JP6286532B2 - 抗cd38抗体及び弱毒化インターフェロンアルファ−2bとの融合物 - Google Patents
抗cd38抗体及び弱毒化インターフェロンアルファ−2bとの融合物 Download PDFInfo
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- C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/40—Immunoglobulins specific features characterized by post-translational modification
- C07K2317/41—Glycosylation, sialylation, or fucosylation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/52—Constant or Fc region; Isotype
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/70—Fusion polypeptide containing domain for protein-protein interaction
- C07K2319/74—Fusion polypeptide containing domain for protein-protein interaction containing a fusion for binding to a cell surface receptor
Description
本出願は、462,000バイトのサイズを有する、2013年4月29日に作成された、Anti-CD38_Antibodies_ST25という名称のテキストファイルとして電子出願された配列表を含む。配列表は参照により本明細書に組み込まれる。
C)、眼がん、食道がん、口腔がん、中咽頭がん、骨肉腫、オストミー卵巣がん(ostomy ovarian cancer)、膵臓がん、副鼻腔がん、副甲状腺がん、耳下腺がん、陰茎がん、末梢神経外胚葉腫瘍、下垂体がん、真性赤血球増加症、前立腺がん、珍しいがん及び関連する障害、腎細胞癌、網膜芽腫、横紋筋肉腫、ロトムンド・トムソン症候群、唾液腺がん、肉腫、神経鞘腫、セザリー症候群、皮膚がん、小細胞肺がん(SCLC)、小腸がん、軟部組織肉腫、脊髄腫瘍、扁平上皮癌(皮膚)、胃がん(stomach cancer)、滑膜肉腫、精巣がん、胸腺がん、甲状腺がん、移行上皮がん(膀胱)、移行上皮がん(腎盂/尿管)、トロホブラストがん、尿道がん、泌尿器系がん、ウロプラキン(uroplakin)、子宮肉腫、子宮がん、膣がん、外陰がん、ワルデンストレームマクログロブリン血症並びにウィルムス腫瘍が挙げられる。ある実施形態において、腫瘍は多発性骨髄腫又は非ホジキンリンパ腫の群から選択される。
他の抗CD38抗体-弱毒化IFN融合タンパク質は、PCT出願番号PCT/AU2012/001323に記載されている。これらのものは、このPCT出願においてX355/02-HC-L0-IFN-アルファ(A145D)IgG4と命名された抗体構築物を含む。本明細書では、X355/02-HC-L0-IFN-アルファ(A145D)IgG4は、A02.1と改名された。抗体の重鎖配列は配列番号11のアミノ酸配列を含み、軽鎖配列は配列番号12のアミノ酸配列を含む。A02.1の可変軽鎖(配列番号14)を、S228P置換(EU番号付け)を含有するヒトIgG4定常領域(配列番号3)上で形式化されたその可変重鎖A02.1(配列番号13)と同時発現した。この抗体は本明細書ではX02.1と呼ばれ、A02.1はIFN-アルファ2bとの融合物を含むが、両抗体が同一の重鎖及び軽鎖配列を共有するにも拘らず、X02.1はそれを含まない。
推定免疫原性エピトープを、Epibase分析ソフトウェア(Lonza社、UK)を用いてA02.1の軽鎖可変領域アミノ酸配列中で同定した。推定免疫原性エピトープを除去するために、A02.1可変軽鎖中に置換を導入した(図4)。より低い推定免疫原性を有する軽鎖を、A145D-弱毒化IFNに融合したS228P置換を含有するIgG4定常領域上で形式化されたA02.12重鎖可変領域(配列番号34)と共にHEK293E細胞中で同時発現させた。生成された抗体バリアントを、Table 10(表12)に詳述する。
