JP2022116283A - 三重特異性タンパク質と使用方法 - Google Patents
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Abstract
Description
本出願は、2017年10月13日に出願された、米国仮特許出願第62/572,381号の利益を主張するものであり、該文献はその全体が引用により本明細書に組み込まれる。
本出願は配列表を包含しており、これは、ASCIIフォーマットで電子的に提出され、その全体を引用することで本明細書に組み込まれる。2018年10月11日に作成された上記ASCIIのコピーは、47517-723_601_SL.txtのファイル名であり、752,020バイトのサイズである。
本明細書で言及されるすべての出版物、特許、および特許出願は、あたかも個々の出版物、特許、または特許出願がそれぞれ参照により本明細書に具体的かつ個別に組み込まれるのと同じ程度にまで、参照により本明細書に組み込まれている。
H2N-(A)-(B)-(C)-COOH、
H2N-(A)-(C)-(B)-COOH、
H2N-(B)-(A)-(C)-COOH、
H2N-(B)-(C)-(A)-COOH、
H2N-(C)-(B)-(A)-COOH、または、
H2N-(C)-(A)-(B)-COOH。
T細胞の応答の特異性は、TCRによって(主要組織適合複合体、MHCの文脈で表示された)抗原の認識によって媒介される。TCRの一部として、CD3は、細胞表面に存在する、CD3γ(ガンマ)鎖、CD3δ(デルタ)鎖、および2つのCD3ε(イプシロン)鎖を含むタンパク質複合体である。完全なTCRを含むために、CD3は、CD3ζ(ゼータ)と同様に、TCRのα(アルファ)とβ(ベータ)鎖と一緒に結合する。固定された抗CD3抗体によるなどしてT細胞上にCD3をクラスター形成することで、T細胞受容体の結合に似ているがそのクローンに典型的な特異性とは無関係のT細胞活性化を引き起こす。
本明細書では、抗原結合ドメインの半減期を延ばすドメインが企図される。そのようなドメインは、限定されないが、アルブミン結合ドメイン、Fcドメイン、小分子、および、当該技術分野で知られている他の半減期延長ドメインを含むものと企図される。
B細胞成熟抗原(BCMA、TNFRSF17、CD269)は、最終分化B細胞上で主として発現する腫瘍壊死ファミリー受容体(TNFR)スーパーファミリーに属する膜貫通タンパク質である。BCMA発現はB細胞血統に制限され、形質細胞と形質芽細胞上に存在し、およびある程度までは記憶B細胞に存在するが、末梢性のナイーブB細胞には事実上存在しない。BCMAは、多発性骨髄腫(MM)細胞、白血病細胞、およびリンパ腫細胞上で発現される。
BCMA結合三重特異性タンパク質は、SEQ ID NO:483-597からなる群から選択されたアミノ酸配列を含む。
いくつかの実施形態において、本明細書に記載される抗BCMA三重特異性結合タンパク質をコードするポリヌクレオチド分子も提供される。いくつかの実施形態において、ポリヌクレオチド分子は、DNA構築物として提供される。他の実施形態において、ポリヌクレオチド分子は、メッセンジャーRNA転写物として提供される。
本開示のBCMA標的三重特異性抗原結合タンパク質は、特定の例において、キメラ抗原受容体(CAR)へと組み込むことができる。操作された免疫エフェクター細胞、例えば、T細胞またはNK細胞は、本明細書に記載されるような抗BCMA単一ドメイン抗体を含有する抗BCMA標的三重特異性タンパク質を含むCARを発現するために使用可能である。1つの実施形態において、本明細書に記載されるような抗BCMA標的三重特異性タンパク質を含むCARは、ヒンジ領域を介して膜貫通ドメインに、さらには共刺激ドメイン、例えば、OX40、CD27、CD28、CD5、ICAM-1、LFA-1(CD11a/CD18)、ICOS(CD278)、あるいは4-1BBから得られる機能的シグナル伝達ドメインに結合される。いくつかの実施形態において、CARはさらに、4-1BBおよび/またはCD3ゼータなどの細胞内シグナル伝達ドメインをコードする配列を含む。
