JP2018535674A - Asct2特異的結合分子及びその使用 - Google Patents
Asct2特異的結合分子及びその使用 Download PDFInfo
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- JP2018535674A JP2018535674A JP2018523019A JP2018523019A JP2018535674A JP 2018535674 A JP2018535674 A JP 2018535674A JP 2018523019 A JP2018523019 A JP 2018523019A JP 2018523019 A JP2018523019 A JP 2018523019A JP 2018535674 A JP2018535674 A JP 2018535674A
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Abstract
Description
本明細書及び添付の特許請求の範囲で使用されるとき、単数形「1つの(a)」、「1つの(an)」及び「その(the)」は、文脈上特に明確に指示されない限り複数の指示対象を含む。用語「1つの(a)」又は「1つの(an)」、並びに用語「1つ以上」及び「少なくとも1つ」は、本明細書では同義的に使用することができる。
本発明は、ASCT2に特異的に結合する抗ASCT2抗体及びその抗原結合断片を提供する。ヒト及びカニクイザルASCT2の完全長アミノ酸(aa)及びヌクレオチド(nt)配列は当該技術分野において公知であり、少なくとも、国立バイオテクノロジー情報センター(NCBI)データベースで検索することができる。NCBIデータベースはオンラインで利用可能である。一部の実施形態において、本明細書に提供される抗ASCT2抗体又はその抗原結合断片はヒト化抗体又はヒト抗体である。一部の実施形態において、抗ASCT2抗体はサイトトキシンにコンジュゲートされ、従って抗ASTC2 ADCと称される。
特定の実施形態において、本開示は、本明細書に記載される抗ASCT2抗体が結合するのと同じエピトープに結合する抗ASCT2抗体を提供する。用語「エピトープ」は、本発明の抗体との結合能を有する標的タンパク質決定基を指す。エピトープは、通常、アミノ酸又は糖側鎖などの分子の化学的に活性な表面基からなり、通常、特異的な三次元構造特性、並びに特異的な電荷特性を有する。立体エピトープと非立体エピトープとは、変性溶媒の存在下で前者への結合は失われるが、後者への結合は失われない点で区別される。かかる抗体は、本明細書において標準的なASCT2結合又は活性アッセイに記載されるものなど、抗体と交差競合する(例えば、それの結合を統計学的に有意な形で競合的に阻害する)その能力に基づき同定することができる。
モノクローナル抗ASCT2抗体は、Kohler and Milstein,Nature 256:495(1975)によって記載されるものなどのハイブリドーマ法を用いて調製することができる。ハイブリドーマ法の使用では、マウス、ハムスター、又は他の適切な宿主動物を上記に記載したとおり免疫し、免疫抗原に特異的に結合し得る抗体のリンパ球による産生を誘発する。リンパ球はまた、インビトロで免疫することもできる。免疫後、リンパ球を単離し、例えばポリエチレングリコールを使用して好適な骨髄腫細胞株と融合することによりハイブリドーマ細胞を形成し、次にそこから未融合のリンパ球及び骨髄腫細胞を選択によって除くことができる。次に、免疫沈降、免疫ブロット法によるか、又はインビトロ結合アッセイ、例えば、ラジオイムノアッセイ(RIA)若しくは酵素結合免疫吸着アッセイ(ELISA)によって決定するとき選択の抗原を特異的に対象とするモノクローナル抗体を産生するハイブリドーマを、標準方法を用いたインビトロ培養か(Goding,Monoclonal Antibodies:Principles and Practice,Academic Press,1986)、或いは動物の腹水腫瘍としてインビボで増殖させることができる。次に、公知の方法を使用してモノクローナル抗体を培養培地又は腹水から精製することができる。
本開示は、異種薬剤にコンジュゲートされた、上記に記載したとおりの抗ASCT2抗体又はその断片を更に提供する。本発明の目的上、「コンジュゲートされた」は、共有結合又はイオン結合によって連結されていることを意味する。特定の態様において、薬剤は、抗菌剤、治療剤、プロドラッグ、ペプチド、タンパク質、酵素、脂質、生物学的反応修飾物質、医薬品、リンホカイン、異種抗体又はその断片、検出可能標識、PEG、又は任意の前記薬剤の2つ以上の組み合わせであってもよい。一部の実施形態において、かかるASCT2結合分子はASCT2−ADCである。
本開示は、ASCT2に特異的に結合するポリペプチド又はその抗原結合断片をコードする核酸配列を含むポリヌクレオチドを提供する。例えば、本発明は、抗ASCT2抗体をコードするか、又はかかる抗体の抗原結合断片をコードする核酸配列を含むポリヌクレオチドを提供する。本発明のポリヌクレオチドはRNAの形態であっても、又はDNAの形態であってもよい。DNAには、cDNA、ゲノムDNA、及び合成DNAが含まれ;且つ二本鎖又は一本鎖であってもよく、及び一本鎖の場合、コード鎖又は非コード鎖(アンチセンス鎖)であってもよい。
本明細書に提供されるASCT2結合分子を調製し、それを必要としている対象に投与する方法は、当業者に周知であり、当業者によって容易に決定される。ASCT2結合分子の投与経路は、例えば、経口、非経口、吸入による、又は局所であり得る。用語の非経口とは、本明細書で使用されるとき、例えば、静脈内、動脈内、腹腔内、筋肉内、皮下、直腸、又は腟内投与を含む。これらの投与形態は全て、明らかに本発明の範囲内にあるものとして企図されるが、投与形態の別の例を挙げるのであれば、注射用、詳細には静脈内若しくは動脈内注射又は点滴用の溶液であろう。通常、好適な医薬組成物は、緩衝液(例えば、酢酸塩、リン酸塩又はクエン酸塩緩衝液)、界面活性剤(例えば、ポリソルベート)、任意選択で安定剤(例えば、ヒトアルブミン)等を含み得る。本明細書の教示と適合性のある他の方法において、本明細書に提供されるASCT2結合分子は有害な細胞集団の部位に直接送達してもよく、それにより罹患組織の治療剤への曝露を増加させることができる。一実施形態において、投与は、例えば吸入又は鼻腔内投与による、気道への直接の投与である。
