JP7486421B2 - Cd22に結合する重鎖抗体 - Google Patents
Cd22に結合する重鎖抗体 Download PDFInfo
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Description
本出願は、2017年12月22日に出願された米国仮特許出願第62/609,759号の出願日の優先権を主張し、この出願の開示は、本明細書に全体が参照により組み込まれる。
配列表
本出願は、ASCIIフォーマットで電子的に提出されており、全体が本明細書で参照により組み込まれる配列表を含む。2019年2月7日に作成された該ASCIIコピーは、TNO-0009-WO_SL.txtという名称であり、サイズが80,329バイトである。
本発明は、CD22に結合するヒト重鎖抗体(例えば、UniAbs(商標))に関する。本発明はさらに、そのような抗体を作製する方法、そのような抗体を含む医薬組成物を含む組成物、及びCD22の発現を特徴とするB細胞障害を処置するためのそれらの使用に関する。
SIGLEC-2(UniProt P20273)としても知られるCD22は、成熟B細胞上で発現される細胞表面受容体である。CD22は、複数のIgドメインを含有し、免疫グロブリンスーパーファミリーのメンバーである。CD22の細胞外ドメインは、CD45細胞表面タンパク質に存在するものを含むシアル酸部分と相互作用する。CD22は、B細胞受容体シグナル伝達の抑制性受容体として機能すると考えられる。CD20及びCD19に加えて、CD22のB細胞発現が制限されるので、B細胞性悪性腫瘍の治療的処置のための魅力的な標的となる。CD22に特異的なモノクローナル抗体は、文献に記載されており(例えば、Jabbour,Elias,et al.“Monoclonal antibodies in acute lymphoblastic leukemia.”Blood 125.26(2015):4010-4016)、標準的なモノクローナル抗体(例えば、エプラツズマブ)及び抗体-薬物コンジュゲート(イノツズマブオゾガマイシン)として治療的に使用されている。加えて、抗CD22キメラ抗原受容体T細胞は、白血病を処置するために診療所で使用されている(Fry,Terry J.,et al.“CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy.”Nature medicine(2017))。
従来のIgG抗体では、重鎖及び軽鎖の会合は、軽鎖定常領域及び重鎖のCH1定常ドメイン間の疎水性相互作用に一部起因している。重鎖及び軽鎖間の疎水性相互作用にも寄与する、重鎖フレームワーク2(FR2)及びフレームワーク4(FR4)領域に追加の残基がある。
GX1SIX2X3X4X5X6Y(配列番号85)
(式中、X1は、DまたはGであり;X2は、S、T、I、またはNであり、X3は、SまたはDであり;X4は、G、S、またはNであり;X5は、D、G、またはSであり;X6は、YまたはHである)のCDR1配列、及び(b)式:
X7X8YX9GX10X11 (配列番号86)
(式中、X7は、IまたはVであり;X8は、YまたはHであり;X9は、SまたはTであり;X10は、A、V、またはSであり;X11は、TまたはAである)のCDR2配列、及び(c)式:
X12RX13DSSX14WRS(配列番号87)
(式中、X12は、T、A、またはKであり;X13は、DまたはEであり;X14は、NまたはSである)のCDR3配列を含む重鎖可変を含む重鎖可変領域を含む。
「含むこと」は、列挙された要素が組成物/方法/キットに必要とされることを意味するが、請求項の範囲内で組成物/方法/キットなどを形成するために他の要素が含まれてもよい。
抗CD22抗体
本発明は、密接に関連するヒトCD22に結合する重鎖のみ抗体のファミリーを提供する。このファミリーの抗体は、本明細書で定義され且つ図1に示されるような一連のCDR配列を含み、図2に記載の配列番号24~84の提供された重鎖可変領域(VH)配列で例示される。抗体のファミリーは、臨床治療薬(複数可)としての有用性に寄与する多数の利点を提供する。抗体は、ある範囲の結合親和性を有するメンバーを含み、所望の結合親和性を有する特定の配列の選択を可能にする。