本明細書に記載されるBCMA三重特異性標的タンパク質は、(i)アミノ酸が遺伝子コードによりコードされたものでないアミノ酸残基で置換され、(ii)成熟ポリペプチドがポリエチレングリコールなどの別の化合物に融合され、または(iii)追加のアミノ酸が、リーダー配列または分泌配列、あるいはタンパク質の精製のための配列などのタンパク質に融合される、誘導体またはアナログを包含する。
いくつかの実施形態において、本明細書に記載される抗BCMA三重特異性結合タンパク質、BCMA三重特異性タンパク質のポリペプチドをコードするポリヌクレオチドを含むベクター、またはこのベクターにより形質転換される宿主細胞、および少なくとも1つの薬学的に許容可能な担体を含む、医薬組成物も提供される。「薬学的に許容可能な担体」との用語は、限定されないが、成分の生物活性の有効性に干渉せず、および投与される患者に対して毒性ではない担体を含む。適切な薬学的担体の例は、当該技術分野で周知であり、リン酸緩衝食塩水、水、油/水エマルジョンなどのエマルジョン、様々なタイプの湿潤剤、無菌液などを含む。そのような担体は、従来の方法によって製剤することができ、適切な用量で被験体に投与することができる。好ましくは、組成物は滅菌される。これらの組成物はまた、防腐剤、乳化剤および分散剤などのアジュバントを含有し得る。微生物の作用の予防は、様々な抗菌剤および抗真菌剤を含めることによって確かなものとなり得る。さらなる実施形態は、凍結乾燥された形態で包まれるか、水性媒体で包まれる、上記のBCMA三重特異性タンパク質の1つ以上を提供する。
特定の実施形態において、本開示のBCMA標的三重特異性タンパク質は、BCMAを発現する腫瘍細胞を有する被験体に投与すると、インビボで腫瘍細胞の成長を減少させる。腫瘍細胞の成長の減少の測定は、当該技術分野で周知の複数の様々な方法によって判定され得る。非限定的な例には、腫瘍寸法の直接測定、切除した腫瘤の測定、および対照被験体との比較、解析の向上のために同位体または発光分子(例えばルシフェラーゼ)を使用する、または使用しない画像処理技術(例えばCTまたはMRI)を介した測定などが挙げられる。特異的な実施形態において、本開示の三重特異性タンパク質の投与は結果として、対照の抗原結合剤と比較して、腫瘍成長の少なくとも約10%、20%、30%、40%、50%、60%、70%、80%、90%、または100%の、腫瘍細胞のインビボ成長の減少をもたらし、腫瘍の完全寛解および消失を示す。更なる実施形態において、本開示の三重特異性タンパク質の投与は結果として、対照の抗原結合剤と比較して、約50-100%、約75-100%、または約90%-100%の、腫瘍細胞のインビボ成長の減少をもたらす。更なる実施形態において、本開示の三重特異性タンパク質の投与は結果として、対照の抗原結合剤と比較して、約50-60%、約70-80%、約80-90%、または約90%-100%の、腫瘍細胞のインビボ成長の減少をもたらす。
ホスホリラーゼ阻害剤;プルプリン;ピラゾロアクリジン;ピリドキシル化したヘモグロビン・ポリオキシエチレン抱合体;rafアンタゴニスト;ラルチトレキセド;ラモセトロン;rasファルネシルタンパク質トランスフェラーゼ阻害剤;ras阻害剤;ras-GAP阻害剤;脱メチル化レテリプチン;レニウムRe 186エチドロネート;リゾキシン;リボザイム;RIIレチンアミド;ログレチミド;ロヒツキン;ロムルチド;ロキニメックス;ラビジノンB1;ラボキシル;サフィンゴル;セイントピン;SarCNU;サルコフィトールA;サルグラモスチム;Sdi 1模倣物;セムスチン;セネスセンス由来の阻害剤1;センスオリゴヌクレオチド;シグナル伝達阻害剤;シグナル伝達モジュレーター;一本鎖抗原結合タンパク質;シゾフィラン;ソブゾキサン;ナトリウムボロカプテート;フェニル酢酸ナトリウム;サルバロル;ソマトメジン結合タンパク質;ソナーミン;スパルホシック酸;スピカマイシンD;スピロマスチン;スプレノペンチン;スポンジスタチン1;スクワラミン;幹細胞阻害剤;幹細胞分割阻害剤;スティピアミド;ストロメリシン阻害剤;サルフィノジン;超活性血管作用性小腸ペプチドアンタゴニスト;サラディスタ;スラミン;スウェインソニン;合成グリコサミノグリカン;タリムスチン;タモキシフェンメチオジド;タウロマスチン;タザロテン;テコガランナトリウム;テガフール;テルラピリウム;テロメラーゼ阻害剤;テモポルフィン;テモゾロミド;テニポシド;テトラクロロデカオキシド;テトラゾミン;サリブラスチン;チオコラリン;トロンボポイエチン;トロンボポイエチン模倣物;チマルファジン;チモポイエチン受容体アゴニスト;チモトリナン;甲状腺刺激ホルモン;スズエチルエチオプロプリン;チラパザミン;チタノセン二塩化物;トプセンチン;トレミフェン;全能性幹細胞因子;翻訳阻害剤;トレチノイン;トリアセチルウリジン;トリシビリン;トリメトレキサート;トリプトレリン;トロピセトロン;テュロステリド;チロシンキナーゼ阻害剤;チルホスチン;UBC阻害剤;ウベニメクス;尿生殖洞由来の成長阻害因子;ウロキナーゼ受容体アンタゴニスト;バプレオチド;バリオリンB;ベクターシステム、赤血球遺伝子治療薬;ベラレゾール;ベラミン;アメリカツリスガラ;ベルテポルフィン;ビノレルビン;ビンザルチン;VITAXIN(登録商標);ボロゾール;ザノテロン;ゼニプラチン;ジラスコルブ;およびジノスタチンスチマラマー。追加の抗癌剤は、5-フルオロウラシルおよびロイコボリンである。サリドマイドおよびトポイソメラーゼ阻害剤を利用する方法での使用時、これらの2つの薬剤は特に有用である。いくつかの実施形態において、本開示の抗BCMA標的三重特異性タンパク質は、ゲムシタビンと組み合わせて使用される。
本開示の他の実施形態に従い、インビトロおよび/またはインビボでBCMAの発現を検出するためのキットが提供される。キットは、前述のBCMA標的三重特異性タンパク質(例えば、標識された抗BCMA単一ドメイン抗体またはその抗原結合フラグメントを含む、三重特異性タンパク質)、および標識を検出するための1つ以上の化合物を含む。いくつかの実施形態において、標識は、蛍光標識、酵素標識、放射性標識、核磁気共鳴活性標識、発光標識、および発色団標識から成る群から選択される。
生体サンプルは、ヒトまたは非ヒト霊長類などの哺乳動物から典型的に得られる。
タンパク質産生
Jeko1、MOLP8、およびOPM2細胞に対する、本開示に係る三重特異性タンパク質を標的とする典型的なBCMAの、結合および細胞毒性活性を評価する方法
異種移植片腫瘍モデル
多発性骨髄腫への、本開示のBCMA三重特異性抗原結合タンパク質の投与に対する概念実証臨床試験プロトコル
本開示の典型的なBCMA標的三重特異性タンパク質を用いる、ヒトおよびカニクイザルのBCMA、CD3ε、およびアルブミンに対する親和性測定
本開示の典型的なBCMA標的三重特異性タンパク質のヒトT細胞結合能力
本開示の典型的なBCMA標的三重特異性タンパク質がBCMA発現細胞に結合する能力
典型的なBCMA標的三重特異性タンパク質がBCMAを発現する癌細胞のT細胞死滅を媒介する能力
標的細胞とエフェクター細胞とのより小さな比率を用いた、BCMAを発現する癌細胞のT細胞死滅を媒介する、典型的なBCMA標的三重特異性タンパク質の能力
標的細胞とエフェクター細胞とのより小さな比率を用いた、経時的研究における、BCMAを発現する癌細胞のT細胞死滅を媒介する、典型的なBCMA標的三重特異性タンパク質の能力
ヒトT細胞にBCMA発現細胞を死滅させる、典型的なBCMA標的三重特異性タンパク質の能力
カニクイザルT細胞にBCMA発現細胞を死滅させる、典型的なBCMA標的三重特異性タンパク質の能力
典型的なBCMA三重特異性抗原結合タンパク質および標的腫瘍細胞に媒介された、T細胞活性化の誘導
本開示の典型的なBCMA標的三重特異性タンパク質の薬物動態
Claims (52)
- B細胞成熟剤(BCMA)結合三重特異性タンパク質であって、BCMA結合三重特異性タンパク質は:
(a)ヒトCD3に特異的に結合する第1のドメイン(A);
(b)半減期延長ドメインである第2のドメイン(B);および、
(c)BCMAに特異的に結合する第3のドメイン(C)を含み、
ここで、ドメインは、H2N-(A)-(C)-(B)-COOH、H2N-(B)-(A)-(C)-COOH、H2N-(C)-(B)-(A)-COOH、H2N-(C)-(A)-(B)-COOH、H2N-(A)-(B)-(C)-COOH、または、H2N-(B)-(C)-(A)-COOHの順序で結合し、ここで、ドメインはリンカーL1およびL2によって結合される、BCMA結合三重特異性タンパク質。 - 第1のドメインは、各々がヒトCD3に特異的に結合することができる、可変軽鎖ドメインと可変重鎖ドメインとを含む、請求項1に記載のBCMA結合三重特異性タンパク質。
- 第1のドメインはヒト化されるか、あるいはヒトである、請求項1に記載のBCMA結合三重特異性タンパク質。
