JP2021518761A - 配列類似性19、メンバーa5抗体を有する抗ファミリー及びその使用方法 - Google Patents
配列類似性19、メンバーa5抗体を有する抗ファミリー及びその使用方法 Download PDFInfo
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Abstract
Description
本明細書全体において、単数の表現は、1つ以上を意味する。例えば、“抗体”は1つ以上の抗体を表すものと理解される。このように、本明細書において単数の表現は“1つ以上の”及び“少なくとも1つの”と同じ意味で使用可能である。
MAPSPRTGSR QDATALPSMS STFWAFMILA
SLLIAYCSQL AAGTCEIVTL DRDSSQPRRT
IARQTARCAC RKGQIAGTTR ARPACVDARI
IKTKQWCDML PCLEGEGCDL LINRSGWTCT
QPGGRIKTTT VS(SEQ ID NO:1)
(II)アイソタイプ2(UniProt:Q7Z5A7−2、可溶性タンパク質):
MQLLKALWAL AGAALCCFLV LVIHAQFLKE
GQLAAGTCEI VTLDRDSSQP RRTIARQTAR
CACRKGQIAG TTRARPACVD ARIIKTKQWC
DMLPCLEGEG CDLLINRSGW TCTQPGGRIK
TTTVS(SEQ ID NO:2)
(III)アイソタイプ3(UniProt:Q7Z5A7−3):
MYHHREWPAR IIKTKQWCDM LPCLEGEGCD
LLINRSGWTC TQPGGRIKTT TVS(SEQ ID NO:3)
用語“FAM19A5”は、細胞によって自然的に発現するFAM19A5の任意の変異体又はアイソタイプを含む。したがって、本明細書に開示された抗体は同種の異なるアイソタイプ(例えば、ヒトFAM19A5の各アイソタイプ)と交差反応できるか、又はヒト以外の種のFAM19A5(例えば、マウスFAM19A5)と交差反応することができる。代案として、抗体はヒトFAM19A5に特異的であり得、他の種とは交差反応性を示さないことがある。FAM19A5又はその任意の変異体及びアイソタイプは、それらを自然的に発現する細胞又は組織から単離したり又は組換え的に生成され得る。ヒトFAM19A5を暗号化するポリヌクレオチドはGenBank受託番号BC039396を有し、次の配列を有する:
“Fc受容体”又は“FcR”は、免疫グロブリンのFc領域に結合する受容体である。IgG抗体に結合するFcRはFcγRファミリーの受容体を含み、これらの受容体の対立形質変異体及び他の方式でスプライシングされた形態を含む。FcγRファミリーは、3個の活性化受容体(マウスにおいてFcγRI、FcγRIII、及びFcγRIV;ヒトにおいてFcγRIA、FcγRIIA、及びFcγRIIIA)と一つの抑制受容体(FcγRIIB)で構成される。ヒトIgG1は大部分のヒトFc受容体と結合し、最も強いFcエフェクター機能を導出する。ヒトIgG1が結合する活性化Fc受容体の種類に対してはマウスIgG2aと同等であると見なされる。一方、ヒトIgG4は最小限のFcエフェクター機能を導出する(Vidarsson G et al.,Front Immunol.5:520(2014年10月20日オンライン公開)参照)。
本発明では、特定の機能的特徴又は特性を特徴とする抗体、例えば単クローン性抗体(monoclonal antibody)を開示する。例えば、ヒトFAM19A5に特異的に結合する抗体は、ヒトにおいて免疫性が高い(すなわち、脱免疫化された)領域又は残基を除去及び/又は変形することによって突然変異(例えば、置換又は除去)された。したがって、本明細書に開示された抗体、すなわち抗FAM19A5抗体は、基準抗体(例えば、脱免疫化されていない相応する抗体、例えば1−65抗体)と比較して、ヒト対象に投与される時に免疫原性を減少させた。
(a)10nM以下のKDを有する可溶性ヒトFAM19A5に結合し;
(b)10nM以下のKDを有する膜結合したヒトFAM19A5に結合し;
(c)反応性神経膠症の発病を減少、逆転、遅延及び/又は予防し;
(d)反応性星状細胞の過度な増殖を抑制し;
(e)ニューロカン及びニューロン膠細胞抗原2(NG2)を含むコンドロイチン硫酸プロテオグリカンの発現を減少させ;
(f)ニューロンの核でc−fos及びpERKの発現を増加させ;
(g)ニューロンの生存を促進し;
(h)ニューロンでGAP43の発現を増加させ;及び
(i)軸索の再成長を促進する。
本発明の他の態様は、明細書で記述された抗体のいずれか一つを暗号化する1つ以上の核酸分子に関する。核酸は全体細胞に、細胞溶解物に、又は部分的に精製された形態や実質的に純粋な形態で存在し得る。核酸は、アルカリ性/SDS処理、CsClバンディング(banding)、カラムクロマトグラフィー、制限酵素、寒天ゲル電気泳動及び当業界に公知の他の技術を含む標準技術によって、他の細胞成分又は他の汚染物、例えば他の細胞核酸(例えば、他の染色体DNA、例えば自然で単離したDNAに連結された染色体DNA)又はタンパク質から精製されたとき、“単離したり”又は“実質的に純粋である”(F Ausubel,et al,,ed.(1987)Current Protocols in Molecular Biology,Greene Publishing and Wiley Interscience,New York参照)。本明細書に開示された核酸は、例えばDNA又はRNAであり得、イントロン配列を含有してもよく、含有しなくてもよい。特定の実施形態において、核酸はcDNA分子である。
