JP7448299B2 - Baff-r抗体及びその使用 - Google Patents
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- JP7448299B2 JP7448299B2 JP2022017156A JP2022017156A JP7448299B2 JP 7448299 B2 JP7448299 B2 JP 7448299B2 JP 2022017156 A JP2022017156 A JP 2022017156A JP 2022017156 A JP2022017156 A JP 2022017156A JP 7448299 B2 JP7448299 B2 JP 7448299B2
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Description
本出願は、2016年6月6日に出願された米国仮特許出願第62/346,324号の優先権を主張し、その全体は参照により本明細書に援用される。
1)アラニン(A)、グリシン(G);
2)アスパラギン酸(D)、グルタミン酸(E);
3)アスパラギン(N)、グルタミン(Q);
4)アルギニン(R)、リジン(K);
5)イソロイシン(I)、ロイシン(L)、メチオニン(M)、バリン(V);
6)フェニルアラニン(F)、チロシン(Y)、トリプトファン(W);
7)セリン(S)、スレオニン(T);及び
8)システイン(C)、メチオニン(M)
は各々、互いについて保存的置換であるアミノ酸を含有する(例えばCreighton,Proteins(1984)を参照)。
mAbの開発のために細菌において産生された従来の組み換え免疫原タンパク質は翻訳後修飾を欠如し、原核生物は真核生物と比較してシャペロンタンパク質及び酸化環境を欠如するので、単純化して折り畳まれる。結果として、かかるタンパク質は、対応する原形質膜にアンカーされた天然タンパク質とは立体配座的構造で異なり得る。さらに、抗体は、標的外のドメイン(標的タンパク質の膜貫通ドメインまたは細胞内ドメイン等)に対して作製され得る。本明細書において記載されるように、真核生物細胞上で発現されるネイティブに折り畳まれ糖鎖付加された免疫原に対するmAbを生成するストラテジーが適用された。特に、ヒトBAFF-Rはマウス線維芽細胞上でネイティブタンパク質としてあり、マウスにおける免疫原として操作された細胞クローンを使用した。ヒト悪性B細胞株及び原発性リンパ腫をインビトロで特異的に結合及び溶解し、異種の腫瘍モデルにおいて薬剤耐性リンパ腫細胞株の増殖をインビボで阻害する、新規のmAbの生成が本明細書において記載される。
動物、細胞株及び原発性ヒト腫瘍サンプル。抗体開発のためにBALB/cマウス及びNOD scidγ(NSG)繁殖ペアを、Jackson Laboratory(Bar Harbor、ME)から購入した。NSG繁殖コロニーはCity of HopeのAnimal Resource Centerによって維持された。マウスは、施設のガイドラインに従って病原体除去動物施設中で飼育した。すべての動物研究は、Institutional Animal Care and Use Committee(IACUC:15020)によって承認された。JeKo-1、SU-DHL-6、Raji、U266及びRLは、ATCC(Manassas(VA))から購入した。Z-138株は、Dr.Michael Wang(MD Anderson Cancer Center)によって提供された。イブルチニブ耐性SP49-IR株は、Dr.Jianguo Tao(University of South Florida)によって開発され提供された。イブルチニブ耐性SP49細胞株(SP49-IR)は、漸増用量のイブルチニブにより細胞を処理することによって確立した。IC50は、SP49-IRについての>100nMに比較して、親SP49では5nMであった。100nMのイブルチニブで、SP49-IR細胞の>90%と比較して、SP49細胞の約5%が生存可能であった。ヒトNK-92 176V細胞は、Conkwest Inc.(San Diego、CA)から得た。ヒト血液及び腫瘍のサンプルのために、培養していない原発性ヒトリンパ腫を、10%のDMSO中で冷凍保存された生存可能な単一細胞懸濁液として、施設内審査委員会に認可されたプロトコール(IRB:2005-0656)下で、MD Anderson Cancer CenterのLymphoma Satellite Tissue Bankから得た。原発性患者サンプルは、マントル細胞リンパ腫(MCL)または慢性リンパ球性白血病(CLL)に罹患する患者からの白血球除去血輸血または血液、ならびにびまん性大細胞型B細胞リンパ腫(DLBCL)または濾胞性リンパ腫(FL)に罹患する患者から切除されたリンパ節を含んでいた。各々のサンプル中の腫瘍細胞は、白血球除去血輸血または血液について80%~98%及びリンパ節生検について50%~60の範囲であった。末梢血単核細胞(PBMC)は、City of HopeのMichael Amini Transfusion Medicine Centerによって提供された(IRB:15283)。