- 第2のドメインはアルブミンに結合する、請求項1に記載のBCMA結合三重特異性タンパク質。
- 第2のドメインはscFv、可変重鎖ドメイン(VH)、可変軽鎖ドメイン(VL)、VHHドメイン、ペプチド、リガンド、あるいは小分子を含む、請求項1に記載のBCMA結合三重特異性タンパク質。
- 第3のドメインは、BCMAに特異的に結合する、VHHドメイン、scFv、VHドメイン、VLドメイン、非Igドメイン、リガンド、ノッチン、あるいは小分子実体を含む、請求項1に記載のBCMA結合三重特異性タンパク質。
- 第3のドメインはVHHドメインを含む、請求項6に記載のBCMA結合三重特異性タンパク質。
- 前記VHHドメインは、相補性決定領域CDR1、CDR2、およびCDR3を含み、ここで、
(a)CDR1のアミノ酸配列は、X1X2X3X4X5X6X7PX8G(SEQ ID NO:1)に記載されるとおりであり、X1はTあるいはSであり;X2はN、D、あるいはSであり;X3はI、D、Q、H、V、あるいはEであり;X4はF、S、E、A、T、M、V、I、D、Q、P、R、あるいはGであり;X5はS、M、R、あるいはNであり;X6はI、K、S、T、R、E、D、N、V、H、L、A、Q、あるいはGであり;X7はS、T、Y、R、あるいはNであり;および、X8はM、G、あるいはYであり;
(b)CDR2のアミノ酸配列はAIX9GX10X11TX12YADSVK(SEQ ID NO:2)に記載される通りであり、ここで、X9はH、N、あるいはSであり;X10はF、G、K、R、P、D、Q、H、E、N、T、S、A、I、L、あるいはVであり;X11はS、Q、E、T、K、あるいはDであり;および、X12はL、V、I、F、Y、あるいはWであり;ならびに、
(c)CDR3のアミノ酸配列はVPWGX13YHPX14X15VX16(SEQ ID NO:3)に記載されるとおりであり、ここで、X13はD、I、T、K、R、A、E、S、あるいはYであり;X14はR、G、L、K、T、Q、S、あるいはNであり;X15はN、K、E、V、R、M、あるいはDであり;および、X16はY、A、V、K、H、L、M、T、R、Q、C、S、あるいはNであり;ここで、CDR1はSEQ ID NO:599ではなく、CDR2はSEQ ID NO:600ではなく、および、CDR3はSEQ ID NO:601ではない、請求項7に記載のBCMA結合三重特異性タンパク質。 - VHHドメインは以下の式:
f1-r1-f2-r2-f3-r3-f4
を含み、
式中、r1はSEQ ID NO:1であり;r2はSEQ ID NO:2であり;および、r3はSEQ ID NO:3であり;ここで、f1、f2、f3、およびf4は、前記BCMA結合三重特異性タンパク質がSEQ ID NO:346あるいは598で記載されるアミノ酸配列に対して約80パーセント(80%)~約99%同一であるように、選択されたフレームワーク残基である、請求項8に記載のBCMA結合三重特異性タンパク質。 - r1は、SEQ ID NOS:4-117のいずれか1つとして記載されるアミノ酸配列を含む、請求項9に記載のBCMA結合三重特異性タンパク質。
- r2は、SEQ ID NOS:118-231のいずれか1つとして記載されるアミノ酸配列を含む、請求項9に記載のBCMA結合三重特異性タンパク質。
- r3は、SEQ ID NOS:232-345のいずれか1つとして記載されるアミノ酸配列を含む、請求項9に記載のBCMA結合三重特異性タンパク質。
- VHHドメインは、SEQ ID NOS:346-460のいずれか1つとして記載されるアミノ酸配列を含む、請求項9に記載のBCMA結合三重特異性タンパク質。
- F1はSEQ ID NO:461または462を含む、請求項9に記載のBCMA結合三重特異性タンパク質。
- F2はSEQ ID NO:463を含む、請求項9に記載のBCMA結合三重特異性タンパク質。
- F3はSEQ ID NO:464または465を含む、請求項9に記載のBCMA結合三重特異性タンパク質。
- F4はSEQ ID NO:466または467を含む、請求項9に記載のBCMA結合三重特異性タンパク質。
- r1はSEQ ID NO:76、114、115、116、または117を含む、請求項9に記載のBCMA結合三重特異性タンパク質。
