JP6844864B2 - ヒト化抗ccr7受容体抗体 - Google Patents
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- JP6844864B2 JP6844864B2 JP2018506333A JP2018506333A JP6844864B2 JP 6844864 B2 JP6844864 B2 JP 6844864B2 JP 2018506333 A JP2018506333 A JP 2018506333A JP 2018506333 A JP2018506333 A JP 2018506333A JP 6844864 B2 JP6844864 B2 JP 6844864B2
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Images
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Description
用語「抗体」はその最も広い意味で使用され、具体的には、例えば、アンタゴニスト、中和抗体、完全長又は無傷のモノクローナル抗体、ポリエピトープ特異性を有する抗CCR7抗体組成物、ポリクローナル抗体、多価抗体、一本鎖抗CCR7抗体を含む単一抗CCR7モノクローナル抗体、並びに、断片が所望の生物及び/又は免疫活性を示しさえすれば、Fab、Fab’、F(ab’)2及びFv断片、ダイアボディ、単一ドメイン抗体(sdAb)を含む抗CCR7抗体の断片(下参照)を網羅する。用語「免疫グロブリン」(Ig)は本明細書では抗体と互換的に使用される。抗体はヒト及び/又はヒト化でも可能である。
これら2つのドメインのフォールディングから、抗原結合のためのアミノ酸残基を与え抗体に抗原結合特異性を授ける6つの超可変ループ(3つのループそれぞれがH及びL鎖由来である)が出てくる。しかし、単一可変ドメイン(又は抗原に特異的な3つのCDRのみを含むFvの半分)でも抗原を認識し結合する能力を有するが、全結合部位よりも親和性は低い。
本発明の抗CCR7抗体
第1の態様では、本発明はCCR7に結合する抗原結合タンパク質を提供する。CCR7に結合する本発明の抗原結合タンパク質は、好ましくは、例えば、抗CCR7抗体、抗体断片、抗体誘導体、抗体変異タンパク質、及び抗体変異体を含む、本明細書で上に定義される最も広い意味での抗CCR7抗体である。本発明の抗CCR抗体は、好ましくは、単離された抗体である。本発明の抗CCR抗体は、霊長類CCR7に結合するのが好ましく、ヒトCCR7に結合するのがさらに好ましい。ヒトCCR7のアミノ酸配列はジェンバンク:EAW60669.1で入手可能である(配列番号75)。この配列のアミノ酸1〜24は、発現中に切断される膜移行シグナルペプチドを含む。ヒトCCR7のアミノ酸25〜59はN終端細胞外ドメインを構成し、このドメインはY32位及びY41位に硫酸化チロシン残基を含む。種々の対立遺伝子変異体は、ジェンバンク:EAW60669.1の配列と比べて1つ又は複数のアミノ酸置換を有するヒトCCR7で知られている。本発明での「ヒトCCR7」は、少なくとも変異体が細胞外ドメイン及びCCR7の機能を有する限り、これらの対立遺伝子変異体を含む。
HVR−H1は配列:G−F/L−T/A/P−F−S/T/R−N/D/S−Y/F−Aを含み;
HVR−H2 H1は配列:I−S−S/D−G/R−G−S/T/F−Y/H/F−T/Pを含み;
HVR−H3 H1は配列:A/T/V/G−R−R/A−A/E/T−Y/G/T−R/V−Y/V−D/*−GTG/*−E/V/D/A/G/*−N/S/D/T−A/S/D−M/L/F−Y/Sを含み;
HVR−L1 H1は配列:Q/S−D/S−I/L/V−G/S/L−D/S/P/G/N−S/N−*/Y/DGKTYを含み;
HVR−L2 H1は配列:A/S/T−T/I/V−Sを含み;
HVR−L3 H1は配列:L/W/Q−Q−Y/F/G/W−A/T/S−S/N/H−S/F/N−P−L/P/Q−Tを含み、「*」はその位置にアミノ酸が存在できないことを示す。
