JP2023510733A - 免疫細胞関与効果を調節するための手段および方法 - Google Patents
免疫細胞関与効果を調節するための手段および方法 Download PDFInfo
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Abstract
Description
本明細書に記載の多価抗体と第2の結合分子との組み合わせは、多価抗体単独の投与とは対照的に、多価抗体のオフタ-ゲット効果が第2の結合分子と組み合わせて投与される場合に軽減される、より大きな治療ウィンドウを提供する。
参照の容易さのために、本明細書における本発明の多価抗体を説明する場合、以下の形式を使用する:TA1=IEAxTA2は、腫瘍関連抗原1結合ドメイン(TA1)、リンカ-(=)、腫瘍関連抗原2結合ドメイン(TA2)を用いて二量体化(x)された免疫細胞関与抗原結合ドメイン(IEA)を表し、そのため、TA1=IEAが「長いア-ム」を構成し、一方、xは二量体化を示し、続いて、多価抗体の「短いア-ム」を指定するTA2を示す。多価抗体が共通の軽鎖を含む場合、対応するVH領域は以下の通りである:TA1(VH1)=IEA(VH2)xTA2(VH3)。
1:ESKYGPP(配列番号69)、
2:EPKSCDKTHT(配列番号70)、
3:GGGGSGGGGS(配列番号71)、
4:ERKSSVESPPSP配列番号72)、
5:ERKCSVESPPSP(配列番号73)、
6:ELKTPLGDTTHT(配列番号74)、
7:ESKYGPPSPSSP(配列番号75)、
8:ERKSSVEAPPVAG(配列番号76)、
9:ERKCSVEAPPVAG(配列番号77)、
10:ESKYGPPAPEFLGG(配列番号78)、
11:EPKSCDKTHTSPPSP(配列番号79)、
12:EPKSCDGGGGSGGGGS(配列番号80)、
13:GGGGSGGGGSAPPVAG(配列番号81)、
14:EPKSCDKTHTAPELLGG(配列番号82)、
15:ERKSSVESPPSPAPPVAG(配列番号83)、
16:ERKCSVESPPSPAPPVAG(配列番号84)、
17:ELKTPLGDTTHTAPEFLGG(配列番号85)、
18:ESKYGPPSPSSPAPEFLGG(配列番号86)、
19:EPKSCDKTHTSPPSPAPELLGG(配列番号87)、
20:ERKSSVEEAAAKEAAAKAPPVAG(配列番号88)、
21:ERKCSVEEAAAKEAAAKAPPVAG(配列番号89)、
22:ESKYGPPEAAAKEAAAKAPEFLGG(配列番号90)、
23:EPKSCDKTHTEAAAKEAAAKAPELLGG(配列番号91)、
24:ELKTPLGDTTHTEAAAKEAAAKAPEFLGG(配列番号92)、
またはそれらのいずれか1つに対して少なくとも約85%の配列同一性を有する配列。
-それを必要とする対象に、本明細書に記載される多価抗体を投与すること、および対象に、本明細書に記載される第2の結合分子を追加で投与すること、
-それを必要とする対象に、本明細書に記載される組成物を投与すること、
-それを必要とする対象に、本明細書に記載される治療用組成物を投与すること、または
-それを必要とする対象に、本明細書に記載される薬学的組成物を投与することを含む。
細胞および細胞株
HCT116(ECACC91091005)は、ヒト結腸がん細胞株である。BxPC3(BxPC-3 ATCC(登録商標)CRL-1687)は、ヒト膵臓がん細胞である。BxPC3細胞は、比較的高レベルのEGFRおよびPD-L1を発現するが、HCT116は、より低レベルのEGFRおよびPD-L1を発現する。
本明細書で調製される多価抗体は、図1に示される一般的な構造を有する2つの重鎖を有する三重特異性抗体である。