CDR1
GX1SIX2X3X4X5X6Y(配列番号85)
(式中、X1は、DまたはGであり、
X2は、S、T、I、またはNであり、
X3は、SまたはDであり、
X4は、G、S、またはNであり、
X5は、D、G、またはSであり、
X6は、YまたはHである)
CDR2
X7X8YX9GX10X11 (配列番号86)
(式中、X7は、IまたはVであり、
X8は、YまたはHであり、
X9は、SまたはTであり、
X10は、A、V、またはSであり、
X11は、TまたはAである)
CDR3
X12RX13DSSX14WRS(配列番号87)
(式中、X12は、T、A、またはKであり、
X13は、DまたはEであり、
X14は、NまたはSである)。
CDR1
GX1SIX2X3X4X5X6Y
(式中、X1は、DまたはGであり、
X2は、S、T、I、またはNであり、
X3は、SまたはDであり、
X4は、G、S、またはNであり、
X5は、D、G、またはSであり、
X6は、YまたはHである)
CDR2
X7X8YX9GX10X11
(式中、X7は、IまたはVであり、
X8は、YまたはHであり、
X9は、SまたはTであり、
X10は、A、V、またはSであり、
X11は、TまたはAである)
CDR3
X12RX13DSSX14WRS
(式中、X12は、T、A、またはKであり、
X13は、DまたはEであり、
X14は、NまたはSである)。
本発明の重鎖抗体は、当該技術分野で既知の方法により調製することができる。好ましい実施形態では、本明細書の重鎖抗体は、内因性免疫グロブリン遺伝子がノックアウトまたは無効化されたトランスジェニックマウス及びラット、好ましくは、ラット、を含むトランスジェニック動物により産生される。好ましい実施形態では、本明細書の重鎖抗体は、UniRat(商標)で産生される。UniRat(商標)は、それらの内因性免疫グロブリン遺伝子がサイレンシングされ、完全ヒトHCAbの多様な天然に最適化されたレパートリーを発現するために、ヒト免疫グロブリン重鎖トランスローカスを使用する。ラットの内因性免疫グロブリン遺伝子座は、様々な技術を使用してノックアウトまたはサイレンシングすることができるが、UniRat(商標)では、亜鉛フィンガー(エンド)ヌクレアーゼ(ZNF)技術を使用して、内因性ラット重鎖J遺伝子座、軽鎖Cκ遺伝子座、及び軽鎖Cλ遺伝子座を不活化した。卵母細胞へのマイクロインジェクションのためのZNF構築物は、IgH及びIgLノックアウト(KO)株を生成し得る。詳細については、例えば、Geurts et al.,2009,Science 325:433を参照のこと。Ig重鎖ノックアウトの特性決定は、Menoret et al.,2010,Eur.J.Immunol.40:2932-2941により報告されている。ZNF技術の利点は、最大数kbの欠失を介して遺伝子または遺伝子座をサイレンシングする非相同末端結合が、相同的統合のための標的部位も提供し得ることである(Cui et al.,2011,Nat Biotechnol 29:64-67)。UniRat(商標)で産生されたヒト重鎖抗体は、UniAbs(商標)と呼ばれ、従来の抗体を用いて攻撃することができないエピトープと結合し得る。それらの高い特異性、親和性、及び小さいサイズにより、それらは、モノ特異的及びポリ特異的用途に最適になる。
好適な薬学的に許容される担体と混合した本発明の1つ以上の抗体を含む医薬組成物を提供することが本発明の別の態様である。本明細書で使用される薬学的に許容される担体は、限定されないが、アジュバント、固体担体、水、緩衝剤、または治療構成成分を保持するために当該技術分野で使用される他の担体、またはそれらの組み合わせを例示する。
本明細書に記載の重鎖のみ抗CD22抗体、多重特異性抗体、及び医薬組成物は、限定しないが、本明細書にさらに記載される状態及び疾患を含む、CD22の発現を特徴とする疾患及び状態の処置に使用することができる。本発明の態様はまた、CD22の発現を特徴とするB細胞障害の処置のための薬剤の調製における、本明細書に記載の抗体の使用に関する。本発明の態様はまた、CD22の発現を特徴とするB細胞障害の処置に使用される、本明細書に記載の抗体に関する。
CD22タンパク質結合