本発明の一好ましい実施形態では、本発明の抗CCR7抗体は1つ又は複数の毒素分子にコンジュゲートされている。使用することが可能である酵素的に活性な毒素及びその断片は、ジフテリアA鎖、ジフテリア毒素の非結合活性断片、外毒素A鎖(緑膿菌(Pseudomonas aeruginosa)由来)、リシンA鎖、アブリンA鎖、モデシンA鎖、αサルシン、シナアブラギリ(Aleurites fordii)タンパク質、ディアンチン(dianthin)タンパク質、ヨウシュヤマゴボウ(Phytolaca americana)タンパク質(PAP1、PAP11、及びPAP−S)、ニガウリ(momordica charantia)阻害剤、クルシン、クロチン、サボンソウ(sapaonaria officinalis)阻害剤、ゲロニン、マイトゲリン(mitogellin)、レストリクトシン、フェノマイシン(phenomycin)、エノマイシン(enomycin)及びトリコテセン類を含む。
本発明の抗CCR7抗体はいくつかの従来の技法のいずれによっても調製することが可能である。本発明の抗CCR7抗体は通常、当技術分野で公知であるいかなる技法でも使用して、組換え発現系で産生される。例えば、Shukla and Thommes(2010年、「Recent advances in large−scale production of monoclonal antibodies and related proteins」、Trends in Biotechnol.28(5):253〜261頁)、Harlow and Lane(1988)「Antibodies:A Laboratory Manual」、Cold Spring Harbor Laboratory Press、Cold Spring Harbor、NY、and Sambrook and Russell(2001)「Molecular Cloning」:A Laboratory Manual (3rd edition)、Cold Spring Harbor Laboratory、Cold Spring Harbor Laboratory Press、NYを参照されたい。当技術分野で公知であるいかなる発現系でも使用して、本発明の組換えポリペプチドを作ることが可能である。一般に、宿主細胞は、所望のポリペプチドをコードするDNAを含む組換え発現ベクターで形質転換される。
他の態様では、本発明は、対象に投与するための、本発明の抗CCR7抗体、すなわち、CCR7受容体に結合する抗体、若しくはその抗原結合断片、又はその医薬誘導体若しくはプロドラッグを、薬学的に許容される担体、アジュバンド、若しくは溶媒と一緒に含む医薬組成物に関する。上記医薬組成物は、それを必要とする対象に有効量の組成物を投与することにより本明細書の下に記載される処置の方法で使用することが可能である。本明細書で使用される用語「対象」とは、哺乳動物として分類されるすべての動物のことであり、霊長類及びヒトを含むがこれらに限定されない。対象は好ましくは任意の年齢又は人種の男性又は女性ヒトである。
静脈内、動脈内、リンパ内、腹腔内、筋肉内、皮下、直腸又は膣投与を含む。静脈内形態の非経口投与が好ましい。「全身投与」とは、経口、静脈内、腹腔内及び筋肉内投与を意味する。治療又は予防効果に必要な抗体の量は、当然のことながら、選択される抗体、処置中の状態の性質及び重症度並びに患者によって変化する。さらに、抗体は、例えば、抗体の減少用量でパルス注入により適切に投与してもよい。投与は注射により与えられるのが好ましく、一部、投与が短時間又は慢性かどうかに応じて、静脈内又は皮下注射が最も好ましい。
本発明の抗体及び医薬組成物は広範囲の疾患、状態、及び適応症の処置に有用になる。処置することが可能な疾患のタイプの例は、がん状態、炎症状態、組織又は臓器移植から生じる状態及び合併症、並びに線維症から生じる又はこれに関連する状態及び合併症を含む。
正常マウス(すなわち、マウス免疫系を備えたマウス)を、ヒトCCR7 N終端細胞外ドメイン由来のアミノ酸配列を含む又は発現している抗原で免疫化した。マウスモノクローナル抗体は標準ハイブリドーマ技術を使用して得た。
2.1 エピトープマッピング
