JP7492336B2 - 多量体il-15に基づく分子 - Google Patents
多量体il-15に基づく分子 Download PDFInfo
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- JP7492336B2 JP7492336B2 JP2019521081A JP2019521081A JP7492336B2 JP 7492336 B2 JP7492336 B2 JP 7492336B2 JP 2019521081 A JP2019521081 A JP 2019521081A JP 2019521081 A JP2019521081 A JP 2019521081A JP 7492336 B2 JP7492336 B2 JP 7492336B2
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Description
本出願は、2017年6月1日に出願された米国特許仮出願第62/513,964号及び2016年10月21日に出願された米国特許仮出願第62/411,216号の優先権を主張する。これらの出願の全内容は参照によりその全体が本明細書に組み込まれる。
インターロイキン-15(IL-15)はエフェクターNK細胞及びCD8+記憶T細胞の発展、増殖及び活性化のための重大なサイトカインである。IL-15はIL-15受容体α(IL-15Rα)と結合し、エフェクター細胞上のIL-2/IL-15受容体βコモンγ鎖(IL-15Rβγc)複合体にトランスで提供される。IL-15及びIL-2はIL-15Rβγcとの結合を共有し、STAT3及びSTAT5経路を通してシグナルを送る。しかしながら、IL-2とは異なり、IL-15はCD4+CD25+FoxP3+調節T(Treg)細胞の維持を支持しないし、活性化CD+8T細胞の細胞死、多発性骨髄腫に対してIL-2の治療的活性を制限していたかもしれない効果を誘発しない。さらに、IL-15はエフェクターCD8+T細胞へ抗アポトーシスシグナルを提供することが知られている唯一のサイトカインである。単独又はIL-15Rαとの複合体としてのどちらかで投与されるIL-15は、実験動物モデル内に定着した充実性腫瘍に対する潜在的抗腫瘍活性を示し、このように、潜在的にがんを治癒することができる最も有望な免疫治療薬の1つとして特定された。
他の実施形態では、該結合ドメインは免疫チェックポイント又はシグナル分子又はそのリガンドに特異的であり、免疫チェックポイント抑制活性の阻害剤として、又は免疫刺激活性のアゴニストとして作用する。かかる免疫チェックポイント及びシグナル分子及びリガンドは、PD-1、PD-L1、PD-L2、CTLA-4、CD28、CD80、CD86、B7-H3、B7-H4、B7-H5、ICOS-L、ICOS、BTLA、CD137L、CD137、HVEM、KIR、4-1BB、OX40L、CD70、CD27、CD47、CIS、OX40、GITR、IDO、TIM3、GAL9、VISTA、CD155、TIGIT、LIGHT、LAIR-1、シグレック(Siglecs)及びA2aRを含む(Pardoll DM. 2012. Nature Rev Cancer 12:252-264, Thaventhiran T, et al. 2012. J Clin Cell Immunol S12:004)。さらに、本発明の好ましい抗体ドメインは、イピリムマブ及び/又はトレメリムマブ(抗CTLA4)、ニボルマブ、ペンブロリズマブ、ピジリズマブ、TSR-042、ANB011、AMP-514及びAMP-224(リガンド-Fc融合)(抗PD1)、アテゾリズマブ(MPDL3280A)、アベルマブ(MSB0010718C)、デュルバルマブ(MEDI4736)、MEDI0680及びBMS-9365569(抗PDL1)、MEDI6469(抗OX40アゴニスト)、BMS-986016、IMP701、IMP731、IMP321(抗LAG3)及びGITRリガンドを含んでいてもよい。
抗体特異的結合ドメインは疾患細胞上の標的と特異的に結合するポリペプチドからなる。あるいは、これらのドメインは疾患状態を支持する他の細胞上の標的、例えば腫瘍の成長を支持する間質細胞上の標的又は疾患介在性免疫抑制を支持する免疫細胞上の標的と結合してもよい。抗原特異的結合ドメインは当該分野で知られている抗体、一本鎖抗体、Fabs、Fv、T細胞受容体結合ドメイン、リガンド結合ドメイン、受容体結合ドメイン、ドメイン抗体、単一ドメイン抗体、ミニボディ、ナノボディ、ペプチボディ又は多様な他の抗体模倣体(例えばアフィマー(affimers)、アフィチン(affitin)、アルファボディ(alphabodies)、アトリマー(atrimers)、CTLA-4に基づく分子、アドネクチン(adnectins)、アンチカリン(anticalins)、クニッツ(Kunitz)ドメインに基づくタンパク質、アビマー(avimers)、ノッチン(knottins)、フィノマー(fynomers)、ダルピン(darpins)、アフィボディ(affibodies)、アフィリン(affilins)、モノボディ及びアルマジロ反復タンパク質に基づくタンパク質(Weidle, UH, et al. 2013. Cancer Genomics & Proteomics 10:155-168))を含む。
