JP7137563B2 - がん治療用の抗Siglec-7抗体 - Google Patents
がん治療用の抗Siglec-7抗体 Download PDFInfo
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- JP7137563B2 JP7137563B2 JP2019527783A JP2019527783A JP7137563B2 JP 7137563 B2 JP7137563 B2 JP 7137563B2 JP 2019527783 A JP2019527783 A JP 2019527783A JP 2019527783 A JP2019527783 A JP 2019527783A JP 7137563 B2 JP7137563 B2 JP 7137563B2
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Description
本願は、2016年8月5日に提出した米国出願第62/371,680号の優先権を主張するものであり、その内容を参照により本明細書に組み込む。
(a)配列番号43に記載のCDR1、CDR2、およびCDR3配列を含む重鎖可変領域、および配列番号69に記載のCDR1、CDR2、およびCDR3配列を含む軽鎖可変領域、
(b)配列番号45に記載のCDR1、CDR2、およびCDR3配列を含む重鎖可変領域、および配列番号69に記載のCDR1、CDR2、およびCDR3配列を含む軽鎖可変領域、
(c)配列番号46に記載のCDR1、CDR2、およびCDR3配列を含む重鎖可変領域、および配列番号69に記載のCDR1、CDR2、およびCDR3配列を含む軽鎖可変領域、
(d)配列番号47に記載のCDR1、CDR2、およびCDR3配列を含む重鎖可変領域、および配列番号69に記載のCDR1、CDR2、およびCDR3配列を含む軽鎖可変領域、
(e)配列番号48に記載のCDR1、CDR2、およびCDR3配列を含む重鎖可変領域、および配列番号69に記載のCDR1、CDR2、およびCDR3配列を含む軽鎖可変領域、
(f)配列番号49に記載のCDR1、CDR2、およびCDR3配列を含む重鎖可変領域、および配列番号69に記載のCDR1、CDR2、およびCDR3配列を含む軽鎖可変領域、
(g)配列番号50に記載のCDR1、CDR2、およびCDR3配列を含む重鎖可変領域、および配列番号69に記載のCDR1、CDR2、およびCDR3配列を含む軽鎖可変領域、
(h)配列番号51に記載のCDR1、CDR2、およびCDR3配列を含む重鎖可変領域、および配列番号69に記載のCDR1、CDR2、およびCDR3配列を含む軽鎖可変領域、
(i)配列番号54に記載のCDR1、CDR2、およびCDR3配列を含む重鎖可変領域配列、および配列番号69に記載のCDR1、CDR2、およびCDR3配列を含む軽鎖可変領域、
(j)配列番号55に記載のCDR1、CDR2、およびCDR3配列を含む重鎖可変領域、および配列番号69に記載のCDR1、CDR2、およびCDR3配列を含む軽鎖可変領域、
(k)配列番号57に記載のCDR1、CDR2、およびCDR3配列を含む重鎖可変領域、および配列番号69に記載のCDR1、CDR2、およびCDR3配列を含む軽鎖可変領域、または
(l)配列番号58に記載のCDR1、CDR2、およびCDR3配列を含む重鎖可変領域、および配列番号69に記載のCDR1、CDR2、およびCDR3配列を含む軽鎖可変領域。態様によっては、前記抗Siglec-7抗体はリガンド阻害活性を持ち、かつ/または1価のFabとして測定した場合にKDが約100pM未満であり、かつ/または内部移行活性が約100pM未満である。態様によっては、前記抗Siglec-7抗体は、1価のFabとして測定した場合にKDが約75pM未満である。態様によっては、前記抗Siglec-7抗体は内部移行活性が約70pM以下である。態様によっては、前記抗Siglec-7抗体は内部移行活性が約25pM未満である。
(a)配列番号53に記載のCDR1、CDR2、およびCDR3配列を含む重鎖可変領域、および配列番号78に記載のCDR1、CDR2、およびCDR3配列を含む軽鎖可変領域、
(b)配列番号54に記載のCDR1、CDR2、およびCDR3配列を含む重鎖可変領域、および配列番号78に記載のCDR1、CDR2、およびCDR3配列を含む軽鎖可変領域、
(c)配列番号51に記載のCDR1、CDR2、およびCDR3配列を含む重鎖可変領域、および配列番号78に記載のCDR1、CDR2、およびCDR3配列を含む軽鎖可変領域、
(d)配列番号55に記載のCDR1、CDR2、およびCDR3配列を含む重鎖可変領域、および配列番号78に記載のCDR1、CDR2、およびCDR3配列を含む軽鎖可変領域、
(e)配列番号58に記載のCDR1、CDR2、およびCDR3配列を含む重鎖可変領域、および配列番号78に記載のCDR1、CDR2、およびCDR3配列を含む軽鎖可変領域、または
(f)配列番号59に記載のCDR1、CDR2、およびCDR3配列を含む重鎖可変領域、および配列番号78に記載のCDR1、CDR2、およびCDR3配列を含む軽鎖可変領域。態様によっては、前記抗Siglec-7抗体はリガンド阻害活性を持ち、かつ/または1価のFabとして測定した場合にKDが約100pM未満であり、かつ/または内部移行活性が約100pM未満である。態様によっては、前記抗Siglec-7抗体は1価のFabとして測定した場合にKDが約75pM未満である。態様によっては、前記抗Siglec-7抗体は内部移行活性が約70pM以下である。態様によっては、前記抗Siglec-7抗体は内部移行活性が約25pM未満である。
(a)配列番号43のアミノ酸配列を含む重鎖可変領域、および配列番号69のアミノ酸配列を含む軽鎖可変領域、
(b)配列番号45のアミノ酸配列を含む重鎖可変領域、および配列番号69のアミノ酸配列を含む軽鎖可変領域、
(c)配列番号46のアミノ酸配列を含む重鎖可変領域、および配列番号69のアミノ酸配列を含む軽鎖可変領域、
(d)配列番号47のアミノ酸配列を含む重鎖可変領域、および配列番号69のアミノ酸配列を含む軽鎖可変領域、
(e)配列番号48のアミノ酸配列を含む重鎖可変領域、および配列番号69のアミノ酸配列を含む軽鎖可変領域、
(f)配列番号49のアミノ酸配列を含む重鎖可変領域、および配列番号69のアミノ酸配列を含む軽鎖可変領域、
(g)配列番号50のアミノ酸配列を含む重鎖可変領域、および配列番号69のアミノ酸配列を含む軽鎖可変領域、