抗原抗体親和性を決定するための動態結合実験を、バイオレイヤー干渉法を使用するOctet QK-384システム(ForteBio)で実施した。抗ヒトIgG Fcキャプチャー(AHC)バイオセンサー(Forte Bio、部品番号:18-5064)をアッセイ緩衝液(1xのPBS、0.1%のBSA、0.02%のTween-20、pH7.2)で水和し、pH1.5の100mMのグリシン中で事前調整した。ベースラインを、アッセイ緩衝液で120秒間確立した。次に、AHCバイオセンサーを、5μg/mLの濃度のUniAbs(商標)で120秒間固定した。別のベースライン(120秒)を、アッセイ緩衝液で確立した。次に、それらを、250nMから開始する、アッセイ緩衝液中のヒトCD22タンパク質の7点の1:2希釈系列に浸漬した。検体列の最後のウェルは、緩衝液及びロードされたバイオセンサー間の非特異的結合を試験するために、アッセイ緩衝液のみを含有し、参照ウェルとして使用した。会合を600秒間観察し、続いて、解離を900秒間観察した。Octet Data Analysis v9.0(ForteBio)を使用して、データ分析を実施した。標準的な1:1結合モデルを使用して、結合動態を分析した。
CD22細胞結合
『ヒト-ラット』のIgH遺伝子座を、いくつかの部分で構築して、組み立てた。これは、ヒトJHの下流のラットC領域遺伝子の改変及び結合、ならびにその後のヒトVH6-Dセグメント領域の上流付加を含む。次に、ヒトVH6、全てのD、全てのJH、及び改変ラットCγ2a/1/2b(ΔCH1)を含む、組み立てられて改変された領域をコードするヒトVH遺伝子の別々のクラスターを有する2つのBAC[BAC6及びBAC3]を、Georgと呼ばれるBACと共注入した。
CD22の組み換え細胞外ドメインでの免疫化。
12匹のUniRat動物(6匹のHC27、6匹のHC28)を組み換えヒトCD22タンパク質で免疫した。Titermax/Alhydrogelアジュバントを使用して標準的なプロトコールに従って動物を免疫した。CD22の組み換え細胞外ドメインを、R&Dシステムズから購入し、滅菌生理食塩水で希釈し、アジュバントと混合した。免疫原をTitermax及びAlhydrogelアジュバントと組み合わせた。Titermax中の免疫原による初回免疫化(プライミング)を左右の脚に投与した。その後の追加免疫をAlhydrogelの存在下で行い、採取3日前に、PBS中の免疫原を用いる追加免疫を実施した。最終採血時にラットから血清を収集し、血清力価を決定した。
血清力価の要約情報は、図6に示される。図6に示されるグラフでは、各線は、個々の動物を表す。グラフの凡例は、個々の各動物のID番号を示す。huCD22+Fcタンパク質、huCD22+Hisタグ、アカゲザルCD22+Hisタグタンパク質タンパク質、及びHisタグオフターゲットタンパク質に対する血清の8点希釈系列の結合活性をELISAで試験した。この動物群の中で、ヒト及びアカゲザルの両方のCD22タンパク質に対する一連の血清反応性レベルが観察された。Hisタンパク質タグに対する血清応答も観察された。
図4は、本明細書に記載の抗CD22重鎖のみ抗体の標的結合活性をまとめたものである。列1は、抗CD22重鎖のみ抗体のクローンID番号を示す。列2は、モル濃度で測定されたタンパク質(KD)への結合親和性を示す。列3は、秒単位で測定されたタンパク質への結合の解離定数(K-off rate)を示す。列4は、バックグラウンドMFIシグナルの倍数として測定されたDaudi細胞への結合を示す。列5は、バックグラウンドMFIシグナルの倍数として測定されたcyno CD22を安定的に発現するCHO細胞への結合を示す。列6は、バックグラウンドMFIシグナルの倍数として測定されたCD22タンパク質を発現しないCHO細胞への結合を示す。