FAM19A5に免疫特異的に結合する抗体又はその断片(例えば、ヒトFAM19A5)は、抗体の合成のために当業界に公知の任意の方法、例えば化学的合成又は組換え発現技術によって生成され得る。本明細書に開示された方法は、特に言及がない限り、分子生物学、微生物学、遺伝子分析、組換えDNA、有機化学、生化学、PCR、オリゴヌクレオチド合成及び変形、核酸混成化、及び当業界技術範囲内の関連分野の従来の技術を利用する。これらの技術は、例えば本明細書で引用された参考文献に詳細に説明されている(例えば、Maniatis T et al.,(1982)Molecular Cloning:A Laboratory Manual,Cold Spring Harbor Laboratory Press;Sambrook J et al.,(1989),Molecular Cloning:A Laboratory Manual,Second Edition,Cold Spring Harbor Laboratory Press;Sambrook J et al.,(2001)Molecular Cloning:A Laboratory Manual,Cold Spring Harbor Laboratory Press,Cold Spring Harbor,NY;Ausubel FM et al.,Current Protocols in Molecular Biology,John Wiley & Sons(1987 and annual updates);Current Protocols in Immunology,John Wiley & Sons(1987 and annual updates)Gait(ed.)(1984)Oligonucleotide Synthesis:A Practical Approach,IRL Press;Eckstein(ed.)(1991)Oligonucleotides and Analogues:A Practical Approach,IRL Press;Birren B et al.,(eds.)(1999)Genome Analysis:A Laboratory Manual,Cold Spring Harbor Laboratory Press参照)。
上記論議された通り、本明細書に開示されたVH及びVL配列を有する抗FAM19A5抗体は、VH及び/又はVL配列、又はこれに付着された定常領域を変形させることによって新しい抗FAM19A5抗体を生成するために利用可能である。したがって、本明細書に開示された他の態様において、本明細書に開示された抗FAM19A5抗体の構造的特徴は、本明細書に開示された抗体の少なくとも1つの機能的特性、例えばヒトFAM19A5への結合を保有する構造的に関連した抗FAM19A5抗体を生成するために用いられる。例えば、操作方法の出発物質は、本明細書に提供のVH及び/又はVL配列、又はその1つ以上のCDR領域である。操作された抗体を生成するために、本明細書に提供された1つ以上のVH及び/又はVL配列又はその1つ以上のCDR領域を有する抗体を実際に製造(すなわち、タンパク質として発現)する必要はない。むしろ、配列に含まれた情報は出発物質として用いられて、元来の配列から由来した“第2世代”配列を生成した後、“第2世代”配列を製造し、タンパク質として発現する。
(a)(i)表3に提示されたCDR1、CDR2及び/又はCDR3配列、又は表5に提示された重鎖可変領域のCDR1、CDR2及び/又はCDR3を含む重鎖可変領域配列;及び(ii)表4に提示されたCDR1、CDR2及び/又はCDR3配列、又は表6に提示された重鎖可変領域のCDR1、CDR2及び/又はCDR3を含む軽鎖可変領域配列を提供する段階;
(b)少なくとも1つの変更された抗体配列を生成するために重鎖可変領域配列及び/又は軽鎖可変領域配列内に少なくとも1つのアミノ酸残基を変更させる段階;及び
(c)変更された抗体配列をタンパク質として発現させる段階。
(1)ヒト対象で減少した免疫原性;
(2)例えば、Biacoreによって測定される時、10nM以下(例えば、0.01nM〜10nM)のKDを有する可溶性ヒトFAM19A5への結合;
(3)例えば、ELISAによって測定される時、10nM以下(例えば、0.01nM〜1nM)のKDを有する膜結合したヒトFAM19A5への結合;
(4)例えば、ELISAによって測定される時、1nM以下(例えば、0.01nM〜1nM)のEC50を有する膜結合したヒトFAM19A5への結合;
(5)反応性神経膠症の発病減少、逆転、遅延及び/又は予防;
(6)反応性星状細胞の過度な増殖抑制;
(7)ニューロカン及びニューロン−神経膠抗原2(NG2)を含むコンドロイチン硫酸プロテオグリカンの発現減少;
(8)ニューロンの核でc−fos及びpERKの発現増加;
(9)ニューロンの生存促進;
(10)ニューロンでGAP43の発現増加;
(11)軸索の再成長促進;及び
(12)本明細書に開示された抗FAM19A5抗体を有するヒトFAM19A5に結合するためのいずれか一方向又は両方向競合。
特定の態様において、本発明は、FAM19A5(例えば、ヒトFAM19A5)及び関連ポリヌクレオチド及び発現ベクターに特異的に結合する本明細書に記述された抗体(又はその抗原結合断片)を発現させる(例えば、組換え的に)細胞(例えば、宿主細胞)(又はその抗原結合断片)を提供する。本発明は抗FAM19A5抗体を暗号化するヌクレオチド配列又は宿主細胞、例えば哺乳動物細胞における組換え発現のための断片を含むポリヌクレオチドを含むベクター(例えば、発現ベクター)を提供する。本発明はまた、本明細書に記述された抗FAM19A5抗体(例えば、ヒト又はヒト化した抗体)を組換え的に発現させるための当該ベクターを含む宿主細胞を提供する。特定の態様において、本発明は、宿主細胞からこのような抗体を発現させる、本明細書に記載された抗体の製造方法を提供する。