- r1はSEQ ID NO:76を含み、r2はSEQ ID NO:190であり、および、r3はSEQ ID NO:304である、請求項9に記載のBCMA結合三重特異性タンパク質。
- r1はSEQ ID NO:114を含み、r2はSEQ ID NO:228を含み、およびr3はSEQ ID NO:342を含む、請求項9に記載のBCMA結合三重特異性タンパク質。
- r1はSEQ ID NO:115を含み、r2はSEQ ID NO:229を含み、およびr3はSEQ ID NO:343を含む、請求項9に記載のBCMA結合三重特異性タンパク質。
- r1はSEQ ID NO:117を含み、r2はSEQ ID NO:231を含み、およびr3はSEQ ID NO:345を含む、請求項9に記載のBCMA結合三重特異性タンパク質。
- r1はSEQ ID NO:116を含み、r2はSEQ ID NO:230を含み、およびr3はSEQ ID NO:344を含む、請求項9に記載のBCMA結合三重特異性タンパク質。
- 第3のドメインは、ヒトVHHドメイン、ヒト化されたVHHドメイン、親和性成熟VHHドメイン、あるいはこれらの組み合わせである、請求項1-23のいずれか1つに記載のBCMA結合三重特異性タンパク質。
- 前記BCMA結合三重特異性タンパク質は、少なくとも12時間、少なくとも20時間、少なくとも25時間、少なくとも30時間、少なくとも35時間、少なくとも40時間、少なくとも45時間、少なくとも50時間、あるいは少なくとも100時間の消失半減期を有する、請求項1-24のいずれか1つに記載のBCMA結合三重特異性タンパク質。
- VHHドメインはCDR1、CDR2、およびCDR3を含み、ならびに、BCMA結合三重特異性タンパク質はSEQ ID NO:598または346として記載される配列を含み、CDR1のアミノ酸位置26、27、28、29、30、31、32、および34;CDR2の位置52、54、55、および57;ならびに、CDR3の位置101、105、106、および108から選択された1つ以上のアミノ酸残基が置換され、ここで、
アミノ酸位置26は、置換される場合、Sで置換され;
アミノ酸位置27は、置換される場合、DあるいはSで置換され;
アミノ酸位置28は、置換される場合、D、Q、H、V、あるいはEで置換され;
アミノ酸位置29は、置換される場合、S、E、A、T、M、T、V、I、D、Q、D、P、R、あるいはGで置換され;
アミノ酸位置30は、置換される場合、M、R、あるいはNで置換され;
アミノ酸位置31は、置換される場合、K、S、T、R、E、D、N、V、H、L、A、Q、あるいはGで置換され;
アミノ酸位置32は、置換される場合、T、Y、R、あるいはNで置換され;
アミノ酸位置34は、置換される場合、GあるいはYで置換され;
アミノ酸位置52は、置換される場合、NあるいはSで置換され;
アミノ酸位置54は、置換される場合、G、K、R、P、D、Q、H、E、N、T、S、A、I、L、あるいはVで置換され;
アミノ酸位置55は、置換される場合、Q、E、T、K、あるいはDで置換され;
アミノ酸位置57は、置換される場合、V、I、F、Y、あるいはWで置換され;
アミノ酸位置101は、置換される場合、I、T、K、R、A、E、S、あるいはYで置換され;
アミノ酸位置105は、置換される場合、G、L、K、T、Q、S、あるいはNで置換され;
アミノ酸位置106は、置換される場合、K、E、V、R、M、あるいはDで置換され;
アミノ酸位置108は、置換される場合、A、V、K、H、L、M、T、R、Q、C、S、あるいはNで置換される、請求項7に記載のBCMA結合三重特異性タンパク質。 - VHHドメインは、ヒト、ヒト化され、親和性成熟され、あるいはこれらの組み合わせである、請求項26に記載のBCMA結合三重特異性タンパク質。
- 第3のドメインは、SEQ ID NO:468として記載される配列を含むヒトBCMAタンパク質に結合する、請求項1-27のいずれか1つに記載のBCMA結合三重特異性タンパク質。
- 第3のドメインはBCMAの細胞外ドメインに結合する、請求項1-27のいずれか1つに記載のBCMA結合三重特異性タンパク質。
