JP2023058410A - Cd47およびcd24を標的とする組換え融合タンパク質、調製物、ならびにそれの使用 - Google Patents
Cd47およびcd24を標的とする組換え融合タンパク質、調製物、ならびにそれの使用 Download PDFInfo
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Abstract
Description
本願は、2021年10月13日に出願された中国特許出願第202111195248.4号の優先権を主張する。
シグナル調節タンパク質(SIRP)は、3つのファミリメンバ、SIRPα(CD172a)、SIRPβ(CD172b)、およびSIRPγ(CD172g)を有する膜貫通型の糖タンパク質である。3つのタンパク質は、同様の細胞外領域を含むが、異なる細胞内ドメインを含む。細胞外領域は、3つの免疫グロブリン様ドメイン、1つのIgVの組みおよび2つのIgCの組みのドメインを含む。SIRPα(CD172a)の細胞内ドメインは、シグナル伝達および対応する細胞機能を阻害することができる2つの阻害シグナル伝達領域を含む。SIRPβ(CD172b)およびSIRPγ(CD172g)は、いかなるシグナル伝達ドメインも有しない大変短い細胞内領域を有する。しかしながら、SIRPβ(CD172b)は、アダプタタンパク質、例えばDAP12を介して、シグナル伝達のために機能することがある。SIRPは、マクロファージ(Mφ)、樹状細胞(DC)、およびニューロン上に主に発現される。
シアル酸結合免疫グロブリン(Ig)様レクチン(Siglec)は、免疫グロブリン様I型膜貫通タンパク質である。Siglecファミリメンバおよび阻害受容体であるSiglec-10は、マクロファージ、B細胞、NK細胞、および活性化T細胞などの免疫細胞上で広範にわたって発現される。Siglec-10は、5つの細胞外Ig様ドメイン、膜貫通領域、および細胞質尾部を有する。Siglec-10のIgV構造ドメインは、シアル酸の認識と関係する、重要なアルギニン残基を含む(Yinら、2020年)。T細胞上のSiglec-10の発現は、T細胞主要組織適合性複合体クラスI(MHC-I)ペプチド複合体の形成、ならびにT細胞受容体関連キナーゼ、LckおよびZAP-70のリン酸化を阻害することによってT細胞の活性化に干渉することが公知である(Yinら、2020年)。B細胞およびNK細胞上のSiglec-10の発現はそれぞれ、BCR媒介およびNK細胞受容体媒介シグナル伝達を阻害する(Yinら、2020年)。
断片結晶化可能領域(Fc領域)は、抗体の尾領域であり、抗体のエフェクタ機能、すなわち、どのように抗体が特定の細胞受容体または他の防御タンパク質と結合するかを決定するドメインである。
単一の腫瘍関連抗原を標的とする抗体は、治療効率を限定することが見出されている。例えば、承認されている抗PD-L1抗体、アベルマブ(BAVENCIO)の全奏効率はわずか33%である。近年、二重または三重特異性融合タンパク質は、開発されており、事前臨床および臨床試験において期待がもてる効果を示している。
ベクタ構築およびタンパク質発現
IMM4701、IMM4701C、IMM4702C、IMM4702H、IMM47、IMM47C、およびIMM47Hの構造を図1に示し、組換え融合タンパク質の完全長コード配列を人工的に設計した。
ジャーカット細胞上のCD47に結合された例示的な組換え融合タンパク質
1×106/mlの細胞密度で100μlのジャーカット細胞(CD47を天然に発現している)を、100μlの連続希釈したIMM4701、IMM4701C、IMM4702C、IMM4702H、IMM01、およびIMM47(3倍希釈、30μg/mlで開始する)それぞれと共に、4℃で1時間インキュベートした。細胞を、冷たいPBSで2回洗浄し、次いで、ヒトIgG-Fc(Cat#F9512、Sigma)に対する100μlのFITC結合二次抗体と共に45分間インキュベートした。細胞を、2回洗浄し、200μlのPBSに再懸濁させた。次いで、細胞を、フローサイトメータ(Merck Millipore、Guava(登録商標)easyCyte 5HT)を用いてFACS分析に供した。
CD24+CD47+MCF-7細胞に結合された例示的な組換え融合タンパク質
1×106/mlの細胞密度で100μlのCD24+CD47+MCF-7細胞を、100μlの連続希釈したIMM4701、IMM4701C、IMM4702C、IMM4702H、IMM01、およびIMM47H(3倍希釈、30μg/mlで開始する)それぞれと共に、4℃で1時間インキュベートし、hIgG-Fcを陰性対照として使用した。細胞を、冷たいPBSで2回洗浄し、次いで、ヒトIgG-Fc(Cat#F9512、Sigma)に対する100μlのFITC結合二次抗体と共に45分間インキュベートした。細胞を、2回洗浄し、200μlのPBSに再懸濁させた。次いで、細胞を、フローサイトメータ(Merck Millipore、Guava(登録商標)easyCyte 5HT)を用いてFACS分析に供した。
