配列を含む、請求項12に記載の抗体。
- 前記重鎖定常ドメインが、配列番号132〜139からなる群から選択されるアミノ酸配列を含む、請求項12に記載の抗体。
- 前記重鎖が、配列番号58〜62からなる群から選択されるアミノ酸配列を含む、請求項1に記載の抗体。
- 前記重鎖が、配列番号60、61、及び129からなる群から選択されるアミノ酸配列を含む、請求項1に記載の抗体。
- (a)前記重鎖が、配列番号62のアミノ酸配列を含み、前記軽鎖が、配列番号52のアミノ酸配列を含み;
(b)前記重鎖が、配列番号62のアミノ酸配列を含み、前記軽鎖が、配列番号53のアミノ酸配列を含み;
(c)前記重鎖が、配列番号62のアミノ酸配列を含み、前記軽鎖が、配列番号54のアミノ酸配列を含み;
(d)前記重鎖が、配列番号62のアミノ酸配列を含み、前記軽鎖が、配列番号55のアミノ酸配列を含み;
(e)前記重鎖が、配列番号62のアミノ酸配列を含み、前記軽鎖が、配列番号56のアミノ酸配列を含み;または
(f)前記重鎖が、配列番号62のアミノ酸配列を含み、前記軽鎖が、配列番号57のアミノ酸配列を含む、請求項1に記載の抗体。 - (a)前記重鎖が、配列番号58のアミノ酸配列を含み、前記軽鎖が、配列番号52のアミノ酸配列を含み;
(b)前記重鎖が、配列番号59のアミノ酸配列を含み、前記軽鎖が、配列番号52のアミノ酸配列を含み;
(c)前記重鎖が、配列番号60のアミノ酸配列を含み、前記軽鎖が、配列番号52のアミノ酸配列を含み;
(d)前記重鎖が、配列番号61のアミノ酸配列を含み、前記軽鎖が、配列番号52のアミノ酸配列を含み;
(e)前記重鎖が、配列番号58のアミノ酸配列を含み、前記軽鎖が、配列番号53のアミノ酸配列を含み;
(f)前記重鎖が、配列番号59のアミノ酸配列を含み、前記軽鎖が、配列番号53のアミノ酸配列を含み;
(g)前記重鎖が、配列番号60のアミノ酸配列を含み、前記軽鎖が、配列番号53のアミノ酸配列を含み;
(h)前記重鎖が、配列番号61のアミノ酸配列を含み、前記軽鎖が、配列番号53のアミノ酸配列を含み;
(i)前記重鎖が、配列番号58のアミノ酸配列を含み、前記軽鎖が、配列番号54のアミノ酸配列を含み;
(j)前記重鎖が、配列番号59のアミノ酸配列を含み、前記軽鎖が、配列番号54のアミノ酸配列を含み;
(k)前記重鎖が、配列番号60のアミノ酸配列を含み、前記軽鎖が、配列番号54のアミノ酸配列を含み;
(l)前記重鎖が、配列番号61のアミノ酸配列を含み、前記軽鎖が、配列番号54のアミノ酸配列を含み;
(m)前記重鎖が、配列番号58のアミノ酸配列を含み、前記軽鎖が、配列番号55のアミノ酸配列を含み;
(n)前記重鎖が、配列番号59のアミノ酸配列を含み、前記軽鎖が、配列番号55のアミノ酸配列を含み;
(o)前記重鎖が、配列番号60のアミノ酸配列を含み、前記軽鎖が、配列番号55のアミノ酸配列を含み;
(p)前記重鎖が、配列番号61のアミノ酸配列を含み、前記軽鎖が、配列番号55のアミノ酸配列を含み;
(q)前記重鎖が、配列番号58のアミノ酸配列を含み、前記軽鎖が、配列番号56のアミノ酸配列を含み;
(r)前記重鎖が、配列番号59のアミノ酸配列を含み、前記軽鎖が、配列番号56のアミノ酸配列を含み;
(s)前記重鎖が、配列番号60のアミノ酸配列を含み、前記軽鎖が、配列番号56のアミノ酸配列を含み;
(t)前記重鎖が、配列番号61のアミノ酸配列を含み、前記軽鎖が、配列番号56のアミノ酸配列を含み;
(u)前記重鎖が、配列番号58のアミノ酸配列を含み、前記軽鎖が、配列番号57のアミノ酸配列を含み;
(v)前記重鎖が、配列番号59のアミノ酸配列を含み、前記軽鎖が、配列番号57のアミノ酸配列を含み;
(w)前記重鎖が、配列番号60のアミノ酸配列を含み、前記軽鎖が、配列番号57のアミノ酸配列を含み;または
(x)前記重鎖が、配列番号61のアミノ酸配列を含み、前記軽鎖が、配列番号57のアミノ酸配列を含む、請求項1に記載の抗体。 - (a)前記重鎖が、配列番号60のアミノ酸配列を含み、前記軽鎖が、配列番号55のアミノ酸配列を含み;
(b)前記重鎖が、配列番号61のアミノ酸配列を含み、前記軽鎖が、配列番号55のアミノ酸配列を含み;
(c)前記重鎖が、配列番号129のアミノ酸配列を含み、前記軽鎖が、配列番号55のアミノ酸配列を含み;
(d)前記重鎖が、配列番号124のアミノ酸配列を含み、前記軽鎖が、配列番号52のアミノ酸配列を含み;または