モノクローナル抗体のエピトープマッピング(図1)は、以前公表されたプロトコルに従って実施された(Slootstraら、1996年 Mol Divers、1:87〜96頁;Timmermanら、2007年、J Mol Recognit、20:283〜99年)。手短に言えば、それぞれのペプチドへの抗体の結合はELISAベースのPEPSCANで試験される。ペプチドアレイは、例えば、遮断液(PBS/1%Tween中4%ウマ血清、5%卵白アルブミン(w/v))に希釈した1mg/mlからなる一次抗体液と一緒にインキュベートする。洗浄後、ペプチドは、25℃で1時間、1000倍希釈の抗体ペルオキシダーゼコンジュゲートと一緒にインキュベートする。洗浄後、ペルオキシダーゼ基質溶液(0.5mg/ml 2,2’−アジノ−ジ−3−エチルベンズチアゾリンスルホネート(ABTS)及び0.05Mのクエン酸緩衝液pH4中0.006%H2O2)を添加した。室温での1時間インキュベーション後、発色現像を測定した。発色現像は電荷結合素子(CCD)−カメラと画像処理システムで定量化した。
得られた抗CCR7モノクローナル抗体(表2)は、確立した標準βアレスチン動員アッセイ(PathHunter(商標)、DiscoverX、Fremont、CA、USA;Southernら、2013年、J Biomol Screen.18(5):599〜609頁)により決定した場合、ヒトCCR7過剰発現チャイニーズハムスター卵巣(CHO)細胞においてCCL19及びCCL21媒介細胞内シグナル伝達を阻害する。
マウスmAb730は、リガンドCCL19及びCCL21により誘導されて内因的にヒトCCR7受容体を発現している、ヒトT細胞リンパ腫細胞の遊走(走化性)を阻害し、IC50はそれぞれ15nM及び6nMである(図2)。
高濃度(267nM)で試験すると、確立した標準βアレスチン動員アッセイ(PathHunter(商標)、DiscoverX、Fremont、CA、USA;Southernら、2013年、J Biomol Screen.18(5):599〜609頁)により決定した場合、mAb729及び730を含む上の表2に収載されるマウス抗ヒトCCR7結合モノクローナル抗体はどれも、ヒトCCR7過剰発現チャイニーズハムスター卵巣(CHO)細胞において検出可能な細胞内アゴニスト効果を誘導しなかった(データは示してない)。IgG2aは負の対照として使用され、CCR7に対する天然リガンドであるCCL21は正の対照として使用された。
2.5.1 Biacore親和性測定
同定されたモノクローナル抗体の親和性は、標準条件下Biacore測定により決定された。モノクローナル抗体は適切なセンサー表面に固定化され、ヒトCCR7のN終端由来の残基19〜49を含む硫酸化抗原SYM1899((pyroGlu)DEVTDDZIGDNTTVDZTLFESLCSKKDVRNK;配列番号76);Zは硫酸化されたチロシンを示す)の溶液をセンサー表面に通した。SYM1899に対するマウスmAb729の得られた親和性値(Kd)は0.7nMであった。
ヒトCCR7発現CHO細胞(106細胞/ml)は4℃で24時間、3倍希釈系列(範囲20nM〜0.11pM)でマウスmAb726〜735と一緒に前インキュベートされた。結合抗体の量は、フィコエリトリン(PE)で標識された二次マウス特異的抗体を用いて染色し、続いてフローサイトメトリーにより検出することにより決定された。EC50値(表3)は、S字結合曲線から最小及び最大プラトー値の50%で決定された。
CDCアッセイでは、正常無処置ヒトT細胞(図3)は、効果的な濃度(範囲33〜0.5nM)での抗CCR7モノクローナル抗体mAb729−2Aを用いた処置に対して安全である。CDCアッセイはCuesta−Mateosら.(2015年、Cancer Immunol Immunother.DOI:10.1007/s00262−015−1670−z)により記載された通りに実施した。
細胞分裂阻害薬及び抗CD20モノクローナル抗体療法に無応答であり抗CD20療法抵抗性だと見なされている患者由来のCD20抵抗性CLL腫瘍B細胞は、補体依存性細胞傷害(CDC)アッセイにおいてmAb729−2A(IC50 0.15nM)により十分に死滅する(図4)。CDCアッセイはCuesta−Mateosら.(2015年、上記)により記載される通りに実施した。
3.1 ヒト化Abの設計及び構築