T細胞は他の免疫細胞型(多核白血球、好酸球、好塩基球、マスト細胞、B細胞、NK細胞)とともに、免疫系の細胞成分を構成する細胞のサブグループである。生理学的状態下で、T細胞は免疫学的監視及び外来抗原の除外において機能する。しかしながら、病的状態下では、T細胞が疾患の因果関係及び伝播において主要な役割を果たしているとの有力な証拠がある。これらの障害において、中央又は末梢いずれかのT細胞の免疫寛容の故障が自己免疫性疾患の因果関係における基本的な経過である。
本発明のタンパク質複合体はFcドメインを含んでいてもよい。例えば、PD-L1 TxMは抗PD-L1 scAb/huIL-15N72D:抗PD-L1 scAb/huIL-15RαSu/huIgG1 Fc融合複合体を含む。IgGのFc領域と別のタンパク質のドメインを結合させる融合タンパク質、例えば多様なサイトカイン及び可溶性受容体が報告されている(例えば、Capon et al., Nature, 337:525-531, 1989; Chamow et al., Trends Biotechnol., 14:52-60, 1996);米国特許第5,116,964号及び第5,541,087号を参照されたい)。該プロトタイプ融合タンパク質はIgG Fcのヒンジ領域でシステイン残基を介して結合したホモ二量体タンパク質であり、重鎖可変及びCH1ドメイン及び軽鎖を伴わない、IgG分子と類似した分子をもたらす。Fcドメインを含む融合タンパク質の二量体の性質は、他の分子との高次相互作用(二価結合又は二重特異性結合)を提供するのに好都合であり得る。構造的相同性のために、Fc融合タンパク質は、類似のアイソトープを有するヒトIgGのそれと比較可能な、薬物動態プロフィールをインビボで示す。IgGクラスのイムノグロブリンはヒトの血液中で最も豊富なタンパク質であり、循環半減期は21日にも届くことがある。IL-15又はIL-15融合タンパク質の循環半減期を引き伸ばすため、及び/又は、その生物学的活性を増加させるために、ヒト重鎖IgGタンパク質のFc部分と共有結合したIL-15αと非共有結合したIL-15ドメインを含む融合タンパク質複合体が本明細書に記載される。
本発明は融合タンパク質複合体を提供する(図1及び図2)。一部の場合では、第一のタンパク質がインターロイキン-15(IL-15)又はその機能性フラグメントと共有結合した第一の生物学的に活性なポリペプチドを含み;第二のタンパク質が可溶性インターロイキン-15受容体α(IL-15Rα)ポリペプチド又はその機能性フラグメントと共有結合した第二の生物学的に活性なポリペプチドを含み、そこで第一のタンパク質のIL-15ドメインが第二のタンパク質の可溶性IL-15Rαドメインと結合して可溶性融合タンパク質複合体を形成する。本発明の融合タンパク質複合体は、第一及び第二のタンパク質の1つ又は両方と結合したイムノグロブリンFcドメイン又はその機能性フラグメントをまた含む。好ましくは、該融合タンパク質と結合したFcドメインは相互作用して融合タンパク質複合体を形成する。かかる複合体はイムノグロブリンFcドメイン間のジスルフィド結合構造によって安定していてもよい。一態様において、本発明の可溶性融合タンパク質複合体はIL-15ポリペプチド、IL-15多様体又はその機能性フラグメント及び可溶性IL-15Rαポリペプチド又はその機能性フラグメントを含み、そこでIL-15及びIL-15Rαポリペプチドの1つ又は両方がイムノグロブリンFcドメイン又はその機能性フラグメントをさらに含む。
本発明の融合複合体は、好ましくはIL-15又はIL-15Rαドメインと生物学的に活性なポリペプチドの間に介入したフレキシブルリンカー配列をまた含む。該リンカー配列は、IL-15又はIL-15Rαドメインに関連した生物学的に活性なポリペプチドの効果的な配置を許容し、両方のドメインの機能的活性を許容するべきである。
本発明により、治療剤としての使用のための融合タンパク質複合体を含む医薬組成物が提供される。一態様では、本発明の融合タンパク質複合体は、例えば薬学的に許容できるバッファー、例えば生理食塩水中に製剤化されて、全身投与される。好ましい投与経路は、例えば、患者における継続的な、持続した又は効果的なレベルの組成物を提供する、膀胱への点滴注入、皮下注射、静脈内注射、腹腔内注射、筋肉内注射、腫瘍内注射、皮内注射を含む。ヒトの患者又は他の動物の治療は、生理的に許容できる担体内の本明細書に特定された治療剤の治療上の有効量を用いて実行される。適した担体及びその製剤が、例えばE. W. MartinによるRemington’s Pharmaceutical Sciencesに記載されている。投与されるべき治療剤の量は、投与形式、患者の年齢及び体重、新生組織形成の臨床症状によって多様である。特定の例では化合物の増加した特異度のために低用量が必要となるであろうが、概して、量は新生組織形成、自己免疫性疾患又は感染症と関連した他の疾患の治療において使用される他の剤のために使用されるものの範囲内であろう。対象の免疫反応を高める、又は当業者に知られている方法によって決定された新生細胞、感染細胞又は自己免疫性細胞の増殖、生存又は侵襲性を低減する用量で化合物は投与される。
新生組織形成、感染症又は自己免疫性疾患の治療のための本発明の融合タンパク質複合体の投与は、他の成分と組み合わせて、前記新生組織形成、感染症又は自己免疫性疾患を改善、低減、又は安定させるのに有効な治療剤内の濃度をもたらす任意の適した方法による。本発明の融合タンパク質複合体は任意の適した担体物質内で適した量で含まれてもよいし、概して該組成物の全体量の重量にして1~95%の量で存在する。該組成物は非経口(例えば、皮下、静脈内、筋肉内、膀胱内、腫瘍内又は腹腔内)投与経路に適している投薬形態で提供されてもよい。例えば、該医薬組成物は慣例的な医薬実務によって製剤化される(例えば、Remington: The Science and Practice of Pharmacy (20th ed.), ed. A. R. Gennaro, Lippincott Williams & Wilkins, 2000及びEncyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New Yorkを参照されたい)。