本明細書に記載された抗体は、例えば標準ELISAによってFAM19A5への結合に対して試験できる。簡単にいうと、微量定量(microtiter)プレートをPBS中の1〜2μg/ml精製FAM19A5でコーティングした後、PBS中の5%ウシ血清アルブミンで遮断した。抗体の希釈液(例えば、FAM19A5−免疫化されたマウスからの血漿の希釈液)を各ウェルに添加して37℃で1〜2時間培養する。プレートをPBS/Tweenで洗浄した後、37℃で1時間ホースラディッシュペルオキシダーゼ(HRP)に共役結合した2次試薬(例えば、ヒト抗体の場合、ヤギ−抗ヒトIgG Fc特異的多クローン性試薬)と共に培養する。洗浄後、プレートにABTS基質(Moss Inc.、製品:ABTS−1000)を展開し、OD 415〜495で分光光度計で分析した。免疫化されたマウスからの血清は次に、ヒトFAM19A5を発現する細胞株に結合するために流動細胞測定法によってさらにスクリーニングされるが、FAM19A5を発現しない対照群細胞株には結合しない。簡単にいうと、1:20希釈でFAM19A5発現CHO細胞を抗FAM19A5抗体と共に培養することによって抗FAM19A5抗体の結合を評価する。細胞を洗浄し、PE標識された抗ヒトIgG Abで結合を検出した。流細胞(flow cytometric)分析はFACScan流細胞分析(Becton Dickinson,San Jose,CA)を用いて行われる。好ましくは、最高の力価を発生させるマウスが融合に用いられるだろう。
本明細書に記載された抗体は、二重特異的分子を形成するのに用いられ得る。抗FAM19A5抗体又はその抗原結合部分は、他の機能性分子、例えば他のペプチド又はタンパク質(例えば、受容体に対する他の抗体又はリガンド)に誘導されたり連結されて少なくとも2個の互いに異なる結合部位又は標的分子に結合する二重特異性分子を生成することができる。IL−6、CNTF、LIF、EGF及びTGFaのようなサイトカインはタンパク質信号トランスデューサー(transducer)及び転写3の活性化剤(STAT3)を活性化させることによって神経膠症及び/又は反応性星状膠細胞症(astrogliosis)の発病のトリガーとして関与してきており(Balasingam et al.,J.Neurosci.l4(2):846−56(1994);Winter et al.,Proc.Natl.Acad.Sci.U SA 20;92(13):5865−9(1995))、これは、CNS損傷後反応性星状膠細胞症の多い様相を調節する。Herrmann J.E.et al.,J.Neurosci.28(28):7231−7243(2008)。例えば、STAT3の不在又は減少は膠細胞繊維酸性タンパク質(GFAP)の弱化した上向き調節、星状細胞肥大の失敗、及び炎症の拡散増加、病変体積増加及びCNS損傷後部分的に弱化した運動回復を招く。Herrmann J.E.et al.,J.Neurosci.28(28):7231−7243(2008)。したがって、例えば、抗FAM19A5抗体は、組合せ治療のための神経膠症の発病及び/又は反応性星状膠細胞症の過度な増殖に関与する任意のタンパク質に特異的に結合する抗体又はscFv、例えばIL−6、CNTF、LIF、EGF又はTGFaに対する抗体に連結され得る。
一実施形態において、抗FAM19A5抗体に付着されたモイエティは、結合モイエティ、標識モイエティ及び生物学的活性モイエティからなる群から選ばれる。
生理学的に許容される担体、賦形剤又は安定剤(Remington’s Pharmaceutical Sciences(1990)Mack Publishing Co,Easton,PA)のうち、所望する程度の純度を有する本明細書に開示された方法に有用な抗体又はその抗原結合部分を含む組成物が開示される。許容される担体、賦形剤又は安定剤は、用いられた投薬量及び濃度において受領者に非毒性であり、緩衝剤、例えばホスフェート、シトレート及び他の有機酸;アスコルビン酸及びメチオニンを含む抗酸化剤;保存剤(例えば、オクタデシルジメチルベンジルアンモニウムクロリド;ヘキサメトニウムクロリド;ベンザルコニウムクロリド;ベンゼトニウムクロリド、フェノール、ブチル又はベンジルアルコール;アルキルパラベン、例えばメチル又はプロピルパラベン;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);低分子量(約10個未満の残基)ポリペプチド;タンパク質、例えば血清アルブミン、ゼラチン、又は免疫グロブリン;親水性重合体、例えばポリビニルピロリドン;アミノ酸、例えばグリシン、グルタミン、アスパラギン、ヒスチジン、アルギニン、又はリシン;単糖類、二糖類、及びグルコース、マンノース、又はデキストリンを含む他の炭水化物;キレート化剤、例えばEDTA;糖、例えばスクロース、マンニトール、トレハロース又はソルビトール;塩形成対イオン(salt−forming counter−ions)、例えばナトリウム;金属複合体(例えば、Zn−タンパク質複合体);及び/又は非イオン界面活性剤、例えばTWEEN(登録商標)、PLURONICS(登録商標)又はポリエチレングリコール(PEG)を含む。
本明細書に記載の1つ以上の抗体、又はその抗原結合部分、二重特異的分子、又はその免疫接合体を含むキットが提供される。特定の実施形態において、本明細書に開示された1つ以上の抗体又はその抗原結合部分のような、製薬学的組成物の成分のうち1つ以上で満たされた1つ以上の容器、選択的な使用説明書を含む製薬学的パック又はキットが提供される。一部の実施形態において、キットは、本明細書に開示された製薬学的組成物及び任意の予防又は治療剤を含有する。
本発明は、本明細書に記載された抗FAM19A5抗体、二重特異的分子又は免疫接合体、又はそれらの組成物をそれを必要とする対象(例えば、ヒト)に投与することを含む、対象でCNSの損傷又は傷害を緩和させる方法を提供する。
実施例1:ヒトFAM19A5タンパク質の発現及び精製