CD24+CD47+REH細胞に結合された例示的な組換え融合タンパク質
1×106/mlの細胞密度で100μlのCD24+CD47+REH細胞を、100μlの連続希釈したIMM4701C、IMM4702C、IMM4702H、IMM01、およびIMM47H(3倍希釈、30μg/mlで開始する)それぞれと共に、4℃で1時間インキュベートし、hIgG-Fcを陰性対照として使用した。細胞を、冷たいPBSで2回洗浄し、次いで、ヒトIgG-Fc(Cat#F9512、Sigma)に対する100μlのFITC結合二次抗体と共に45分間インキュベートした。細胞を、2回洗浄し、200μlのPBSに再懸濁させた。次いで、細胞を、フローサイトメータ(Merck Millipore、Guava(登録商標)easyCyte 5HT)を用いてFACS分析に供した。
例示的な組換え融合タンパク質により阻害されるCD47-SIRPα相互作用
3μg/mlで50μlのSIRPα-mFc(マウスIgG1 Fcと結合された野性型ヒトSIRPα、配列識別番号36)を、50μlの連続希釈したIMM4701、IMM4701C、IMM4702C、IMM4702H、およびIMM01(3倍希釈、30μg/mlで開始する)それぞれと共に混合し、hIgG1-Fcを陰性対照として使用した。得られた混合物を、96ウェルプレートの、それぞれ1×106/mlのCD47+CD24+MCF-7細胞を50μl含有するウェルに加え、プレートを4℃で45分間インキュベートした。細胞を、PBSで洗浄し、マウスIgG-Fc(Cat#405307、Biolegend)に対する100μlのPE結合二次抗体と共に45分間インキュベートした。細胞を、2回洗浄し、200μlのPBSに再懸濁させ、FACS分析に供した。
例示的組換え融合タンパク質により誘導される、CD24+CD47+MCF-7細胞に対する高い抗体依存性細胞媒介細胞傷害性(ADCC)
1mMのCFSE(Cat#21888-25mg、Sigma)を1:500で希釈し、MCF-7細胞を標識するために使用した。
%溶解=(%IMM47C、IMM4701、またはIMM4701Cで処置したPI陽性標的細胞-%陰性対照で処置したPI陽性標的細胞)/(100-%陰性対照で処置したPI陽性標的細胞)×100
に基づいて、ADCCによって引き起こされた細胞溶解の百分率を算出した。
例示的組換え融合タンパク質により誘導される、CD24+CD47+REH細胞に対する高い抗体依存性細胞媒介細胞傷害(ADCC)
1mMのCFSE(Cat#21888-25mg、Sigma)を1:500で希釈し、REH細胞を標識するために使用した。
%溶解=(%IMM47C、IMM4701C、IMM4702C、またはIMM4702Hで処置したPI陽性標的細胞-%陰性対照で処置したPI陽性標的細胞)/(100-%陰性対照で処置したPI陽性標的細胞)×100
に基づいて、ADCCによって引き起こされた細胞溶解の百分率を算出した。
例示的組換え融合タンパク質により誘導される、CD24+MC38-hCD24細胞に対する高い抗体依存性細胞媒介細胞傷害(ADCC)
1mMのCFSE(Cat#21888-25mg、Sigma)を1:500で希釈し、MC38-hCD24細胞を標識するために使用した。
%溶解=(%IMM4701C、IMM4701で処置したPI陽性標的細胞-%陰性対照で処置したPI陽性標的細胞)/(100-%陰性対照で処置したPI陽性標的細胞)×100
に基づいて、ADCCによって引き起こされた細胞溶解の百分率を算出した。
例示的な組換え融合タンパク質により示される強力な抗腫瘍活性
40匹の6~8週令のSCIDマウスそれぞれの左背中に、0.36mgのベータ-エストラジオール遅延放出錠を埋め込み、3日後にマウス1匹当たり1×107cellのMCF-7ヒト乳癌細胞を右の側腹部に皮下注射した。腫瘍体積が100~150mm3に達した際、マウスを1つの群に8匹ずつ、5つの群にランダムに分け、この日を0日目とした。その日から、マウスそれぞれに、PBS、IMM47C(2.5mg/kg)、IMM01(2.5mg/kg)、IMM4701C(3mg/kg)、およびIMM01+IMM47C(2.5mg/kg+2.5mg/kg)の腹腔内注射を週2回、4週間与えた。4週目の終わりに投与を停止し、PBS群における平均腫瘍体積が3000mm3に達して実験を終了するまでマウスを観察した。
腫瘍サイズおよび体重を3~4日毎に測定した。