本発明の融合タンパク質複合体を含む医薬組成物は、投薬形態、剤形においては注射、注入又は移植(皮下、静脈内、筋肉内、腫瘍内、膀胱内、腹腔内)によって、又は慣例的な、非毒性の薬学的に許容できる担体及びアジュバントを含む、適した送達装置又は移植片を介して、非経口で投与される。かかる組成物の製剤化及び調製は製剤処方の分野における当業者にはよく知られている。剤形化は上記のRemington: The Science and Practice of Pharmacy内に見出すことができる。
任意選択的に、本発明の融合タンパク質複合体は、任意の他の標準的治療と組み合わせて投与される;かかる方法は当業者には知られており、E. W. MartinによるRemington’s Pharmaceutical Sciencesに記載されている。望ましい場合は、本発明の融合タンパク質複合体は、限定されないが免疫療法、治療抗体、標的療法、手術、放射線治療、又は化学療法を含む、任意の慣例的な抗新生組織形成療法と組み合わせて投与される。
本発明の融合タンパク質複合体を含む医薬組成物は、新生組織形成、感染症又は自己免疫性疾患の改善における使用のためにキット又は医薬システムに組み入れられてもよい。本発明のこの態様によるキット又は医薬システムは、その中に厳重に密閉された1又はそれ以上の容器手段、例えばバイアル、チューブ、アンプル、ボトル等を有する輸送手段、例えば箱、カートン、チューブを含む。本発明のキット又は医薬システムは、本発明の融合タンパク質複合体の使用に関連した指示書をまた含んでいてもよい。
概して、本発明の融合タンパク質複合体(例えばTxM複合体の成分)の調製は本明細書に記載の手順によって、及び認識された組み換えDNA技術によって完成され得る。
本発明により、本発明の融合タンパク質(例えばTxMの成分)をコードする核酸配列、特にDNA配列がさらに提供される。好ましくは、該DNA配列は染色体外複製、例えばファージ、ウイルス、プラスミド、ファージミド、コスミド、YAC又はエピソームに適したベクターによって運搬される。特に、本明細書に記載の調製方法を容易にするため、及び該融合タンパク質の有意な量を入手するために望ましい融合タンパク質をコードするDNAベクターを使用することができる。該DNA配列は、適した発現ベクター、すなわち挿入されたタンパク質をコードする配列の転写及び翻訳に必要な要素を含むベクターに挿入されてもよい。該タンパク質をコードする配列を発現するために多様な宿主ベクター系を活用してもよい。これらはウイルス(例えばワクシニアウイルス、アデノウイルス等)に感染した哺乳類細胞系;ウイルス(例えばバキュロウイルス)に感染した昆虫細胞系;微生物、例えば酵母ベクターを含む酵母、又はバクテリオファージDNA、プラスミドDNA又はコスミドDNAで形質転換された細菌を含む。活用する宿主ベクター系によって、任意の数の適した転写及び翻訳要素を使用してもよい。上記のSambrook et al.及び上記のAusubel et al.を参照されたい。
本発明の融合タンパク質複合体(例えばTxM)の成分を発現するために複数の戦略を用いることができる。例えば、本発明の融合タンパク質複合体の1又はそれ以上の成分をコードする構築物を、制限酵素を用いて適したベクターに組み込み、該構築物の挿入のために該ベクターに切れ目を入れ、続いてライゲーションすることができる。該遺伝子構築物を含むベクターを、それから該融合タンパク質の発現のために適した宿主に組み込む。概して上記のSambrook et al.を参照されたい。適したベクターの選択を、クローニングプロトコルに関する因子に基づいて経験的に行うことができる。例えば、該ベクターは用いられる宿主細胞と比較され、それに適したレプリコンを有するべきである。該ベクターは発現されるべき融合タンパク質複合体をコードするDNA配列と適合することが可能でなければならない。適した宿主細胞は真核細胞及び原核細胞を含み、好ましくは容易に形質転換することができ、培養培地で迅速な成長を示す細胞を含む。具体的には、好ましい宿主細胞は原核細胞、例えば大腸菌、枯草菌等、及び真核細胞、例えば動物細胞及び酵母菌株、例えばS. cerevisiaeを含む。哺乳類の細胞、特にJ558、NSO、SP2-O又はCHOが概して好まれる。他の適した宿主は、例えば昆虫細胞、例えばSf9を含む。慣例的な培養状態が用いられる。上記のSambrookを参照されたい。適した形質転換又はトランスフェクション細胞株をそれから選択することができる。本発明の融合タンパク質複合体を発現する細胞を既知の手順によって決定することができる。例えばイムノグロブリンと結合した融合タンパク質複合体の発現を、結合したイムノグロブリンに特異的なELISAによって、及び/又はイムノブロッティングによって決定することができる。IL-15又はIL-15Rαドメインと結合した生物学的に活性なポリペプチドを含む融合タンパク質を検出する他の方法が実施例において開示される。
リンパ腫はBリンパ球又はTリンパ球が正常細胞より速く分裂する、又は意図されるより長く生きるときに発生する血液のがんの一種である。例えば、B細胞リンパ腫はホジキンリンパ腫及び多くの非ホジキンリンパ腫の両方を含む。B細胞リンパ腫はCD20を発現する。