マウスモノクローナル抗体抗ヒトCCR7 MAb729がヒト化のために選択された。IMGT及びKabat由来の抗体番号付け方式を使用して、mAb729中でCDRが同定された(上の表1参照)。これら2つの番号付け方式は、マウス抗体の異なる残基をCDRに属すると同定し、組合せIMGT/Kabat CDR配列はCDRループ立体構造の最適保持のために使用された。本明細書で使用されるマウスmAb729のヒト化変異体のコードはmAb650である。
4.1 免疫原SYM1899への結合
免疫原SYM1899への抗体650変異体の結合を評価するELISAでは、硫酸化ペプチドはヒトCCR7のN終端(残基19〜49;配列番号76)に由来していた。100ng/ウェルのSYM1899はコーティング緩衝液中で96ウェルMaxisorpプレート上に固定化した。コーティング緩衝液は取り除き、200μl/ウェルの遮断液(3%w/vセミスキムミルク粉末、PBS)を添加し、室温で2時間撹拌した。プレートはPBS−T(0.001%v/vTween20)で6回洗浄した。抗体650変異体はPBS中1μg/mlまで希釈し、PBS中連続1対1希釈を濃度0.0078μg/mlまで行った。それぞれの抗体希釈液の3通りのウェル当たり100μlを、PBSの負の対照に加えてプレートに添加し、撹拌しながら室温で2時間インキュベートした。プレートはPBS−Tで6回洗浄した。100μl/ウェルのヤギ抗ヒトHRP(Fc特異的)(PBS中1対60000)を添加し、プレートは撹拌しながら室温で1時間インキュベートした。プレートはPBS−Tで6回、PBS中1回洗浄した。100μl/ウェルのTMB基質溶液を添加し37℃で10分間インキュベートした。ウェル当たり50μlの1M HClを添加し、プレートは直ちにBioliseプレート読取り装置上450nmで読み取った。
同じ軽鎖変異体を含む3つのヒト化抗ヒトCCR7 IgG1mAb(LC1、すなわち、重鎖*軽鎖:1*1=HC1 LC1;2*1=HC2 LC1;及び3.1=HC3 LC1)及びキメラ抗ヒトCCR7mAb(Fabマウス/Fcヒト:0*0=HC0 LC0)は、抗体依存性細胞傷害(ADCC)アッセイ(n=2)により決定した場合、慢性リンパ性白血病患者由来の悪性T細胞の50〜60%を死滅させた(図5)。アレムツズマブ(ALEM)及びリツキサン(RTX)は正の対照として使用し、mAb IGG1は負の対照として使用した。ADCCアッセイはSomovilla−Crespoら(2013年、J.of Hematol.&Oncol.6:89頁)により記載されている通りに実施した。
抗CCR7 mAb650−H1L1のアンタゴニスト活性は、本質的には下記の通り、確立した活性内部移行アッセイ(PathHunter(商標)、DiscoverX、Fremont、CA、USA)により決定された場合、CCL19誘導CCR7受容体内部移行の阻害により実証される(IC50 0.4155μg/ml=2.8nM;試験された範囲:267〜0.014nM)(図6)。
EFC技術を使用して、DiscoverRx社は受容体内部移行を研究するためのいくつかの方法を開発した。PathHunter(登録商標)活性化GPCR内部移行アッセイはアレスチン媒介GPCR内部移行の定量的測定を提供し、生細胞中の細胞膜由来の非標識アレスチン結合GPCRの動きをモニターすることを可能にする。
アッセイシグナルは、12.5又は15μL(50%v/v)のPathHunter検出試薬カクテルの単回添加、続いて室温で1時間のインキュベーションを通じて発生させた。化学発光シグナル検出のためにPerkinElmer Envision(商標)装置を用いて、シグナル発生に続いてマイクロプレートを読み取った。
複合活性はCBISデータ解析スイート(ChemInnovation、CA)を使用して解析した。アンタゴニストモードアッセイでは、パーセント阻害は以下の式:%阻害=100%×(1−(試験試料の平均RLU−溶媒対照の平均RLU)/(EC80対照の平均RLU−溶媒対照の平均RLU))を使用して計算した。
CCR7のCCL19誘導細胞内シグナル伝達は、本質的には下記の通り、確立したβアレスチン動員アッセイ(PathHunter(商標)、DiscoverX、Fremont、CA、USA)により決定された場合、mAb650−H1L1、マウスmAb729のヒト化版により効果的に阻害される(IC50 9.5622μg/ml=63.7nM;試験された範囲:267〜0.014nM)(図7)。
アレスチン経路