Hek293細胞を、配列番号47を有する重鎖および配列番号98を有する軽鎖を含む三重特異性抗体および単一特異性PD-L1抗体の発現に使用した。トランスフェクションの2日前に、Hek293細胞ストックを1:1の比率で293培地に分割し、155rpmの軌道振盪速度で、37℃および8% CO2で一晩インキュベ-トした。細胞を、トランスフェクションの前日に、5×10e5細胞/mLの密度に希釈した。懸濁細胞をプレ-トに播種し、通気性シ-ルで覆い、285rpmの軌道振盪速度で、37℃および8% CO2で一晩インキュベ-トした。トランスフェクションの日に、293-F培養培地をポリエチレンイミン(PEI)直鎖状(MW 25,000)と混合した。産生される各IgGについて、293F培養培地-PEIミックスを、それぞれの発現ベクタ-DNA(IgGヘテロ二量体については、各重鎖をコ-ドするDNA)に添加した。混合物を室温で20分間インキュベ-トした後、穏やかに細胞に添加した。トランスフェクションの翌日、293-F培地で希釈したペニシリン-ストレプトマイシン(Pen Strep)を各培養物に添加した。培養物を、トランスフェクションの7日後の採取まで、285rpmの軌道振盪速度で、37℃および8% CO2でインキュベ-トした。培養物を5分間、500gで遠心分離し、IgGを含有する上清を、10~12μmのメルトブロ-ポリプロピレンフィルタ-プレ-トを使用して濾過し、精製前に-20℃で保管した。
BxPC3およびHCT116細胞株を使用して、T細胞媒介性細胞殺滅活性を測定する。
殺滅率=(100-(RLU試料/RLU IgGなし)×100)。
1.組成物であって、第1の腫瘍抗原(TA1)に結合する第1の可変ドメイン、第2の腫瘍抗原(TA2)に結合する第2の可変ドメイン、および免疫細胞関与抗原(IEA)に結合する第3の可変ドメインを含む多価抗体を含み、組成物が、TA1またはTA2に結合する第2の結合分子をさらに含む、組成物。
2.免疫細胞関与抗原(IEA)に結合する第3の可変ドメイン、および第2の腫瘍抗原(TA2)に結合する第2の可変ドメインが、Fc領域と関連し、第1の腫瘍抗原(TA1)に結合する第1の可変ドメインが、免疫細胞関与抗原(IEA)に結合する第3の可変ドメインに連結される、態様1に記載の組成物。
3.免疫細胞関与抗原(IEA)に結合する第3の可変ドメイン、および第1の腫瘍抗原(TA1)に結合する第1の可変ドメインが、Fc領域と関連し、第2の腫瘍抗原(TA2)に結合する第2の可変ドメインが、免疫細胞関与抗原(IEA)に結合する第3の可変ドメインに連結される、態様1に記載の組成物。
4.第1、第2、および/または第3の可変ドメインが、共通の軽鎖可変領域を含む、態様1~3のいずれか一項に記載の組成物。
5.免疫細胞関与抗原に結合する可変ドメインが、CD3、TCR-α鎖、TCR-β鎖、CD2、CD4、CD5、CD7、CD8、CD137、CD28、CD16、CD16A、CD64、OX40、CD27、CD40、ICOS、GITR、NKG2D、NKp46、NKp44、またはNKp30、好ましくはCD3、TCR-α鎖、TCR-β鎖、CD2、またはCD5、より好ましくはCD3に結合する、態様1~4のいずれか一項に記載の組成物。
6.第1の腫瘍関連抗原(TA1)に結合する可変ドメインが、PD-L1、PD-L2、HVEM、CD47、B7-H3、B7-H4、B7-H7、またはSiglec-15、好ましくはPD-L1またはPD-L2、より好ましくはPD-L1に結合する、態様1~5のいずれか一項に記載の組成物。
7.第2の腫瘍関連抗原(TA2)に結合する可変ドメインが、CLEC12AまたはEGFR、好ましくはEGFRに結合する、態様1~6のいずれか一項に記載の組成物。
8.第2の結合分子が、TA1に結合する、態様1~7のいずれか一項に記載の組成物。
9.第2の結合分子が、二価の単一特異性抗体である、態様1~8のいずれか一項に記載の組成物
10.第2の結合分子が、低減されたエフェクタ-機能を有する、態様9に記載の組成物。
11.態様1~10のいずれか一項に記載の多価抗体および第2の結合分子を含む、部分のキット。
12.態様1~10のいずれか一項に記載の多価抗体および第2の結合分子を含む、薬学的組成物。
13.治療を必要とする対象、特にがんを有する対象の治療に使用するための、態様1~10のいずれか一項に記載の多価抗体および第2の結合分子の組み合わせ、態様1~10のいずれか一項に記載の組成物、態様11に記載の部分のキット、または態様12に記載の薬学的組成物。
14.がんの治療の方法であって、
-それを必要とする対象に、態様1~10のいずれか一項に記載の多価抗体を投与すること、および対象に、態様1~10のいずれか一項に記載の第2の結合分子を追加で投与すること、または
-それを必要とする対象に、態様1~10のいずれか一項に記載の組成物を投与すること、または
-それを必要とする対象に、態様12に記載の薬学的組成物を投与すること、を含む、方法。