本開示は、特定の癌など、ASCT2過剰発現によって特徴付けられる疾患の診断において有用な診断方法を更に提供し、この方法は、個体の細胞又は組織におけるASCT2の発現レベルを計測するステップと、計測された発現レベルを正常細胞又は組織における標準的なASCT2発現と比較するステップとを含み、ここで、標準と比較した発現レベルの増加は、本明細書に提供されるASCT2結合分子によって治療可能な障害であることを示す。
本開示は、本明細書に記載されるASCT2結合分子を含む、且つ本明細書に記載される方法の実施に使用することのできるキットを更に提供する。特定の実施形態において、キットは1つ以上の容器に少なくとも1つの精製抗ASCT2抗体又はその抗原結合断片を含む。一部の実施形態において、キットは1つ以上の容器に少なくとも1つの精製ASCT2−ADCを含む。一部の実施形態において、キットには、全ての対照、アッセイの実施に関する説明書、並びに結果の分析及び発表に必要な任意のソフトウェアを含め、検出アッセイの実施に必要及び/又は十分な構成要素の全てが含まれる。当業者は、本開示のASCT2結合分子を当該技術分野において周知の確立されたキットフォーマットの1つに容易に組み込み得ることを容易に認識するであろう。
本明細書に提供されるASCT2結合分子は、当該技術分野において公知の任意の方法による免疫特異的結合に関するアッセイにおいて使用することができる。用いることのできるイムノアッセイとしては、限定はされないが、ウエスタンブロット、RIA、ELISA、ELISPOT、「サンドイッチ」イムノアッセイ、免疫沈降アッセイ、沈降反応、ゲル内拡散沈降反応、免疫拡散アッセイ、凝集反応アッセイ、補体結合アッセイ、イムノラジオメトリックアッセイ、蛍光イムノアッセイ、及びプロテインAイムノアッセイなどの技法を用いた競合及び非競合アッセイシステムが挙げられる。かかるアッセイは常法であり、当該技術分野において周知である。例えば、Ausubel et al.,eds,(1994)Current Protocols in Molecular Biology(John Wiley&Sons,Inc.,NY)Vol.1(参照により全体として本明細書に援用される)を参照されたい。
実施形態1.中性アミノ酸トランスポーター2(ASCT2)のエピトープに特異的に結合する抗体又はその抗原結合断片であって、重鎖可変領域(VH)の3つの重鎖相補性決定領域(HCDR)と軽鎖可変領域(VL)の3つの軽鎖相補性決定領域(LCDR)[HCDR1のアミノ酸配列は配列番号10に示され、HCDR2のアミノ酸配列は配列番号22に示され、HCDR3のアミノ酸配列は配列番号23に示され、LCDR1のアミノ酸配列は配列番号13に示され、LCDR2のアミノ酸配列は配列番号24に示され、及びLCDR3のアミノ酸配列は配列番号25に示される]とを含む抗体又はその抗原結合断片と同じASCT2エピトープに特異的に結合する、抗体又はその抗原結合断片。
IHCによって分析した正常組織及び腫瘍組織におけるASCT2タンパク質発現
ASCT2のタンパク質発現を評価するため、正常ヒト及びヒト腫瘍ホルムアルデヒド固定組織の切片でIHCを行った。クエン酸塩緩衝液(pH=6.0)による抗原回復処理後、製造者のプロトコルに従い抗ASCT2ウサギポリクローナル抗体(EMD Millipore、Billerica,MA;カタログ番号ABN73)によって組織を試験した。HT29細胞株を陽性対照として使用し、及び初代ヒトヘパトサイト細胞を陰性対照として使用してプロトコルの最適化を実施した。
様々な癌性組織にわたってASCT2発現をIHCによって判定した。結腸癌、肺扁平上皮癌、頭頸部癌、及び前立腺癌組織を含めた固形腫瘍、並びにAML、MM、及びDLBCLなどの血液癌に強力なASCT2膜発現が観察された。加えて、卵巣子宮内膜癌組織及び黒色腫組織にASCT2高発現が観察された。以下の表2は、ヒト癌組織におけるASCT2発現の概要を提供する。
免疫化及びハイブリドーマ作成
ヒトASCT2遺伝子を有するプラスミドのDNA免疫化(Chowdhury et al.,J.Immunol.Methods 249:147,2001)により、ASCT2に対する抗体を作成した。ヒトASCT2の遺伝子を発現プラスミドpcDNA3.1(Invitrogen、Carlsbad,CA)にクローニングした。8週齢VelocImmune IIマウス(Regeneron、Tarrytown,NY)の尾基底部に100μgのASCT2発現プラスミドをPBS中1mg/mLで1週間おきに皮内注射した。初回の注射後28日目から開始して2週間間隔で被験血液を採取し、フローサイトメトリーによってASCT2特異抗体をアッセイした。被験血液の段階希釈物を、ASCT2又は無関係の細胞表面タンパク質のいずれかを発現する293F細胞と共にインキュベートした。56日目及び70日目、比力価が最も高いマウスを犠牲にした。リンパ節及び脾臓からリンパ球を単離し、ポリエチレングリコール(Roche Diagnostics、Indianapolis,IN)融合方法に従い骨髄腫細胞株P3x/63Ag8.653と1:1比で融合させた。ヒポキサンチン−アミノプテリン−チミジン(HAT)含有ハイブリドーマ成長培地で融合した細胞を選択した。
ASCT2を発現するHEK 293F細胞への結合に関してハイブリドーマ上清を評価した。ASCT2を発現するHEK 293F細胞に特異的に結合することがフローサイトメトリーによって分かった上清について、ASCT2発現癌細胞株のパネルによるフローサイトメトリー染色によってASCT2特異的結合を更に確認した。最後に、確認された上清を更なる結合評価のためヒトIgG1に変換した。