(h)配列番号51のアミノ酸配列を含む重鎖可変領域、および配列番号69のアミノ酸配列を含む軽鎖可変領域、
(i)配列番号54のアミノ酸配列を含む重鎖可変領域、および配列番号69のアミノ酸配列を含む軽鎖可変領域、
(j)配列番号55のアミノ酸配列を含む重鎖可変領域、および配列番号69のアミノ酸配列を含む軽鎖可変領域、
(k)配列番号57のアミノ酸配列を含む重鎖可変領域、および配列番号69のアミノ酸配列を含む軽鎖可変領域、または
(l)配列番号58のアミノ酸配列を含む重鎖可変領域、および配列番号69のアミノ酸配列を含む軽鎖可変領域。態様によっては、前記抗Siglec-7抗体はリガンド阻害活性を持ち、かつ/または1価のFabとして測定した場合にKDが約100pM未満であり、かつ/または内部移行活性が約100pM未満である。態様によっては、前記抗Siglec-7抗体は1価のFabとして測定した場合にKDが約75pMである。態様によっては、前記抗Siglec-7抗体は内部移行活性が約70pM以下である。態様によっては、前記抗Siglec-7抗体は内部移行活性が約25pM未満である。
(a)配列番号53のアミノ酸配列を含む重鎖可変領域、および配列番号78のアミノ酸配列を含む軽鎖可変領域、
(b)配列番号54のアミノ酸配列を含む重鎖可変領域、および配列番号78のアミノ酸配列を含む軽鎖可変領域、
(c)配列番号51のアミノ酸配列を含む重鎖可変領域、および配列番号78のアミノ酸配列を含む軽鎖可変領域、
(d)配列番号55のアミノ酸配列を含む重鎖可変領域、および配列番号78のアミノ酸配列を含む軽鎖可変領域、
(e)配列番号58のアミノ酸配列を含む重鎖可変領域、および配列番号78のアミノ酸配列を含む軽鎖可変領域、または
(f)配列番号59のアミノ酸配列を含む重鎖可変領域、および配列番号78のアミノ酸配列を含む軽鎖可変領域。態様によっては、前記抗Siglec-7抗体はリガンド阻害活性を持ち、かつ/または1価のFabとして測定した場合にKDが約100pM未満であり、かつ/または内部移行活性が約100pM未満である。態様によっては、前記抗Siglec-7抗体は1価のFabとして測定した場合にKDが約75pM未満である。態様によっては、前記抗Siglec-7抗体は内部移行活性が約70pM以下である。態様によっては、前記抗Siglec-7抗体は内部移行活性が約25pM未満である。
本明細書に用いられる単数形「a」、「an」、および「the」は特に断りがなければ複数を含む。従って、例えば、「1つの抗体」という場合、そのような分子の2つ以上組み合わせたものを含む場合がある。
1 mllllllpll wgrervegqk snrkdysltm qssvtvqegm cvhvrcsfsy pvdsqtdsdp
61 vhgywfragn diswkapvat nnpawavqee trdrfhllgd pqtknctlsi rdarmsdagr
121 yffrmekgni kwnykydqls vnvtalthrp nilipgtles gcfqnltcsv pwaceqgtpp
181 miswmgtsvs plhpsttrss vltlipqpqh hgtsltcqvt lpgagvttnr tiqlnvsypp
241 qnltvtvfqg egtastalgn ssslsvlegq slrlvcavds npparlswtw rsltlypsqp
301 snplvlelqv hlgdegeftc raqnslgsqh vslnlslqqe ytgkmrpvsg vllgavggag
361 atalvflsfc vifivvrscr kksarpaadv gdigmkdant irgsasqgnl teswaddnpr
421 hhglaahssg eereiqyapl sfhkgepqdl sgqeatnney seikipk(配列番号108)
抗Siglec-7抗体
(a)配列番号43に記載のCDR1、CDR2、およびCDR3配列を含む重鎖可変領域、および配列番号69に記載のCDR1、CDR2、およびCDR3配列を含む軽鎖可変領域、
(b)配列番号45に記載のCDR1、CDR2、およびCDR3配列を含む重鎖可変領域、および配列番号69に記載のCDR1、CDR2、およびCDR3配列を含む軽鎖可変領域、
(c)配列番号46に記載のCDR1、CDR2、およびCDR3配列を含む重鎖可変領域、および配列番号69に記載のCDR1、CDR2、およびCDR3配列を含む軽鎖可変領域、
(d)配列番号47に記載のCDR1、CDR2、およびCDR3配列を含む重鎖可変領域、および配列番号69に記載のCDR1、CDR2、およびCDR3配列を含む軽鎖可変領域、
(e)配列番号48に記載のCDR1、CDR2、およびCDR3配列を含む重鎖可変領域、および配列番号69に記載のCDR1、CDR2、およびCDR3配列を含む軽鎖可変領域、
(f)配列番号49に記載のCDR1、CDR2、およびCDR3配列を含む重鎖可変領域、および配列番号69に記載のCDR1、CDR2、およびCDR3配列を含む軽鎖可変領域、
(g)配列番号50に記載のCDR1、CDR2、およびCDR3配列を含む重鎖可変領域、および配列番号69に記載のCDR1、CDR2、およびCDR3配列を含む軽鎖可変領域、
(h)配列番号51に記載のCDR1、CDR2、およびCDR3配列を含む重鎖可変領域、および配列番号69に記載のCDR1、CDR2、およびCDR3配列を含む軽鎖可変領域、
(i)配列番号54に記載のCDR1、CDR2、およびCDR3配列を含む重鎖可変領域配列、および配列番号69に記載のCDR1、CDR2、およびCDR3配列を含む軽鎖可変領域、
(j)配列番号55に記載のCDR1、CDR2、およびCDR3配列を含む重鎖可変領域、および配列番号69に記載のCDR1、CDR2、およびCDR3配列を含む軽鎖可変領域、
(k)配列番号57に記載のCDR1、CDR2、およびCDR3配列を含む重鎖可変領域、および配列番号69に記載のCDR1、CDR2、およびCDR3配列を含む軽鎖可変領域、または
(l)配列番号58に記載のCDR1、CDR2、およびCDR3配列を含む重鎖可変領域、および配列番号69に記載のCDR1、CDR2、およびCDR3配列を含む軽鎖可変領域。
(a)配列番号53に記載のCDR1、CDR2、およびCDR3配列を含む重鎖可変領域、および配列番号78に記載のCDR1、CDR2、およびCDR3配列を含む軽鎖可変領域、
(b)配列番号54に記載のCDR1、CDR2、およびCDR3配列を含む重鎖可変領域、および配列番号78に記載のCDR1、CDR2、およびCDR3配列を含む軽鎖可変領域、
