JP6905966B2 - 血液脳関門輸送の安全性を改善するための方法 - Google Patents
血液脳関門輸送の安全性を改善するための方法 Download PDFInfo
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Description
「血液脳関門」又は「BBB」とは、脳毛細血管内皮原形質膜内の密着結合によって形成される、末梢循環と脳及び脊髄(すなわち、CNS)の間の生理的関門を指し、これにより、分子の脳への輸送を、尿素(60ダルトン)などの非常に小さい分子でさえも制限する関門が創出される。脳内の血液脳関門、脊髄内の血液−脊髄関門、及び網膜内の血液網膜関門はCNS内の連続した毛細血管関門であり、本明細書では、集合的に血液脳関門又はBBBと称される。BBBは、関門が毛細血管内皮細胞ではなく上衣細胞で構成される血液−CSF関門(脈絡嚢)も含む。
A.抗BBB−R抗体及びそのコンジュゲートの作製
本発明の方法及び製造品では、BBB−Rに結合する抗体を使用する又は組み入れる。抗体の作製又はスクリーニングのために使用するBBB−R抗原は、例えば、所望のエピトープを含有するBBB−Rの可溶性の形態又はその一部(例えば細胞外ドメイン)であってよい。その代わりに又はそれに加えて、細胞表面においてBBB−Rを発現している細胞を使用して抗体を生成又はスクリーニングすることができる。抗体を生成するために有用なBBB−R他の形態及び提示は、当業者には明らかになるであろう。本発明のBBB−Rの例としては、トランスフェリン受容体(TfR)、インスリン受容体、インスリン様増殖因子受容体(IGF−R)、低密度リポタンパク質受容体関連タンパク質1(LRP1)及びLRP8など、グルコーストランスポーター1(Glut1)及びヘパリン結合性上皮増殖因子様増殖因子(HB−EGF)が挙げられる。
本発明に従って使用される抗体の治療用製剤は、所望の程度の純度を有する抗体を任意選択の薬学的に許容される担体、賦形剤又は安定剤(Remington's Pharmaceutical Sciences 16版、Osol, A.編 (1980))と混合して凍結乾燥製剤又は水溶液の形態にすることにより、保管用に調製される。許容できる担体、賦形剤、又は安定剤は、使用される投与量及び濃度でレシピエントに対して非毒性のものであり、それらとして、リン酸、クエン酸、及び他の有機酸などの緩衝液;アスコルビン酸及びメチオニンを含めた抗酸化剤;防腐剤(例えば、塩化オクタデシルジメチルベンジルアンモニウム(octadecyldimethylbenzyl ammonium chloride)など);塩化ヘキサメトニウム;塩化ベンザルコニウム、塩化ベンゼトニウム;フェノール、ブチル若しくはベンジルアルコール;メチルパラベン若しくはプロピルパラベンなどのアルキルパラベン;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残基未満)のポリペプチド;血清アルブミン、ゼラチン、若しくは免疫グロブリンなどのタンパク質;ポリビニルピロリドンなどの親水性ポリマー;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、若しくはリシンなどのアミノ酸;グルコース、マンノース、若しくはデキストリンを含めた単糖、二糖、及び他の炭水化物;EDTAなどのキレート化剤;スクロース、マンニトール、トレハロース若しくはソルビトールなどの糖;ナトリウムなどの塩形成性対イオン;金属錯体(例えばZn−タンパク質複合体);並びに/又はTWEEN(商標)、PLURONICS(商標)若しくはポリエチレングリコール(PEG)などの非イオン性界面活性物質が挙げられる。