15.がんを有する個体の治療のための医薬品の製造のための、態様1~10のいずれか一項に記載の多価抗体および第2の結合分子を含む組成物、または態様1~10のいずれか一項に記載の多価抗体および第2の結合分子を含む部分のキットの、使用。
16.多価抗体および第2の結合分子が、単一の組成物として、または2つの別個の組成物として同時に投与される、態様13に記載の治療に使用するための組み合わせ、態様14に記載の治療の方法、または態様15に記載の使用。
17.多価抗体が、第2の結合分子の前に投与される、態様13に記載の治療に使用するための組み合わせ、態様14に記載の治療の方法、または態様15に記載の使用。
18.第2の結合分子が、多価抗体の前に投与される、態様13に記載の治療に使用するための組み合わせ、態様14に記載の治療の方法、または態様15に記載の使用。
19.態様1~10のいずれか一項に記載の多価抗体の第1、第2、および第3の可変ドメインの重鎖可変領域をコ-ドする核酸を含むベクタ-であって、ベクタ-が、態様1~10のいずれか一項に記載の第2の結合分子の重鎖可変領域をコ-ドする異なる核酸をさらに含む、ベクタ-。
20.態様1~10のいずれか一項に記載の多価抗体の第1、第2、および第3の可変ドメインの重鎖可変領域をコ-ドする核酸を含む宿主細胞であって、宿主細胞が、態様1~10のいずれか一項に記載の第2の結合分子の重鎖可変領域をコ-ドする異なる核酸をさらに含む、宿主細胞。
配列番号1:重鎖可変領域
EVQLVQSGAEVKKPGSSVKVSCKASGGTFRSFGISWVRQAPGQGLEWMGGFIPVLGTANYAQKFQGRVTIIADKSTNTAYMELSSLRSEDTAVYYCARRGNWNPFDPWGQGTLVTVSS
配列番号2:KabatによるHCDR1
SFGIS
配列番号3:KabatによるHCDR2
GFIPVLGTANYAQKFQG
配列番号4:KabatによるHCDR3
RGNWNPFDP
配列番号5:重鎖可変領域QVQLVQSGAEVKKPGSSVKVSCKASGDAFKSKTFTISWVRQAPGQGLEWLGGIIPLFGTITYAQKFQGRVTITADKSTNTAFMELSSLRSEDTAMYYCTRRGNWNPFDPWGQGTLVTVSS
配列番号6:KabatによるHCDR1
SKTFTIS
配列番号7:KabatによるHCDR2
GIIPLFGTITYAQKFQG
配列番号8:重鎖可変領域EVQLVQSGSELKKPGSSVKVSCKASGVTFNSRTFTISWVRQAPGQGLEWLGSIIPIFGTITYAQKFQGRVTITADKSTSTAFMELTSLRSEDTAIYYCTRRGNWNPFDPWGQGTLVTVSS
配列番号9:KabatによるHCDR1
SRTFTIS
配列番号10:KabatによるHCDR2
SIIPIFGTITYAQKFQG
配列番号11:重鎖可変領域QVQLVQSGGGLVQPGGSLRLSCATSGFKFSSYALSWVRQAPGKGLEWVSGISGSGRTTWYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGGYSYGPYWYFDLWGRGTLVTVSS
配列番号12:KabatによるHCDR1
SYALS
配列番号13:KabatによるHCDR2
GISGSGRTTWYADSVKG
配列番号14:KabatによるHCDR3
DGGYSYGPYWYFDL
配列番号15:重鎖可変領域EVQLVQSGAEVKKPGESLKISCKGSGYSFTRFWIGWVRQMPGKGLEWMGIIYPGDSDTRYSPSFQGQVTISADKSTSTAYLQWSSLKASDTGMYYCVRHIRYFDWSEDYHYYLDVWGKGTTVTVSS
配列番号16:KabatによるHCDR1
RFWIG
配列番号17:KabatによるHCDR2
IIYPGDSDTRYSPSFQG
配列番号18:KabatによるHCDR3
HIRYFDWSEDYHYYLDV
配列番号19:重鎖可変領域EVQLVESGAEVKKPGESLKISCKGSGYSFTRYWIGWVRQMPGKGLEWMGIIYPGDSDTRYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCVRNIRYFVWSEDYHYYMDVWGKGTTVTVSS
配列番号20:KabatによるHCDR1
RYWIG
配列番号21:KabatによるHCDR3
NIRYFVWSEDYHYYMDV
配列番号22:重鎖可変領域EVQLVESGGGLVQPGRSLRLSCATSGFNFDDYTMHWVRQAPGKGLEWVSDISWSSGSIGYADSVKGRFTISRDNAKNSLWLQMNSLRTEDTALYFCAKDHRGYGDYEGGGFDYWGQGTLVTVSS
配列番号23:KabatによるHCDR1
DYTMH
配列番号24:KabatによるHCDR2
DISWSSGSIGYADSVKG
配列番号25:KabatによるHCDR3
DHRGYGDYEGGGFDY
配列番号26:重鎖可変領域EVQLVQSGAEVKKPGSSVKVSCKASGGIFSTYAISWVRQAPGQGLEWMGGIIPIFDTPNYAQKFQGRVTITADKSTSTAYMDLSSLRSEDTAVYYCAKNVRGYSAYDLDYWGQGTLVTVSS
配列番号27:KabatによるHCDR1
TYAIS
配列番号28:KabatによるHCDR2
GIIPIFDTPNYAQKFQG
配列番号29:KabatによるHCDR3
NVRGYSAYDLDY
配列番号30:重鎖可変領域QVQLVQSGSELKKPGASVKVSCKASGYTFTSYSMNWVRQAPGQGLEWMGWINTNTGNPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARDHDFRTGRAFDIWGQGTTVTVSS
配列番号31:KabatによるHCDR1
SYSMN
配列番号32:KabatによるHCDR2
WINTNTGNPTYAQGFTG
配列番号33:KabatによるHCDR3
DHDFRTGRAFDI
配列番号34:重鎖可変領域EVQLVESGGDVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVISYDGSNKYYADSVKGRFTISRDNSKSTLFLQMNSLRAEDTAVYFCVRGLPITMVRGAYSFDYWGQGTLVTVSS
配列番号35:KabatによるHCDR1
SYGMH
配列番号36:KabatによるHCDR2
VISYDGSNKYYADSVKG
配列番号37:KabatによるHCDR3
GLPITMVRGAYSFDY
配列番号38:重鎖可変領域EVQLVQSGAEVKKPGSSVKVSCKASGDTFNTYSITWVRQAPGQGLEWMGSIVPIFGTINNAQKFQGRVTITADKSANTAYMELSSLRSEDTAVYYCARDNTMVRGVDYYYMDVWGKGTMVTVSS
配列番号39:KabatによるHCDR1
TYSIT
配列番号40:KabatによるHCDR2
SIVPIFGTINNAQKFQG
配列番号41:KabatによるHCDR3
DNTMVRGVDYYYMDV
配列番号42:重鎖可変領域QVQLVQSGAEVKKPGSSVKVSCKASGDTFRSYGITWVRQAPGQGLEWMGGIIPIFGTTNYAQKFQGRVTITADKSTSTVYMELSSLRSEDTAVYYCARRRGYSNPHWLDPWGQGTLVTVSS
配列番号43:KabatによるHCDR1
SYGIT
配列番号44:KabatによるHCDR2
GIIPIFGTTNYAQKFQG
配列番号45:KabatによるHCDR3
RRGYSNPHWLDP
配列番号46:重鎖配列EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSAASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELGRGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN
配列番号47:重鎖QVQLVQSGAEVKKPGSSVRVSCKASGGTFNTYAINWVRQAPGQGLEWVGRIIPIFGTANYAQKFQGRVTISADKSTTTAYMELSSLRSEDTAVFYCAKDETGYSSSNFQHWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELGRGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN
配列番号48:KabatによるHCDR1
TYAIN
配列番号49:KabatによるHCDR2