3つの異なるCD22陽性バーキットリンパ腫腫瘍細胞株(Daudi、Raji、及びRamos)を色素標識し、前活性化ヒトT細胞の存在下で、漸増量の二重特異性抗体と共にインキュベートした。二重特異性抗体は、図5Dに概略的に示されるように、抗CD22 VH結合ドメインと対になった抗CD3結合アームから構成された。陰性対照抗体は、CD22に結合しないVH結合ドメインを含んでいた。CD22陰性K562細胞は、特異的溶解を示さなかった(データを示さず)。同じ抗CD3結合ドメインと対になった3つの異なる抗CD22重鎖のみ結合ドメインを組み込んだ3つの二重特異性抗体のデータは、陰性対照と比較して図5Aに示され、活性化T細胞のリダイレクトを介してCD22陽性Daudi腫瘍細胞の抗体媒介性殺傷を示す。2つの異なる抗CD3結合ドメインと対になった同じ抗CD22重鎖のみ結合ドメインを組み込む2つの二重特異性抗体のデータは、陰性対照と比較して図5Bに示され、活性化T細胞のリダイレクトを介してCD22陽性Raji腫瘍細胞の抗体媒介性殺傷を示す。2つの異なる抗CD3結合ドメインと対になった同じ抗CD22重鎖のみ結合ドメインを組み込む2つの二重特異性抗体のデータは、陰性対照と比較して図5Cに示され、活性化T細胞のリダイレクトを介してCD22陽性Ramos腫瘍細胞の抗体媒介性殺傷を示す。
Claims (22)
- (a)配列番号1のCDR1配列、配列番号11のCDR2配列、及び配列番号18のCDR3配列、または
(b)配列番号1のCDR1配列、配列番号12のCDR2配列、及び配列番号19のCDR3配列、または
(c)配列番号1のCDR1配列、配列番号12のCDR2配列、及び配列番号20のCDR3配列、
を含む重鎖可変領域を含む、CD22に結合する重鎖のみ抗体。 - CDR1配列、CDR2配列、及びCDR3配列が、ヒトVHフレームワークに存在する、請求項1に記載の重鎖のみ抗体。
- 重鎖可変領域が配列番号24と少なくとも95%の同一性を有する配列を含む、請求項1に記載の重鎖のみ抗体。
- 重鎖可変領域配列が配列番号24を含む、請求項3に記載の重鎖のみ抗体。
- 重鎖可変領域が配列番号25と少なくとも95%の同一性を有する配列を含む、請求項1に記載の重鎖のみ抗体。
- 重鎖可変領域配列が配列番号25を含む、請求項5に記載の重鎖のみ抗体。
- 重鎖可変領域が配列番号32と少なくとも95%の同一性を有する配列を含む、請求項1に記載の重鎖のみ抗体。
- 重鎖可変領域配列が配列番号32を含む、請求項7に記載の重鎖のみ抗体。
- 重鎖定常領域配列をさらに含む、請求項1~8のいずれか1項に記載の重鎖のみ抗体。
- 重鎖定常領域配列がCH1配列を欠く、請求項9に記載の重鎖のみ抗体。
- 重鎖定常領域配列がCH2ドメイン及びCH3ドメインを含む、請求項9に記載の重鎖のみ抗体。
- ヒトIgG4 Fc領域をさらに含む、請求項1~11のいずれか1項に記載の重鎖のみ抗体。
- ヒトIgG4 Fc領域が変異型ヒトIgG4 Fc領域である、請求項12に記載の重鎖のみ抗体。
- 多重特異性である、請求項1~13のいずれか1項に記載の重鎖のみ抗体。
- 二重特異性である、請求項14に記載の重鎖のみ抗体。
- エフェクター細胞に対する結合親和性を有する、請求項14に記載の重鎖のみ抗体。
- T細胞抗原に対する結合親和性を有する、請求項14に記載の重鎖のみ抗体。
- CD3に対する結合親和性を有する、請求項17に記載の重鎖のみ抗体。
- 請求項1~18のいずれか1項に記載の重鎖のみ抗体をコードするポリヌクレオチド。
- 請求項16~18のいずれか一項に記載の重鎖のみ抗体を含む、びまん性大B細胞リンパ腫(DLBCL)、及び非ホジキンリンパ腫(NHL)からなる群から選択されるB細胞障害を治療するための医薬。
- 請求項16~18のいずれか一項に記載の重鎖のみ抗体を含む、B細胞慢性リンパ球性白血病を治療するための医薬。
- 請求項16~18のいずれか一項に記載の重鎖のみ抗体を含む、濾胞性リンパ腫を治療するための医薬。
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PH12020550964A1 (en) | 2021-03-22 |
CN111683966A (zh) | 2020-09-18 |
CO2020008925A2 (es) | 2020-10-30 |
KR20200104342A (ko) | 2020-09-03 |
PE20201171A1 (es) | 2020-10-28 |
JP2021506325A (ja) | 2021-02-22 |
AU2018392088A2 (en) | 2020-08-27 |
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