本発明の抗BBB−R抗体(それを含む多重特異性抗体を含む)は、種々のin vivo方法において利用することができる。例えば、本発明は、治療用化合物を、赤血球集団に対する影響を低下させる又は排除しながら血液脳関門を通して輸送する方法であって、治療用化合物(例えばBBB−Rと脳抗原の両方に結合する多重特異性抗体)とカップリングした抗BBB−R抗体をBBBに曝露し、その結果、抗体により、抗体とカップリングした治療用化合物がBBBを通って輸送されることを含む方法を提供する。別の例では、本発明は、神経性障害薬を血液脳関門を通して輸送する方法であって、脳障害薬(例えばBBB−Rと脳抗原の両方に結合する多重特異性抗体)とカップリングした本発明の抗BBB−R抗体をBBBに曝露し、その結果、抗体により、抗体とカップリングした神経性障害薬がBBBを通って輸送され、赤血球集団に対する影響は低下する又は排除されることを含む方法を提供する。一実施態様では、本発明のBBBは哺乳動物(例えばヒト)、例えば、これだけに限定することなく、アルツハイマー病(AD)、脳卒中、認知症、筋ジストロフィー(MD)、多発性硬化症(MS)、筋萎縮性側索硬化症(ALS)、嚢胞性線維症、アンジェルマン症候群、リドル症候群、パーキンソン病、ピック病、パジェット病、癌、外傷性脳損傷などを含めた神経性障害を有する哺乳動物(例えばヒト)におけるものである。
本発明の別の態様では、上記の障害を治療、予防及び/又は診断するために有用な材料を含有する製造品が提供される。製造品は、容器及び容器上の又は容器に付随するラベル又は添付文書を含む。適切な容器としては、例えば、ビン、バイアル、シリンジ、IV用溶液バッグなどが挙げられる。容器は、ガラス又はプラスチックなどの種々の材料から形成されていてよい。容器には、組成物が単独で又は状態を治療、予防及び/又は診断するために有効な別の組成物と組み合わせて保持されており、及び滅菌アクセスポートがあってよい(例えば、容器は、皮下注射針で穴をあけることができる静脈内注射用溶液バッグ又は止め栓を有するバイアルであってよい)。組成物中の少なくとも1種の活性薬剤は本発明の抗体である。ラベル又は添付文書には、組成物が選択された状態の治療に使用するためのものであることが示されている。さらに、製造品は、(a)本発明の抗体を含む組成物が含有される第1の容器と、(b)別の細胞傷害性剤又は他の点での治療剤を含む組成物が含有される第2の容器とを含んでよい。本発明のこの実施態様では、製造品は、組成物を、特定の状態の治療に使用することができることが示された添付文書をさらに含んでよい。その代わりに又はそれに加えて、製造品は、注射用静菌水(BWFI)、リン酸緩衝食塩水、リンゲル液及びブドウ糖溶液などの薬学的に許容される緩衝液を含む第2の(又は第3の)容器をさらに含んでよい。製造品は、他の緩衝液、希釈剤、フィルター、針、及びシリンジを含めた商業的観点及び使用者の観点から望ましい他の材料をさらに含んでよい。
低親和性抗TfR抗体の生成及び特徴付け
この分野では、トランスフェリン受容体(TfR)の、トランスフェリンを血液脳関門(BBB)を通して輸送する天然の能力を活用して、異種分子を血流から脳内に輸送することができることが理解されている(例えば、国際公開第9502421号を参照されたい)。出願人らは、この系に対する重要な改変、すなわち、抗トランスフェリン受容体抗体(抗TfR)とコンジュゲートした異種分子の脳内への輸送及び脳内での保持が、特定の範囲内で抗TfRのトランスフェリン受容体に対する親和性を低下させることによって実質的に増強されることを以前に開発した(Sci. Transl. Med. 3、84ra43 (2011))。
抗TfR投薬の網状赤血球に対する影響
予想外に、マウスを単一特異性の抗TfRA又は抗TfRDで処置すると、1mg/kg以上の全ての用量レベルで、二重特異性の抗TfRA/BACE1又は抗TfRD/BACE1で処置したマウスでは観察されなかった普通でない急性の臨床徴候が観察された(表3参照)。