RIIPIFGTANYAQKFQG
配列番号50:KabatによるHCDR3
DETGYSSSNFQH
配列番号51:重鎖配列EVQLVESGGGLVQPGGSLRLSCAASGFTFSRYWMSWVRQAPGKGLEWVANIKQDGSEKYYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREGGWFGELAFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV
FSCSVMHEALHNHYTQKSLSLSPGK
配列番号52:重鎖可変領域QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVRQAPGQGLEWMGWISAYNANTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCAKDRHWHWWLDAFDYWGQGTLVTVSS
配列番号53:KabatによるHCDR1
SYGIS
配列番号54:KabatによるHCDR2
WISAYNANTNYAQKLQG
配列番号55:KabatによるHCDR3
DRHWHWWLDAFDY
配列番号56:重鎖可変領域QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVRQAPGQGLEWMGWISAYNANTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCAKDLYGHWWLDAFDYWGQGTLVTVSS
配列番号57:KabatによるHCDR3
DLYGHWWLDAFDY
配列番号58:重鎖可変領域QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVRQAPGQGLEWMGWISAYNANTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCAKGPGSHWWLDAFDYWGQGTLVTVSS
配列番号59:KabatによるHCDR3
GPGSHWWLDAFDY
配列番号60:重鎖可変領域QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVRQAPGQGLEWMGWISAYNANTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCAKDRGWHWWLDAFDYWGQGTLVTVSS
配列番号61:KabatによるHCDR3
DRGWHWWLDAFDY
配列番号62:重鎖可変領域QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVRQAPGQGLEWMGWISAYNANTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCAKDRHWHWWLDGFDYWGQGTLVTVSS
配列番号63:KabatによるHCDR3
DRHWHWWLDGFDY
配列番号64:重鎖可変領域QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYMHWVRQAPGQGLEWMGIINPSGGSTSYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCAKGTTGDWFDYWGQGTLVTVSS
配列番号65:KabatによるHCDR1
SYYMH
配列番号66:KabatによるHCDR2
IINPSGGSTSYAQKFQG
配列番号67:KabatによるHCDR3
GTTGDWFDY
配列番号68:重鎖可変領域EVQLVETGAEVKKPGASVKVSCKASDYIFTKYDINWVRQAPGQGLEWMGWMSANTGNTGYAQKFQGRVTMTRDTSINTAYMELSSLTSGDTAVYFCARSSLFKTETAPYYHFALDVWGQGTTVTVSS
配列番号69:リンカ-1
ESKYGPP
配列番号70:リンカ-2
EPKSCDKTHT
配列番号71:リンカ-3
GGGGSGGGGS
配列番号72:リンカ-4
ERKSSVESPPSP
配列番号73:リンカ-5
ERKCSVESPPSP
配列番号74:リンカ-6
ELKTPLGDTTHT
配列番号75:リンカ-7
ESKYGPPSPSSP