(c)配列番号51に記載のCDR1、CDR2、およびCDR3配列を含む重鎖可変領域、および配列番号78に記載のCDR1、CDR2、およびCDR3配列を含む軽鎖可変領域、
(d)配列番号55に記載のCDR1、CDR2、およびCDR3配列を含む重鎖可変領域、および配列番号78に記載のCDR1、CDR2、およびCDR3配列を含む軽鎖可変領域、
(e)配列番号58に記載のCDR1、CDR2、およびCDR3配列を含む重鎖可変領域、および配列番号78に記載のCDR1、CDR2、およびCDR3配列を含む軽鎖可変領域、または
(f)配列番号59に記載のCDR1、CDR2、およびCDR3配列を含む重鎖可変領域、および配列番号78に記載のCDR1、CDR2、およびCDR3配列を含む軽鎖可変領域。
Fcの設計
癌の治療
Mylteni GentleMACSを用いて、製造者の指示に従ってヒト一次腫瘍試料に由来する細胞を含む試料を準備した。細胞を蛍光活性化細胞選別により分析して、生存率マーカーとしてCD3、CD8、CD16、CD45、および7-AADを含む免疫細胞表面マーカーを決定した。CD8+T細胞を7-AAD- CD45+ CD3+ CD8+として同定し、ゲートを設定した。抗Siglec-7-PE(クローンS7.7、Biolegend)を用いてSiglec-7濃度を検出した。その結果から、Siglec-7の発現の百分率(図4)と濃度(図5)が腫瘍のサブセットのCD8+腫瘍浸潤性T細胞表面で高くなっていることが判明した。
腫瘍細胞表面のリガンド濃度を評価した。組み換えSiglec-7-Fc融合タンパク質の特異的結合を用いて、新しい一次腫瘍から単離した細胞表面でのSiglec-7リガンドの濃度を評価した。特異性の対照として、0.1U/mLのシアリダーゼ/ノイラミニダーゼ(Roche)で細胞を処理して、細胞表面からシアル酸を取り除いた。その結果から、Siglec-7リガンドが腫瘍の様々なサブセットに由来する腫瘍細胞の表面で検出されたことが判明した(図6)。細胞のシアリダーゼ処理(すなわち、細胞膜からのシアログリカンの「剥ぎ取り」)により、結合が取り除かれた。
Siglec-7への結合に関して抗体群を評価した。その結果から、市販の抗Siglec-7抗体に比べてKD値が向上した抗Siglec-7抗体が確認された(図7)。
濃度を高めた抗Siglec-7抗体の存在下、組換えSiglec-7-FcをA375細胞に加えて、細胞表面での複合体の結合を検出した。その結果から、抗Siglec-7抗体は、Siglec-7と様々な能力を持つA375ヒトメラノーマ細胞の表面に存在するリガンドとの相互作用を阻害することが判明した(図8)。また、この抗体は市販の抗Siglec-7抗体に対してリガンド阻害活性が向上していることが判明した。
抗Siglec-7抗体の濃度を高めて、一次ヒト末梢血単核球(PBMC)を24時間インキュベートし、競合しない抗Siglec-7抗体を用いてNK細胞の細胞表面に残留したSiglec-7を検出した。その結果から、抗Siglec-7抗体が様々な能力を持つ一次ヒトNK細胞表面のSiglec-7を内部移行させた(図9)ことが判明した。またこの抗体は、市販あるいは上記の抗Siglec-7抗体に比べて内部移行活性が向上していたことが判明した。モノクローナル抗体3F1を用いてヒトNK細胞表面のSiglec-7の素早い濃度依存性の抗体誘導内部移行を評価した。3F1は、市販のS7.7抗体に比べてより能力の高い内部移行活性を示した(図10)。
モノクローナル抗体16H11および8A2を用いてヒト化抗体を生成し、ヒト化内部移行抗Siglec7抗体を生成した。
KDの測定
Fortebioを用いた抗体競合
リガンド阻害アッセイ
内部移行アッセイ
一次腫瘍分析
配列番号15 軽鎖可変領域配列(16H11);下線部はKabatおよびChothiaの両方に規定されたCDR
DIQMTQSPASLSASVGETVTITCRASGNIHNYLAWFQQKQGKSPHFLVYSAKALADGVPSRFSGSGSGTQYSLKINSLQPEDFGTYYCQHFWSSPYTFGGGTKLEIK
配列番号16 軽鎖可変領域配列(2G12);下線部はKabatおよびChothiaの両方に規定されたCDR
DIVLTQSHKFMSTSVGDRVTITCKASQDVSTAVAWYQQKPGQSPKLLIYWTSTRHTGVPDRFTGSGSGTDHTLT
配列番号18 軽鎖可変領域配列(8A2);下線部はKabatおよびChothiaの両方に規定されたCDR
QIVLTQSPAIMSASPGEKVTMTCSASSRVIFMYWYQQKPGSSPRLLIYDTSNLASGVPVRFSGGGSGTSYSLTISRMEAEDAATYYCQQWSSYPPTFGAGTKLELK
配列番号17 軽鎖可変領域配列(5D1);下線部はKabatおよびChothiaの両方に規定されたCDR
DIQMTQTTSSLSASLGDRVTIICRASQDISNFLNWYQQKPDGTVKLLMYDTSILQSGVPSRFSGRGSGADYSLTINNLEQEDLATYFCQQGKTLPYTFGGGTKLEIK
配列番号25 軽鎖可変領域配列(4B12);下線部はKabatおよびChothiaの両方に規定されたCDR
DIVMTQSQKFMSTSVGDRVSVTCKASQNVGTNVAWYQQKPGQSPKAVIYSASYRNSGVPDRFTGSGSGTDFTLTISNVQSEDLTEYFCQQYNNYPYTFGGGTKLEIK
配列番号29~78 16A11由来のヒト化可変領域配列:
配列番号29 ヒト化VH領域386-1アミノ酸配列;下線部はChothiaに規定されたCDR
QVQLVQSGAEVKKPGSSVKVSCKASGYDFSNFWISWVRQAPGQGLEWMGGIYPGDGEINYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARDDYLRAMDYWGQGTLVTVSS
配列番号30 ヒト化VH領域392-3アミノ酸配列;下線部はChothiaに規定されたCDR
QVQLVQSGAEVKKPGSSVKVSCKASGYTFSNFWISWVRQAPGQGLEWMGGIYPGDGEINYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARDDYLRAMDYWGQGTLVTVSS
配列番号31 ヒト化VH領域392-4アミノ酸配列;下線部はChothiaに規定されたCDR