組換えヒトFAM19A5タンパク質を下に説明されたとおりに生成して精製し、この精製されたタンパク質を結合親和性分析に基づく抗体スクリーニング分析に使用した。まず、FAM19A5遺伝子を発現するLPS−hTプラスミドをバクテリアに形質転換し、タンパク質過発現を誘導した。生成されたFAM19A5タンパク質をNi−NTA親和性クロマトグラフィー(Qiagen,Valencia,CA,USA)を用いて精製した。イミダゾールを漸次高い濃度で使用してNi−カラムからHis−タグされたFAM19A5タンパク質を除去した。溶液中タンパク質発現をクマシーブリリアントブルー(Coomassie Brilliant Blue)R−250染料を用いて測定した。FAM19A5イミダゾール含有溶液だけを取り、PBSを用いてFAM19A5タンパク質を濃縮した。濃縮が完了した時、FAM19A5タンパク質の純度と濃度をウェスタンブロット分析を用いて測定した。次いで、濃縮されたタンパク質を用いてFAM19A5−特異的抗体に対してスクリーニングした。
1.免疫化
FAM19A5タンパク質をニワトリの免疫化のための抗原として使用した。合成ペプチドKLH共役結合体(conjugate)50μgを750μLリン酸緩衝食塩水(PBS)に混合し、37℃で30分間インキュベーションした。その後、2%スクアレン内毒素MPL(モノホスホリレート脂質A種)から毒素を除去し、油中水(water in oil)エマルジョン補助剤(RIBI+MPL+TDM+CWS補助剤、Sigma,St Louis,Mo,USA)を含有するTDW及びCWSの細胞壁成分のミコバクテリアをエマルジョン化し、その後、3匹のニワトリ及び4匹のウサギに皮下注射した。ニワトリ及びウサギは免疫化中に略2〜3週間隔で総3回及び4回免疫化した。FAM19A5タンパク質を過発現させたHEK293T細胞の細胞溶離液を用いて、免疫化された動物から得られた抗体の力価(titer)を免疫ブロッティングを用いて測定した。
TRI試薬(Invitrogen,Carlsbad,CA,USA)を用いて、前記説明された免疫化されたニワトリの脾臓、骨髄及び滑液嚢(synovial sac)からRNAを抽出した。Oligo−dTプライマーとSUPERSCRIPTTMIII第1鎖合成システム(First−Strand Synthesis System)(Invitrogen)を用いて第1鎖cDNAを合成した。動物の免疫システムから得られたcDNAに対して、拡張型高忠実度PCRシステム(Expand High Fidelity PCR System)(Roche Molecular Systems,IN,USA)を用いて単鎖可変領域ライブラリーを生成した。各反応においてcDNA 1μL、各プライマー60pmol、10倍反応緩衝溶液10μL、8μLの2.5mM dNTP(Promega,Madison,WI,USA)、及びTaq DNA重合酵素0.5μLを水と混合した。最終体積は100μLであった。PCR反応を次の条件を用いて行った:30サイクル(i)94℃で15秒、(ii)56℃で30秒、及び(iii)72℃で90秒、その後72℃で10分間最終延長。約350bpの長さを有する断片を含むPCR生成物を1.5%寒天ゲル上にローディングし、電気泳動後にQIAGEN Gel II抽出キット(QIAGEN,Valencia,CA,USA)を用いてヌクレオチド断片を精製した。精製されたPCR生成物をOD 260nmで読み取って定量した(1ユニットOD=50μL/mL)。
PCR生成物のscFv断片とベクターpComb3X−SS(The Scripps Research Institute CA,USA)をSfiI制限酵素で切断(digest)した。精製された重複PCT生成物10μgをSfiI 360ユニット(16ユニット当たりμg DNA,Roche Molecular Systems,Pleasanton,CA,USA)、10倍反応緩衝液20μL及び水と混合して最終体積200μLにした。pComb3X−SSベクター20μgをSfiI 120ユニット(6ユニット当たりμg DNA)、10倍反応緩衝液20μL及び水と混合して最終体積200μLにした。混合物を50℃で8時間切断した。その後、scFv断片(約700bp)及びベクター(約3,400bp)を含む切断された生成物を1%寒天ゲル上にローディングし、ゲル抽出キットII QIAGEN(QIAGEN,Valencia,CA,USA)を用いて精製した。SfiI−制限されたpComb3Xベクター1,400ngと切断されたscFv断片700ngを5倍リガーゼ緩衝液、10μLのT4DNAリガーゼ(Invitrogen,Carlsbad,CA,USA)及び水と混合して最終体積200μLにした。混合物を16℃で16時間インキュベーションしてライゲーションを行った。
磁気ビーズ(Dynabeads M−270 Epoxy,Invitrogen)を用いてバイオパンニングを行った。室温で約1×107ビーズを組換えFAM19A5タンパク質5μgで室温で20時間ビーズとタンパク質を共に回転撹拌してコーティングした。コーティングが完了するとビーズをリン酸緩衝食塩水(PBS)で4回洗浄し、室温で3% BSAを含有するPBS中で1時間遮断した。その後、コーティングされたビーズを前記説明されたファージディスプレイされたscFvと共に室温で2時間培養した。抗原コーティングされたビーズに結合しないファージを除去するために、ビーズを0.05% Tween 20/PBSで洗浄した。その後、結合したファージを50μLの0.1Mグリシン/塩化水素(0.1Mグリシン−HCl、pH2.2)で溶出し、塩化水素と共に2M Tris(Tris−HCl、pH9.1)3μLで中和した。このファージ含有上澄液を用いて大腸菌ER2738細胞を感染させ、VCSM13ヘルパーファージを用いて一晩増幅し救済(rescue)した。また、50μg/mLカナマイシンを含有するLB寒天板上にファージ−感染された培養物をブロット(blotting)することによって、ファージ−感染された培養物からのファージ力価によって投入(インプット)及び生成(アウトプット)を決定した。翌日、PEG−8000及びNaClを用いてファージを沈殿させ、次いでこれをバイオパンニングに使用した。バイオパンニングは、前記過程を反復することによって最大で総5回行った。各増幅においてファージをスクリーニングし、FAM19A5タンパク質に対する高い親和性のために選択した。