配列番号76:リンカ-8
ERKSSVEAPPVAG
配列番号77:リンカ-9
ERKCSVEAPPVAG
配列番号78:リンカ-10
ESKYGPPAPEFLGG
配列番号79:リンカ-11
EPKSCDKTHTSPPSP
配列番号80:リンカ-12
EPKSCDGGGGSGGGGS
配列番号81:リンカ-13
GGGGSGGGGSAPPVAG
配列番号82:リンカ-14
EPKSCDKTHTAPELLGG
配列番号83:リンカ-15
ERKSSVESPPSPAPPVAG
配列番号84:リンカ-16
ERKCSVESPPSPAPPVAG
配列番号85:リンカ-17
ELKTPLGDTTHTAPEFLGG
配列番号86:リンカ-18
ESKYGPPSPSSPAPEFLGG
配列番号87:リンカ-19
EPKSCDKTHTSPPSPAPELLGG
配列番号88:リンカ-20
ERKSSVEEAAAKEAAAKAPPVAG
配列番号89:リンカ-21
ERKCSVEEAAAKEAAAKAPPVAG
配列番号90:リンカ-22
ESKYGPPEAAAKEAAAKAPEFLGG
配列番号91:リンカ-23
EPKSCDKTHTEAAAKEAAAKAPELLGG
配列番号92:リンカ-24
ELKTPLGDTTHTEAAAKEAAAKAPEFLGG
配列番号93:軽鎖可変領域
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPTFGQGTKVEIK
配列番号94:IMGTによるLCDR1
QSISSY
配列番号95:IMGTによるLCDR2
AAS
配列番号96:IMGTによるLCDR3
QQSYSTPPT
配列番号97:軽鎖定常領域
RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
配列番号98:軽鎖配列
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
配列番号99:IGKV1-39/jk5軽鎖可変領域
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK
配列番号100:CH1配列
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRV
配列番号101:ヒンジ
EPKSCDKTHTCPPCP
配列番号102:CH2配列
APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAK
配列番号103:修飾CH3配列
GQPREPQVYTKPPSREEMTKNQVSLKCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
配列番号104:修飾CH3配列
GQPREPQVYTDPPSREEMTKNQVSLTCEVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
配列番号105:軽鎖配列
DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
配列番号106:軽鎖配列
EIVLTQSPGTLSLSPGERATLSCRASQRVSSSYLAWYQQKPGQAPRLLIYDASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSLPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
配列番号107:IgVk1-39 V領域
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTP
配列番号108:IgVk 3-20 V領域
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSP
配列番号109:IgVk3-15 V領域
EIVMTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQKPGQAPRLLIYGASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYNNWP
配列番号110:IgVL3-21 V領域
SYVLTQPPSVSVAPGETARITCGGDNIGRKSVYWYQQKSGQAPVLVIYYDSDRPSGIPERFSGSNSGNTATLTISRVEAGDEADYYCQVWDGSSDH