実施例1:抗PD-L1結合ドメイン(PD-L1 TxM)を含むIL-15に基づく融合タンパク質複合体の生成及び特性化
がん細胞は免疫チェックポイント分子及びリガンド、例えばPD-L1によって調節される多様な免疫阻害経路を刺激することが可能である。これらのチェックポイント分子を阻害する抗体は抗腫瘍免疫を高めることが示されている。IL-15はNK細胞及びCD8+細胞を活性化させ、拡大させる一方で、それらの細胞溶解性活性を増加させる。Ig分子のFc領域はNK細胞及びマクロファージのFcγ受容体と相互作用することができ、標的疾患細胞に対して抗体依存性細胞傷害(ADCC)又は抗体依存性細胞食作用(ADCP)を介在する。下記に詳細に記載されているように、抗PD-L1結合ドメインと融合したIL-15N72D:IL-15RαSu/Fc骨格を含むタンパク質複合体が生成される。これらの複合体は抗PD-L1結合ドメインを介して腫瘍細胞を認識し、IL-15活性を介してNK細胞及びT細胞反応を誘発させ、Fc結合ドメインを介してADCC及びCDCを刺激する。
(シグナルペプチド)
(抗ヒトPD-L1 scAb)
(VL)
(リンカー)
(VH)
(ヒトIL-15N72D)
(シグナルペプチド)
(抗ヒトPD-L1 scAb)
(VL)
(リンカー)
(VH)
(ヒトIL-15N72D)
(リーダー配列)
(抗ヒトPD-L1 scAb)
(VL)
(リンカー)
(VH)
(ヒトIL-15Rαスシドメイン)
(ヒトIgG1 CH2-CH3(Fc)ドメイン)
(リーダー配列)
(抗ヒトPD-L1 scAb)
(VL)
(リンカー)
(VH)
(ヒトIL-15Rαスシドメイン)
(ヒトIgG1 CH2-CH3(Fc)ドメイン)
(シグナルペプチド)
(抗ヒトPD-L1 scAb)
(VL)
(リンカー)
(VH)
(ヒトIL-15N72D)
(シグナルペプチド)
(抗ヒトPD-L1 scAb)
(VL)
(リンカー)
(VH)
(ヒトIL-15N72D)
(リーダー配列)
(抗ヒトPD-L1 scAb)
(VL)
(リンカー)
(VH)
(ヒトIL-15Rαスシドメイン)
(ヒトIgG1 CH2-CH3(Fc)ドメイン)
(リーダー配列)
(抗ヒトPD-L1 scAb)
(VL)
(リンカー)
(VH)
(ヒトIL-15Rαスシドメイン)
(ヒトIgG1 CH2-CH3(Fc)ドメイン)
(シグナルペプチド)
(抗マウスPD-L1 scAb)
(VL)
(リンカー)
(VH)
(ヒトIL-15N72D)
(シグナルペプチド)
(抗マウスPD-L1 scAb)
(VL)
(リンカー)
(VH)
(ヒトIL-15N72D)
(シグナルペプチド)
(抗マウスPD-L1 scAb)
(VL)
(リンカー)
(VH)
(ヒトIL-15Rαスシドメイン)
(マウスIgG2a CH2-CH3ドメイン)
(シグナルペプチド)
(抗マウスPD-L1 scAb)
(VL)
(リンカー)
(VH)
(ヒトIL-15Rαスシドメイン)
(マウスIgG2a CH2-CH3ドメイン)
ELISAに基づく技術によりPD-L1 TxM複合体の形成が裏付けられた。図4Aでは、トランスフェクションされたCHO細胞に由来する細胞上清中の抗ヒトPD-L1 scAb/IL-15N72D:抗ヒトPD-L1 scAb/huIL-15RαSu/huIgG1 Fc融合タンパク質複合体を、捕捉抗体、抗ヒトIgG抗体(Jackson ImmunoResearch)及び検出抗体、ビオチン化抗ヒトIL-15抗体(BAM 247, R&D Systems)を有するhuIgG1/huIL-15に特異的なELISAを用いて検出した。
PD-L1 TxMがインビボで免疫反応を刺激する能力をマウス内で評価した。C57BL/6マウスに200μlのPBS、ALT-803(0.4mg/kg、対照)、4Hマウス特異的PD-L1 TxM(200μg、2C2(T4M-mPD-L1))又は2Hマウス特異的PD-L1 TxM(200μg、PDN3(T2M-mPD-L1))を皮下注射した。処置から3日後、脾臓及びリンパ節を採取した。抗CD4、CD8、NK及びCD19Absを用いる免疫細胞サブセットの染色に続くフローサイトメトリーのために脾細胞及びリンパ球を調製した。図15Aに示されるように、ALT-803、2H PD-L1 TxM及び4H PD-L1 TxMでの処置はこれらのタンパク質の免疫刺激性活性と一致して脾臓重量の増加を誘発した。特に、2H PD-L1 TxM処置は、これらの複合体で観察されるIL-15活性における差異と一致して、4H PD-L1 TxMと比較して脾臓重量における重大な増加を誘発した。2H PD-L1 TxM及び4H PD-L1 TxMでの処置は、PBS対照群と比較して、マウスの脾臓及びリンパ節におけるCD8 T細胞及びNK細胞のパーセンテージの増加をまたもたらした(図15B及び図15C)。これらの免疫反応はこれらのTxM複合体のIL-15生物活性と一致している。
実施例1~3に記載された融合タンパク質複合体と同様に、CTLA4及びPD-L1を認識する結合ドメインを含む本発明の融合タンパク質を生成した。具体的には、一本鎖抗CTLA4抗体とhuIL-15N72D及びIL-15RαSu/Fc鎖を結合する構築物を製造した。抗CTLA4一本鎖抗体(抗CTLA4scAb)配列はフレキシブルリンカー配列を介して結合した重鎖及び軽鎖V抗体ドメイン抗体のコーディング領域を含む。一本鎖抗体ドメインはVH-リンカー-VL又はVL-リンカー-VHフォーマットのどちらかに配置されていてもよい。一部の場合では、抗CTLA4scAbはIL-15N72D及び/又はIL-15RαSu/Fc鎖のC末端と結合している。他の場合では、抗CTLA4はIL-15N72D及び/又はIL-15RαSu/Fc鎖のN末端と結合している。これらの構築物において、マウス又はヒトCTLA4分子のいずれかに特異的な抗CTLA4scAbsを使用した。