ハイブリドーマを限界希釈によってサブクローニングした。プロテインAアフィニティー精製IgGサブクローンの上清を親ハイブリドーマについて上記に記載したとおりフローサイトメトリーによってASCT2特異抗体に関してスクリーニングした。サブクローニングしたハイブリドーマのmRNAをDynabeads mRNA Directキット(Invitrogen)を使用して単離した。SuperScript III逆転写酵素(Invitrogen)及びランダムヘキサマープライマーを使用してcDNAの第1の鎖を合成した。ヒトIg VL及びVH遺伝子をNovagen(登録商標)変性Ig−プライマー(EMD Millipore、カタログ番号69830)のセットでPCR増幅した。PCR増幅したVL及びVH産物をプラスミドpCR2.1−TOPO(Invitrogen)にクローニングし、シーケンシングした。各ハイブリドーマからのVH及びVL遺伝子をPCRによって再増幅して、ヒトIgGκ pOEベクターにクローニングするための制限酵素部位を加え、ここで、VLは、ヒトc−κと融合したBssHII/BsiWI部位にクローニングされ、及びVHは、ヒトIgG−1重鎖定常領域(又はFab作成についてはCH1領域)と融合したBsrGI/SalI部位にクローニングされた。得られたpOEプラスミドをDNAシーケンシングによって確認した。
ASCT2結合抗体のADC媒介細胞傷害性の評価
親抗体のインターナリゼーションを確かめるため、及びそれらが細胞傷害性ペイロードを送達することができるかどうかを予測するため、製造者の指示に従いHum−ZAP抗体インターナリゼーションアッセイ(Advanced Targeting Systems、San Diego,CA)で親抗体を試験した。簡潔に言えば、ASCT2陽性WiDr細胞を組織培養処理96ウェルプレートの1ウェル当たり1,000細胞の密度で培養培地に播き、37℃/5%CO2で一晩接着させた。被験物質を調製するため、リボソーム不活性化タンパク質であるサポリンにコンジュゲートした二次抗体(ヤギ抗ヒトIgG)と共に各親抗体を室温で30分間インキュベートして二次コンジュゲートを形成した。次に、この二次コンジュゲートの段階希釈物を調製し、細胞が入ったウェルに加えた。
ツブリシンペイロードにコンジュゲートした抗ASCT2抗体によるADC媒介死滅を確認するため、リード抗体1E8及び17C10をツブリシンクラスの毒素と直接コンジュゲートし、コンジュゲート抗体による細胞傷害性死滅をASCT2陽性結腸癌細胞で試験した。簡潔に言えば、SW48細胞を組織培養処理96ウェルプレートの1ウェル当たり1,000細胞の密度で培養培地に播き、37℃/5%CO2で一晩接着させた。被験物質を調製するため、ツブリシンペイロードとコンジュゲートした各抗体(ASCT2リード1E8及び17C10、及びアイソタイプ対照)を段階希釈し、それぞれのウェルに加えた。37℃/5%CO2で72時間インキュベートした後、上記に記載したとおり、CellTiter−Glo(登録商標)発光生存率アッセイを用いて相対的細胞傷害性を決定した。
標準的なオーバーラップPCR方法を用いて、抗ASCT2抗体1E8及び17C10のCH2領域のアミノ酸S239及びV240間にシステイン残基を導入した。「239挿入」又は「239i」と称されるこのシステインは、抗ASCT2 ADC抗体の調製において細胞傷害薬のコンジュゲーション部位として働くことになる。Maia挿入を含む重鎖骨格のアミノ酸配列を配列番号9に示す。導入されたシステインを含む抗体を、本質的に以下に記載するとおり、ツブリシンペイロード(ツブリシンAZ1508)又はピロロベンゾジアゼピン(PBD)ペイロード(SG3249又はSG3315)にコンジュゲートした。
ADCペイロード(AZ1508、SG3249、SG3315)に関して判定した全ての化合物が、リンカー及び抗体のチオール残基に容易にコンジュゲートするマレイミド基を含み、チオール−マレイミド連結を形成する。マレイミド基を含むサイトトキシン(例えば、ツブリシン1508)は、本発明の抗ASCT2抗体(例えば、17c10、1e8)に操作して入れた特異的システイン残基にコンジュゲートし得る。或いは又は任意選択で、古典的なコンジュゲーション方法を用いて細胞傷害剤を記載の抗体に付加してもよい。サイトトキシンを抗体上の天然のリジン及びシステイン残基にコンジュゲートする方法は、当該技術分野において周知である。部位特異的コンジュゲーション(操作されたシステイン残基における)及び古典的コンジュゲーション(天然システイン残基における)の代表的な方法を以下に提供する。
結腸直腸癌細胞におけるASCT2抗体のASCT2特異的結合
特定のハイブリドーマクローンの結合がASCT2抗原に特異的であったかどうかを決定するため、ASCT2発現のshRNAノックダウン後に結合を評価した。簡潔に言えば、WiDr細胞に、ASCT2 shRNA又は非標的shRNA(NTshRNA)を発現するレンチウイルスを形質導入した。感染後72時間で2つの抗ASCT2ハイブリドーマクローン17c10及び1e8の結合を評価した。図4に見られるとおり、ASCT2発現をノックダウンすると、それぞれのクローンの結合が有意に消失し、ASCT2 mAb 17c10及び1e8の抗原特異的結合が更に確認された。
標的抗原との結合時における抗体のインターナリゼーションは、所望のADC効果の実現に必須である。従って、ASCT2抗体のインターナリゼーション特性を調べた。Alexa 488にコンジュゲートした抗ASCT2抗体17c10(17c10−Alexa 488)と共にWiDr細胞を様々な時間にわたってインキュベートした。次に、細胞を洗浄し、抗Alexa 488抗体と共に又は無しで氷上で45分間インキュベートして細胞表面シグナルをクエンチした。総シグナル及びクエンチされたシグナル(インターナライズされた抗体を表す)の蛍光強度をフローサイトメトリー解析によって計測した。図5Aに見られるとおり、抗ASCT2抗体17c10は、インターナリゼーションを示さなかったアイソタイプ対照抗体と比較して、時間と共にインターナリゼーションの増加を示した。
ツブリシンAZ1508にコンジュゲートした抗ASCT2抗体(17C10−AZ1508)で細胞を様々な時間にわたってパルスした。その後、ADC含有培地を新鮮培地に交換し、細胞を更に4日間インキュベートした。CTGキットを使用することにより細胞生存率を計測した。未処理対照細胞に対するパーセンテージとして用量反応曲線をプロットし、代表的なグラフを図5Bに示す。上記に記載したとおりIC50値を計算し、結果を以下の表4に要約する。
ASCT2を発現するヒト、カニクイザル、及びCHO由来細胞株を利用して、ASCT2特異抗体の結合親和性及び交差反応性を評価した。フルオロフォア標識抗体を力価測定することにより見かけの親和性を計測した。代表的な結果を以下の表6に要約し、及び図6に示す。