QVQLVQSGAEVKKPGSSVKVSCKASGGDFSNFWISWVRQAPGQGLEWMGGIYPGDGEINYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARDDYLRAMDYWGQGTLVTVSS
配列番号32 ヒト化VH領域393-4アミノ酸配列;下線部はChothiaに規定されたCDR
QVQLVQSGAEVKKPGSSVKVSCKASGYDFSNFWISWVRQAPGQGLEWMGGIIPGDGEINYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARDDYLRAMDYWGQGTLVTVSS
配列番号33 ヒト化VH領域393-8アミノ酸配列;下線部はChothiaに規定されたCDR
QVQLVQSGAEVKKPGSSVKVSCKASGYDFSNFWISWVRQAPGQGLEWMGGIYPIDGEINYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARDDYLRAMDYWGQGTLVTVSS
配列番号34 ヒト化VH領域394-2アミノ酸配列;下線部はChothiaに規定されたCDR
QVQLVQSGAEVKKPGSSVKVSCKASGYDFSNFWISWVRQAPGQGLEWMGGIYPGDGTINYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARDDYLRAMDYWGQGTLVTVSS
配列番号35 ヒト化VH領域394-4アミノ酸配列;下線部はChothiaに規定されたCDR
QVQLVQSGAEVKKPGSSVKVSCKASGYDFSNFWISWVRQAPGQGLEWMGGIYPGDGEANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARDDYLRAMDYWGQGTLVTVSS
配列番号36 ヒト化VH領域400-5アミノ酸配列;下線部はChothiaに規定されたCDR
QVQLVQSGAEVKKPGSSVKVSCKASGYDFSSYAISWVRQAPGQGLEWMGGIYPGDGEINYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARDDYLRAMDYWGQGTLVTVSS
配列番号37 ヒト化VH領域400-7アミノ酸配列;下線部はChothiaに規定されたCDR
QVQLVQSGAEVKKPGSSVKVSCKASGYDFSSFWISWVRQAPGQGLEWMGGIYPGDGEINYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARDDYLRAMDYWGQGTLVTVSS
配列番号38 ヒト化VH領域400-9アミノ酸配列;下線部はChothiaに規定されたCDR
QVQLVQSGAEVKKPGSSVKVSCKASGYDFSSYWISWVRQAPGQGLEWMGGIYPGDGEINYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARDDYLRAMDYWGQGTLVTVSS
配列番号39 ヒト化VH領域400-14アミノ酸配列;下線部はChothiaに規定されたCDR
QVQLVQSGAEVKKPGSSVKVSCKASGYDFSNYAISWVRQAPGQGLEWMGGIYPGDGEINYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARDDYLRAMDYWGQGTLVTVSS
配列番号40 ヒト化VH領域401-1アミノ酸配列;下線部はChothiaに規定されたCDR
QVQLVQSGAEVKKPGSSVKVSCKASGYDFSNFWISWVRQAPGQGLEWMGGIYPGFGEINYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARDDYLRAMDYWGQGTLVTVSS
配列番号41 ヒト化VH領域417-8アミノ酸配列;下線部はChothiaに規定されたCDR
QVQLVQSGAEVKKPGSSVKVSCKASGYDFSNFWMNWVRQAPGQGLEWMGGIYPGDGEINYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARDDYLRAMDVWGQGTMVTVSS
配列番号42 ヒト化VH領域417-17 アミノ酸配列;下線部はChothiaに規定されたCDR
QVQLVQSGAEVKKPGSSVKVSCKASGYDFSNFWMNWVRQAPGQGLEWMGGIYPGDGEINYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARDDYLRAMDIWGQGTMVTVSS
配列番号43 ヒト化VH領域387-11アミノ酸配列;下線部はChothiaに規定されたCDR
QVQLVQSGAEVKKPGSSVKVSCKGSGYDFSNFWMNWVRQAPGQGLEWMGQIYPGDGEIKYNQKFQGRVTLTADESTSTAYMELSSLRSEDTAVYFCARDDYLRAMDYWGQGTLVTVSS
配列番号44 ヒト化VH領域410-1アミノ酸配列;下線部はChothiaに規定されたCDR
QVQLVQSGAEVKKPGSSVKVSCKASGYDFSNFWMNWVRQAPGQGLEWMGGIYPGDGEINYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARDDYLRAMDYWGQGTLVTVSS
配列番号45 ヒト化VH領域438-4アミノ酸配列;下線部はChothiaに規定されたCDR
QVQLVQSGAEVKKPGSSVKVSCKASGYDFSNFWMNWVRQAPGQGLEWMGQIYPGDGEIKYNQKFQGRVTLTADESTSTAYMELSSLRSEDTAVYFCARDDYLRAMDYWGQGTLVTVSS
配列番号46 ヒト化VH領域440-2アミノ酸配列;下線部はChothiaに規定されたCDR
QVQLVQSGAEVKKPGSSVKVSCKGSGYDFSNFWMNWVRQAPGQGLEWMGQIYPGDGEIKYNQKFQGRVTITADESTSTAYMELSSLRSEDTAVYFCARDDYLRAMDYWGQGTLVTVSS