単一の遺伝子構築物中で上記の抗CD38抗体の免疫原性、製造性又は効力を改善する置換を組み合わせることにより、高度に最適化された抗CD38抗体及び抗CD38抗体-弱毒化IFN融合タンパク質を取得した。Table 12(表14)は、そのような組合せ置換をまとめたものであり、HEK293E細胞中で同時発現された後、試験された重鎖と軽鎖との組合せを詳述するものである。
機能的な抗CD38抗体-弱毒化IFN融合タンパク質を得ることができるかどうかを決定するために、PCT/AU2012/001323に記載の抗体X910/12-HC-L0-IFN-アルファ(A145D)IgG4に由来する重鎖(配列番号110)及び軽鎖(配列番号112)、並びにPCT/AU2012/001323に記載の抗体X913/15-HC-L0-IFN-アルファ(A145D)IgG4に由来する重鎖(配列番号111)及び軽鎖(配列番号113)を、様々な組合せで互いに、並びに以下の実施例に記載の重鎖及び軽鎖と対形成させた。重鎖と軽鎖との対の概要を、Table 14(表16)に列挙する。
A02.1のin vivoでの効力を、実施例5に記載されるようなNCI-H929 s.c.多発性骨髄腫モデルにおいて予め試験した。A02.1は、強力な抗腫瘍活性を有することが示された。データは、PCT/AU2012/001323に提示されている。
アネキシンVアッセイ及びカスパーゼアッセイを用いて、強力なアポトーシス活性及びカスパーゼ活性化が弱毒化IFNを含有する抗CD38抗体-弱毒化IFN融合タンパク質に依存することが示された(Table 16a(表19)、図18)。アネキシンVアッセイにおいて、弱毒化IFN含有タンパク質(A02.1及びA02.6)は、弱毒化IFNを含有しないタンパク質(X02.1及びX02.6)よりも2倍高い活性を有していた。
HEK-293E細胞中での抗体及び抗体-融合構築物の生成。タンパク質構築物をコードするDNAプラスミド(抗体及び抗体-IFN-アルファ2b関連構築物)を、HiSpeed Plasmid Maxiキット(Qiagen社、Valencia、CA)を用いて調製した後、市販のトランスフェクション試薬及びOptiMEM培地(Invitrogen社、Carlsbad、CA)を用いて、HEK293E細胞(CNRC社、Montreal、Canada)中にトランスフェクトし、0.45%(w/v)のD-(+)-グルコース(Sigma社、Castle Hill、NSW)、25μg/mLのゲネチシン(Invitrogen社、Carlsbad、CA)、及び1x GlutaMAX(Invitrogen社、Carlsbad、CA)を添加したF17合成培地中で増殖させた。5%CO2を供給し、120rpmで振とうしながらインキュベータ中で6日間発現させた後、培養培地を単離し、Protein A Mab Select SuRe(商標)アガロースビーズ(GE Healthcare社、Piscataway、NJ)を用いる親和性精製にかけた。精製されたタンパク質構築物を、PD Midi-Trap G-25カラム(GE Healthcare社、Piscataway、NJ)又はHiPrep 26/10脱塩カラム(HiTrap Desalting HiPrep 26/10 Desalting)を用いて、0.2MアルギニンHCl、25mMクエン酸、71.5mM水酸化ナトリウム、pH6.0中でバッファー交換した。次いで、精製されたタンパク質構築物を、50kDa Amicon Ultra遠心分離フィルター装置(Millipore社、Billerica、MA)を用いて濃縮した後、280nmで吸光度を読み取ることによりタンパク質濃度を決定した。
タンパク質構築物をコードするDNAプラスミド(抗体及び抗体-IFN-アルファ2b関連構築物)を、HiSpeed Plasmid Maxi Kit(Qiagen社、Valencia、CA)を用いて調製した後、市販のトランスフェクション試薬及びOptiPro SFM(商標)培地(Invitrogen社、Carlsbad、CA)を用いて、CHO細胞(Lonza社)中にトランスフェクトし、Freestyle(商標)CHO Expression Medium(Invitrogen社、Carlsbad、CA)中で増殖させた。10%CO2を供給し、120rpmで振とうしながらインキュベータ中で6日間発現させた後、培養培地を単離し、Protein A Mab Select SuReアガロースビーズ(GE Healthcare社、Piscataway、NJ)を用いる親和性精製にかけた。精製されたタンパク質構築物を、PD Midi-Trap G-25カラム(GE Healthcare社、Piscataway、NJ)又はHiPrep 26/10脱塩カラム(HiTrap Desalting HiPrep 26/10 Desalting)を用いて、0.2MアルギニンHCl、25mMクエン酸、71.5mM水酸化ナトリウム、pH6.0中でバッファー交換した。次いで、精製されたタンパク質構築物を、50kDa Amicon Ultra遠心分離フィルター装置(Millipore社、Billerica、MA)を用いて濃縮した後、280nmで吸光度を読み取ることによりタンパク質濃度を決定した。