バイオパンニングから選択されたクローンを分析するために、ファージディスプレイされたscFvから個別クローンを無作為に選択し、ELISAを用いてクローンがFAM19A5組換えタンパク質に結合することを確認した。FAM19A5組換えタンパク質を0.1M NaHCO3緩衝剤に希釈し、タンパク質をウェル当たり100ngを用いて16時間4℃で96ウェル微量定量プレートをコーティングした。翌日、プレートを1時間37℃で3% BSA/PBSで遮断した。その後、ファージ上澄液を6% BSA/PBSと混合し、37℃で2時間培養した。その後、上澄液を含有するプレートを0.05% Tween 20/PBSで洗浄した。HRP−共役結合したM13抗体(a−M13−HRP,Pierce Chemical Co,Rockford,IL,USA)を1/5,000に希釈した。希釈された抗体50μLをプレートに添加し、37℃で1時間インキュベーションした。インキュベーション及び洗浄後、色展開(color development)のためにプレートに0.05Mクエン酸緩衝溶液、1μg/mLの2,2’−アジノ−ビス(3−エチルベンゾチアゾリン−6−スルホン酸)(ABTS,Amresco,Solon,OH,USA)、及び0.1% H2O2を添加した。各ウェルに対する吸光度を405nmで測定した。
1.抗FAM19A5抗体(クローン1−65)の脱免疫化
ヒト対象に投与される時、免疫原性の危険を減少させるために、抗FAM19A5抗体(例えば、1−65)内で高い免疫原性の特定領域を確認するためにシリコ(silico)分析(EpiScreen Immunogenicity Analysis,Antitope Ltd.,UK)を行った。無差別(promiscuous)MHCクラスII結合ペプチドを確認するために、iTopeTM(Abzena plc.,UK)を全配列にわたって重なった9−merペプチドに対して行った。潜在的なT細胞エピトープは、34個の異なるMHCクラスII対立遺伝子に対する相互作用の分析によって予測された。クローン1−65は総13個の非ジャームライン無差別MHCクラスII結合ペプチドを含有した(図2)。1−65抗体及びSS01−13(すなわち、脱免疫化後1−65抗体)の重鎖可変領域及び軽鎖可変領域の配列整列が図1A及び図1Bにそれぞれ提供されている。
複合抗体ライブラリーは、免疫原性と関連したCD4+T細胞エピトープを回避するように設計されている。ライブラリー構築のために最も相同性であるヒトジャームラインを選択するために、クローン1−65のフレームワークをIgBLASTデータベース(NCBI)で分析した。ヒトジャームラインIGLV3−25*02、IGLJ2*01、IGHV3−23*02及びIGHJ1*01遺伝子は、クローン1−65に対して選択された(図1)。最も相同性であるヒトジャームライン配列においてクローン1−65の同一でない特定アミノ酸残基MHCクラスII結合領域を相応するアミノ酸に置き換えるようにライブラリーを構築した。特に、ペプチド中のp1、p4、p6、p7及びp9残基は、MHCクラスII対立遺伝子の結合グルーブ(groove)との相互作用に重要である(James EA,Moustakas AK,Bui J,Nouv R,Papadopoulos GK,Kwok WW.J Immunol.2009;183(5):3249−58)。
陽性クローンを単離させるために、バイオパンニング及びファージ酵素免疫分析を前述のように行った(Barbas CF.Phage display:実験室説明書。Cold Spring Harbor,NY:Cold Spring Harbor Laboratory Press:2001)。FAM19A5に対する反応性を有するファージクローンを選択し、そのヌクレオチド配列をサンガー(sanger)配列化によって決定した。FAM19A5に対する親和性が維持される最も少ない数の無差別MHCクラスII結合エピトープを有するscFvクローンが最終的に選択された。
部位指向された突然変異誘発ライブラリーを構築するために、クローン1−65scFvを暗号化する遺伝子をPCRの鋳型として用いた。CDR−H2のS53は、前述したようにNNK変性コドン(N=A、T、G又はC、K=G又はT)を暗号化するオリゴヌクレオチドで無作為化された(Lee HK,Jin J,Kim SI,Kang MJ,Yi EC,Kim JE et al.,Biochem Biophys Res Commun.2017;493(1):325−31)。重複延長PCRによって増幅されたscFv断片を前記ファージミドベクター内にサブクローニングし、上述したようにファージ製造のためにER2738(New England BioLabs)内に形質転換させた。
本明細書に開示された個別のる抗FAM19A5抗体のFAM19A5タンパク質に対する結合親和度をさらに評価するために、SPR及びELISA分析をともに用いた。