抗ASCT2抗体17c10は、SLC1Aファミリーの他のメンバーであるASCT1(SLC1A4)に対して親和性を有しない。shRNAによってASCT1発現をサイレンシングしても、図7Aに示されるグラフに見られるとおり、SKMEL−2細胞における17c10のASCT2特異的結合は消失しない。shRNAのノックダウン効率をウエスタンブロット分析によって更に確認した。更に、図7Bに示されるグラフに見られるとおり、それぞれのshRNAによってASCT1発現をサイレンシングした細胞の細胞傷害プロファイルに変化は観察されなかった。結果を表6に要約する。
ツブリシンAZ1508にコンジュゲートした抗ASCT2抗体クローン17c10及び1e8について、CHOK1細胞で安定に発現するcyno ASCT2、CHOK1細胞で安定に発現するヒトASCT2、及びCHOK1細胞で発現する対照分子に対する結合を評価した。ASCT2抗体17c10(図8A)及びASCT2抗体1e8(図8B)は、ツブリシン1508ペイロードにコンジュゲートしたとき、ヒトASCT2及びcyno ASCT2を発現するCHOK1細胞において強力な細胞傷害活性を示すが、非トランスフェクトCHOK1又はCHOK1−ABCB5では示さない。これらの結果を以下の表7に要約する。
17c10のVH及びVLドメインのアミノ酸配列をVBASEデータベースにある既知のヒト生殖系列配列とアラインメントし、最も近縁の生殖細胞系列を配列類似性によって同定した。VHドメインについて、これはIgVh4−34*01であった。VLドメインについて、これはIgKv1−5*03であった。17c10は、生殖細胞系列化プロセスにVHドメインの1フレームワーク残基及びVLドメインの5残基を復帰させることが含まれた。VHドメインにおいて、復帰突然変異はKabat位置82aであり、ここではスレオニン(T)をセリン(S)に復帰させた。VLドメインにおいて、突然変異はKabat位置13、21、39、70、及び76であり、ここではKabat位置13でスレオニン(T)をアラニン(A)に復帰させ;Kabat位置21でロイシン(L)をイソロイシン(I)に復帰させ;Kabat位置39でアスパラギン(N)をリジン(K)に復帰させ;Kabat位置70でアスパラギン酸塩(D)をグルタミン酸塩(E)に復帰させ、及びKabat位置76でスレオニン(T)をセリン(S)に復帰させた。これらの変化は、これらの突然変異を含むVH及びVLドメインを合成し、且つ制限消化及びライゲーションを用いて既存のVH及びVLを置き換えることにより作製した。生殖細胞系列化した17c10及び元の(非生殖細胞系列化)17c10の両方ともにIgGとして発現させ、複数のASCT2発現細胞株に対するそれらの親和性をフローサイトメトリーによって評価した。図9A〜図9Dに見られるとおり、WiDr細胞、又はHuASCT2若しくはCyASCT2を発現するCHO細胞に対する生殖細胞系列化17c10又は親17c10の結合に差はなかった。
17c10抗体をPBD(SG3315)又はツブリシン(AZ1508)ペイロードと上記に記載したとおり部位特異的コンジュゲーション部位でコンジュゲートした。各アッセイについて薬物−抗体比(DAR)は約2.0と推定された。膵癌、結腸癌、肺癌、頭頸部扁平上皮癌(HNSCC)、前立腺癌、及びASCT2陰性肺癌など、様々な適応からの癌細胞を用いて細胞傷害アッセイを実施した。図10A〜図10Fに示されるとおり、AZ1508にコンジュゲートした17c10 ADC抗体は、ツブリシンに結合した対照抗体よりも高い細胞傷害活性を有した。SG3249又はSG3315にコンジュゲートした抗ASCT2抗体17c10も、ツブリシンAZ1508に結合した、又はPBD SG3249に結合した、又はSG3315に結合した対照抗体よりも高い細胞傷害活性を有した。SG3249にコンジュゲートした17c10を用いた細胞傷害アッセイの結果を示すグラフを図11Aに示し、及びSG3315にコンジュゲートした17c10を用いた細胞傷害アッセイの結果を示すグラフを図11Bに示す。以下の表8にIC50値を要約する。
全てのインビボ手順はAAALAC認証施設の施設内ガイドラインに従い実施し、MedImmune,LLC施設内動物管理・使用委員会によって承認された。ASCT2−ADC抗体が腫瘍細胞を死滅させる能力を試験するため、WiDr(100μl/106細胞/マウス)又は原発性膵腫瘍(PDX)を雌3〜5週齢ヌードマウス(Charles River Laboratories、Wilmington,MA)の右側腹部に皮下接種した。マウスを数週間生かして腫瘍を発達させた。腫瘍が約150〜200mm3に達したところでマウスを無作為化して治療群(10匹マウス/群)に割り付けた。その後、マウスに種々の用量の抗ASCT2 ADC(17c10−Az1508又は17c10−SG3315又は17c10−SG3249)又はアイソタイプ対照薬物−コンジュゲート抗体を静脈内注射した。治療した異種移植マウスの体重及び腫瘍容積をそれぞれの時間にわたってモニタした。腫瘍容積は、以下の式:(最も短い直径)2×(最も長い直径)×0.5を用いて計算し、及び結果を図12A、図12B、及び図12Cに示す。
抗ASCT2 mAbの精製方法を開発した。簡潔に言えば、回収した細胞培養液をMAbSelect Sure樹脂(GE Healthcare)を使用して実施されるプロテインA捕捉ステップに供して細胞培養上清からタンパク質を捕捉し、工程関連及び生成物関連の不純物を除去した。全ての工程ステップを300cm/時の線形流量で実施した。樹脂は50mMトリス、pH7.4で平衡化し、及びカラムに30g/L樹脂のロードチャレンジとなるように馴化培地をロードした。カラムを50mMトリス、pH7.4で再平衡化し、次に、馴化培地中に存在する不純物が低下し且つ過剰な軽鎖が減少するように最適化した2回の洗浄ステップに曝した。最初の洗浄ステップは50mMトリス、500mM塩化ナトリウム、pH7からなり、2回目の洗浄は50mM酢酸ナトリウム、500mM塩化ナトリウム、pH5.0を含んだ。次に、カラムを50mMトリス、pH7.4で再平衡化し、25mM酢酸ナトリウム、pH3.6で生成物を溶出させた。溶出ピークの上り側の0.5ODから下り側の0.5ODまでの生成物を回収した。各精製サイクル後、カラムを100mM酢酸でストリッピングし、次に50mMトリス、pH7.4で再平衡化し、0.1N水酸化ナトリウムで衛生化し、及び2%(v/v)ベンジルアルコール、100mM酢酸ナトリウム、pH5.0に保存した。このステップの典型的な収率は70〜75%である。