Claims (32)
- 治療用組成物であって、第1の腫瘍抗原(TA1)に結合する第1の可変ドメイン、第2の腫瘍抗原(TA2)に結合する第2の可変ドメイン、および免疫細胞関与抗原(IEA)に結合する第3の可変ドメインを含む多価抗体を含み、前記組成物が、TA1またはTA2に結合する第2の結合分子をさらに含む、治療用組成物。
- 前記多価抗体が、Fc領域を含む、請求項1に記載の治療用組成物。
- 免疫細胞関与抗原(IEA)に結合する前記第3の可変ドメイン、および第2の腫瘍抗原(TA2)に結合する前記第2の可変ドメインが、Fc領域と関連し、第1の腫瘍抗原(TA1)に結合する前記第1の可変ドメインが、免疫細胞関与抗原(IEA)に結合する前記第3の可変ドメインに連結される、請求項1または2に記載の治療用組成物。
- 免疫細胞関与抗原(IEA)に結合する前記第3の可変ドメイン、および第1の腫瘍抗原(TA1)に結合する前記第1の可変ドメインが、Fc領域と関連し、第2の腫瘍抗原(TA2)に結合する前記第2の可変ドメインが、免疫細胞関与抗原(IEA)に結合する前記第3の可変ドメインに連結される、請求項1または2に記載の治療用組成物。
- 前記第1、第2、および/または第3の可変ドメインが、共通の軽鎖可変領域を含む、請求項1~4のいずれか一項に記載の治療用組成物。
- 免疫細胞関与抗原に結合する前記可変ドメインが、CD3、TCR-α鎖、TCR-β鎖、CD2、CD4、CD5、CD7、CD8、CD137、CD28、CD16、CD16A、CD64、OX40、CD27、CD40、ICOS、GITR、NKG2D、NKp46、NKp44、またはNKp30、好ましくはCD3、TCR-α鎖、TCR-β鎖、CD2、またはCD5、より好ましくはCD3に結合する、請求項1~5のいずれか一項に記載の治療用組成物。
- 第1の腫瘍関連抗原(TA1)に結合する前記可変ドメインが、PD-L1、PD-L2、HVEM、CD47、B7-H3、B7-H4、B7-H7、またはSiglec-15、好ましくはPD-L1またはPD-L2、より好ましくはPD-L1に結合する、請求項1~6のいずれか一項に記載の治療用組成物。
- 第2の腫瘍関連抗原(TA2)に結合する前記可変ドメインが、CLEC12AまたはEGFR、好ましくはEGFRに結合する、請求項1~7のいずれか一項に記載の治療用組成物。
- 前記第1の腫瘍関連抗原(TA1)が、非腫瘍細胞上で発現される、請求項1~8のいずれか一項に記載の治療用組成物。
- 前記第2の結合分子が、TA1に結合する、請求項1~9のいずれか一項に記載の治療用組成物。
- 前記第2の結合分子が、二価の単一特異性抗体である、請求項1~10のいずれか一項に記載の治療用組成物。
- 前記第2の結合分子が、前記多価抗体の前記第1の可変ドメインもしくは第2の可変ドメインのTA1もしくはTA2に対する結合親和性と同等である、それと等しい、またはそれよりも低いTA1またはTA2に対する結合親和性を有する、請求項1~11のいずれか一項に記載の治療用組成物。
- 前記第2の結合分子が、低減されたエフェクタ-機能を有する、請求項1~12のいずれか一項に記載の治療用組成物。
- 請求項1~13のいずれか一項に記載の多価抗体および第2の結合分子を含む、部分のキット。
- 請求項1~13のいずれか一項に記載の治療用組成物、および前記組成物を投与することを必要とする対象にそれを行うための説明書を含む、部分のキット。
- 前記キットが、同時にまたは連続的に前記多価抗体および第2の結合分子を投与することを必要とする対象に、それを行うための説明書を含む、請求項14または15に記載の部分のキット。
- 前記キットが、前記多価抗体を投与する前に、前記第2の結合分子を投与するための説明書を含む、請求項14~16のいずれか一項に記載の部分のキット。
- 請求項1~13のいずれか一項に記載の多価抗体および第2の結合分子と、薬学的に許容される担体、希釈剤、または賦形剤と、を含む、薬学的組成物。
- 非腫瘍細胞への前記多価抗体の結合を軽減もしくは低減するため、かつ/または前記多価抗体によって誘導された非腫瘍細胞の細胞殺滅を軽減もしくは低減するための、請求項1~13のいずれか一項に記載の多価抗体および第2の結合分子の組み合わせ、請求項1~13のいずれか一項に記載の多価抗体および第2の結合分子を含む組成物、請求項1~13のいずれか一項に記載の治療用組成物、請求項14~17のいずれか一項に記載の部分のキット、または請求項18に記載の薬学的組成物。