(e)前記重鎖が、配列番号124のアミノ酸配列を含み、前記軽鎖が、配列番号55のアミノ酸配列を含む、請求項1に記載の抗体。 - ヒトSIRP−αポリペプチドを発現するマクロファージによる食作用を亢進する、請求項1〜28のいずれか1項に記載の抗体。
- ヒトSIRP−αポリペプチドを発現する樹状細胞の活性化を亢進する、請求項1〜28のいずれか1項に記載の抗体。
- CD47を発現する腫瘍のインビボ成長を阻害する、請求項1〜30のいずれか1項に記載の抗体。
- 薬剤にコンジュゲートされる、請求項1〜31のいずれか1項に記載の抗体。
- 二重特異性抗体である、請求項1〜31のいずれか1項に記載の抗体。
- ヒトSIRP−αポリペプチドの細胞外ドメインに結合する第1の抗原結合ドメインと、がん細胞によって発現される抗原に結合する第2の抗原結合ドメインとを含む、請求項33に記載の抗体。
- 前記がん細胞によって発現される前記抗原が、CD19、CD20、CD22、CD30、CD33、CD38、CD52、CD56、CD70、CD74、CD79b、CD123、CD138、CS1/SLAMF7、Trop−2、5T4、EphA4、BCMA、ムチン1、ムチン16、PD−L1、PTK7、STEAP1、エンドセリンB型受容体、メソテリン、EGFRvIII、ENPP3、SLC44A4、GNMB、ネクチン4、NaPi2b、LIV−1A、グアニル酸シクラーゼC、DLL3、EGFR、HER2、VEGF、VEGFR、インテグリンαVβ3、インテグリンα5β1、MET、IGF1R、TRAILR1、TRAILR2、RANKL、FAP、テネイシン、Ley、EpCAM、CEA、gpA33、PSMA、TAG72、ムチン、CAIX、EPHA3、葉酸受容体α、GD2、GD3、及びNY−ESO−1/LAGE、SSX−2、MAGEファミリータンパク質、MAGE−A3、gp100/pmel17、Melan−A/MART−1、gp75/TRP1、チロシナーゼ、TRP2、CEA、PSA、TAG−72、未成熟ラミニン受容体、MOK/RAGE−1、WT−1、SAP−1、BING−4、EpCAM、MUC1、PRAME、サバイビン、BRCA1、BRCA2、CDK4、CML66、MART−2、p53、Ras、β−カテニン、TGF−βRII、HPV E6またはHPV E7に由来するペプチドを含むMHC/ペプチド複合体からなる群から選択される、請求項34に記載の抗体。
- ヒトSIRP−αポリペプチドの細胞外ドメインに結合する第1の抗原結合ドメインと、免疫細胞によって発現される抗原に結合する第2の抗原結合ドメインとを含む、請求項33に記載の抗体。
- 前記免疫細胞によって発現される前記抗原が、BDCA2、BDCA4、ILT7、LILRB1、LILRB2、LILRB3、LILRB4、LILRB5、Siglec−3、Siglec−7、Siglec−9、Siglec−15、FGL−1、CD200、CD200R、CSF−1R、CD40、CD40L、CD163、CD206、DEC205、CD47、CD123、アルギナーゼ、IDO、TDO、AhR、EP2、COX−2、CCR2、CCR−7、CXCR1、CX3CR1、CXCR2、CXCR3、CXCR4、CXCR7、TGF−β RI、TGF−β RII、c−Kit、CD244、L−セレクチン/CD62L、CD11b、CD11c、CD68、41BB、CTLA4、PD1、PD−L1、PD−L2、TIM−3、BTLA、VISTA、LAG−3、CD28、OX40、GITR、CD137、CD27、HVEM、CCR4、CD25、CD103、KIrg1、Nrp1、CD278、Gpr83、TIGIT、CD154、CD160、TNFR2、PVRIG、DNAM、及びICOSからなる群から選択される、請求項36に記載の抗体。
- ヒトSIRP−αポリペプチドの細胞外ドメインに結合する第1の抗原結合ドメインと、ナチュラルキラー(NK)細胞によって発現される抗原に結合する第2の抗原結合ドメインとを含む、請求項33に記載の抗体。
- 前記NK細胞によって発現される前記抗原が、NKR−P1A、CD94、KLRG1、KIR2DL5A、KIR2DL5B、KIR2DL1、KIR2DL2、KIR2DL3、KIR2DS2、KIR2DS3、KIR2DS4、KIR2DS5、KIR3DS1、KIR2DS1、CD94、NKG2D、CD160、CD16、NKp46、NKp30、NKp44、DNAM1、CRTAM、CD27、NTB−A、PSGL1、CD96、CD100、NKp80、SLAMF7、及びCD244からなる群から選択される、請求項38に記載の抗体。