Agilent 1100クロマトグラフィーシステムに接続されたPOROS A/20 2.1×30mm Idカラム(Applied Biosystems社)を用いるプロテインA HPLCにより、上清を分析した。カラムをPBS pH7.4で平衡化し、pH2.2に調整されたPBSを用いてタンパク質を溶出させた。PBS中の既知量のモノクローナル抗体を用いて、標準曲線を作成した。215nm又は280nmの波長でのクロマトグラムを、製造業者のソフトウェアを用いて積分し、曲線下面積(AUC)を報告し、作成された標準曲線に対して内挿し、濃度を見積もった。
多発性骨髄腫細胞株ARP-1は、University of Arkansas Medical Center(Little Rock、AK)のMyeloma InstituteのディレクターであるBart Barlogie MD、phDからの贈り物であった。それは、Hardin J.ら(1994) Blood. 84:3063〜70頁に記載されている。多発性骨髄腫細胞株NCI-H929(H929)は、ATCC(CRL-9068、Gazdar, Blood 67: 1542〜1549頁、1986から購入したものであった。
Daudi細胞増殖アッセイ:このアッセイを用いて、CD38を展示する細胞上でのIFN及び抗体-IFN融合タンパク質構築物の抗増殖活性を定量した。Daudi細胞は、細胞表面関連抗原としてCD38を発現する。Promega社(Madison、Wisconsin)からのCellTiter-Glo(登録商標)試薬、カタログ番号G7570を用いて、細胞の生存能力を測定した。これは、ATPの定量化に基づいて培養物中の細胞の生存能力を決定する発光に基づくアッセイである。シグナル強度は、マイクロタイタープレートウェル中の生細胞数に比例する。アッセイの詳細は以下の通りである:Daudi細胞(ATCC、Manassas、VAから得られた)を、T75フラスコ(TPP社、Trasadingen、Switzerland、カタログ番号90076)中で、10%ウシ胎仔血清(FBS;Hyclone社、Logan、UT、カタログ番号SH30070.03)を含むRPMI1640(Mediatech,Inc.社、Manassas、VA、カタログ番号10-040-CV)中に0.5×105〜0.8×105個の生細胞/mLの好ましい密度となるまで培養した。細胞を400×gで5分間遠心分離し、上清を廃棄し、細胞ペレットをRPMI1640+10%FBS中に再懸濁することにより収獲した。次いで、細胞を計数し、RPMI1640+10%FBS中で密度を3.0×105細胞/mLに調整した。次いで、50μLの細胞懸濁液を、96穴丸底組織培養プレート(以後、「実験プレート」と呼ぶ)(TPP社、カタログ番号92067)の各ウェルにアリコートした。別の滅菌96穴プレート(以後、「希釈プレート」と呼ぶ;Costar、Corning、NY、カタログ番号3879)上で、被験物質をRPMI1640+10%FBS中で2回、連続希釈した。次いで、50μL/ウェルを希釈プレートから実験プレートに移した。次いで、実験プレートを5%CO2と共に37℃で4日間インキュベートした。製造業者により供給されたアッセイバッファーと、アッセイ基質[以後、「CellTiter-Glo(登録商標)試薬」と呼ばれ、製造業者の説明書に従って混合されたもの]との混合物を、100μL/ウェルで実験プレートに添加した。プレートを、2分間振とうした。