(シグナルペプチド)
(抗ヒトCTLA-4 scAb)
(VL)
(リンカー)
(VH)
(ヒトIL-15Rαスシドメイン)
(ヒトIgG1 CH2-CH3(Fc)ドメイン)
(シグナルペプチド)
(抗ヒトCTLA-4 scAb)
(VL)
(リンカー)
(VH)
(ヒトIL-15Rαスシドメイン)
(ヒトIgG1 CH2-CH3(Fc)ドメイン)
(シグナルペプチド)
(抗マウスCTLA-4 scAb)
(VL)
(リンカー)
(VH)
(ヒトIL-15Rαスシドメイン)
(マウスIgG2a CH2-CH3ドメイン)
(シグナルペプチド)
(抗マウスCTLA-4 scAb)
(VL)
(リンカー)
(VH)
(ヒトIL-15Rαスシドメイン)
(マウスIgG2a CH2-CH3ドメイン)
(シグナルペプチド)
(抗ヒトPD1 scAb)
(VL)
(リンカー)
(VH)
(ヒトIL-15N72D)
(シグナルペプチド)
(抗ヒトPD1 scAb)
(VL)
(リンカー)
(VL)
(ヒトIL-15N72D)
実施例1~4に記載の融合タンパク質複合体と同様に、CD47、GITR、ssDNA及び他の疾患関連標的(すなわちCD20、CD19等)を認識する結合ドメインを含む、本発明の融合タンパク質複合体を生成した。
(シグナルペプチド)
(ナノボディの抗マウスCD47 Vh鎖)
(ヒトIL-15N72D)
(シグナルペプチド)
(ナノボディの抗マウスCD47 Vh鎖)
(ヒトIL-15N72D)
(シグナルペプチド)
(ナノボディの抗マウスCD47 Vh鎖)
(ヒトIL-15Rαスシドメイン)
(マウスIgG2a CH2-CH3(Fc)ドメイン)
(シグナルペプチド)
(ナノボディの抗マウスCD47 Vh鎖)
(ヒトIL-15Rαスシドメイン)
(マウスIgG2a CH2-CH3(Fc)ドメイン)
(シグナルペプチド)
(抗ヒトCD47 scAb)
(VL)
(リンカー)
(VH)
(ヒトIL-15N72D)
(シグナルペプチド)
(抗ヒトCD47 scAb)
(VL)
(リンカー)
(VH)
(ヒトIL-15N72D)
(シグナルペプチド)
(抗ヒトCD47 scAb)
(VL)
(リンカー)
(VH)
(ヒトIL-15Rαスシドメイン)
(ヒトIgG1 CH2-CH3(Fc)ドメイン)
(シグナルペプチド)
(抗ヒトCD47 scAb)
(VL)
(リンカー)
(VH)
(ヒトIL-15Rαスシドメイン)
(ヒトIgG1 CH2-CH3(Fc)ドメイン)
(シグナルペプチド)
(ヒトGITRL)
(ヒトIL-15N72D)
(シグナルペプチド)
(ヒトGITRL)
(ヒトIL-15Rαスシドメイン)
(ヒトIgG1 CH2-CH3(Fc)ドメイン)
(シグナルペプチド)
(ヒトGITRL)
(ヒトIL-15Rαスシドメイン)
(ヒトIgG1 CH2-CH3(Fc)ドメイン)
(シグナルペプチド)
(TNT scAb)
(VL)
(リンカー)
(VH)
(ヒトIL-15N72D)
(シグナルペプチド)
(TNT scAb)
(VL)
(リンカー)
(VH)
(ヒトIL-15N72D)
(シグナルペプチド)
(TNT scAb)
(VL)
(リンカー)
(VH)
(ヒトIL-15Rαスシドメイン)
(ヒトIgG1 CH2-CH3(Fc)ドメイン)
(シグナルペプチド)
(TNT scAb)
(VL)
(リンカー)
(VH)
(ヒトIL-15Rαスシドメイン)
(ヒトIgG1 CH2-CH3(Fc)ドメイン)
(シグナルペプチド)
(hOAT scAb)
(VL)
(リンカー)
(VH)
(ヒトIL-15Rαスシドメイン)
(ヒトIgG1 CH2-CH3(Fc)ドメイン)
(シグナルペプチド)
(hOAT scAb)
(VL)
(リンカー)
(VH)
(ヒトIL-15Rαスシドメイン)
(ヒトIgG1 CH2-CH3(Fc)ドメイン)
(シグナルペプチド)
(CD33 scAb)
(VL)
(リンカー)
(VH)
(ヒトIL-15N72D)
(シグナルペプチド)
(CD33 scAb)
(VL)
(リンカー)
(VH)
(ヒト IL-15N72D)
(シグナルペプチド)
(CD33 scAb)
(VL)
(リンカー)
(VH)
(ヒトIL-15Rαスシドメイン)
(ヒトIgG1 CH2-CH3(Fc)ドメイン)
(シグナルペプチド)
(CD33 scAb)
(VL)
(リンカー)
(VH)
(ヒトIL-15Rαスシドメイン)
(ヒトIgG1 CH2-CH3(Fc)ドメイン)
(シグナルペプチド)
(ヒトLFA-1 Iドメイン(K287C/K294C))
(ヒトIL-15Rαスシドメイン)
(ヒトIgG1 CH2-CH3(Fc)ドメイン)
(シグナルペプチド)
(ヒトLFA-1 Iドメイン(K287C/K294C)
(ヒトIL-15Rαスシドメイン)
(ヒトIgG1 CH2-CH3(Fc)ドメイン)
(シグナルペプチド)
(hDLL4)
(ヒトIL-15Rαスシドメイン)
(ヒトIgG1 CH2-CH3(Fc)ドメイン)
(シグナルペプチド)
(hDLL4)
(ヒトIL-15Rαスシドメイン)
(ヒトIgG1 CH2-CH3(Fc)ドメイン)
(シグナルペプチド)
(haTIM3scFv:VL-リンカー-VH scFv)