ヒトBAFF-Rに対するモノクローナル抗体の生成。BAFF-Rの生物学的に意義のあるエピトープへの治療抗体を生成するために、真核生物細胞表面発現系が使用され、そこで、内在性細胞表面タンパク質は、適切な翻訳後修飾によりそれらのネイティブな立体配座で提供される。マウス線維芽細胞(L)細胞クローンを、細胞表面GFPタグ付加されたヒトBAFF-Rを発現するように操作した。BAFF-R発現L細胞クローンを生成し、GFP発現について特徴づけた(図1A)。クローンD2Cを増やし、これを使用して、方法及び図7A中で免疫付与スケジュールに従ってBALB/cマウスに成功裡に免疫付与した。
提供されたBAFF-R mAbは、NHL、CLL及びALLを含む複数のB細胞腫瘍タイプに対する単一剤として着実なインビボの抗腫瘍効果を誘発した。さらに、抗体は確立された腫瘍を根絶し、それはインビボで長期の無腫瘍生存を導いた。
キメラ抗体(クローン90)は、その結合特異性及び細胞毒性効果を保持しながらヒト化された。CDRのコンピューター分析及び予測された構造を介して、重鎖の3つのバリアント及び軽鎖の3つのバリアントを、変動するヒト抗体への類似度により産生した。合計9つの組み合わせのバリアントを、ヒト化された重鎖及び軽鎖から構築した。これらのバリアントはすべて、2.6~5.0nMの範囲のKD値であり、結合親和性において親キメラ抗体に匹敵することが証明された(表1)。
高い結合親和性及び生物活性を備えた抗体を使用して、インビボの研究のためのキメラ抗原受容体(CAR)T細胞を構築した。重鎖可変ドメイン及び軽鎖可変ドメインのためのDNA配列を一本鎖(sFv)フォーマットへとアレンジし、4-1BBモチーフと一緒にT細胞シグナル伝達ドメイン(δ鎖)へ操作した。操作されたCAR遺伝子を共発現GFPと一緒に、精製された健康なドナー由来のCD8+ T細胞の中へレンチウイルス経由で導入した。CAR-T細胞をGFPの発現について細胞選別し、動物研究のためにCD3及びCD28のビーズによりインビトロで増やした。NSGマウスに、ルシフェラーゼを発現するJeKo-1 MCL株(JeKo-1-luci)を攻撃投与した。腫瘍を発達させ、腫瘍細胞の目視可能な集団が観察されるまで、生物発光画像化によってモニタリングし、それはおよそ腫瘍攻撃投与の9日後であった。マウスに、腫瘍攻撃投与の9及び15日後に、5×106のCAR-T細胞(抗BAFF-R及び抗CD19)の2回の用量を投与した。対照群に、無処理のT細胞または食塩水(PBS)を投与した。CAR-T療法の治療的抗腫瘍効果を評価するために、マウスを3日ごとに厳密にモニタリング及び画像化して腫瘍発達を追跡した。
Claims (41)
- 軽鎖可変領域及び重鎖可変領域を含む、B細胞活性化因子受容体(BAFF-R)抗体であって、
前記軽鎖可変領域が、
配列番号1に記載のCDR L1、配列番号2に記載のCDR L2、及び配列番号3に記載のCDR L3を含み;
前記重鎖可変領域が、
配列番号4に記載のCDR H1、配列番号5に記載のCDR H2、及び配列番号6に記載のCDR H3を含む、
前記抗体。 - 前記抗体がヒト化抗体である、請求項1に記載の抗体。
- 前記軽鎖可変領域が、配列番号18、配列番号20または配列番号22の配列を含む、請求項1または2に記載の抗体。
- 前記重鎖可変領域が、配列番号24、配列番号26または配列番号28の配列を含む、請求項1または2に記載の抗体。
- 前記抗体がキメラ抗体である、請求項1に記載の抗体。
- 前記軽鎖可変領域が配列番号14の配列を含む、請求項5に記載の抗体。
- 前記重鎖可変領域が配列番号16の配列を含む、請求項5に記載の抗体。
- 前記抗体がIgGである、請求項1~7のいずれか一項に記載の抗体。
- 前記抗体がIgG1である、請求項1~8のいずれか一項に記載の抗体。
- 前記抗体がFab’断片である、請求項1~7のいずれか一項に記載の抗体。
- 前記抗体が一本鎖抗体(scFv)である、請求項1~7のいずれか一項に記載の抗体。
- 前記抗体が、約5nMよりも低い平衡解離定数(KD)でBAFF-Rタンパク質と結合することができる、請求項1~11のいずれか一項に記載の抗体。
- 前記抗体が、約4nMよりも低い平衡解離定数(KD)でBAFF-Rタンパク質と結合することができる、請求項1~12のいずれか一項に記載の抗体。
- 前記抗体がBAFF-Rタンパク質に結合している、請求項1~13のいずれか一項に記載の抗体。
- 前記BAFF-Rタンパク質がヒトBAFF-Rタンパク質である、請求項14に記載の抗体。
- 前記BAFF-Rタンパク質が細胞の一部を形成する、請求項13または14に記載の抗体。
- 前記BAFF-Rタンパク質が前記細胞の表面上で発現される、請求項16に記載の抗体。
- 前記細胞がリンパ球様細胞である、請求項16または17に記載の抗体。
- 前記細胞がB細胞である、請求項16~18のいずれか一項に記載の抗体。
- 前記細胞ががん細胞である、請求項16~19のいずれか一項に記載の抗体。
- 前記がん細胞がリンパ腫細胞である、請求項20に記載の抗体。
- 請求項1~21のいずれか一項に記載の抗体をコードする、単離された核酸。
- 治療有効量の請求項1~21のいずれか一項に記載の抗体及び薬学的に許容される賦形剤を含む、医薬組成物。
- 請求項1~21のいずれか一項に記載の抗体またはその機能的断片を含む、キメラ抗原受容体(CAR)。
- がんの治療を必要とする対象においてがんを治療するための医薬組成物であって、治療有効量の請求項24に記載のキメラ抗原受容体を含む、前記医薬組成物。
- がんの治療を必要とする対象においてがんを治療するための医薬組成物であって、治療有効量の請求項1~21のいずれか一項に記載の抗体を含む、前記医薬組成物。