ツブリシン(AZ1508)をマレイミド化学によって2つの操作された遊離システイン残基に部位特異的にコンジュゲートすることにより抗体−薬物コンジュゲートを調製した。
PBD(SG3249)をマレイミド化学によって2つの操作された遊離システイン残基に部位特異的にコンジュゲートすることにより、抗体−薬物コンジュゲートを調製した。工程順序は、上記に要約したツブリシンコンジュゲーションについての考察と同じであり、但し正確な条件は異なる。
元の17c10 VH;配列番号1
GYYWS
17c10生殖細胞系列化HCDR2(Kabat付番);配列番号11
EIHHSGGANYNPSLKS
17c10生殖細胞系列化HCDR3(Kabat付番);配列番号12
GQGKNWHYDYFDY
17c10生殖細胞系列化LCDR1(Kabat付番);配列番号13
RASQSIRSWLA
17c10生殖細胞系列化LCDR2(Kabat付番);配列番号14
KASILKI
17c10生殖細胞系列化LCDR3(Kabat付番);配列番号15
QQYYSYSRT
1e8生殖細胞系列化HCDR1 (Kabat付番);配列番号16
GYYWS
1e8生殖細胞系列化HCDR2(Kabat付番);配列番号17
EIHHSGSTNYNPSLKS
1e8生殖細胞系列化HCDR3(Kabat付番);配列番号18
GQGKNWNYDYFDY
1e8生殖細胞系列化LCDR1(Kabat付番);配列番号19
RASQSIRSWLA
1e8生殖細胞系列化LCDR2(Kabat付番);配列番号20
KASSLKS
1e8生殖細胞系列化LCDR3(Kabat付番);配列番号21
QQYYSFSRT
コンセンサスHCDR2;配列番号22
EIHHSGX1X2NYNPSLKS;式中、X1はS又はGであり、及びX2はA又はTである
コンセンサスHCDR3;配列番号23
GQGKNWX1YDYFDY;式中、X1はH又はNである
コンセンサスLCDR2;配列番号24
KASX1LKX2;式中、X1はI又はSであり、及びX2はI又はSである
コンセンサスLCDR3;配列番号25
QQYYSX1SRT;式中、X1はY又はFである
ヒトκ軽鎖;配列番号26
Claims (20)
- 中性アミノ酸トランスポーター2(ASCT2)のエピトープに特異的に結合する抗体又はその抗原結合断片であって、重鎖可変領域(VH)の3つの重鎖相補性決定領域(HCDR)と軽鎖可変領域(VL)の3つの軽鎖相補性決定領域(LCDR)とを含み、配列番号10又は配列番号16のアミノ酸配列のHCDR1、配列番号11又は配列番号17のアミノ酸配列のHCDR2、配列番号12又は配列番号18のアミノ酸配列のHCDR3、配列番号13又は配列番号19のアミノ酸配列のLCDR1、配列番号14又は配列番号20のアミノ酸配列のLCDR2、及び配列番号15又は配列番号21のアミノ酸配列のLCDR3を含む、抗体又はその抗原結合断片。
- 前記VHが、配列番号1、配列番号3、配列番号5、及び配列番号7から選択されるアミノ酸配列を含み、前記VLが、配列番号2、配列番号4、配列番号6、及び配列番号8から選択されるアミノ酸配列を含む、請求項1に記載の抗体又は抗原結合断片。
- 前記VHが配列番号5のアミノ酸配列を含み、且つ前記VLが配列番号6のアミノ酸配列を含む、請求項1又は2に記載の抗体又は抗原結合断片。
- 前記VHがアミノ酸配列の配列番号7を含み、且つ前記VLがアミノ酸配列の配列番号8を含む、請求項1又は2に記載の抗体又は抗原結合断片。
- 位置239のセリン(S)と位置240のバリン(V)との間にシステイン(C)挿入を含むIgG定常領域を含む、請求項1〜4のいずれか一項に記載の抗体又は抗原結合断片。
- 前記抗体が配列番号9のアミノ酸配列の重鎖を含む、請求項5に記載の抗体又は抗原結合断片。
- 前記抗体が細胞表面上のASCT2に結合すると、前記抗体が細胞にインターナライズする、請求項1〜6のいずれか一項に記載の抗体又は抗原結合断片。
- ヒトκ定常領域及びヒトλ定常領域からなる群から選択される軽鎖定常領域を含む、請求項1〜8のいずれか一項に記載の抗体又は抗原結合断片。
- 前記抗体が配列番号26のヒトκ定常領域を含む、請求項9に記載の抗体又は抗原結合断片。
- 抗菌剤、治療剤、プロドラッグ、ペプチド、タンパク質、酵素、脂質、生物学的反応修飾物質、医薬品、リンホカイン、異種抗体、異種抗体の断片、検出可能標識、ポリエチレングリコール(PEG)、放射性同位元素からなる群から選択されるサイトトキシン又は任意の前記サイトトキシンの2つ以上の組み合わせからなる群から選択されるサイトトキシンに更にコンジュゲートされる、請求項1〜9のいずれか一項に記載の抗体又は抗原結合断片。
- サイトトキシンにコンジュゲートされる、請求項10に記載の抗体又は抗原結合断片。
- 前記サイトトキシンがツブリシン誘導体及びピロロベンゾジアゼピンから選択される、請求項11に記載の抗体又は抗原結合断片。
- 前記ツブリシン誘導体がツブリシンAZ1508である、請求項12に記載の抗体又は抗原結合断片。
- 前記ピロロベンゾジアゼピンがSG3315及びSG3249から選択される、請求項12に記載の抗体又は抗原結合断片。
- 前記抗体がヒトASCT2及びカニクイザルASCT2に結合する、請求項1〜14のいずれか一項に記載の抗体又は抗原結合断片。
- 前記抗体がヒトASCT1に特異的に結合しない、請求項1〜15のいずれか一項に記載の抗体又は抗原結合断片。
- 請求項1〜16のいずれか一項に記載の抗体又は抗原結合断片と薬学的に許容可能な担体とを含む医薬組成物。
- 請求項1〜16のいずれか一項に記載の抗体又はその抗原結合断片をコードするポリヌクレオチド又はポリヌクレオチドの組み合わせ。
- 請求項18に記載のポリヌクレオチドを含む宿主を培養するステップを含む、請求項1〜16のいずれか一項に記載の抗体又はその抗原結合断片を作製する方法。
- 対象におけるASCT2の過剰発現によって特徴付けられる癌を治療する方法であって、治療を必要としている対象に、請求項1〜16のいずれか一項に記載の抗体若しくは抗原結合断片又は請求項17に記載の医薬組成物の有効量を投与するステップを含む方法。