配列番号47 ヒト化VH領域441-2アミノ酸配列;下線部はChothiaに規定されたCDR
QVQLVQSGAEVKKPGSSVKVSCKGSGYDFSNFWMNWVRQAPGQGLEWMGQIYPGDGEIKYNQKFQGRVTLTADESTSTAYMELSSLRSEDTAVYYCARDDYLRAMDIWGQGTMVTVSS
配列番号48 ヒト化VH領域443-1アミノ酸配列;下線部はChothiaに規定されたCDR
QVQLVQSGAEVKKPGSSVKVSCKGSGYDFSNFWMNWVRQAPGQGLEWMGQIYPGDGEIKYNQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARDDYLRAMDIWGQGTMVTVSS
配列番号49 ヒト化VH領域444-2アミノ酸配列;下線部はChothiaに規定されたCDR
QVQLVQSGAEVKKPGSSVKVSCKASGYDFSNFWMNWVRQAPGQGLEWMGQIYPGDGEIKYNQKFQGRVTITADESTSTAYMELSSLRSEDTAVYFCARDDYLRAMDYWGQGTLVTVSS
配列番号50 ヒト化VH領域445-3アミノ酸配列;下線部はChothiaに規定されたCDR
QVQLVQSGAEVKKPGSSVKVSCKASGYDFSNFWMNWVRQAPGQGLEWMGQIYPGDGEIKYNQKFQGRVTLTADESTSTAYMELSSLRSEDTAVYYCARDDYLRAMDIWGQGTMVTVSS
配列番号51 ヒト化VH領域446-7アミノ酸配列;下線部はChothiaに規定されたCDR
QVQLVQSGAEVKKPGSSVKVSCKASGYDFSNFWMNWVRQAPGQGLEWMGQIYPGDGEIKYNQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARDDYLRAMDIWGQGTMVTVSS
配列番号52 ヒト化VH領域447-2アミノ酸配列;下線部はChothiaに規定されたCDR
QVQLVQSGAEVKKPGSSVKVSCKASGYDFSNFWMNWVRQAPGQGLEWMGQIYPGDGEINYNQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARDDYLRAMDIWGQGTMVTVSS
配列番号53 ヒト化VH領域449-4アミノ酸配列;下線部はChothiaに規定されたCDR
QVQLVQSGAEVKKPGSSVKVSCKASGYDFSNFWMNWVRQAPGQGLEWMGGIYPGDGEIKYNQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARDDYLRAMDIWGQGTMVTVSS
配列番号54 ヒト化VH領域449-6アミノ酸配列;下線部はChothiaに規定されたCDR
QVQLVQSGAEVKKPGSSVKVSCKGSGYDFSNFWMNWVRQAPGQGLEWMGGIYPGDGEIKYNQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARDDYLRAMDIWGQGTMVTVSS
配列番号55 ヒト化VH領域463-2アミノ酸配列;下線部はChothiaに規定されたCDR
QVQLVQSGAEVKKPGSSVKVSCKASGYDFSNFWMNWVRQAPGQGLEWMGQIYPGDGEIKYNQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARDDYLRAMDYWGQGTLVTVSS
配列番号56 ヒト化VH領域465-2アミノ酸配列;下線部はChothiaに規定されたCDR
QVQLVQSGAEVKKPGSSVKVSCKASGYDFSNFWMNWVRQAPGQGLEWMGQIYPGDGEINYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARDDYLRAMDIWGQGTMVTVSS
配列番号57 ヒト化VH領域465-17アミノ酸配列;下線部はChothiaに規定されたCDR
QVQLVQSGAEVKKPGSSVKVSCKASGYDFSNFWMNWVRQAPGQGLEWMGQIYPGDGEIKYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARDDYLRAMDIWGQGTMVTVSS
配列番号58 ヒト化VH領域484-6アミノ酸配列;下線部はChothiaに規定されたCDR
QVQLVQSGAEVKKPGSSVKVSCKASGYDFSNYWMNWVRQAPGQGLEWMGQIYPGDGEIKYNQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARDDYLRAMDIWGQGTMVTVSS
配列番号59 ヒト化VH領域484-7アミノ酸配列;下線部はChothiaに規定されたCDR
QVQLVQSGAEVKKPGSSVKVSCKASGYDFSNYWMNWVRQAPGQGLEWMGQIYPGDGEIKYNQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARDDYLRAMDYWGQGTLVTVSS
配列番号60 ヒト化VH領域485-4アミノ酸配列;下線部はChothiaに規定されたCDR
QVQLVQSGAEVKKPGSSVKVSCKASGYDFSNFAMNWVRQAPGQGLEWMGQIYPGDGEIKYNQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARDDYLRAMDYWGQGTLVTVSS
配列番号61 ヒト化VH領域485-5アミノ酸配列;下線部はChothiaに規定されたCDR
QVQLVQSGAEVKKPGSSVKVSCKASGYDFSNFAMNWVRQAPGQGLEWMGQIYPGDGEIKYNQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARDDYLRAMDIWGQGTMVTVSS
配列番号62 ヒト化VL領域381-1アミノ酸配列;下線部はChothiaに規定されたCDR
DIQMTQSPSSLSASVGDRVTITCRASGNIHNYLAWYQQKPGKAPKLLLYSAKRLESGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQHFWSSPYTFGGGTKVEIK
配列番号63 ヒト化VL領域390-8アミノ酸配列;下線部はChothiaに規定されたCDR
DIQMTQSPSSLSASVGDRVTITCRASGNIHNSLAWYQQKPGKAPKLLLYSAKRLESGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQHFWSSPYTFGGGTKVEIK
配列番号64 ヒト化VL領域391-1アミノ酸配列;下線部はChothiaに規定されたCDR
DIQMTQSPSSLSASVGDRVTITCRASGNIHNYLAWYQQKPGKAPKLLLYAASRLESGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQHFWSSPYTFGGGTKVEIK
配列番号65 ヒト化VL領域391-8アミノ酸配列;下線部はChothiaに規定されたCDR
DIQMTQSPSSLSASVGDRVTITCRASGNIHNYLAWYQQKPGKAPKLLLYSASRLESGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQHFWSSPYTFGGGTKVEIK
配列番号66 ヒト化VL領域395-1アミノ酸配列;下線部はChothiaに規定されたCDR
DIQMTQSPSSLSASVGDRVTITCRASGGIHNYLAWYQQKPGKAPKLLLYSAKRLESGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQHFWSSPYTFGGGTKVEIK
配列番号67 ヒト化VL領域395-4アミノ酸配列;下線部はChothiaに規定されたCDR
DIQMTQSPSSLSASVGDRVTITCRASQNIHNYLAWYQQKPGKAPKLLLYSAKRLESGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQHFWSSPYTFGGGTKVEIK
配列番号68 ヒト化VL領域396-2アミノ酸配列;下線部はChothiaに規定されたCDR
DIQMTQSPSSLSASVGDRVTITCRASGNISNYLAWYQQKPGKAPKLLLYSAKRLESGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQHFWSSPYTFGGGTKVEIK
配列番号69 ヒト化VL領域418-2アミノ酸配列;下線部はChothiaに規定されたCDR
DIQMTQSPSSLSASVGDRVTITCRASGNIHNYLAWYQQKPGKAPKFLLYSAKRLESGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQHFWSSPYTFGGGTKVEIK
配列番号70 ヒト化VL領域419-2アミノ酸配列;下線部はChothiaに規定されたCDR
DIQMTQSPSSLSASVGDRVTITCRASQNIHNYLAWYQQKPGKAPKFLLYSAKRLESGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQHFWSSPYTFGGGTKVEIK
配列番号71 ヒト化VL領域421-3アミノ酸配列;下線部はChothiaに規定されたCDR
DIQMTQSPSSLSASVGDRVTITCRASGNIHNYLAWYQQKPGKAPKFLLYSAKRLESGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQHFWSSPYTFGQGTKLEIK
配列番号72 ヒト化VL領域424-1アミノ酸配列;下線部はChothiaに規定されたCDR
DIQMTQSPSSLSASVGDRVTITCRASGNIHNYLAWYQQKPGKAPKLLLYSAKRLASGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQHFWSSPYTFGGGTKVEIK
配列番号73 ヒト化VL領域425-3アミノ酸配列;下線部はChothiaに規定されたCDR
DIQMTQSPSSLSASVGDRVTITCRASGNIHNYLAWYQQKPGKAPKLLLYSAKRLEDGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQHFWSSPYTFGGGTKVEIK
配列番号74 ヒト化VL領域426-2アミノ酸配列;下線部はChothiaに規定されたCDR
DIQMTQSPSSLSASVGDRVTITCRASQNIHNYLAWYQQKPGKAPKLLLYSAKRLASGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQHFWSSPYTFGGGTKVEIK
配列番号75 ヒト化VL領域427-1アミノ酸配列;下線部はChothiaに規定されたCDR
DIQMTQSPSSLSASVGDRVTITCRASQNIHNYLAWYQQKPGKAPKLLLYSAKRLEDGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQHFWSSPYTFGGGTKVEIK
配列番号76 ヒト化VL領域435-7アミノ酸配列;下線部はChothiaに規定されたCDR
DIQMTQSPSSLSASVGDRVTITCRASQNIHNYLAWYQQKPGKAPKFLLYSAKRLEDGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQHFWSSPYTFGGGTKVEIK
配列番号77 ヒト化VL領域439-5アミノ酸配列
DIQMTQSPSSLSASVGDRVTITCRASQNIHNYLAWYQQKPGKAPKFLLYSAKRLEDGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQHFWSSPYTFGQGTKLEIK
配列番号78 ヒト化VL領域448-3アミノ酸配列
DIQMTQSPSSLSASVGDRVTITCRASQNIHNYLAWYQQKPGKAPKFLLYSAKRLESGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQHFWSSPYTFGQGTKLEIK
配列番号104~107 8A2由来のヒト化可変領域配列:
配列番号104 ヒト化重鎖可変領域配列RHA;下線部はChothiaに規定されたCDR