本明細書に開示された抗FAM19A5抗体が特定免疫細胞の食細胞能に影響を及ぼすか否かを評価するために、BV細胞(固定化したネズミ小膠細胞株)を使用した。簡単にいうと、BV2細胞を96−ウェルプレート(5×103/100μL/ウェル)上にプレーティングし、6時間37℃の5% CO2でインキュベーションした。次いで、細胞をヒトFAM19A5−Fcタンパク質(0.25μM、ロット番号170815)単独で又は抗FAM19A5抗体1−65、SS01−13−S5又はS5−SGの様々な濃度(3.125μg/mL、6.25μg/mL、12.5μg/mL又は25μg/mL)に組み合わせて処理した。対照群の細胞をPBS単独で処理した。処理された細胞をさらに16時間37℃の5% CO2でインキュベーションした。インキュベーション後、PHRODOTMGreen E.coli BioParticles(Thermofisher,P35366)を細胞に添加した(15μg/100μL/ウェル)。その後、INCUCYTE(登録商標)(Sartorius)を用いて1時間ごとに緑色蛍光強度を測定し、BioParticlesの食細胞吸収を観察した。
本明細書に開示された抗FAM19A5抗体の生体内機能を評価するために、外傷性脳損傷(TBI)マウスモデルが用いられ得る。簡単にいうと、マウスに個別の抗FAM19A5抗体が投与されるだろう。TBI誘導(TBI5D)後に動物を犠牲させることができる。抗FAM19A5抗体の効果、例えば、外傷性脳損傷後ペナンブラ(penumbra)部位の反応性神経膠症の発病が測定されるだろう。
本開示内容の抗FAM19A5抗体の抗癌効果を評価するために、誘導性マウス黒色腫モデルが用いられ得る。簡単にいうと、黒色腫は、雄Tyr::CreER;Braf+/+;Ptenlox/loxマウス(Jackson Lab,USA)を雌Tyr::CreER;BrafCA/CA;Ptenlox/loxと交配することによってTyr::CreER;BrafCA/+;Ptenlox/loxマウスを生産することができる。Dankort D.,et al.,Nat Genet 41(5):544−52(2009)参照。黒色腫は出生後約7週目に自発的に誘導されるだろう。マウスは、腫瘍体積及び黒色腫の数によって分類され得る。
本明細書に開示された抗FAM19A5抗体の生体内機能を評価するために、慢性収縮損傷(CCI)のマウスモデルが用いられ得る。簡単にいうと、マウスには個別の抗FAM19A5抗体が投与され得る。次いで、投与して約1週後に陰嚢神経ライゲーションによって末梢神経損傷が動物で誘導され得る。損傷後に様々な時点で、機械的異痛(allodynia)(物理的外部刺激に対する反応)及び熱痛覚過敏(hyperalgesia)(温度上昇に対する反応)がともに動物で評価され得る。機械的異痛はボンフレイ(Von Frey)モノフィラメント(0.16g)を損傷した足に複数回適用し、動物が疼痛に反応する頻度を観察して評価される。熱痛覚過敏はハーグリーブス(Hargreaves)試験を用いて評価され、ここで、放射形熱刺激(強度:30)が損傷した足に適用され、足引っ込め遅延時間が決定される。
Claims (62)
- 重鎖CDR1、CDR2及びCDR3、及び軽鎖CDR1、CDR2及びCDR3を含む配列類似性19、メンバーA5(FAM19A5)タンパク質(“抗FAM19A5抗体”)を有するヒトファミリーに特異的に結合する単離した抗体又はその抗原結合部分であって、重鎖CDR1、CDR2及びCDR3はそれぞれ、SEQ ID NO:5、6及び7に提示されたアミノ酸配列を含み、これらのそれぞれは任意に1個、2個又は3個の突然変異を含み、軽鎖CDR1はCDR2及びCDR3はそれぞれ、SEQ ID NO:8、9及び10のアミノ酸配列を含み、軽鎖CDR1、CDR2及びCDR3のうち少なくとも1つは1個、2個又は3個の突然変異を含み、及び、抗体はSEQ ID NO:11として提示されたVH及びSEQ ID NO:12として提示されたVLを含む基準抗体に比べてヒトにおいて減少した免疫原性を有することを特徴とする、単離した抗体又はその抗原結合部分。
- 重鎖CDR3がSEQ ID NO:7に提示されたアミノ酸配列(GSASYITAATIDA)を含むことを特徴とする、請求項1に記載の抗体。
- 重鎖CDR1が任意に1個、2個又は3個の突然変異と共に、SEQ ID NO:5に提示されたアミノ酸配列(SYQMG)を含むことを特徴とする、請求項1又は2に記載の抗体。
- 重鎖CDR2が任意に1個、2個又は3個の突然変異と共に、SEQ ID NO:6に提示されたアミノ酸配列(VINKSGSDTS)を含むことを特徴とする、請求項1〜3のいずれかに記載の抗体。
- 突然変異がSEQ ID NO:6のアミノ酸1においてバリンの脂肪族アミノ酸への置換を含むことを特徴とする、請求項4に記載の抗体。
- 突然変異がSEQ ID NO:6のアミノ酸5においてセリンの脂肪族アミノ酸への置換を含むことを特徴とする、請求項4又は5に記載の抗体。
- 脂肪族アミノ酸がアラニン又はグリシンを含むことを特徴とする、請求項5又は6に記載の抗体。
- 軽鎖CDR3が任意に1個、2個又は3個の突然変異と共に、SEQ ID NO:10に提示されたアミノ酸配列(GNDDYSSDSGYVGV)を含むことを特徴とする、請求項1〜7のいずれかに記載の抗体。
- 軽鎖CDR1が1個、2個又は3個の突然変異と共に、SEQ ID NO:8に提示されたアミノ酸配列(SGGGSSGYGYG)を含むことを特徴とする、請求項1〜8のいずれかに記載の抗体。
- 突然変異がSEQ ID NO:8のアミノ酸4においてグリシンの脂肪族アミノ酸への置換を含むことを特徴とする、請求項9に記載の抗体。
- 脂肪族アミノ酸は、アラニン、バリン、ロイシン又はイソロイシンを含むことを特徴とする、請求項10に記載の抗体。
- 軽鎖CDR2は1個、2個、3個又は4個の突然変異と共に、SEQ ID NO:9(WNDKRPS)に提示されたアミノ酸配列を含むことを特徴とする、請求項1〜11のいずれかに記載の抗体。
- 突然変異はSEQ ID NO:9のアミノ酸1においてトリプトファンの塩基性アミノ酸への置換を含むことを特徴とする、請求項12に記載の抗体。
- 塩基性アミノ酸がアルギニン、ヒスチジン又はリシンを含むことを特徴とする、請求項13に記載の抗体。