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Claims (15)
- 抗CD24抗体またはそれの抗体断片と、CD47結合ペプチドとを備え、
前記抗CD24抗体またはそれの抗体断片は、重鎖可変領域、重鎖定常領域、および軽鎖可変領域を有し、前記重鎖可変領域は、配列識別番号7、8、および9に記載されるアミノ酸配列をそれぞれ有する、重鎖可変CDR1(HV-CDR1)、HV-CDR2、およびHV-CDR3を含み、前記軽鎖可変領域は、配列識別番号10、11、および12に記載されるアミノ酸配列をそれぞれ有する、軽鎖可変CDR1(LV-CDR1)、LV-CDR2、およびLV-CDR3を含み、前記重鎖定常領域は、FcR結合親和性を有し、前記重鎖可変領域のC末端に連結され、
前記CD47結合ペプチドは、配列識別番号1に対して少なくとも95%の配列同一性を有するアミノ酸配列を有する、シグナル調節タンパク質(SIRP)細胞外ドメインを有し、
前記CD47結合ペプチドは、前記抗CD24抗体またはそれの抗体断片に連結された、
組換え融合タンパク質。 - 前記抗CD24抗体またはそれの抗体断片の少なくとも1つのパラトープは、前記パラトープを構成する前記重鎖可変領域または前記軽鎖可変領域のN末端にて前記CD47結合ペプチドに連結された、請求項1に記載の組換え融合タンパク質。
- 前記抗CD24抗体またはそれの抗体断片の各パラトープは、前記パラトープを構成する前記重鎖可変領域または前記軽鎖可変領域のN末端にて前記CD47結合ペプチドに連結された、請求項2に記載の組換え融合タンパク質。
- 前記重鎖可変領域および前記軽鎖可変領域は、i)それぞれ配列識別番号2および3、ii)それぞれ配列識別番号2および4、またはiii)それぞれ配列識別番号5および6に記載されるアミノ酸配列を含む、請求項1~3のいずれか一項に記載の組換え融合タンパク質。
- 前記重鎖定常領域は、配列識別番号13の前記アミノ酸配列を含む、請求項1~4のいずれか一項に記載の組換え融合タンパク質。
- 前記軽鎖可変領域の前記C末端に連結された、配列識別番号14の前記アミノ酸配列を有する軽鎖定常領域をさらに含む、請求項1~5のいずれか一項に記載の組換え融合タンパク質。
- 前記抗CD24抗体またはそれの抗体断片は、リンカを介して前記CD47結合ペプチドに連結された、請求項1~6のいずれか一項に記載の組換え融合タンパク質。
- 前記リンカは、-(Gly-Gly-Gly-Gly-Ser)3-(配列識別番号15)、-(Gly-Gly-Gly-Gly-Ser)2-(配列識別番号16)、または-(Gly-Gly-Gly-Gly-Ser)4-(配列識別番号17)である、請求項7に記載の組換え融合タンパク質。
- i)配列識別番号18の前記アミノ酸配列を有するCD47結合ペプチド-リンカ-抗CD24重鎖可変領域-重鎖定常領域断片、および配列識別番号20の前記アミノ酸配列を有する抗CD24軽鎖可変領域-軽鎖定常領域断片、
ii)配列識別番号18の前記アミノ酸配列を有するCD47結合ペプチド-リンカ-抗CD24重鎖可変領域-重鎖定常領域断片、および配列識別番号22の前記アミノ酸配列を有する抗CD24軽鎖可変領域-軽鎖定常領域断片、
iii)配列識別番号24の前記アミノ酸配列を有する抗CD24重鎖可変領域-重鎖定常領域断片、および配列識別番号26の前記アミノ酸配列を有するCD47結合ペプチド-リンカ-抗CD24軽鎖可変領域-軽鎖定常領域断片、または
iv)配列識別番号28の前記アミノ酸配列を有する抗CD24重鎖可変領域-重鎖定常領域断片、および配列識別番号30の前記アミノ酸配列を有するCD47結合ペプチド-リンカ-抗CD24軽鎖可変領域-軽鎖定常領域断片
を備える、請求項1~8のいずれか一項に記載の組換え融合タンパク質。 - 請求項1~9のいずれか一項に記載の組換え融合タンパク質をエンコードする核酸分子。
- 請求項10に記載の核酸分子を含む発現ベクタ。
- 請求項11に記載の発現ベクタを含む宿主細胞。
- 請求項1~9のいずれか一項に記載の組換え融合タンパク質と、少なくとも1種の薬学的に許容される賦形剤とを含む医薬組成物。
- それを必要とする対象の、CD47および/またはCD24の過剰発現と関連付けられる疾患の処置における使用のための、請求項13に記載の医薬組成物。
- 前記疾患は、急性骨髄球性白血病(AML)、慢性骨髄球性白血病(CML)、急性リンパ芽球性白血病(ALL)、非ホジキンリンパ腫(NHL)、多発性骨髄腫(MM)、膀胱癌、卵巣癌、前立腺癌、肺癌、大腸癌、乳癌、膵臓癌、腎細胞癌、子宮頚癌、子宮内膜癌、胆管癌、胃腺癌、および神経膠芽腫からなる群より選択される、請求項14に記載の使用のための医薬組成物。
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