特に、単一特異性で処置したマウスでは、処置の5分以内に投薬後嗜眠が示され、マウスは動かなくなり、反応しなくなり(いくつかの動物では時々、痙攣性の動きがあった)、その後、投薬の20−25分後までにだらしなく、体を丸めた外観が生じた。そのような観察された影響は処置後数時間のうちに消滅した。ある特定の単一特異性抗体で処置したマウスでは、時々の血尿、並びに投与の1時間後に末端心臓血液採取が二重特異性で処置した動物からの採取と比較して難しかったことに基づいて、明らかな低血圧があると思われた。マウスの未成熟の赤血球では末梢血流中に存在するためにTfRが発現されることが公知であり(図2A参照)、マウスにおいて観察された影響は、そのような血液細胞が傷害を受けたとすると説明することができるので、マウスにおいて未成熟の赤血球(網状赤血球)に対する抗体による処置の影響を調査した。
エフェクター機能を調節することの影響
TfRに対する親和性及び結合価が異なることに加えて、前述の実験で使用した単一特異性抗TfR抗体及び二重特異性抗TfR抗体は、それらのエフェクター機能の程度も異なった。単一特異性抗TfR抗体は、CHO細胞において産生させたものであり、哺乳動物型のグリコシル化及び野生型エフェクター機能を有した。二重特異性抗TfR/BACE1抗体は、当技術分野で周知の以下の方法の1つ又は複数を使用してFcγ受容体と相互作用する能力を著しく低下させた又は排除したものである:Fc領域に変異N297G又はN297Aが存在することに起因してグリコシル化を抑止すること(Atwalら、Sci. Transl. Med. 3、84ra43 (2011);Fares Al-Ejehら、Clin. Cancer Res. (2007) 13: 5519s-5527s)、抗体Fc領域を、エフェクター機能が完全に抑止されることが既知である、265位におけるアスパラギン酸からアラニンへの変異(D265A)を含有するように改変すること(例えば、米国特許7332581号を参照されたい)、又は抗体を、大腸菌に産生させることなどの、野生型哺乳動物グリコシル化が妨げられる様式で作製すること。
%ADCC=100×(試料シグナル−AICC)÷(最大の溶解−自発性放出)
試料希釈物のADCC値を抗体濃度に対してプロットし、GraphPad(商標)(GraphPad Software Inc.)を使用して用量反応曲線を4パラメータモデルにあてはめた。
Fc又はBACE1の結合の調節の影響
Fc腕及びBACE1腕の役割を、網状赤血球枯渇の媒介におけるそれらの潜在的な関与についてそれぞれ別々に調査した。完全なエフェクター機能及び正常なグリコシル化を有する野生型IgG1のFc領域を有する単一特異性抗TfR及び二重特異性抗TfRを生成した。簡単に述べると、記載されている通り、TfR(ホール)半抗体及びIgG(ノブ)半抗体をCHOにおいて別々に発現させ、in vitroでアニーリングさせた(Carter, P. (2001) J. Immunol. Methods 248、7-15;Ridgway, J. B.、Presta, L. G.、及びCarter, P. (1996) Protein Eng. 9、617-621;Merchant, A. M.、Zhu, Z.、Yuan, J. Q.、Goddard, A.、Adams, C. W.、Presta, L. G.、及びCarter, P. (1998) Nat. Biotechnol. 16、677-681;Atwell, S.、Ridgway, J. B.、Wells, J. A.、及びCarter, P. (1997) J. Mol. Biol. 270、26-35)。抗TfR IgG抗体、抗TfR/IgG抗体又は抗TfR/BACE1抗体から、固定化ペプシンで消化することによってF(ab’)2断片を生成した。抗体を100mMの酢酸ナトリウム、pH4.2中で再構成し、固定化ペプシン樹脂(IgG1mg当たり固定ゲル0.3mL)と一緒に37℃で一晩、回転させながらインキュベートした。インキュベートした後、試料を遠心分離して、固定化ペプシンをF(ab’)2消化混合物から分離した。