アンタゴニスト調節フォーマット:アンタゴニスト決定では、細胞はアンタゴニストと一緒に前インキュベートされ、続いてEC80濃度でアゴニストチャレンジを行った。試料ストックの中間希釈を実施してアッセイ緩衝液中5×試料を作成した。5μLの5×試料を細胞に添加し、37℃又は室温で30分間インキュベートした。溶媒濃度は1%であった。アッセイ緩衝液中6×EC80アゴニストを5μl、細胞に添加し、37℃又は室温で90又は180分間インキュベートした。
アッセイシグナルは、12.5又は15μL(50%v/v)のPathHunter検出試薬カクテルの単回添加、続いて室温で1時間のインキュベーションを通じて発生させた。化学発光シグナル検出のためにPerkinElmer Envision(商標)装置を用いて、シグナル発生に続いてマイクロプレートを読み取った。
複合活性はCBISデータ解析スイート(ChemInnovation、CA)を使用して解析した。アンタゴニストモードアッセイでは、パーセント阻害は以下の式:%阻害=100%×(1−(試験試料の平均RLU−溶媒対照の平均RLU)/(EC80対照の平均RLU−溶媒対照の平均RLU))を使用して計算した。
mAb650−H1L1は、本質的には下記の通り、確立したcAMP二次メッセンジャー経路アッセイ(PathHunter(商標)、DiscoverX、Fremont、CA、USA)により決定された場合、CCL19誘導CCR7依存性細胞内cAMPシグナル伝達を阻害する(IC50 1.609μg/ml=10.7nM;試験された範囲:267〜0.014nM)(図8)。
DiscoverRx社は、cAMPを通じて内因的にシグナルを送るタグされていないGPCRを安定的に発現している細胞株のパネルを開発していた。Hit Hunter(登録商標)cAMPアッセイは、機能的エンドポイントとしてβガラクトシダーゼ(β−Gal)を用いた酵素断片補完(EFC)と呼ばれるDiscoverRx社が開発した技術を使用して同種非画像化アッセイフォーマットにおいてGi及びGs二次メッセンジャーシグナル伝達を介してGPCRの活性化をモニターする。
インバースアゴニストフォーマット
インバースアゴニスト決定では、細胞はEC20フォルスコリンの存在下で試料と一緒に前インキュベートした。培養液は細胞から吸引し、15μLの2対1HBSS/10mM HEPES:cAMP XS+Ab試薬で置き換えた。試料ストックの中間希釈を実施して、4×EC20フォルスコリンを含有するアッセイ緩衝液中4×試料を作成した。4.5μLの4×試料を細胞に添加し、37℃又は室温で30又は60分間インキュベートした。最終アッセイ溶媒濃度は1%であった。
適切な複合インキュベーション後、アッセイシグナルは、20μLのcAMP XS+ED/CL溶解カクテルと一緒の1時間のインキュベーション、続いて20μLのcAMP XS+EA試薬と一緒の室温で3時間のインキュベーションを通じて発生させた。化学発光シグナル検出のためにPerkinElmer Envision(商標)装置を用いて、シグナル発生に続いてマイクロプレートを読み取った。
複合活性はCBISデータ解析スイート(ChemInnovation、CA)を使用して解析した。Giインバースアゴニストモードアッセイでは、パーセント活性は以下の式:%インバースアゴニスト活性=100%×((試験試料の平均RLU−EC20フォルスコリンの平均RLU)/(フォルスコリン正の対照の平均RLU−EC20対照の平均RLU))を使用して計算する。
5.1 アロタイプ転換されCDC増強された突然変異体の設計
ヒト化抗CCR7mAb650変異体1−1、2−1及び3−1の最初のアロタイプ(コードについては上記4.2参照)は十分に強いCDCエフェクター機能を生じなかった。したがって、3つの変異体1−1、2−1及び3−1のアロタイプはヒトアロタイプG1m17,1に転換されて変異体11−17、21−17、31−17を与え、それぞれが配列番号79に描かれている重鎖定常領域を有していた。CDCエフェクター機能をさらに増強するため、これら3つの変異体の重鎖定常領域はE333A置換(Idusogieら、2000年、J. Immunol.164:4178〜4184頁により記載されている)を導入することによりさらに改変されて、変異体11−AE、21−AE、31−AEを与え、それぞれが配列番号80に描かれている重鎖定常領域を有していた。さらに、11−17抗体の重鎖のHVR−H3(CDR3)アミノ酸配列を配列番号81のアミノ酸配列に変更することにより、対照抗体「11−x」を構築し、この抗体はCCR7を認識し結合する能力を完全に消失させた。抗体は500ml培養液体積中CHO細胞において一過性に発現され、精製され下記のさらなる試験のために、「0−0」とも呼ばれるキメラHC0 LC0抗体(上参照)と共に使用された。