iLite遺伝子リポーターアッセイ:「オフターゲット」iLiteアッセイ(PBL Interferon Source社、Piscataway、NJ、カタログ番号51100)を、ヒトIgG遮断工程を加えて、大部分は製造業者により記載されたように実施した。iLite細胞株は、「細胞表面上での、MHCクラスII抗原、特に、ヒトリンパ球抗原(HLADR)の発現を特徴とする市販の前単球性ヒト細胞株から誘導された安定なトランスフェクト細胞株」として製造業者によって記載されている。この細胞株は、安定にトランスフェクトされたルシフェラーゼ遺伝子を含有し、その発現は、発光出力に基づいてインターフェロン活性を定量することができる、インターフェロン応答エレメント(IRE)により誘導される。製造業者により供給されたiLiteプレート(以後、アッセイプレートと呼ぶ)及び希釈剤を-80℃の冷凍庫から取り出し、室温に平衡化させた。次いで、ウェルあたり50μLの希釈剤をアッセイプレートに添加した。製造業者により供給されたリポーター細胞のバイアルを-80℃の冷凍庫から取り出し、37℃の水浴中で解凍した。次いで、細胞の25μLアリコートを、アッセイプレートの各ウェルに分注した。次に、RPMI1640+10%FBS(Sigma Chemicals社、St.Louis、MO;カタログ番号I4506)中に希釈された8mg/mLのヒトIgG 12.5μLを各ウェルに添加した。内容物を混合し、37℃で15分間インキュベートした。別の「希釈プレート」上で、被験物質をRPMI1640+10%FBS中で2回、連続希釈した。次いで、12.5μLの被験物質を希釈プレートからアッセイプレートに移した。次いで、アッセイプレートを、5%CO2と共に37℃で17時間インキュベートした。製造業者により供給されたアッセイバッファーと、基質とを-80℃の冷凍庫から取り出し、2時間、室温に平衡化させた。製造業者により供給されたアッセイバッファーを、製造業者により供給された基質バイアルに添加し、製造業者の説明書に従ってよく混合して、「発光溶液」を作出した。次いで、100μLの発光溶液を、アッセイプレートの各ウェルに添加した。プレートを2分間振とうした。次いで、プレートを暗室中、室温で5分間インキュベートし、発光測定チャンネル上、Victor 3V Multilabel Counter上で最終的に読み取り、発光を測定し、RLUとして提示した。データを、「オンターゲット(Daudi)アッセイ」について記載されたようにGraphpad Prism 5を用いて分析した。iLiteアッセイにおいて抗CD38抗体-IFN融合タンパク質構築物を試験するために、製造業者により供給された希釈剤に0.25mg/mLの抗CD38抗体を添加した(同じ抗体クローンを、iLite細胞上に発現されるCD38への抗CD38抗体-IFN融合タンパク質構築物の任意の結合を遮断するために、抗体-IFN融合タンパク質構築物として試験する)。
骨髄腫腫瘍増殖に対する、異なる用量のA10.38及びA10.0抗CD38抗体-弱毒化IFN-アルファ融合タンパク質構築物の効果を、非CD38-標的化融合タンパク質構築物と比較した。これらの比較のために、NCI-H929 s.c.多発性骨髄腫モデルを用いた。
A02.12は、タンパク質の定常領域がHC-L0-IFN-アルファ(A145D)IgG4(配列番号9)である抗CD38抗体-弱毒化IFN融合タンパク質を含む。この抗体の重鎖可変領域を、A145D弱毒化IFN-アルファ2b(配列番号10)に融合したIgG1定常領域上で再形式化した。HEK293E細胞中でのこの重鎖と、X02.107(配列番号65)の軽鎖との同時発現により、抗体A02.112が得られた。フローサイトメトリーに基づくCD38結合アッセイ及び効力アッセイを用いる抗体A02.12及びA02.112の比較により、ヒトIgG4定常領域を用いて作成されたものと同等の強力な生物活性を有する抗体-弱毒化IFN融合タンパク質をもたらす、ヒトIgG1などの他の抗体定常領域を用いることもできることが示される(Table 16b(表20))。
ラット由来抗CD38抗体R5D1、R5E8及びR10A2は、PCT/AU2012/001323に記載されており、ヒト化のためにこれらを選択した。これらの抗体の可変領域を、米国特許出願公開第2003/0039649号に記載のようにスーパーヒト化した。簡単に述べると、標準構造を、そのそれぞれのアミノ酸配列の検査により各げっ歯類重鎖及び軽鎖に割り当てた。R10A2は標準構造2-1-1/1-2(VL/VH)を割り当てられ、R5E8は標準構造4-1-1/1-2を割り当てられ、R5D1は標準構造2-1-1/1-2を割り当てられた。同じ標準構造のヒト生殖系列配列を、ドナーCDRの移植のためのアクセプターフレームワークとして用いた。結合活性の維持にとって重要である可能性が高いと見なされるその配列内の位置にアミノ酸置換を含有する、得られるスーパーヒト化抗体遺伝子のバリアントも設計した。様々な重鎖スーパーヒト化可変領域を、図7に示す。様々な軽鎖スーパーヒト化可変領域を、図8に示す。