次いで、強力な陽イオン交換樹脂であるSPセファロース(1mLのHiTrap(商標)カラム(Supelco))を使用してF(ab’)2断片を精製した。試料を50mMのNaOAc、pH5.0にローディングし、20カラム体積にわたって0−0.5MのNaCl勾配を用いて溶出し、 その後、試料をPBS、pH7.4に対して透析した。これらの抗体及びF(ab’)2を用い、上記と同じ手順で、静脈内25mg/kg用量の単一特異性F(ab’)2又は静脈内50mg/kg用量の二重特異性F(ab’)2若しくはコントロールF(ab’)2若しくは抗体を使用してマウス実験を実施した。全血試料を、抗体/F(ab’)2を静脈内注射した24時間後の総網状赤血球数について評価した。結果が図5A−5Cに示されている。
結合親和性のさらなる操作
いくらかの上記の結果により、観察される網状赤血球枯渇の程度に対して親和性及び用量成分が存在することが示唆された(図2C)。親和性及び用量が網状赤血球枯渇にどのように影響を及ぼすかをよりよく理解するために、実施例2において実施したマウスへの投薬実験を、2つの異なる用量レベル(25mg/kg及び50mg/kg)の低親和性抗TfR抗体、具体的には抗TfRE/BACE1を追加して繰り返した。抗TfREでは、試験したいずれの用量においても網状赤血球への影響は基本的になかったが(図6A)、同様の用量の抗TfRA/BACE1又は抗TfRD/BACE1では、網状赤血球が枯渇した。実施例1において考察されている結果から、抗TfRE/BACE1は抗TfRD/BACE1よりも血漿曝露の持続及び脳内での存続は良好であるが、血液脳関門を通るロバストな輸送は劣ることが観察された。抗TfRD/BACE1投与により網状赤血球枯渇が生じるが、抗TfRE/BACE1投与では網状赤血球枯渇が生じないことを考慮して、TfRに対して抗TfRDの親和性と抗TfREの親和性の間の親和性を有するバリアント抗TfRを生成して、BBB輸送及び脳内での存続を犠牲にすることなく抗体の安全性プロファイルを改善することができるかどうかを確かめた。
BBB浸透性の評価
異種分子を脳内に輸送するために血液脳関門輸送受容体を利用することの懸念は、BBB自体が損なわれる可能性があることである。したがって、抗TfRを投薬した際のBBBの抗体に対する浸透性を調査した。野生型マウスに、コントロールIgGを50mg/kgで、又は示されている同時注射する抗体の組合せのそれぞれを25mg/kgで静脈内投与した。静脈内注射した24時間後の平均の脳内への抗体の取り込みを、一般的なヒト−Fc ELISAを実施例1に従って使用し、又は抗BACE1特異的ELISAを実施例1に記載のものと同様の手順に従って使用して評価した。BACE1細胞外ドメインをコートタンパク質として使用し、Fc特異的ポリクローナル抗体である、西洋ワサビペルオキシダーゼとコンジュゲートしたF(ab’)2ヤギ抗ヒトIgGを用いて検出を実施した。このアッセイのLLOQ値は抗BACE1についてはおよそ2.56ng/gであり、抗TfRD/BACE1については12.8ng/gであった。実施例1に記載のものと同じ手順を使用して投与後の脳内Aβ1−40レベルを測定した。
網状赤血球レベルに対する多数回投薬の影響
前述の試験は、抗TfR抗体の単回投薬並びに網状赤血球レベルに対して生じる影響及び同時に生じる急性臨床症状に焦点を合わせた。より長い期間にわたって複数回投薬した後に異なる影響が観察されるかどうかを確認するために、さらなる試験を行った。単回の静脈内投薬の代わりに、マウスに、25mg/kgの抗TfRD/BACE1又はIgGコントロールを、1週間に1回、合計4週間にわたって静脈内投薬したこと以外は前述の実施例に記載のものと同じプロトコールを使用した。2回目の注射の1日後、4日後又は7日後及び4回目の注射の1日後、4日後又は7日後に組織/血液を採取し、上記のプロトコールを使用して処理した。さらに、血清試料について、直接ビリルビン、血清鉄、総鉄結合能及び不飽和鉄結合能を、Integra(商標)400(Roche、Indianapolis、IN)を製造者の説明書に従って使用して比色定量アッセイによって決定した。各時点及び各処置群についてマウス6匹を使用した。