次に、抗体11−17、21−17、31−17、11−AE、21−AE、31−AE、11−x及びキメラAb 0−0の性能を種々のアッセイで試験した。
Claims (17)
- 超可変領域HVR−H1、HVR−H2、HVR−H3、HVR−L1、HVR−L2及びHVR−L3を含み、
HVR−H1は配列番号6を含み;
HVR−H2 H1は配列番号13を含み;
HVR−H3 H1は配列番号19を含み;
HVR−L1 H1は配列番号27を含み;
HVR−L2 H1は配列番号31を含み;及び
HVR−L3 H1は配列番号36を含み、
抗体が、
a)重鎖可変領域のアミノ酸配列が配列番号1であり、軽鎖可変領域のアミノ酸配列が配列番号2であるマウス抗CCR7抗体のKdの10倍を超えないKdにより定義される配列番号76のアミノ酸配列を有する合成抗原に対する最小親和性;及び
b)CCL19及びCCL21から選択される少なくとも1つのCCR7−リガンドにより、CCR7依存性細胞内シグナル伝達とCCR7受容体内部移行のうちの少なくとも1つを阻害するための100nM以下のIC50
のうちの少なくとも1つを有するヒト化抗CCR7抗体。 - 抗体の重鎖可変ドメインが、HFR1、HVR−H1、HFR2、HVR−H2、HFR3、HVR−H3及びHFR4の順で作動可能に連結されている、HFR1〜HFR4の4つの重鎖フレームワーク領域及びHVR−H1〜HVR−H3の3つの超可変領域を含み、抗体の軽鎖可変ドメインが、LFR1、HVR−L1、LFR2、HVR−L2、LFR3、HVR−L3及びLFR4の順で作動可能に連結されている、LFR1〜LFR4の4つの軽鎖フレームワーク領域及びHVR−L1〜HVR−L3の3つの超可変領域を含み、HFR1〜HFR4の重鎖フレームワーク領域が:
i)それぞれ配列番号40、43、45及び48;
ii)それぞれ配列番号41、44、46及び49;又は
iii)それぞれ配列番号42、44、47及び49
のアミノ酸配列を有し、LFR1〜LFR4の軽鎖フレームワーク領域が:
iv)それぞれ配列番号50、52、55及び58;又は
v)それぞれ配列番号51、53、56及び59
のアミノ酸配列を有する、請求項1に記載のヒト化抗CCR7抗体。 - 抗体の重鎖可変ドメインが配列番号61、62及び63のうちの少なくとも1つに少なくとも95%配列同一性を有するアミノ酸配列を含み、抗体の軽鎖可変ドメインが配列番号64及び65のうちの少なくとも1つに少なくとも95%配列同一性を有するアミノ酸配列を含む、請求項1又は2に記載のヒト化抗CCR7抗体。
- 抗体の重鎖可変ドメインが配列番号61のアミノ酸配列を含み、抗体の軽鎖可変ドメインが配列番号64のアミノ酸配列を含む、請求項3に記載のヒト化抗CCR7抗体。
- 抗体がIgG1、IgG2、IgG3又はIgG4領域である重鎖定常領域を含む、請求項1〜4のいずれか一項に記載のヒト化抗CCR7抗体。
- 抗体が、C1q結合、補体依存性細胞傷害、Fc受容体結合、抗体依存性細胞傷害、及び食作用からなる群から選択される少なくとも1つのエフェクター機能を有する機能的Fc領域を含む、請求項1〜5のいずれか一項に記載のヒト化抗CCR7抗体。
- 抗体がアロタイプG1m17,1の重鎖定常領域を含む、請求項1〜6のいずれか一項に記載のヒト化抗CCR7抗体。
- 前記重鎖定常領域がE333A置換を含む、請求項7に記載のヒト化抗CCR7抗体。
- 請求項1〜8のいずれか一項に記載のヒト化抗CCR7抗体を含む医薬組成物。
- がん、炎症状態、組織若しくは臓器移植から生じる状態、又は線維症から生じる状態を処置するための請求項9に記載の医薬組成物。
- がんがその腫瘍細胞がCCR7受容体を発現しているがんである、請求項10に記載の医薬組成物。