(VL)
(リンカー)
(VH)
(ヒトIL-15Rαスシドメイン)
(ヒトIgG1 CH2-CH3(Fc)ドメイン)
(シグナルペプチド)
(haTIM3scFv:VL-リンカー-VH scFv)
(VL)
(リンカー)
(VH)
(ヒトIL-15Rαスシドメイン)
(ヒトIgG1 CH2-CH3(Fc)ドメイン)
(シグナルペプチド)
(N6 scFv:VL-リンカー-VH scFv)
(VL)
(リンカー)
(VH)
(ヒトIL-15Rαスシドメイン)
(ヒトIgG1 CH2-CH3(Fc)ドメイン)
(シグナルペプチド)
(2G12 scFv:VL-リンカー-VH scFv)
(VL)
(リンカー)
(VH)
(ヒトIL-15Rαスシドメイン)
(ヒトIgG1 CH2-CH3(Fc)ドメイン)
(シグナルペプチド)
(VRC07(523)scFv:VL-リンカー-VH scFv)
(VL)
(リンカー)
(VH)
(ヒトIL-15Rαスシドメイン)
(ヒトIgG1 CH2-CH3(Fc)ドメイン)
(シグナルペプチド)
(10-1074 scFv: VL-リンカー-VH scFv)
(VL)
(リンカー)
(VH)
(ヒトIL-15Rαスシドメイン)
(ヒトIgG1 CH2-CH3(Fc)ドメイン)
(シグナルペプチド)
(N6 scFv:VL-リンカー-VH scFv)
(VL)
(リンカー)
(VH)
(ヒトIL-15Rαスシドメイン)
(ヒトIgG1 CH2-CH3(Fc)ドメイン)
(シグナルペプチド)
(2G12 scFv:VL-リンカー-VH scFv)
(VL)
(リンカー)
(VH)
(ヒトIL-15Rαスシドメイン)
(ヒトIgG1 CH2-CH3(Fc)ドメイン)
(シグナルペプチド)
(VRC07(523)scFv:VL-リンカー-VH scFv)
(VL)
(リンカー)
(VH)
(ヒトIL-15Rαスシドメイン)
(ヒトIgG1 CH2-CH3(Fc)ドメイン)
(シグナルペプチド)
(10-1074)scFv:VL-リンカー-VH scFv)
(VL)
(リンカー)
(VH)
(ヒトIL-15Rαスシドメイン)
(ヒトIgG1 CH2-CH3(Fc)ドメイン)
CTLA-4陽性免疫細胞を用いてCTLA-4 TxMの結合活性を評価した。マウス特異的CTLA-4 TxMの調査において、マウスのリンパ球におけるCTLA-4の発現は、まず抗CD3 Ab(2C11、4μg/ml)によって4日間にわたり誘発された。PE抗マウスCTLA-4抗体(クローンUC10-4B9)又はPEアルメニアンハムスターIgGアイソトープ対照での染色によってCTLA-4発現を評価した。図21Aに示されるように、フローサイトメトリー分析によりマウスCTLA-4が著しく誘発されたことが明らかになった。マウス特異的CTLA-4 TxM(100μl上清)の添加により、陽性対照抗mCTLA-4抗体(クローンHB304)に行ったように、抗マウスCTLA-4抗体結合を阻害することができた。ヒト特異的CTLA-4 TxMの調査のために、ヒトPBMC中のCTLA-4の発現が抗CD3 Ab(OKT3:4μg/ml)によって3日間にわたり誘発された。それからPE抗ヒトCTLA-4抗体(クローンBNI3、Biolegend)又はPEマウスIgG2a、κアイソタイプ対照で細胞を染色した。上記に記載の結果と一致して、ヒト特異的CTLA-4 TxM(CL-8-100ul)はヒト免疫細胞の表面上のCTLA-4を阻害することができた(図21B)。これらの結果はCTLA-4 TxM複合体の特異性を明らかにしている。
実施例2に示されるように、TxM複合体のIL-15免疫刺激性活性を、IL-2Rβ/γを保有する免疫細胞、例えば32Dβ細胞株の増殖に基づいて評価した。簡潔には、増加する濃度の精製したTxMタンパク質を、200μLのIMDM:10%のFBS培地内の32Dβ細胞(104細胞/ウェル)に添加し、細胞を3日間にわたり37℃でインキュベートした。4時間後、吸収度を(正常化のための600nmの参照波長で)570nmと測定し、代謝的に活性な細胞によるPrestoBlue、すなわちレザズリンに基づく溶液の減少に基づいて細胞増殖を決定した。TxM複合体のIL-15生物活性の半値有効濃度(EC50)を、吸収度とTxMタンパク質濃度間の関係に基づいてそれから決定した。表1は、本発明の結合ドメインを含む多様なTxM複合体のIL-15 EC50の値を示す。その結果により、2つのscAb/結合ドメイン(すなわち二頭(2H)の抗PD-L1 scAb/IL-15N72D:抗PD-L1 scAb/IL-15RαSu/Fc複合体)又は4つのscAb/結合ドメイン(すなわち四頭(4H)の抗PD-L1 scAb/IL-15N72D:抗PD-L1 scAb/IL-15RαSu/Fc複合体)又は異なる標的化ドメインの組み合わせ(すなわち腫瘍標的化ドメイン/抗PDL1scAb TxM複合体)を有するものを含む、多様な精製されたTxM複合体の免疫刺激性活性が裏付けられた。
本発明はその詳細な記載と共に記載されている一方、前述の記載は説明を意図しており、本発明の範囲を限定することを意図しておらず、それは添付の請求項の範囲によって定義される。他の態様、便宜、修正が以下の請求項の範囲内に存在する。
また、本発明は以下の実施形態を含む。
[1]
少なくとも2の可溶性タンパク質を含む単離された可溶性融合タンパク質複合体であって、
第一の可溶性タンパク質がインターロイキン-15(IL-15)ポリペプチドドメインを含み、かつ第二の可溶性タンパク質がイムノグロブリンFcドメインと融合した可溶性のIL-15受容体αスシ結合ドメイン(IL-15RαSu)であって、