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US4816567A (en) | 1983-04-08 | 1989-03-28 | Genentech, Inc. | Recombinant immunoglobin preparations |
US4683195A (en) | 1986-01-30 | 1987-07-28 | Cetus Corporation | Process for amplifying, detecting, and/or-cloning nucleic acid sequences |
DE3590766C2 (ja) | 1985-03-30 | 1991-01-10 | Marc Genf/Geneve Ch Ballivet | |
US5618920A (en) | 1985-11-01 | 1997-04-08 | Xoma Corporation | Modular assembly of antibody genes, antibodies prepared thereby and use |
DE3600905A1 (de) | 1986-01-15 | 1987-07-16 | Ant Nachrichtentech | Verfahren zum dekodieren von binaersignalen sowie viterbi-dekoder und anwendungen |
US5681718A (en) | 1986-03-14 | 1997-10-28 | Celltech Limited | Methods for enhanced production of tissue plasminogen activator in cell culture using alkanoic acids or salts thereof |
US5225539A (en) | 1986-03-27 | 1993-07-06 | Medical Research Council | Recombinant altered antibodies and methods of making altered antibodies |
US4946778A (en) | 1987-09-21 | 1990-08-07 | Genex Corporation | Single polypeptide chain binding molecules |
US5763192A (en) | 1986-11-20 | 1998-06-09 | Ixsys, Incorporated | Process for obtaining DNA, RNA, peptides, polypeptides, or protein, by recombinant DNA technique |
GB8823869D0 (en) | 1988-10-12 | 1988-11-16 | Medical Res Council | Production of antibodies |
US5530101A (en) | 1988-12-28 | 1996-06-25 | Protein Design Labs, Inc. | Humanized immunoglobulins |
CA2016842A1 (en) | 1989-05-16 | 1990-11-16 | Richard A. Lerner | Method for tapping the immunological repertoire |
CA2016841C (en) | 1989-05-16 | 1999-09-21 | William D. Huse | A method for producing polymers having a preselected activity |
AU652539B2 (en) | 1989-05-16 | 1994-09-01 | Medical Research Council | Co-expression of heteromeric receptors |
GB9015198D0 (en) | 1990-07-10 | 1990-08-29 | Brien Caroline J O | Binding substance |
US6172197B1 (en) | 1991-07-10 | 2001-01-09 | Medical Research Council | Methods for producing members of specific binding pairs |
EP0814159B1 (en) | 1990-08-29 | 2005-07-27 | GenPharm International, Inc. | Transgenic mice capable of producing heterologous antibodies |
US5545806A (en) | 1990-08-29 | 1996-08-13 | Genpharm International, Inc. | Ransgenic non-human animals for producing heterologous antibodies |
US5625126A (en) | 1990-08-29 | 1997-04-29 | Genpharm International, Inc. | Transgenic non-human animals for producing heterologous antibodies |
US5661016A (en) | 1990-08-29 | 1997-08-26 | Genpharm International Inc. | Transgenic non-human animals capable of producing heterologous antibodies of various isotypes |
US5633425A (en) | 1990-08-29 | 1997-05-27 | Genpharm International, Inc. | Transgenic non-human animals capable of producing heterologous antibodies |