- 前記がんが慢性リンパ性白血病(CLL)、マントル細胞リンパ腫(MCL)、濾胞性リンパ腫、大細胞型B細胞リンパ腫、AIDS関連リンパ腫、リンパ形質細胞性リンパ腫、バーキットリンパ腫、B細胞性急性リンパ性白血病、ホジキン病、成人T細胞白血病/リンパ腫、菌状息肉腫、慢性骨髄増殖性症候群の急性転化、骨髄異形成症候群の急性転化、乳がん、非小細胞肺がん、メラノーマ、胃がん、頭頸部扁平上皮癌及び結腸癌からなる群から選択される、請求項10又は11に記載の医薬組成物。
- 炎症状態が、炎症性腸疾患、クローン病、潰瘍性大腸炎、喘息、アレルギー性気管支炎、気道平滑筋過形成、線維性肺疾患、関節リウマチ、多発性硬化症、乾癬、アテローム性動脈硬化症、HIV感染及びAIDSにおける炎症状態からなる群から選択される、又は組織若しくは臓器移植が腎臓、心臓、皮膚、及び肺移植のうちの1つ又は複数である、請求項10に記載の医薬組成物。
- 線維症が、肝線維症及び肝硬変、腎線維症、肺線維症、皮膚線維症、心血管線維症、消化管線維症からなる群から選択される、請求項10に記載の医薬組成物。
- 請求項1〜8のいずれか一項に記載のヒト化抗CCR7抗体をコードするヌクレオチド配列を含む核酸分子。
- 前記核酸分子は抗体の重鎖可変ドメイン及び軽鎖可変ドメインのうちの少なくとも1つをコードするヌクレオチド配列を含み、前記コードヌクレオチド配列は宿主細胞における前記コードヌクレオチド配列の発現のための調節配列に作動可能に連結されている、請求項15に記載のヒト化抗CCR7抗体をコードするヌクレオチド配列を含む核酸分子。
- 請求項15又は16に記載の核酸分子を含む宿主細胞。
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SI3334457T1 (sl) * | 2015-08-10 | 2021-01-29 | Pepmab B.V. | Protitelesa humaniziranega ANTI-CCR7 receptorja |
GB201820006D0 (en) * | 2018-12-07 | 2019-01-23 | Lifearc | Humanised anti-IL17BR antibody |
CN113557244A (zh) * | 2018-12-18 | 2021-10-26 | 弹射器治疗有限公司 | 预防或治疗移植物抗宿主病(GvHD)的抗CCR7 mAb的用途 |
US20220380476A1 (en) * | 2019-10-09 | 2022-12-01 | Catapult Therapeutics B.V. | Use of an anti-CCR7 antibody in combination therapies with a BTK inhibitor and/or BCL2- inhibitor for treating hematological malignancies |
US20230181756A1 (en) * | 2020-04-30 | 2023-06-15 | Novartis Ag | Ccr7 antibody drug conjugates for treating cancer |
TW202216771A (zh) * | 2020-06-26 | 2022-05-01 | 德商拜耳廠股份有限公司 | 用於治療應用之ccr8抗體 |
JP2024505600A (ja) | 2021-02-03 | 2024-02-06 | モーツァルト セラピューティクス, インコーポレイテッド | 結合剤およびそれを使用する方法 |
CN112957472B (zh) * | 2021-02-05 | 2021-11-16 | 无锡市第五人民医院 | 靶向ccl19/ccr7的乙型肝炎免疫治疗剂及其用途 |
WO2023076876A1 (en) | 2021-10-26 | 2023-05-04 | Mozart Therapeutics, Inc. | Modulation of immune responses to viral vectors |
KR20230161759A (ko) * | 2022-05-19 | 2023-11-28 | 국민대학교산학협력단 | Ccr7의 활성 조절 항체 |