- リンカーL1とL2はそれぞれ独立して、(GS)n(SEQ ID NO:472)、(GGS)n(SEQ ID NO:473)、(GGGS)n(SEQ ID NO:474)、(GGSG)n(SEQ ID NO:475)、(GGSGG)n(SEQ ID NO:476)、(GGGGS)n(SEQ ID NO:477)、(GGGGG)n(SEQ ID NO:478)、または(GGG)n(SEQ ID NO:479)から選択され、ここで、nは1、2、3、4、5、6、7、8、9、あるいは10である、請求項1-29のいずれか1つに記載のBCMA結合三重特異性タンパク質。
- リンカーL1とL2はそれぞれ独立して、(GGGGS)4(SEQ ID NO:480)または(GGGGS)3(SEQ ID NO:481)である、請求項1-30のいずれか1つに記載のBCMA結合三重特異性タンパク質。
- ドメインはH2N-(C)-(B)-(A)-COOHの順序で結合される、請求項1-31のいずれか1つに記載のBCMA結合三重特異性タンパク質。
- BCMA結合三重特異性タンパク質は約80kDa未満である、請求項1-32のいずれか1つに記載のBCMA結合三重特異性タンパク質。
- BCMA結合三重特異性タンパク質は約50~約75kDaである、請求項1-32のいずれか1つに記載のBCMA結合三重特異性タンパク質。
- BCMA結合三重特異性タンパク質は約60kDa未満である、請求項1-32のいずれか1つに記載のBCMA結合三重特異性タンパク質。
- BCMA結合三重特異性タンパク質は少なくとも約50時間の消失半減期を有する、請求項1-35のいずれか1つに記載のBCMA結合三重特異性タンパク質。
- BCMA結合三重特異性タンパク質は少なくとも約100時間の消失半減期を有する、請求項1-36のいずれか1つに記載のBCMA結合三重特異性タンパク質。
- BCMA結合三重特異性タンパク質は、同じBCMAへのIgGと比較して、組織への浸透性を増加させた、請求項1-37のいずれか1つに記載のBCMA結合三重特異性タンパク質。
- BCMA結合三重特異性タンパク質は、SEQ ID NO:483-597からなる群から選択された配列を含む、請求項1-38のいずれか1つに記載のBCMA結合三重特異性タンパク質。
- BCMA結合三重特異性タンパク質は、SEQ ID NO:520で記載される配列を含む、請求項1-39のいずれか1つに記載のBCMA結合三重特異性タンパク質。
- 請求項1-40のいずれか1つのBCMA結合三重特異性タンパク質、および薬学的に許容可能な担体を含む、医薬組成物。
- 請求項1-40のいずれか1つのBCMA結合三重特異性タンパク質の産生のためのプロセスであって、前記プロセスは、BCMA結合三重特異性タンパク質の発現を可能にする条件下で、請求項1-40のいずれか1つのBCMA結合三重特異性タンパク質をコードする核酸配列を含むベクターを用いて形質転換されたかトランスフェクトされた宿主を培養する工程と、培養物から生成されたタンパク質を回収および精製する工程とを含む、
プロセス。 - 被験体におけるBCMAに関連する腫瘍性疾患、自己免疫疾患、あるいは感染症の処置または改善のための方法であって、請求項41の医薬組成物を被験体に投与する工程を含む、方法。
- 被験体はヒトである、請求項43に記載の方法。
- 前記方法はさらに、BCMA結合三重特異性タンパク質と組み合わせて1つ以上の追加の薬剤を投与する工程を含む、請求項43または44に記載の方法。
- 腫瘍性疾患の処置あるいは改善を含み、ここで、BCMA結合三重特異性タンパク質は、BCMAを発現する腫瘍細胞に選択的に結合する、請求項43-45のいずれか1つに記載の方法。
- 腫瘍性疾患の処置あるいは改善を含み、腫瘍性疾患は、原発性癌あるいはその転移を含む、請求項43-46のいずれか1つに記載の方法。
- 腫瘍性疾患はB細胞系統の癌を含む、請求項47に記載の方法。
- B細胞系統の癌は、多発性骨髄腫、白血病、リンパ腫、あるいはその転移である、請求項48に記載の方法。
- B細胞成熟剤(BCMA)結合三重特異性タンパク質であって、BCMA結合三重特異性タンパク質は:
(a)ヒトCD3に特異的に結合する第1のドメイン(A);
(b)半減期延長ドメインである第2のドメイン(B);および、
(c)BCMAに特異的に結合する第3のドメイン(C)を含み、
ここで、第3のドメインは、SEQ ID NOS:346-460のいずれか1つとして記載されるアミノ酸配列を含む、BCMA結合三重特異性タンパク質。 - B細胞成熟剤(BCMA)結合三重特異性タンパク質であって、BCMA結合三重特異性タンパク質は:
(a)ヒトCD3に特異的に結合する第1のドメイン(A);
(b)半減期延長ドメインである第2のドメイン(B);および、
(c)BCMAに特異的に結合する第3のドメイン(C)を含み、
ここで、第3のドメインは相補性決定領域CDR1、CDR2、およびCDR3を含み、ここで、CDR1は、SEQ ID NOS:4-117のいずれか1つとして記載されるアミノ酸配列を含み、CDR2はSEQ ID NOS:118-231のいずれか1つとして記載されるアミノ酸配列を含み、および、CDR3は、SEQ ID NOS:232-345のいずれか1つとして記載されるアミノ酸配列を含む、BCMA結合三重特異性タンパク質。 - 被験体におけるBCMAに関連する腫瘍性疾患、自己免疫疾患、あるいは感染症の処置または改善のための方法であって、
BCMA結合三重特異性タンパク質を含む医薬組成物を被験体に投与する工程を含み、
ここで、BCMA結合三重特異性タンパク質は、
(a)ヒトCD3に特異的に結合する第1のドメイン(A);
(b)半減期延長ドメインである第2のドメイン(B);および、
(c)BCMAに特異的に結合する第3のドメイン(C)を含み、
ここで、ドメインは、H2N-(A)-(C)-(B)-COOH、H2N-(B)-(A)-(C)-COOH、H2N-(C)-(B)-(A)-COOH、H2N-(C)-(A)-(B)-COOH、H2N-(A)-(B)-(C)-COOH、H2N-(B)-(C)-(A)-COOHの順序で結合し、ここで、ドメインはリンカーL1およびL2によって結合される、方法。
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KR102569133B1 (ko) | 2023-08-21 |
KR20220107324A (ko) | 2022-08-02 |
CR20200196A (es) | 2020-06-05 |
JP7385707B2 (ja) | 2023-11-22 |
US11136403B2 (en) | 2021-10-05 |
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JP7084990B2 (ja) | 2022-06-15 |
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BR112020007196A2 (pt) | 2020-12-01 |
DOP2020000071A (es) | 2020-08-15 |
WO2019075359A1 (en) | 2019-04-18 |
IL273918A (en) | 2020-05-31 |
US20190112381A1 (en) | 2019-04-18 |
MX2020003915A (es) | 2020-10-08 |
EA202090817A1 (ru) | 2020-09-08 |
PH12020550258A1 (en) | 2021-03-01 |
CL2020000991A1 (es) | 2020-10-23 |
EP3694529B1 (en) | 2024-06-26 |
KR102425983B1 (ko) | 2022-07-29 |
CN111630070A (zh) | 2020-09-04 |
ECSP20025070A (es) | 2020-06-30 |
JP2020537644A (ja) | 2020-12-24 |
KR20220153683A (ko) | 2022-11-18 |
CA3078969A1 (en) | 2019-04-18 |
KR102464826B1 (ko) | 2022-11-08 |
US20220112297A1 (en) | 2022-04-14 |
CO2020005645A2 (es) | 2020-05-15 |
KR20200066343A (ko) | 2020-06-09 |
AU2018347582A1 (en) | 2020-05-07 |
ZA202002094B (en) | 2023-12-20 |
EP3694529A4 (en) | 2021-11-10 |
PE20201183A1 (es) | 2020-11-03 |
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