- 請求項1〜39のいずれか1項に記載の抗体をコードする、ポリヌクレオチド。
- 請求項40に記載のポリヌクレオチドを含む、ベクター。
- 請求項40に記載のポリヌクレオチドまたは請求項41に記載のベクターを含む、宿主細胞。
- 前記抗体が産生されるように、請求項42に記載の宿主細胞を培養することを含む、抗体を産生する方法。
- 前記宿主細胞から前記抗体を回収することをさらに含む、請求項43に記載の方法。
- 個体のがんを治療するか、個体のがんの進行を遅らせる方法であって、請求項1〜39のいずれか1項に記載の抗体の有効量を前記個体に投与することを含む、前記方法。
- 前記がんによって発現される抗原に結合する第2の抗体の有効量を前記個体に投与することをさらに含む、請求項45に記載の方法。
- 前記がん細胞によって発現される前記抗原が、CD19、CD20、CD22、CD30、CD33、CD38、CD52、CD56、CD70、CD74、CD79b、CD123、CD138、CS1/SLAMF7、Trop−2、5T4、EphA4、BCMA、ムチン1、ムチン16、PTK7、STEAP1、エンドセリンB型受容体、メソテリン、EGFRvIII、ENPP3、SLC44A4、GNMB、ネクチン4、NaPi2b、LIV−1A、グアニル酸シクラーゼC、DLL3、EGFR、HER2、VEGF、VEGFR、インテグリンαVβ3、インテグリンα5β1、MET、IGF1R、TRAILR1、TRAILR2、RANKL、FAP、テネイシン、Ley、EpCAM、CEA、gpA33、PSMA、TAG72、ムチン、CAIX、EPHA3、葉酸受容体α、GD2、GD3、及びNY−ESO−1/LAGE、SSX−2、MAGEファミリータンパク質、MAGE−A3、gp100/pmel17、Melan−A/MART−1、gp75/TRP1、チロシナーゼ、TRP2、CEA、PSA、TAG−72、未成熟ラミニン受容体、MOK/RAGE−1、WT−1、SAP−1、BING−4、EpCAM、MUC1、PRAME、サバイビン、BRCA1、BRCA2、CDK4、CML66、MART−2、p53、Ras、β−カテニン、TGF−βRII、HPV E6またはHPV E7に由来するペプチドを含むMHC/ペプチド複合体からなる群から選択される、請求項46に記載の方法。
- 免疫療法剤の有効量を前記個体に投与することをさらに含む、請求項45〜47のいずれか1項に記載の方法。
- 前記免疫療法剤が、第2の抗体を含む、請求項48に記載の方法。
- 前記第2の抗体が、BDCA2、BDCA4、ILT7、LILRB1、LILRB2、LILRB3、LILRB4、LILRB5、Siglec−3、Siglec−7、Siglec−9、Siglec−15、FGL−1、CD200、CD200R、CSF−1R、CD40、CD40L、CD163、CD206、DEC205、CD47、CD123、アルギナーゼ、IDO、TDO、AhR、EP2、COX−2、CCR2、CCR−7、CXCR1、CX3CR1、CXCR2、CXCR3、CXCR4、CXCR7、TGF−β RI、TGF−β RII、c−Kit、CD244、L−セレクチン/CD62L、CD11b、CD11c、CD68、41BB、CTLA4、PD1、PD−L1、PD−L2、TIM−3、BTLA、VISTA、LAG−3、CD28、OX40、GITR、CD137、CD27、HVEM、CCR4、CD25、CD103、KIrg1、Nrp1、CD278、Gpr83、TIGIT、CD154、CD160、TNFR2、PVRIG、DNAM、及びICOSからなる群から選択される抗原に結合する、請求項49に記載の方法。
- 前記第2の抗体が、PD−1に結合する、請求項50に記載の方法。
- 前記第2の抗体が、PD−L1に結合する、請求項50に記載の方法。
- 前記免疫療法剤が、ワクチン、腫瘍溶解性ウイルス、養子細胞療法、サイトカイン、または小分子剤を含む、請求項48に記載の方法。
- ナチュラルキラー(NK)細胞によって発現される抗原に結合する第2の抗体の有効量を前記個体に投与することをさらに含む、請求項45〜53のいずれか1項に記載の方法。