- 突然変異がSEQ ID NO:9のアミノ酸2においてアスパラギンの酸性アミノ酸への置換を含むことを特徴とする、請求項12〜14のいずれかに記載の抗体。
- 酸性アミノ酸はアスパラギン酸又はグルタミン酸を含むことを特徴とする、請求項15に記載の抗体。
- 突然変異はSEQ ID NO:9のアミノ酸3においてアスパラギン酸のヒドロキシル又は硫黄/セレニウム含有アミノ酸への置換を含むことを特徴とする、請求項12〜16のいずれかに記載の抗体。
- ヒドロキシル又は硫黄/セレニウム含有アミノ酸がセリンを含むことを特徴とする、請求項17に記載の抗体。
- 突然変異はSEQ ID NO:9のアミノ酸4においてリシンの酸性アミノ酸への置換を含むことを特徴とする、請求項12に記載の抗体。
- 酸性アミノ酸はアスパラギン酸又はグルタミン酸を含むことを特徴とする、請求項19に記載の抗体。
- 重鎖CDR1、CDR2及びCDR3、及び軽鎖CDR1、CDR2及びCDR3を含むヒトFAM19A5タンパク質(“抗FAM19A5抗体”)に特異的に結合する単離した抗体又はその抗原結合部分であって、(i)重鎖CDR1はSEQ ID NO:5に提示されたアミノ酸配列を含み;(ii)重鎖CDR2はSEQ ID NO:6に提示されたアミノ酸配列を含み;(iii)重鎖CDR3はSEQ ID NO:7に提示されたアミノ酸配列を含み;(iv)軽鎖CDR1はSEQ ID NO:13に提示されたアミノ酸配列を含み;(v)軽鎖CDR2はSEQ ID NO:14に提示されたアミノ酸配列を含み;及び(vi)軽鎖CDR3はSEQ ID NO:10に提示されたアミノ酸配列を含むことを特徴とする、単離した抗体又はその抗原結合部分。
- 重鎖CDR1、CDR2及びCDR3、及び軽鎖CDR1、CDR2及びCDR3を含むヒトFAM19A5タンパク質(“抗FAM19A5抗体”)に特異的に結合する単離した抗体又はその抗原結合部分であって、(i)重鎖CDR1はSEQ ID NO:5に提示されたアミノ酸配列を含み;(ii)重鎖CDR2はSEQ ID NO:27に提示されたアミノ酸配列を含み;(iii)重鎖CDR3はSEQ ID NO:7に提示されたアミノ酸配列を含み;(iv)軽鎖CDR1はSEQ ID NO:13に提示されたアミノ酸配列を含み;(v)軽鎖CDR2はSEQ ID NO:29に提示されたアミノ酸配列を含み;及び(vi)軽鎖CDR3はSEQ ID NO:10に提示されたアミノ酸配列を含むことを特徴とする、単離した抗体又はその抗原結合部分。
- 重鎖CDR1、CDR2及びCDR3、及び軽鎖CDR1、CDR2及びCDR3を含み、ヒトFAM19A5タンパク質(“抗FAM19A5抗体”)に特異的に結合する単離した抗体又はその抗原結合部分であって、(i)重鎖CDR1はSEQ ID NO:5に提示されたアミノ酸配列を含み;(ii)重鎖CDR2はSEQ ID NO:28に提示されたアミノ酸配列を含み;(iii)重鎖CDR3はSEQ ID NO:7に提示されたアミノ酸配列を含み;(iv)軽鎖CDR1はSEQ ID NO:13に提示されたアミノ酸配列を含み;(v)軽鎖CDR2はSEQ ID NO:29に提示されたアミノ酸配列を含み;及び(vi)軽鎖CDR3はSEQ ID NO:10に提示されたアミノ酸配列を含むことを特徴とする、単離した抗体又はその抗原結合部分。
- 重鎖可変領域(VH)及び軽鎖可変領域(VL)を含み、VHはSEQ ID NO:17、30又は31に提示されたアミノ酸配列と少なくとも約80%、少なくとも約85%、少なくとも約90%、少なくとも約95%、少なくとも約96%、少なくとも約97%、少なくとも約98%、少なくとも約99%又は約100%同じアミノ酸配列を含み;及び/又は、VLはSEQ ID NO:18又は32に提示されたアミノ酸配列と少なくとも約80%、少なくとも約85%、少なくとも約90%、少なくとも約95%、少なくとも約96%、少なくとも約97%、少なくとも約98%、少なくとも約99%又は約100%同じアミノ酸配列を含むことを特徴とする、請求項1〜23のいずれかに記載の抗体。
- 抗体は重鎖可変領域(VH)及び軽鎖可変領域(VL)を含む基準抗体と交差競合し、VHはSEQ ID NO:11に提示されたアミノ酸配列を含み、及びVLはSEQ ID NO:12に提示されたアミノ酸配列を含むことを特徴とする、請求項1〜24のいずれかに記載の抗体。
- 抗体は重鎖可変領域(VH)及び軽鎖可変領域(VL)を含む基準抗体と交差競合し、VHはSEQ ID NO:30に提示されたアミノ酸配列を含み、及びVLはSEQ ID NO:32に提示されたアミノ酸配列を含むことを特徴とする、請求項1〜24のいずれかに記載の抗体。
- 抗体は重鎖可変領域(VH)及び軽鎖可変領域(VL)を含む基準抗体と交差競合し、VHはSEQ ID NO:31に提示されたアミノ酸配列を含み、及びVLはSEQ ID NO:32に提示されたアミノ酸配列を含むことを特徴とする、請求項1〜24のいずれかに記載の抗体。
- 抗体は重鎖可変領域(VH)及び軽鎖可変領域(VL)を含む基準抗体と交差競合し、VHはSEQ ID NO:31に提示されたアミノ酸配列を含み、及びVLはSEQ ID NO:32に提示されたアミノ酸配列を含むことを特徴とする、請求項1〜24のいずれかに記載の抗体。
- 抗体はIgG1、IgG2、IgG3、IgG4、その変異体及びこれらの任意の組合せからなる群から選ばれることを特徴とする、請求項1〜28のいずれかに記載の抗体。
- キメラ抗体、ヒト抗体又はヒト化した抗体である、請求項1〜29のいずれかに記載の抗体。
- Fab、Fab’、F(ab’)2、Fv又は単鎖Fv(scFv)を含む、請求項1〜30のいずれかに記載の抗体。
- scFVである、請求項31に記載の抗体。