A10.0抗体を、抗体の機能的活性に対する影響を最小にしながら、抗体の生物物理的及びin silicoでの免疫原性に対して正の効果をもたらすために、可変重鎖及び/又は軽鎖配列に対する変化により最適化した。
A10.0重鎖及び軽鎖可変領域のin silicoでの免疫原性の分析を、Epibaseソフトウェアパッケージを用いて作製した。A10.0の重鎖及び軽鎖可変領域中にいくつかのアミノ酸置換を導入して、潜在的な免疫原性エピトープを除去した。ヒト化重鎖(配列番号156)と整列させた、生成された重鎖可変領域バリアントのアミノ酸配列アラインメントを、図9に示す。ヒト化軽鎖(配列番号161)と整列させた、軽鎖可変領域バリアントのアミノ酸配列アラインメントを、図10に示す。タンパク質を生成させるためにHEK293E細胞中で同時発現された重鎖及び軽鎖バリアントの詳細を、Table 20(表24)にまとめる。
A10.0とA10.38は、共通の軽鎖を共有する。機能的活性に対する影響を最小にしながら、抗体の生物物理的特性及びin silicoでの免疫原性特性に対する正の効果を得るために、A10.0の最適化された軽鎖配列を、A10.38抗体の重鎖と対形成させた。重鎖及び軽鎖の変化及び対の概要を、Table 24(表28)に記載する。
抗CD38抗体A10.0(弱毒化IFN融合物)とX10.0(融合なし)との相対的効力を、実施例5に概略されたアネキシンV、カスパーゼ及び細胞増殖アッセイを用いて比較した。A10.38及びX10.38の相対的効力も比較した。Table 26(表30)。
10A2バリアントA10.0及びA10A2.0のin vivoでの効力をNCI-H929 s.c.マウス多発性骨髄腫モデルにおいて評価した。図27。両方ともこのモデルにおいて強力な抗腫瘍活性を有することが示された。そのようなモデルを用いて、本明細書に記載の他のタンパク質構築物の抗腫瘍活性について試験することができた。
野生型及び弱毒化インターフェロン145Dに融合した親A10A2.0キメラ抗体と比較した10A2バリアントA10.0、A10.38、A10A2.37及びA10A2.39のオフターゲット活性を、iLiteリポーター遺伝子アッセイ及び/又はHEK Blueアッセイにおいて評価し、図28及び図29に示す。EC50値を図28及び図29に提供する。オフターゲット活性は、インターフェロンの弱毒化及び機能を回復するためにCD38に標的化される抗体の必要性を確認する。
上記の抗CD38抗体-弱毒化IFN融合タンパク質の選択物を精製し、細胞に基づくアッセイにおいてCD38陽性細胞への結合について分析した。さらに、効力アッセイを繰り返して、これらの抗CD38抗体-弱毒化IFN融合タンパク質のそれぞれの相対的活性をより正確に決定した。これらの様々なアッセイのための方法は、実施例5に記載されている。これらのアッセイのそれぞれの結果を、Table 27(表31)に記載する。
A10.0は、タンパク質の定常領域がHC-L0-IFN-アルファ(A145D)IgG4(配列番号9)である抗CD38抗体-弱毒化IFN融合タンパク質を含む。遺伝子合成を用いて、このタンパク質の定常領域をHC-L0-IFN-アルファ(A145D)IgG1(配列番号10)と置き換え、A10.0軽鎖(配列番号161)と対形成させ、A10.59と命名した。タンパク質は発現され、機能的アッセイにおいて強力であることがわかった(Table 28(表32))。前記実施例において試験したタンパク質の大部分をヒトIgG4定常領域上で構築したが、これらのデータは、ヒトIgG1などの他の抗体定常領域を用いることもでき、得られる抗体-弱毒化IFN融合構築物がヒトIgG4定常領域を用いる構築物と同等の強力な生物活性を有することを示している。
Claims (24)
- CD38に特異的に結合し、配列番号156のアミノ酸配列を含む重鎖可変領域及び配列番号185のアミノ酸配列を含む軽鎖可変領域を含む抗体と、弱毒化されたヒトインターフェロンアルファ-2bを含む、抗CD38抗体-弱毒化インターフェロンアルファ-2b融合構築物。
- 抗体がヒトIgG1重鎖定常領域を含む、請求項1に記載の構築物。
- 抗体がヒトIgG4重鎖定常領域を含む、請求項1に記載の構築物。
- ヒトIgG4重鎖定常領域が、EU番号付けシステムによる228位にプロリンを含む、請求項3に記載の構築物。
- ヒトIgG4重鎖定常領域が、EU番号付けシステムによる定常領域の252位にチロシン、254位にトレオニン、及び256位にグルタミン酸を含む、請求項3又は4に記載の構築物。