- 前記がんが、リンパ腫、白血病、または骨髄腫である、請求項25または26に記載の医薬組成物。
- 前記リンパ腫が、マントル細胞リンパ腫、濾胞性リンパ腫、びまん性大細胞型B細胞リンパ腫、辺縁帯リンパ腫、またはバーキットリンパ腫である、請求項27に記載の医薬組成物。
- 前記白血病が、リンパ芽球性白血病、慢性リンパ球性白血病、または有毛細胞白血病である、請求項27に記載の医薬組成物。
- 前記骨髄腫が多発性骨髄腫である、請求項27に記載の医薬組成物。
- 第2の治療剤をさらに含む、請求項25~27のいずれか一項に記載の医薬組成物。
- 前記治療剤がCD20抗原と結合することができるキメラモノクローナル抗体である、請求項31に記載の医薬組成物。
- 前記治療剤がリツキシマブである、請求項31または32に記載の医薬組成物。
- 自己免疫疾患の治療を必要とする対象において自己免疫疾患の治療をするための医薬組成物であって、治療有効量の請求項1~21のいずれか一項に記載の抗体を含む、前記医薬組成物。
- 前記自己免疫疾患が、関節リウマチ、全身性紅斑性狼瘡、多発性硬化症、糸球体腎炎、シェーグレン症候群、または自己免疫性溶血性貧血である、請求項34に記載の医薬組成物。
- 第2の治療剤をさらに含む、請求項35に記載の医薬組成物。
- 細胞の分裂増殖を阻害するインビトロの方法であって、
(i)請求項1~21のいずれか一項に記載のBAFF-R抗体と細胞を接触させ、それによって接触させた細胞を形成することと;
(ii)前記BAFF-R抗体が、前記接触させた細胞上のBAFF-Rタンパク質を結合するようにし、それによって前記細胞の分裂増殖を阻害することと、
を含む、前記方法。 - 前記細胞がリンパ球様細胞である、請求項37に記載の方法。
- 前記細胞がB細胞である、請求項37または38に記載の方法。
- 前記細胞ががん細胞である、請求項37~39のいずれか一項に記載の方法。
- 前記細胞がリンパ腫細胞である、請求項37~40のいずれか一項に記載の方法。
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CN109641957B (zh) | 2016-06-06 | 2022-10-04 | 希望之城 | Baff-r抗体及其用途 |
WO2018160622A1 (en) | 2017-02-28 | 2018-09-07 | Endocyte, Inc. | Compositions and methods for car t cell therapy |
US11311576B2 (en) | 2018-01-22 | 2022-04-26 | Seattle Children's Hospital | Methods of use for CAR T cells |
CN113412124A (zh) * | 2018-12-19 | 2021-09-17 | 希望之城 | Baff-r双特异性t细胞衔接子抗体 |
CN111499723B (zh) * | 2020-05-28 | 2021-04-09 | 广州百暨基因科技有限公司 | 一种嵌合抗原受体及其应用 |
CN114149504B (zh) * | 2020-09-07 | 2024-01-12 | 白先宏 | Baff-r结合分子及其应用 |
EP4240494A1 (en) | 2020-11-06 | 2023-09-13 | Novartis AG | Anti-cd19 agent and b cell targeting agent combination therapy for treating b cell malignancies |
CA3233246A1 (en) * | 2021-09-29 | 2023-04-06 | Dragonfly Therapeutics, Inc. | Antibodies targeting baff-r and use thereof |
WO2024018350A1 (en) * | 2022-07-19 | 2024-01-25 | Novartis Ag | Treatment of aiha with baff or baff receptor inhibitory antibodies |
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US20220041743A1 (en) | 2022-02-10 |
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US20200190204A1 (en) | 2020-06-18 |
US11136405B2 (en) | 2021-10-05 |
CN116041514A (zh) | 2023-05-02 |
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WO2017214170A2 (en) | 2017-12-14 |
CN109641957A (zh) | 2019-04-16 |
CN109641957B (zh) | 2022-10-04 |
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JP2022070921A (ja) | 2022-05-13 |
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