- scFvはVH及びVLを含み、VHはSEQ ID NO:17、30又は31に提示されたアミノ酸配列を含み、及びVLはSEQ ID NO:18又は32に提示されたアミノ酸配列を含むことを特徴とする、請求項32に記載の抗体。
- 次の特性のいずれか1つ以上を表す、請求項1〜33のいずれかに記載の抗体:
(a)酵素結合免疫吸着分析(ELISA)によって測定される時、10nM以下のKDを有する可溶性ヒトFAM19A5に結合し;
(b)ELISAによって測定される時、10nM以下のKDを有する膜結合したヒトFAM19A5に結合し;
(c)反応性神経膠症の発病を減少、逆転、遅延及び/又は予防し;
(d)反応性星状細胞の過度な増殖を抑制し;
(e)ニューロカン及びニューロン膠抗原2(NG2)を含むコンドロイチン硫酸プロテオグリカンの発現を減少させ;
(f)ニューロンの核でc−fos及びpERKの発現を増加させ;
(g)ニューロンの生存を促進し;
(h)ニューロンでGAP43の発現を増加させ;
(i)軸索の再成長を促進し;
(j)例えば、腫瘍で血管の正常化を誘導し;
(k)腫瘍の成長を抑制し;
(l)免疫細胞の腫瘍への浸潤を向上させ;
(m)ニューロン細胞の腫瘍への浸潤を向上させ;
(n)大食細胞又は小膠細胞の食作用を向上させ;
(o)大食細胞又は小膠細胞のミトコンドリア膜電位を増加させ;
(p)骨髄由来抑制細胞(MDSC)の腫瘍への補充を減少させ;
(q)腫瘍で壊死及び浮腫を減少させ;
(r)腫瘍の組織透過性を減少させ;及び
(s)腫瘍で血流量を増加させる。 - 請求項1〜34のいずれか一項の抗体を暗号化する核酸。
- 請求項35の核酸を含むベクター。
- 請求項36のベクターを含む細胞。
- 製剤に連結された請求項1〜34のいずれか一項の抗体を含む免疫接合体。
- 請求項1〜34のいずれか一項の抗体、請求項35の核酸、請求項36のベクター、請求項37の細胞又は請求項38の免疫接合体及び担体を含む組成物。
- 請求項1〜34のいずれか一項の抗体、請求項35の核酸、請求項36のベクター、請求項37の細胞又は請求項38の免疫接合体及び使用説明書を含むキット。
- 適切な条件下で請求項37の細胞を培養して抗体を単離させる段階を含む、ヒトFAM19A5タンパク質に特異的に結合する抗体の製造方法。
- 必要とする対象で疾患又は病態を治療する、請求項1〜34のいずれかに記載の抗体。
- 疾患又は病態が腫瘍、線維症、緑内障、気分障害、神経退行性疾患(例えば、アルツハイマー病)、脳卒中又は神経病性疼痛を含むことを特徴とする、請求項42に記載の抗体。
- 疾病又は病態が腫瘍であることを特徴とする、請求項43に記載の抗体。
- 腫瘍が黒色腫、膵癌、神経膠腫、乳癌、リンパ腫、肺癌、腎臓癌、前立腺癌、線維肉腫、結腸腺癌腫、肝癌又は卵巣癌を含むことを特徴とする、請求項43又は44に記載の抗体。
- 神経膠腫が多形膠芽細胞腫(GBM)であることを特徴とする、請求項45に記載の抗体。
- 抗体が血管の正常化を誘導することを特徴とする、請求項44〜46のいずれかに記載の抗体。
- 血管の正常化は、増加した連結性、増加した壁厚、減少した血管径、より規則的な血管方向及び分布パターン、増加した血管数、漏れ及び透過性減少、血管における増加した血管周囲細胞適用範囲及び近接性、増加した酸素化又はこれらの組合せを含む血管の特性変化を伴うことを特徴とする、請求項47に記載の抗体。
- 抗体が腫瘍の成長を抑制することを特徴とする、請求項44〜48のいずれかに記載の抗体。
- 抗体が免疫細胞の腫瘍への浸潤を向上させることを特徴とする、請求項44〜48のいずれかに記載の抗体。
- 免疫細胞が大食細胞、樹状細胞、Tリンパ球、Bリンパ球、自然殺害(NK)細胞又はこれらの組合せを含むことを特徴とする、請求項50に記載の抗体。
- 免疫細胞が肥大をさらに示すことを特徴とする、請求項50又は51に記載の抗体。
- 免疫細胞の腫瘍への浸潤強化は、神経細胞の腫瘍への浸潤増加を伴うことを特徴とする、請求項50〜52のいずれかに記載の抗体。
- ニューロン細胞は、星状細胞、神経膠細胞又はこれらの組合せを含むことを特徴とする、請求項53に記載の抗体。
- 抗体が大食細胞又は小膠細胞の食作用を向上させることを特徴とする、請求項44〜54のいずれかに記載の抗体。
- 抗体は大食細胞又は小膠細胞のミトコンドリア膜電位を増加させることを特徴とする、請求項44〜55のいずれかに記載の抗体。
- 抗体が骨髄由来抑制細胞(MDSC)の腫瘍への補充を減少させることを特徴とする、請求項44〜56のいずれかに記載の抗体。
- 抗体が腫瘍の壊死及び浮腫を減少させることを特徴とする、請求項44〜57のいずれかに記載の抗体。
- 抗体が腫瘍の組織透過性を減少させることを特徴とする、請求項44〜58のいずれかに記載の抗体。
- 抗体が腫瘍の血流量を増加させることを特徴とする、請求項44〜59のいずれかに記載の抗体。
- 追加の治療剤を投与することを特徴とする、請求項42〜60のいずれかに記載の抗体。
- 追加の治療剤が化学療法、免疫療法、放射線療法又はこれらの組合せを含むことを特徴とする、請求項61に記載の抗体。
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CA3098805A1 (en) | 2019-11-14 |
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US20210054062A1 (en) | 2021-02-25 |
JP2022185058A (ja) | 2022-12-13 |
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KR20240056644A (ko) | 2024-04-30 |
AU2019265888A1 (en) | 2020-11-26 |
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