- 弱毒化されたヒトインターフェロンアルファ2bが、配列番号648のアミノ酸配列と比較して、145位にアラニンからアスパラギン酸への置換を含む、請求項1から5のいずれか一項に記載の構築物。
- 弱毒化されたヒトインターフェロンアルファ2bが、配列番号647、配列番号649、配列番号650、又は配列番号651のアミノ酸配列を含む、請求項1から5のいずれか一項に記載の構築物。
- 抗体がヒト化抗体である、請求項1から7のいずれか一項に記載の構築物。
- 請求項1から8のいずれか一項に記載の構築物と、薬学的に許容される担体とを含む組成物。
- B細胞リンパ腫、多発性骨髄腫、非ホジキンリンパ腫、慢性骨髄性白血病、慢性リンパ性白血病又は急性骨髄性白血病の処置のための、請求項1から8のいずれか一項に記載の構築物、又は請求項9に記載の組成物。
- CD38とヒトインターフェロンアルファ-2bの受容体とを表面に発現する腫瘍細胞を含む腫瘍を処置する医薬を製造するための、請求項1から8のいずれか一項に記載の構築物の使用。
- CD38に特異的に結合する抗体であって、配列番号665の重鎖CDR1、CDR2、及びCDR3、並びに、配列番号666の軽鎖CDR1、CDR2、及びCDR3を含む抗体と、弱毒化されたヒトインターフェロンアルファ-2bを含む、抗CD38抗体-弱毒化インターフェロンアルファ-2b融合構築物。
- 重鎖CDR1は、配列番号514のアミノ酸配列を含み、重鎖CDR2は、配列番号516のアミノ酸配列を含み、重鎖CDR3は、配列番号518のアミノ酸配列を含み、軽鎖CDR1は、配列番号608のアミノ酸配列を含み、軽鎖CDR2は、配列番号591のアミノ酸配列を含み、軽鎖CDR3は、配列番号612のアミノ酸配列を含む、請求項12に記載の抗CD38抗体-弱毒化インターフェロンアルファ-2b融合構築物。
- 重鎖可変領域は、配列番号156のアミノ酸配列と少なくとも95%の同一性を有するアミノ酸配列を含み、軽鎖可変領域は、配列番号185のアミノ酸配列と少なくとも95%の同一性を有するアミノ酸配列を含み、重鎖可変領域又は軽鎖可変領域における、すべてのアミノ酸置換は、CDRの外に存在する、請求項12又は13に記載の抗CD38抗体-弱毒化インターフェロンアルファ-2b融合構築物。
- 抗体がヒトIgG1重鎖定常領域を含む、請求項12から14のいずれか一項に記載の構築物。
- 抗体がヒトIgG4重鎖定常領域を含む、請求項12から14のいずれか一項に記載の構築物。
- ヒトIgG4重鎖定常領域が、EU番号付けシステムによる228位にプロリンを含む、請求項16に記載の構築物。
- ヒトIgG4重鎖定常領域が、EU番号付けシステムによる定常領域の252位にチロシン、254位にトレオニン、及び256位にグルタミン酸を含む、請求項16又は17に記載の構築物。
- 弱毒化されたヒトインターフェロンアルファ2bが、配列番号648のアミノ酸配列と比較して、145位にアラニンからアスパラギン酸への置換を含む、請求項12から18のいずれか一項に記載の構築物。
- 弱毒化されたヒトインターフェロンアルファ2bが、配列番号647、配列番号649、配列番号650、又は配列番号651のアミノ酸配列を含む、請求項12から18のいずれか一項に記載の構築物。
- 抗体がヒト化抗体である、請求項12から20のいずれか一項に記載の構築物。
- 請求項12から21のいずれか一項に記載の構築物と、薬学的に許容される担体とを含む組成物。
- B細胞リンパ腫、多発性骨髄腫、非ホジキンリンパ腫、慢性骨髄性白血病、慢性リンパ性白血病又は急性骨髄性白血病の処置のための、請求項12から20のいずれか一項に記載の構築物、又は請求項22に記載の組成物。
- CD38とヒトインターフェロンアルファ-2bの受容体とを表面に発現する腫瘍細胞を含む腫瘍を処置するための医薬を製造するための、請求項12から20のいずれか一項に記載の構築物の使用。
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US11319356B2 (en) | 2014-10-29 | 2022-05-03 | Teva Pharmaceuticals Australia Pty Ltd | Interferon alpha 2B variants |
JP2018087218A (ja) * | 2018-02-02 | 2018-06-07 | テバ・ファーマシューティカルズ・オーストラリア・ピーティワイ・リミテッド | 抗cd38抗体及び弱毒化インターフェロンアルファ−2bとの融合物 |
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