第一又は第二の可溶性タンパク質のうちの1つが疾患の抗原、免疫チェックポイント分子又は免疫シグナル分子と特異的に結合する結合ドメインをさらに含むものであって、
第一の可溶性タンパク質のIL-15ドメインが第二の可溶性タンパク質のIL-15RαSuドメインと結合して可溶性融合タンパク質複合体を形成する、
可溶性融合タンパク質複合体。
[2]
第一又は第二の可溶性タンパク質のうちの1つが疾患の抗原、免疫チェックポイント分子又は免疫シグナル分子と特異的に結合する第二の結合ドメインをさらに含む、[1]に記載の可溶性融合タンパク質複合体。
[3]
前記IL-15ポリペプチドがN72D変異体を含むIL-15多様体(IL-15N72D)である、[1]又は[2]に記載の可溶性融合タンパク質複合体。
[4]
前記結合ドメインが、ポリペプチドリンカー配列によってイムノグロブリン重鎖可変ドメインと共有結合したイムノグロブリン軽鎖可変ドメインを含む、[1]~[3]のいずれか1項に記載の可溶性融合タンパク質複合体。
[5]
前記結合ドメインが、プログラム細胞死リガンド(PD-L1)、プログラム細胞死1(PD-1)、細胞傷害性Tリンパ球に関連したタンパク質4(CTLA-4)、分化抗原群33(CD33)、分化抗原群47(CD47)、グルココルチコイドに誘発される腫瘍壊死因子受容体(TNFR)群に関する遺伝子(GITR)、リンパ球機能に関連した抗原1(LFA-1)、組織因子(TF)、デルタ様タンパク質4(DLL4)、一本鎖DNA又はT細胞イムノグロブリン及びムチンドメイン含有-3(Tim-3)を含む1又はそれ以上の分子と特異的に結合する、[1]~[4]のいずれか1項に記載の可溶性融合タンパク質複合体。
[6]
第一の可溶性タンパク質が配列番号:2、6、10、18、20、24、28、32又は38のうちの1つに示されたアミノ酸配列を含む、[1]~[5]のいずれか1項に記載の可溶性融合タンパク質複合体。
[7]
第二の可溶性タンパク質が配列番号:4、8、12、14、16、22、26、30、34、36、40、42、44、46、51、52、53又は54のうちの1つに示されたアミノ酸配列を含む、[1]~[5]のいずれか1項に記載の可溶性融合タンパク質複合体。
[8]
[1]~[7]のいずれか1項に記載の第二の可溶性融合タンパク質複合体と共有結合した[1]~[7]のいずれか1項に記載の第一の可溶性融合タンパク質複合体を含む、可溶性融合タンパク質複合体。
[9]
第一の可溶性融合タンパク質複合体が、第一の可溶性融合タンパク質複合体のFcドメインと第二の可溶性融合タンパク質複合体のFcドメインを結合するジスルフィド結合によって、第二の可溶性融合タンパク質複合体と共有結合される、[8]に記載の可溶性融合タンパク質複合体。
[10]
[6]に記載の第一の可溶性タンパク質をコードする核酸配列であって、前記核酸配列が配列番号:1、5、9、17、19、23、27、31又は37のうちの1つに示された配列を含む核酸配列。
[11]
前記核酸配列が前記可溶性タンパク質をコードする配列と作動可能に結合されたプロモーター、翻訳開始シグナル及びリーダー配列をさらに含む、[10]に記載の核酸配列。
[12]
[7]に記載の第二の可溶性タンパク質をコードする核酸配列であって、前記核酸配列が配列番号:3、7、11、13、15、21、25、29、33、35、39、41、43、45、47、48、49又は50のうちの1つに示された配列を含む核酸配列。
[13]
前記核酸配列が、可溶性タンパク質をコードする配列と作動可能に結合されたプロモーター、翻訳開始シグナル及びリーダー配列をさらに含む、[12]に記載の核酸配列。
[14]
[11]及び/又は[13]に記載の核酸配列を含むDNAベクター。
[15]
前記疾患の抗原が新生組織形成、感染症又は自己免疫性疾患と関連している、[1]~[9]のいずれか1項に記載の可溶性融合タンパク質複合体。
[16]
標的細胞を殺傷する方法であって:
a)複数の細胞を[1]に記載の可溶性融合タンパク質複合体に接触させ、そこで複数の細胞が[1]又は[2]に記載のIL-15ドメインによって認識されたIL-15受容体(IL-15R)鎖を保有する免疫細胞をさらに含むか、あるいは[1]又は[2]に記載の結合ドメインによって認識された疾患の抗原、チェックポイント又はシグナル分子、及び標的細胞を保有する免疫細胞をさらに含むこと;
b)IL-15R若しくはシグナル分子を介して、又はチェックポイント分子の阻害を介して、免疫細胞を活性化させること;
c)活性化免疫細胞によって標的細胞を殺傷すること;
を含む方法。
[17]
標的細胞を殺傷する方法であって:
a)複数の細胞を[2]に記載の可溶性融合タンパク質複合体に接触させ、そこで複数の細胞が[1]又は[2]に記載のFcドメインによって認識されたFc受容体鎖を保有する免疫細胞、及び[1]又は[2]に記載の抗原に特異的な結合ドメインによって認識された抗原を保有する標的細胞をさらに含むこと;
b)免疫細胞を結合し活性化させるのに十分な標的細胞上の抗原と免疫細胞上のFc受容体鎖間の特異的な結合複合体(架橋)を形成すること;
c)結合した活性化免疫細胞によって標的細胞を殺傷すること;
を含む方法。
[18]
標的細胞が腫瘍細胞、感染細胞又は自己免疫性疾患に関連した細胞である、[16]又は[17]に記載の方法。
[19]
結合ドメインが抗PD-L1抗体を含む、[16]又は[17]に記載の方法。
[20]
対象の免疫反応を刺激する方法であって、[1]~[9]又は[15]のいずれか1項に記載の可溶性融合タンパク質複合体の有効量を対象に投与することを含む方法。