WO1992009690A2 (en) | 1990-12-03 | 1992-06-11 | Genentech, Inc. | Enrichment method for variant proteins with altered binding properties |
ATE463573T1 (de) | 1991-12-02 | 2010-04-15 | Medimmune Ltd | Herstellung von autoantikörpern auf phagenoberflächen ausgehend von antikörpersegmentbibliotheken |
EP1291360A1 (en) | 1991-12-13 | 2003-03-12 | Xoma Corporation | Methods and materials for preparation of modified antibody variable domains and therapeutic uses thereof |
US5639641A (en) | 1992-09-09 | 1997-06-17 | Immunogen Inc. | Resurfacing of rodent antibodies |
US5641870A (en) | 1995-04-20 | 1997-06-24 | Genentech, Inc. | Low pH hydrophobic interaction chromatography for antibody purification |
WO1997008320A1 (en) | 1995-08-18 | 1997-03-06 | Morphosys Gesellschaft Für Proteinoptimierung Mbh | Protein/(poly)peptide libraries |
US7264963B1 (en) | 1995-08-18 | 2007-09-04 | Morphosys Ag | Protein(poly)peptide libraries |
US5714352A (en) | 1996-03-20 | 1998-02-03 | Xenotech Incorporated | Directed switch-mediated DNA recombination |
EP1133565B1 (en) | 1999-07-02 | 2010-09-22 | MorphoSys AG | Generation of specific binding partners binding to (poly)peptides encoded by genomic dna fragments or ests |
JP4336498B2 (ja) | 2000-12-12 | 2009-09-30 | メディミューン,エルエルシー | 延長した半減期を有する分子ならびにその組成物および用途 |
US7658921B2 (en) | 2000-12-12 | 2010-02-09 | Medimmune, Llc | Molecules with extended half-lives, compositions and uses thereof |
US7538195B2 (en) | 2002-06-14 | 2009-05-26 | Immunogen Inc. | Anti-IGF-I receptor antibody |
EP1521769B1 (de) | 2002-07-09 | 2015-09-09 | Dömling, Alexander | Tubulysinkonjugate |
AU2003266233A1 (en) | 2002-07-09 | 2004-01-23 | Morphochem Aktiengesellschaft Fur Kombinatorische Chemie | Novel tubulysin analogues |
GB0216648D0 (en) | 2002-07-18 | 2002-08-28 | Lonza Biologics Plc | Method of expressing recombinant protein in CHO cells |
DK1578446T3 (en) | 2002-11-07 | 2015-06-29 | Immunogen Inc | ANTI-CD33 ANTIBODIES AND PROCEDURES FOR TREATING ACUTE MYELOID LEUKEMIA BY USING IT |
DE10254439A1 (de) | 2002-11-21 | 2004-06-03 | GESELLSCHAFT FüR BIOTECHNOLOGISCHE FORSCHUNG MBH (GBF) | Tubulysine, Herstellungsverfahren und Tubulysin-Mittel |
EP1725585A2 (en) | 2004-03-10 | 2006-11-29 | Lonza Ltd | Method for producing antibodies |
WO2006024497A1 (en) | 2004-08-30 | 2006-03-09 | Lonza Biologics Plc. | Affinity- plus ion exchange- chromatography for purifying antibodies |
WO2006076734A2 (en) * | 2005-01-14 | 2006-07-20 | Medical College Of Georgia Research Institute | Prodrugs of short-chain fatty acids and treatment methods |
RU2008141912A (ru) | 2006-03-23 | 2010-04-27 | Новартис АГ (CH) | Противоопухолевые лекарства на основе антител к клеточным антигенам |
US7691980B2 (en) | 2007-01-09 | 2010-04-06 | Bio-Rad Laboratories, Inc. | Enhanced capacity and purification of antibodies by mixed mode chromatography in the presence of aqueous-soluble nonionic organic polymers |