QVQLQESGPGLVKPSETLSLTCTVSGFSLTTYGWSWIRQPPGKGLEWIGYIWGGGNTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCAKHKGTSHAMEYWGQGTMVTVSS
配列番号105:ヒト化軽鎖可変領域配列RKA;下線部はChothiaに規定されたCDR
EIVLTQSPATLSLSPGERATLSCRASSRVIFLAWYQQKPGQAPRLLIYDTSNKATGVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQWSSYPPTFGGGTKVEIK
配列番号106 ヒト化重鎖可変領域配列RHB;下線部はChothiaに規定されたCDR
QVQLQESGPGLVKPSETLSLTCTVSGFSLTTYGVDWVRQPPGKGLEWIGVIWGGGNTNYNSSLKSRVTISKDTSKNQVFLKLSSVTAADTAVYYCAKHKGTSHAMEYWGQGTMVTVSS
配列番号107 ヒト化軽鎖可変領域配列RKB;下線部はChothiaに規定されたCDR
QIVLTQSPATLSLSPGERATLSCRASSRVIFMYWYQQKPGQSPRLLIYDTSNLATGVPARFSGGGSGTDYTLTISSLEPEDFAVYYCQQWSSYPPTFGGGTKVEIK
Claims (15)
- Siglec-7に結合する抗Siglec-7抗体であって、以下:
以下:
HCDR1配列GYDFSNF(配列番号79)又は変異HCDR1配列GYDFSNY(配列番号89);
HCDR2配列YPGDGE(配列番号:80);
HCDR3配列DDYLRAMDY(配列番号:81)又は変異HCDR3配列DDYLRAMDV(配列番号:91)若しくはDDYLRAMDI(配列番号:92);
を含む重鎖可変領域、及び
以下:
LCDR1配列RASGNIHNYLA(配列番号:93)又は変異LCDR1配列RASQNIHNYLA(配列番号:100);
LCDR2配列SAKALAD又は変異LCDR2配列SAKRLES(配列番号:94)、又はSAKRLED(配列番号:103);及び
LCDR3配列QHFWSSPYT(配列番号:95)
を含む軽鎖可変領域、
を含む、抗Siglec-7抗体。 - 前記抗体が、以下:
HCDR1配列GYDFSNF(配列番号:79)又はGYDFSNY(配列番号:89);
HCDR2配列YPGDGE(配列番号:80);
HCDR3配列DDYLRAMDY(配列番号:81)又はDDYLRAMDI(配列番号:92);
LCDR1配列RASGNIHNYLA(配列番号:93)又はRASQNIHNYLA(配列番号:100);
LCDR2配列SAKRLES(配列番号:94);及び
LCDR3配列QHFWSSPYT(配列番号:95);
を含む、請求項1に記載の抗Siglec-7抗体。 - 前記抗体が、以下:
a)HCDR1配列GYDFSNF(配列番号:79),
HCDR2配列YPGDGE(配列番号:80),及び
HCDR3配列DDYLRAMDY(配列番号:81);
を含む重鎖可変領域、及び以下:
LCDR1配列RASGNIHNYLA(配列番号:93),
LCDR2配列SAKRLES(配列番号:94),及び
LCDR3配列QHFWSSPYT(配列番号:95);
を含む軽鎖可変領域;
b)HCDR1配列GYDFSNF(配列番号:79),
HCDR2配列YPGDGE(配列番号:80),及び
HCDR3配列DDYLRAMDI(配列番号:92);
を含む重鎖可変領域、及び以下:
LCDR1配列RASGNIHNYLA(配列番号:93),
LCDR2配列SAKRLES(配列番号:94), 及び
LCDR3配列QHFWSSPYT(配列番号:95) ;
を含む軽鎖可変領域;
c)HCDR1配列GYDFSNY(配列番号89),
HCDR2配列YPGDGE(配列番号:80), 及び
HCDR3配列DDYLRAMDI(配列番号:92);
を含む重鎖可変領域、及び以下:
LCDR1配列RASGNIHNYLA(配列番号:93),
LCDR2配列SAKRLES(配列番号:94), 及び
LCDR3配列QHFWSSPYT(配列番号:95);
を含む軽鎖可変領域;又は
(d)HCDR1配列GYDFSNY(配列番号:89),
HCDR2配列YPGDGE(配列番号:80),及び
HCDR3配列DDYLRAMDY(配列番号:81);
を含む重鎖可変領域、及び以下:
LCDR1配列RASGNIHNYLA(配列番号:93),
LCDR2配列SAKRLES(配列番号:94), 及び
LCDR3配列QHFWSSPYT(配列番号:95);
を含む軽鎖可変領域;
を含む、請求項2に記載の抗Siglec-7抗体。 - 前記抗体が、以下:
a)HCDR1配列GYDFSNF(配列番号:79),
HCDR2配列YPGDGE(配列番号:80),及び
HCDR3配列DDYLRAMDI(配列番号:92) ;
を含む重鎖可変領域、及び以下:
LCDR1配列RASQNIHNYLA(配列番号:100),
LCDR2配列SAKRLES(配列番号:94),及び
LCDR3配列QHFWSSPYT(配列番号:95) ;
を含む軽鎖可変領域;
b)HCDR1配列GYDFSNY(配列番号:89),
HCDR2配列YPGDGE(配列番号:80),及び
HCDR3配列DDYLRAMDY(配列番号:81) ;
を含む重鎖可変領域、及び以下:
LCDR1配列RASQNIHNYLA(配列番号:100),
LCDR2配列SAKRLES(配列番号:94),及び
LCDR3配列QHFWSSPYT(配列番号:95) ;
を含む軽鎖可変領域;
(c)HCDR1配列GYDFSNY(配列番号:89),
HCDR2配列YPGDGE(配列番号:80),及び
HCDR3配列DDYLRAMDI(配列番号:92) ;
を含む重鎖可変領域、及び以下:
LCDR1配列RASQNIHNYLA(配列番号:100),
LCDR2配列SAKRLES(配列番号:94),及び
LCDR3配列QHFWSSPYT(配列番号:95) ;
を含む軽鎖可変領域;又は
(d)HCDR1配列GYDFSNF(配列番号:79),
HCDR2配列YPGDGE(配列番号:80),及び
HCDR3配列DDYLRAMDY(配列番号:81) ;
を含む重鎖可変領域、及び以下:
LCDR1配列RASQNIHNYLA(配列番号:100),
LCDR2配列SAKRLES(配列番号:94),及び
LCDR3配列QHFWSSPYT(配列番号:95) ;
を含む軽鎖可変領域;