- 薬剤として使用するための、請求項1~13のいずれか一項に記載の多価抗体および第2の結合分子の組み合わせ、請求項1~13のいずれか一項に記載の多価抗体および第2の結合分子を含む組成物、請求項1~13のいずれか一項に記載の治療用組成物、請求項14~17のいずれか一項に記載の部分のキット、または請求項18に記載の薬学的組成物。
- 治療を必要とする対象、特にがんを有する対象の治療に使用するための、請求項1~13のいずれか一項に記載の多価抗体および第2の結合分子の組み合わせ、請求項1~13のいずれか一項に記載の多価抗体および第2の結合分子を含む組成物、請求項1~13のいずれか一項に記載の治療用組成物、請求項14~17のいずれか一項に記載の部分のキット、または請求項18に記載の薬学的組成物。
- がんの治療のための薬剤の製造における、請求項1~13のいずれか一項に記載の多価抗体および第2の結合分子の組み合わせ、請求項1~13のいずれか一項に記載の多価抗体および第2の結合分子を含む組成物、請求項1~13のいずれか一項に記載の治療用組成物、請求項14~17のいずれか一項に記載の部分のキット、または請求項18に記載の薬学的組成物の、使用。
- TA1またはTA2を発現する非腫瘍細胞への、請求項1~13のいずれか一項に記載の多価抗体の結合を軽減または低減するための方法であって、前記方法が、前記多価抗体と併せてTA1またはTA2に結合する、請求項1~13のいずれか一項に記載の第2の結合分子を使用することを含む、方法。
- 前記非腫瘍細胞がTA1を発現し、前記第2の結合分子がTA1に結合する、請求項23に記載の方法。
- TA1またはTA2を発現する非腫瘍細胞への前記多価抗体の結合が、前記第2の結合分子を使用しない方法において、TA1またはTA2を発現する非腫瘍細胞への前記多価抗体の結合と比較して低減される、請求項23または24に記載の方法。
- がんの治療の方法であって、前記方法が、
-それを必要とする対象に、請求項1~13のいずれか一項に記載の多価抗体を投与すること、および前記対象に、請求項1~13のいずれか一項に記載の第2の結合分子を追加で投与すること、
-それを必要とする対象に、請求項1~13のいずれか一項に記載の多価抗体および第2の結合分子を含む組成物を投与すること、または
-それを必要とする対象に、請求項1~13のいずれか一項に記載の治療用組成物を投与すること、または
-それを必要とする対象に、請求項18に記載の薬学的組成物を投与すること、を含む、方法。 - 前記多価抗体および第2の結合分子が、単一の組成物として、または2つの別個の組成物として同時に投与される、請求項19~21のいずれか一項に記載の使用のための組み合わせ、組成物、治療用組成物、もしくは部分のキット、または請求項23~26のいずれか一項に記載の方法。
- 前記多価抗体が、前記第2の結合分子の前に投与される、請求項19~21のいずれか一項に記載の使用のための組み合わせ、組成物、治療用組成物、もしくは部分のキット、または請求項23~26のいずれか一項に記載の方法。
- 前記第2の結合分子が、前記多価抗体の前に投与される、請求項19~21のいずれか一項に記載の使用のための組み合わせ、組成物、治療用組成物、もしくはキット、または請求項23~26のいずれか一項に記載の方法。
- 請求項1~13のいずれか一項に記載の多価抗体の前記第1、第2、および第3の可変ドメインの重鎖可変領域をコ-ドする核酸を含むベクタ-であって、前記ベクタ-が、請求項1~13のいずれか一項に記載の第2の結合分子の前記重鎖可変領域をコ-ドする異なる核酸をさらに含む、ベクタ-。
- 請求項1~13のいずれか一項に記載の多価抗体の前記第1、第2、および第3の可変ドメインの重鎖可変領域をコ-ドする核酸を含む宿主細胞であって、前記宿主細胞が、請求項1~13のいずれか一項に記載の第2の結合分子の前記重鎖可変領域をコ-ドする異なる核酸をさらに含む、宿主細胞。
- 前記宿主細胞が、請求項1~13のいずれか一項に記載の多価抗体の前記第1、第2、および第3の可変ドメインの前記軽鎖可変領域、ならびに第2の結合分子の前記軽鎖可変領域をコ-ドする核酸をさらに含む、請求項31に記載の宿主細胞。
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