血液中及び骨髄中の赤血球前駆細胞に対するエフェクターを含有する二重特異性及びエフェクターを欠く二重特異性の影響
骨髄中の赤血球前駆細胞集団に対する抗体投薬の影響を解明するために追加的な実験を実施した。まず、抗TfR/BACE1を投薬した後の網状赤血球の喪失の時間経過を調査するために、野生型マウスに、コントロールIgG又はエフェクター機能を欠く抗TfRD/BACE1を50mg/kgで、滅菌PBS中200μLの単回のボーラスとして静脈内注射した(群当たりn=6)1時間後、4時間後、16時間後、及び24時間後に血液及び骨髄を単離した。示されている投薬後の時点で動物から血液及び骨髄を回収した。イソフルラン麻酔後に眼窩出血を血液抽出のために使用し、片側の大腿骨から骨髄を回収し、単一細胞懸濁液を調製した。次いで、細胞を70ミクロンの細胞濾過器で濾過した。細胞を洗浄し、設定した体積のPBSに再懸濁させた。固定体積の細胞懸濁液を固定濃度のFITC標識蛍光ビーズに加え、フローサイトメーターで分析し、試料当たり5000のビーズ事象を収集して細胞数を得た。赤血球集団の定量的分析をフローサイトメトリーによって決定した。血液及び骨髄のどちらにおいても、別個の赤血球系細胞の集団をそれらのTer119 マーカー(マウス成熟赤血球及び赤血球前駆体細胞でのみ発現されることが決定されているマーカー)の発現、TfR発現、及び側方散乱プロファイルによってゲーティングした(以前にPanigaら、"Expression of Prion Protein in Mouse Erythroid Progenitors and Differentiating Murine Erythroleukemia Cells." PLoS One 6、9 (2011);図9A及び9Bに記載されている通り)。簡単に述べると、試料を抗マウスTer119−PE(eBioscience)及びビオチン化抗マウスTfRと一緒に、その後ストレプトアビジン−eFluor450(eBioscience)と一緒に氷上で20分インキュベートした。試料を0.5%BSA、2mMのEDTAを含有するPBSで洗浄し、BD LSR Fortessa多色フローサイトメーターに流し、FlowJo software(Ashland、OR)を使用して解析した。
ヒト赤白血病細胞株及び初代骨髄単核細胞に対するエフェクターを含有する単一特異性抗体及び二重特異性抗体並びにエフェクターを欠く単一特異性抗体及び二重特異性抗体の影響
前述の実施例では、ヒトTfRを特異的に認識しない抗マウスTfR抗体を使用した。マウス試験において観察された網状赤血球枯渇がマウスの系に独特のものであるかを確認するために、ヒトTfRに結合する抗TfRを利用して別の実験を実施した。
試料希釈物のADCC値を抗体濃度に対してプロットし、SoftMax Proを使用して用量反応曲線を4パラメータモデルにあてはめた。
Claims (40)
- 対象において化合物を血液脳関門を横断して輸送するための剤であって、抗体により、抗体とカップリングした化合物が血液脳関門を横断して輸送されるように化合物とカップリングした、トランスフェリン受容体(TfR)と5nMから50μMの親和性で結合する抗体を含み、抗体を対象に投与した際の対象における赤血球レベルの低下が減少する又は排除されるように、
抗体のエフェクター機能又は補体活性化機能は、抗体のアイソタイプをエフェクター機能が天然に低下している又は排除されているアイソタイプに改変することにより、低下している又は排除されているか、あるいは
エフェクター機能又は補体活性化機能は、Fc領域を改変すること、抗体上にすでに存在する炭水化物基を除去すること、又は抗体を野生型グリコシル化が起こらないように改変することにより、同じアイソタイプの野生型抗体と比較して低下している又は排除されており、