- 前記NK細胞によって発現される前記抗原が、NKR−P1A、CD94、KLRG1、KIR2DL5A、KIR2DL5B、KIR2DL1、KIR2DL2、KIR2DL3、KIR2DS2、KIR2DS3、KIR2DS4、KIR2DS5、KIR3DS1、KIR2DS1、CD94、NKG2D、CD160、CD16、NKp46、NKp30、NKp44、DNAM1、CRTAM、CD27、NTB−A、PSGL1、CD96、CD100、NKp80、SLAMF7、及びCD244からなる群から選択される、請求項54に記載の方法。
- 化学療法剤または小分子抗がん剤の有効量を前記個体に投与することをさらに含む、請求項45〜55のいずれか1項に記載の方法。
- 標的化小分子阻害剤の有効量を前記個体に投与することをさらに含む、請求項45〜56のいずれか1項に記載の方法。
- 前記標的化小分子阻害剤が、VEGFR及び/またはPDGFR阻害剤、EGFR阻害剤、ALK阻害剤、CDK4/6阻害剤、PARP阻害剤、mTOR阻害剤、KRAS阻害剤、TRK阻害剤、BCL2阻害剤、IDH阻害剤、PI3K阻害剤、DNA損傷応答(DDR)阻害剤、または低メチル化剤である、請求項57に記載の方法。
- 個体の自己免疫疾患または炎症性疾患を治療するか、個体の自己免疫疾患または炎症性疾患の進行を遅らせる方法であって、請求項1〜39のいずれか1項に記載の前記抗体の有効量を前記個体に投与することを含む、前記方法。
- 前記自己免疫疾患または炎症性疾患が、多発性硬化症、関節リウマチ、脊椎関節症、全身性エリテマトーデス、抗体媒介性の炎症性疾患または自己免疫疾患、移植片対宿主病、敗血症、糖尿病、乾癬、乾癬性関節炎、アテローム性動脈硬化症、シェーグレン症候群、全身性進行性硬化症、強皮症、急性冠症候群、虚血再灌流、クローン病、潰瘍性大腸炎、子宮内膜症、糸球体腎炎、IgA腎症、多発性嚢胞腎疾患、重症筋無力症、特発性肺線維症、肺線維症、肝硬変、心房線維症、心筋線維症、骨髄線維症、後腹膜線維症、喘息、アトピー性皮膚炎、急性呼吸促迫症候群(ARDS)、血管炎及び自己免疫性炎症性筋炎からなる群から選択される、請求項59に記載の方法。
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JP7393342B2 (ja) | 2023-12-06 |
KR20200133376A (ko) | 2020-11-27 |
CL2020002414A1 (es) | 2021-01-29 |
CN112040979A (zh) | 2020-12-04 |
BR112020018927A2 (pt) | 2021-01-05 |
EP4144372A3 (en) | 2023-06-14 |
AU2019240111A1 (en) | 2020-09-17 |
CL2021002209A1 (es) | 2022-03-04 |
MX2020009774A (es) | 2020-10-08 |
US20220324996A1 (en) | 2022-10-13 |
JOP20200206A1 (ar) | 2020-08-27 |
WO2019183266A1 (en) | 2019-09-26 |
EP4144372A2 (en) | 2023-03-08 |
RU2020134294A (ru) | 2022-04-22 |
PH12020551391A1 (en) | 2021-11-22 |
PE20201265A1 (es) | 2020-11-19 |
US20190352419A1 (en) | 2019-11-21 |
CA3094098A1 (en) | 2019-09-26 |
MA52091A (fr) | 2021-01-27 |
RU2020134294A3 (ja) | 2022-04-22 |
US11292850B2 (en) | 2022-04-05 |
US11939393B2 (en) | 2024-03-26 |
EP3768314A4 (en) | 2022-01-05 |
EP3768314A1 (en) | 2021-01-27 |
IL277337A (en) | 2020-10-29 |
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