FR2912314B1 (fr) * | 2007-02-09 | 2012-08-03 | Geneuro Sa | Composition pharmaceutique comprenant des anticorps diriges contre l'enveloppe de herv-w. |
US20110263650A1 (en) | 2007-07-20 | 2011-10-27 | Helmholtz-Zentrum Für Infektions-Forschung Gmbh | Tubulysin D Analogues |
WO2009134279A1 (en) | 2007-07-20 | 2009-11-05 | The Regents Of The University Of California | Tubulysin d analogues |
WO2009055562A1 (en) | 2007-10-25 | 2009-04-30 | Endocyte, Inc. | Tubulysins and processes for preparing |
PE20091163A1 (es) * | 2007-11-01 | 2009-08-09 | Wyeth Corp | Anticuerpos para gdf8 |
US8168586B1 (en) | 2007-11-21 | 2012-05-01 | Celera Corporation | Cancer targets and uses thereof |
EP2287174B8 (en) | 2008-01-18 | 2016-12-07 | Bio-Rad Laboratories, Inc. | Enhanced purification of antibody fragments by apatite chromatography |
JP5470817B2 (ja) | 2008-03-10 | 2014-04-16 | 日産自動車株式会社 | 電池用電極およびこれを用いた電池、並びにその製造方法 |
CN102099468B (zh) * | 2008-07-17 | 2014-01-15 | 协和发酵麒麟株式会社 | 抗-系统asc氨基酸转运蛋白2(asct2)抗体 |
US20110171219A1 (en) | 2008-09-19 | 2011-07-14 | Fahar Merchant | Treating cancer stem cells using targeted cargo proteins |
JP2012508017A (ja) | 2008-11-07 | 2012-04-05 | ファブラス エルエルシー | 抗dll4抗体及びその使用 |
JP2013535220A (ja) | 2010-08-06 | 2013-09-12 | エンドサイト,インコーポレイテッド | ツブリシンを調製するためのプロセス |
US20150140555A1 (en) * | 2012-05-25 | 2015-05-21 | National University Of Singapore | Method of identifying foetal erythroblast |
CA2885340C (en) | 2012-10-12 | 2016-11-08 | Spirogen Sarl | Pyrrolobenzodiazepines and conjugates thereof |
JP6136279B2 (ja) | 2013-01-15 | 2017-05-31 | 株式会社ジェイテクト | 転がり軸受装置 |
TWI503850B (zh) | 2013-03-22 | 2015-10-11 | Polytronics Technology Corp | 過電流保護元件 |
TWI510996B (zh) | 2013-10-03 | 2015-12-01 | Acer Inc | 控制觸控面板的方法以及使用該方法的可攜式電腦 |
GB201317982D0 (en) | 2013-10-11 | 2013-11-27 | Spirogen Sarl | Pyrrolobenzodiazepines and conjugates thereof |
AR100006A1 (es) | 2014-04-11 | 2016-08-31 | Medimmune Llc | Derivados de tubulisina |
AU2015243377A1 (en) | 2014-04-11 | 2016-09-15 | Medimmune, Llc | Bispecific HER2 antibodies |
WO2015155345A1 (en) | 2014-04-11 | 2015-10-15 | Medimmune Limited | Antibodies and antibody-drug conjugates |
US9816280B1 (en) | 2016-11-02 | 2017-11-14 | Matthew Reitnauer | Portable floor |
WO2018089393A1 (en) | 2016-11-10 | 2018-05-17 | Medimmune, Llc | Binding molecules specific for asct2 and uses thereof |
-
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011087091A1 (ja) * | 2010-01-15 | 2011-07-21 | 協和発酵キリン株式会社 | 抗システムascアミノ酸トランスポーター2(asct2)抗体 |
WO2015157595A1 (en) * | 2014-04-11 | 2015-10-15 | Medimmune, Llc | Conjugated compounds comprising cysteine-engineered antibodies |
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