を含む、請求項2に記載の抗Siglec-7抗体。 - Siglec-7に結合する抗Siglec-7抗体であって、当該抗体が、以下:
配列番号41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 57, 58,又は59のいずれか1つのアミノ酸配列と、CDRにおいて100%、それ以外の領域において90%以上の同一性を有する重鎖可変領域;及び
配列番号69, 70, 71, 76, 77,又は78のいずれか1つのアミノ酸配列と、CDRにおいて100%、それ以外の領域において90%以上の同一性を有する軽鎖可変領域;
を含む、抗Siglec-7抗体。 - 前記抗体が、以下:
配列番号41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 57, 58,又は59のいずれか1つのアミノ酸配列を含む重鎖可変領域;及び
配列番号69, 70, 71, 76, 77,又は78のいずれか1つのアミノ酸配列を含む軽鎖可変領域;
を含む、請求項5に記載の抗Siglec-7抗体。 - 前記抗体が、以下:
配列番号43, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 57, 58,又は59のいずれか1つのアミノ酸配列と、CDRにおいて100%、それ以外の領域において90%以上の同一性を有する重鎖可変領域;及び
配列番号69,又は78のいずれか1つのアミノ酸配列と、CDRにおいて100%、それ以外の領域において90%以上の同一性を有する軽鎖可変領域;
を含む、請求項5に記載の抗Siglec-7抗体。 - 前記抗体が、以下:
配列番号43, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 57, 58,又は59のいずれか1つのアミノ酸配列を含む重鎖可変領域;及び
配列番号69又は78のいずれか1つのアミノ酸配列を含む軽鎖可変領域;
を含む、請求項7に記載の抗Siglec-7抗体。 - 前記抗体が、以下:
配列番号43, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 57,又は58のいずれか1つのアミノ酸配列を含む重鎖可変領域;及び
配列番号69のアミノ酸配列を含む軽鎖可変領域;
を含む、請求項8に記載の抗Siglec-7抗体。 - 前記抗体が、以下:
配列番号51, 52, 54, 55, 57, 58,又は59のいずれか1つのアミノ酸配列を含む重鎖可変領域;及び
配列番号78のアミノ酸配列を含む軽鎖可変領域;
を含む、請求項8に記載の抗Siglec-7抗体。 - 前記抗体が、以下:
(a)配列番号55のアミノ酸配列を含む重鎖可変領域、及び配列番号69のアミノ酸配列を含む軽鎖可変領域;
(b)配列番号57のアミノ酸配列を含む重鎖可変領域、及び配列番号69のアミノ酸配列を含む軽鎖可変領域;
(c)配列番号59のアミノ酸配列を含む重鎖可変領域、及び配列番号78のアミノ酸配列を含む軽鎖可変領域;
を含む、請求項8に記載の抗Siglec-7抗体。 - 前記抗体が:
(a)一価フォームである;
(b)多価Fabフォームである;又は
(c)IgGである;
請求項1~11のいずれか1項に記載の抗Siglec-7抗体。 - 請求項1~11のいずれか1項に記載の抗Siglec-7抗体を含む、二重特異性又は多重特異性抗体。
- シアル化Siglec-7リガンドを発現する腫瘍の治療のための、請求項1~12のいずれか1項に記載の抗体、又は請求項13に記載の二重特異性又は多重特異性抗体を含有する医薬組成物。
- 前記腫瘍が、Siglec-7を発現するCD8+浸潤T細胞の数が増大したものである、請求項14に記載の医薬組成物。
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SG10202107880XA (en) | 2017-05-12 | 2021-09-29 | Harpoon Therapeutics Inc | Mesothelin binding proteins |
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EP3737410A4 (en) * | 2018-01-11 | 2022-04-20 | Allakos, Inc. | ANTI-SIGLEC-7 ANTIBODIES WITH REDUCED EFFECTOR FUNCTION |
KR20210086623A (ko) | 2018-09-25 | 2021-07-08 | 하푼 테라퓨틱스, 인크. | Ddl3 결합 단백질 및 사용 방법 |
WO2021024020A1 (en) | 2019-08-06 | 2021-02-11 | Astellas Pharma Inc. | Combination therapy involving antibodies against claudin 18.2 and immune checkpoint inhibitors for treatment of cancer |
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WO2022135666A1 (en) | 2020-12-21 | 2022-06-30 | BioNTech SE | Treatment schedule for cytokine proteins |
TW202245808A (zh) | 2020-12-21 | 2022-12-01 | 德商拜恩迪克公司 | 用於治療癌症之治療性rna |
WO2022135667A1 (en) | 2020-12-21 | 2022-06-30 | BioNTech SE | Therapeutic rna for treating cancer |
CA3225254A1 (en) | 2021-07-13 | 2023-01-19 | BioNTech SE | Multispecific binding agents against cd40 and cd137 in combination therapy for cancer |
TW202333802A (zh) | 2021-10-11 | 2023-09-01 | 德商拜恩迪克公司 | 用於肺癌之治療性rna(二) |
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