さらに、Fc領域の改変又は野生型グリコシル化が起こらないような抗体の改変は、297位の野生型アスパラギン残基がグリシンで置き換えられる変異以外である、剤。 - 対象は、神経性障害を有する、請求項1に記載の剤。
- 化合物とカップリングした、TfRと5nMから50μMの親和性で結合する抗体を含む、神経性障害を治療するための薬学的組成物であって、
網状赤血球レベルへの抗体の影響、対象の急性臨床症状の重症度若しくは存在、またはこれらの何れもが減少するように、抗体のエフェクター機能又は補体活性化機能は、抗体のアイソタイプをエフェクター機能が天然に低下している又は排除されているアイソタイプに改変することにより、低下している又は排除されているか、あるいは
エフェクター機能又は補体活性化機能は、Fc領域を改変すること、抗体上にすでに存在する炭水化物基を除去すること、又は抗体を野生型グリコシル化が起こらないように改変することにより、同じアイソタイプの野生型抗体と比較して低下している又は排除されており、
さらに、Fc領域の改変又は野生型グリコシル化が起こらないような抗体の改変は、297位の野生型アスパラギン残基がグリシンで置き換えられる変異以外である、薬学的組成物。 - 神経性障害が、アルツハイマー病(AD)、脳卒中、認知症、筋ジストロフィー(MD)、多発性硬化症(MS)、筋萎縮性側索硬化症(ALS)、嚢胞性線維症、アンジェルマン症候群、リドル症候群、パーキンソン病、ピック病、パジェット病、癌、又は外傷性脳損傷である、請求項2に記載の剤又は請求項3に記載の薬学的組成物。
- 化合物は、イメージング剤である、請求項1若しくは2に記載の剤又は請求項3若しくは4に記載の薬学的組成物。
- 化合物は、神経性障害を治療する薬物である、請求項2に記載の剤又は請求項3若しくは4に記載の薬学的組成物。
- 化合物は、抗体、アプタマー、タンパク質、ペプチド、阻害性核酸又は小分子である、請求項1から4及び6のいずれか一項に記載の剤又は薬学的組成物。
- 抗体が多重特異性抗体であり、化合物が多重特異性抗体の一部分を形成する、請求項1から4及び6のいずれか一項に記載の剤又は薬学的組成物。
- 多重特異性抗体が、TfRに結合する第1の抗原結合部位と、脳抗原に結合する第2の抗原結合部位とを含む、請求項8に記載の剤又は薬学的組成物。
- 脳抗原が、ベータ−セクレターゼ1(BACE1)、Abeta、上皮増殖因子受容体(EGFR)、ヒト上皮増殖因子受容体2(HER2)、tau、アポリポタンパク質E4(ApoE4)、アルファ−シヌクレイン、CD20、ハンチンチン、プリオンタンパク質(PrP)、ロイシンリッチリピートキナーゼ2(LRRK2)、パーキン、プレセニリン1、プレセニリン2、ガンマセクレターゼ、細胞死受容体6(DR6)、アミロイド前駆体タンパク質(APP)、p75ニューロトロフィン受容体(p75NTR)、又はカスパーゼ6である、請求項9に記載の剤又は薬学的組成物。
- 多重特異性抗体がTfRとBACE1の両方に結合する、或いは多重特異性抗体がTfRとAbetaの両方に結合する、請求項10に記載の剤又は薬学的組成物。
- 抗体のグリコシル化を減少させること、抗体のアイソタイプをエフェクター機能が天然に低下している又は排除されているアイソタイプに改変すること、及びFc領域を改変することから選択される方法によってエフェクター機能を低下させる又は排除する、請求項1から11のいずれか一項に記載の剤又は薬学的組成物。
- 抗体上にすでに存在する炭水化物基を除去すること、及び抗体を野生型グリコシル化が起こらないように改変することから選択される方法によって抗体のグリコシル化を減少させる、請求項1から12のいずれか一項に記載の剤又は薬学的組成物。
- 抗体を非哺乳動物細胞の産生系で産生させる、又は抗体を合成的に作製する、請求項1から13のいずれか一項に記載の剤又は薬学的組成物。