[21]
治療を必要とする対象の新生組織形成、感染症又は自己免疫性疾患の治療方法であって、前記対象に[1]~[15]又は[17]のいずれか1項に記載の可溶性融合タンパク質複合体を含む医薬組成物の有効量を投与することを含み、それにより前記新生組織形成、感染症又は自己免疫性疾患を治療することを含む方法。
[22]
前記新生組織形成が、膠芽腫、前立腺癌、血液のがん、B細胞新生物、多発性骨髄腫、B細胞リンパ腫、B細胞非ホジキンリンパ腫、ホジキンリンパ腫、急性リンパ性白血病、急性骨髄性白血病、皮膚T細胞性リンパ腫、T細胞リンパ種、充実性腫瘍、尿路上皮/膀胱腫瘍、黒色腫、肺癌、腎細胞癌、乳癌、胃癌及び食道癌、前立腺癌、膵癌、結腸直腸癌、卵巣癌、非小細胞肺癌、並びに頭部及び頸部の扁平上皮癌からなる群から選択される、[21]に記載の方法。
[23]
前記有効量が約1~100μg/kg間の前記融合タンパク質複合体である、[21]又は[22]に記載の方法。
[24]
前記融合タンパク質複合体が少なくとも1週間に1回投与される、[21]又は[22]に記載の方法。
[25]
前記医薬組成物が全身、局所、静脈内、皮下又は腫瘍内に投与される、[21]~[24]のいずれか1項に記載の方法。
[26]
前記融合タンパク質複合体が対象の免疫反応を誘発する、[21]~[25]のいずれか1項に記載の方法。
[27]
前記融合タンパク質複合体が免疫細胞の増殖を増加させる、[21]~[26]のいずれか1項に記載の方法。
[28]
前記融合タンパク質複合体が、前記新生物形成、感染症又は自己免疫性疾患に関連した細胞に対する免疫細胞の反応を刺激する、[21]~[27]のいずれか1項に記載の方法。
[29]
配列番号:1、3、5、7、9、11、13、15、17、19、21、23、25、27、29、31、33、35、37、35、39、41、43、45、47、48、49又は50を含む核酸配列。
[30]
配列番号:2、4、6、8、9、10、12、14、16、18、20、22、24、26、28、30、32、34、36、38、40、42、44、46、51、52、53又は54を含むペプチド。
[31]
ヒト免疫不全ウイルス(HIV)感染を予防又は治療する方法であって、配列番号:51、52、53又は54を含む可溶性融合タンパク質複合体の治療上の有効量を含む組成物を対象に投与することを含む方法。
[32]
[1]~[9]又は[15]のいずれか1項に記載の単離された可溶性融合タンパク質複合体、[10]、[12]又は[29]のいずれか1項に記載の核酸配列、[14]に記載のDNAベクター、[30]に記載のペプチド配列を含む医薬組成物。
Claims (4)
- 少なくとも2の可溶性タンパク質を含む単離された可溶性融合タンパク質複合体であって、
第一の可溶性タンパク質がインターロイキン-15(IL-15)ポリペプチドドメインを含み、かつ第二の可溶性タンパク質がイムノグロブリンFcドメインと融合した可溶性のIL-15受容体αスシ結合ドメイン(IL-15RαSu)であって、
第一の可溶性タンパク質が結合ドメインを含み、免疫チェックポイント分子又は免疫シグナル分子と特異的に結合し、配列番号2または配列番号6に示されるアミノ酸配列と実質的に同一であって、
第一の可溶性タンパク質のIL-15ポリペプチドドメインが第二の可溶性タンパク質のIL-15RαSuドメインと結合して可溶性融合タンパク質複合体を形成する、
可溶性融合タンパク質複合体。 - 第一又は第二の可溶性タンパク質のうちの1つが疾患の抗原、免疫チェックポイント分子又は免疫シグナル分子と特異的に結合する第二の結合ドメインをさらに含む、請求項1に記載の可溶性融合タンパク質複合体。
- 前記第二の結合ドメインが、プログラム細胞死リガンド(PD-L1)、プログラム細胞死1(PD-1)、細胞傷害性Tリンパ球に関連したタンパク質4(CTLA-4)、分化抗原群33(CD33)、分化抗原群47(CD47)、グルココルチコイドに誘発される腫瘍壊死因子受容体(TNFR)群に関する遺伝子(GITR)、リンパ球機能に関連した抗原1(LFA-1)、組織因子(TF)、デルタ様タンパク質4(DLL4)、一本鎖DNA又はT細胞イムノグロブリン及びムチンドメイン含有-3(Tim-3)を含む1又はそれ以上の分子と特異的に結合する、請求項2に記載の可溶性融合タンパク質複合体。
- 第二の可溶性タンパク質が配列番号:4、8、12、14、16、22、26、30、34、36、40、42、44、46、51、52、53又は54のうちの1つに示されたアミノ酸配列を含む、請求項1~3のいずれか1項に記載の可溶性融合タンパク質複合体。
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CN118562016A (zh) | 2024-08-30 |
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CA3200275A1 (en) | 2018-04-26 |
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EP3529263A1 (en) | 2019-08-28 |
IL266100A (en) | 2019-06-30 |
SG11201903306SA (en) | 2019-05-30 |
IL266100B2 (en) | 2023-02-01 |
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