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US5595756A (en) * | 1993-12-22 | 1997-01-21 | Inex Pharmaceuticals Corporation | Liposomal compositions for enhanced retention of bioactive agents |
WO2007003216A1 (en) * | 2005-07-06 | 2007-01-11 | Universidad Autónoma de Madrid | Anti-ccr7 receptor antibodies for the treatment of cancer |
WO2009139853A2 (en) * | 2008-05-14 | 2009-11-19 | Kim, Eldar | Human monoclonal antibodies against human chemokine receptor ccr7 |
JP5315495B2 (ja) * | 2010-09-28 | 2013-10-16 | 積水化学工業株式会社 | 抗ヒトccr7抗体、ハイブリドーマ、核酸、ベクター、細胞、医薬組成物、並びに、抗体固定化担体 |
US20150344580A1 (en) | 2012-06-05 | 2015-12-03 | Eldar Kim | Human Monoclonal Antibodies Against Human Chemokine Receptor CCR7 |
WO2014151834A2 (en) * | 2013-03-15 | 2014-09-25 | Amgen Inc. | Methods and compositions relating to anti-ccr7 antigen binding proteins |
SI3334457T1 (sl) * | 2015-08-10 | 2021-01-29 | Pepmab B.V. | Protitelesa humaniziranega ANTI-CCR7 receptorja |
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PT3334457T (pt) | 2020-09-24 |
EA037397B1 (ru) | 2021-03-24 |
CN109069620B (zh) | 2022-04-26 |
EP3334457B1 (en) | 2020-08-26 |
IL257359A (en) | 2018-04-30 |
MX2018001596A (es) | 2018-05-02 |
ES2828368T3 (es) | 2021-05-26 |
HUE051920T2 (hu) | 2021-03-29 |
US11254749B2 (en) | 2022-02-22 |
EP3334457A1 (en) | 2018-06-20 |
CA2994214C (en) | 2024-03-12 |
CA2994214A1 (en) | 2017-02-16 |
WO2017025569A1 (en) | 2017-02-16 |
AU2016305283B2 (en) | 2022-05-26 |
US10640565B2 (en) | 2020-05-05 |
US20220135693A1 (en) | 2022-05-05 |
IL257359B (en) | 2022-03-01 |
DK3334457T3 (da) | 2020-09-21 |
KR20180030931A (ko) | 2018-03-26 |
US20180237529A1 (en) | 2018-08-23 |
SI3334457T1 (sl) | 2021-01-29 |
JP2018522568A (ja) | 2018-08-16 |
AU2016305283A1 (en) | 2018-02-22 |
BR112018002877A2 (pt) | 2018-11-06 |
CN109069620A (zh) | 2018-12-21 |
EA201890447A1 (ru) | 2018-11-30 |
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