- Fc領域の一部を欠失させることによって、又は、抗体を、エフェクター機能若しくは補体活性化機能に適格なFc領域若しくは非Fc領域を含まないように操作することによって、エフェクター機能又は補体活性化機能を低下させる又は排除する、あるいは、
改変が、238位、239位、248位、249位、252位、254位、265位、268位、269位、270位、272位、278位、289位、292位、293位、294位、295位、296位、297位、298位、301位、303位、322位、324位、327位、329位、333位、338位、340位、373位、376位、382位、388位、389位、414位、416位、419位、434位、435位、437位、438位、及び439位から選択される、1つ又は複数のFc受容体との結合が損なわれるようなFc領域の点変異;270位、322位、329位、及び321位から選択される、C1qとの結合が損なわれるようなFc領域の点変異、Fc領域の一部の排除、並びにCH1ドメインの132位における点変異から選択される、請求項12から14のいずれか一項に記載の剤又は薬学的組成物。 - 対象がヒトである、請求項1から15のいずれか一項に記載の剤又は薬学的組成物。
- 抗体のFc領域は、297位に、その位置の野生型アスパラギン残基が、その位置におけるグリコシル化に干渉する、グリシン以外の別のアミノ酸で置き換えられるような変異を含む、請求項1から16のいずれか一項に記載の剤又は薬学的組成物。
- エリスロポエチン(EPO)、鉄補給剤、ビタミンC、葉酸、及びビタミンB12、及び同じ対象若しくは別の対象由来の赤血球若しくは網状赤血球から選択される更なる剤と共投与するためである、請求項1から17のいずれか一項に記載の剤又は薬学的組成物。
- 抗体によってTfRとトランスフェリンとの結合が損なわれない、請求項1から18のいずれか一項に記載の剤又は薬学的組成物。
- 抗体が、TfRに対し30nMから30μMの親和性を有する、請求項1から19のいずれか一項に記載の剤又は薬学的組成物。
- 抗体が、TfRに対して30nMから1μMまでの親和性を有する、請求項1から19のいずれか一項に記載の剤又は薬学的組成物。
- 化合物とカップリングした抗体が、TfRに対して50nMから1μMの親和性を有する、請求項1から19のいずれか一項に記載の剤又は薬学的組成物。
- 化合物とカップリングした抗体が、TfRに対して30秒から5分まで、又は30秒から2分までの解離半減期を有する、請求項1から22のいずれか一項に記載の剤又は薬学的組成物。
- 安全性が改善された、化合物をBBBを横断して輸送するために有用な抗体を作出する方法であって、5nMから50μMの親和性でTfRと結合する、トランスフェリン受容体(TfR)に特異的な抗体を選択することと、
抗体を投与した際の対象における赤血球レベルの低下が、改変されていない抗体と比較して減少する又は排除されるように、抗体のエフェクター機能又は補体活性化機能を同じアイソタイプの野生型抗体に対して低下させるか又は排除して、網状赤血球レベルへの抗体の影響を減少させるか又は対象における急性臨床症状の重症度若しくは存在を減少させるか或いはこれらの何れもを減少させることとを含み、
エフェクター機能又は補体活性化機能は、抗体のアイソタイプをエフェクター機能が天然に低下している又は排除されているアイソタイプに改変することにより、低下又は排除されるか、あるいは
抗体のエフェクター機能又は補体活性化機能は、Fc領域を改変すること、抗体上にすでに存在する炭水化物基を除去すること、又は抗体を野生型グリコシル化が起こらないように改変することにより、同じアイソタイプの野生型抗体と比較して低下又は排除され、
さらに、Fc領域の改変又は野生型グリコシル化が起こらないような抗体の改変は、297位の野生型アスパラギン残基がグリシンで置き換えられる変異以外である、方法。 - 化合物は、イメージング剤である、請求項24に記載の方法。
- 化合物は、神経性障害を治療する薬物である、請求項24に記載の方法。
- 化合物は、抗体、アプタマー、タンパク質、ペプチド、阻害性核酸又は小分子である、請求項26に記載の方法。
- 抗体が多重特異性抗体であり、化合物が多重特異性抗体の一部分を形成する、請求項24又は26に記載の方法。
- 多重特異性抗体が、TfRに結合する第1の抗原結合部位と、脳抗原に結合する第2の抗原結合部位とを含む、請求項28に記載の方法。
- 脳抗原が、ベータ−セクレターゼ1(BACE1)、Abeta、上皮増殖因子受容体(EGFR)、ヒト上皮増殖因子受容体2(HER2)、tau、アポリポタンパク質E4(ApoE4)、アルファ−シヌクレイン、CD20、ハンチンチン、プリオンタンパク質(PrP)、ロイシンリッチリピートキナーゼ2(LRRK2)、パーキン、プレセニリン1、プレセニリン2、ガンマセクレターゼ、細胞死受容体6(DR6)、アミロイド前駆体タンパク質(APP)、p75ニューロトロフィン受容体(p75NTR)、又はカスパーゼ6である、請求項29に記載の方法。
- 多重特異性抗体がTfRとBACE1の両方に結合する、或いは多重特異性抗体がTfRとAbetaの両方に結合する、請求項30に記載の方法。
- 抗体のグリコシル化を減少させること、抗体のアイソタイプをエフェクター機能が天然に低下している又は排除されているアイソタイプに改変すること、及びFc領域を改変することから選択される方法によってエフェクター機能を低下させる又は排除する、請求項24から31のいずれか一項に記載の方法。
- 抗体上にすでに存在する炭水化物基を除去すること、及び抗体を野生型グリコシル化が起こらないように改変することから選択される方法によって抗体のグリコシル化を減少させる、請求項24から32のいずれか一項に記載の方法。
- 抗体を非哺乳動物細胞の産生系で産生させる、又は抗体を合成的に作製する、請求項24から33のいずれか一項に記載の方法。
- 抗体のFc領域は、297位に、その位置の野生型アスパラギン残基がその位置におけるグリコシル化に干渉する、グリシン以外の別のアミノ酸で置き換えられるような変異を含む、請求項32又は33に記載の方法。
- Fc領域の一部を欠失させることによって、又は、抗体を、エフェクター機能若しくは補体活性化機能に適格なFc領域を含まないように操作することによって、エフェクター機能又は補体活性化機能を低下させる又は排除するか、或いは、
改変が、238位、239位、248位、249位、252位、254位、265位、268位、269位、270位、272位、278位、289位、292位、293位、294位、295位、296位、297位、298位、301位、303位、322位、324位、327位、329位、333位、338位、340位、373位、376位、382位、388位、389位、414位、416位、419位、434位、435位、437位、438位、及び439位から選択される、1つ又は複数のFc受容体との結合が損なわれるようなFc領域の点変異;270位、322位、329位、及び321位から選択される、C1qとの結合が損なわれるようなFc領域の点変異、Fc領域の一部の排除、並びにCH1ドメインの132位における点変異から選択される、請求項24から35のいずれか一項に記載の方法。 - 抗体が、TfRに対し、30nMから30μM、又は30nMから1μMの親和性を有する、請求項24から36のいずれか一項に記載の方法。
- 抗体がTfRに対し50nMから1μMの親和性を有する、請求項24から36のいずれか一項に記載の方法。
- 抗体がTfRに対し約30秒から5分、または30秒から2分までの解離半減期を有する、請求項24から38のいずれか一項に記載の方法。
- 抗体によってTfRとトランスフェリンの結合が阻害されない、請求項24から39のいずれか一項に記載の方法。
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