JP7011764B2 - 抗体アジュバント複合体 - Google Patents
抗体アジュバント複合体 Download PDFInfo
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- JP7011764B2 JP7011764B2 JP2018565261A JP2018565261A JP7011764B2 JP 7011764 B2 JP7011764 B2 JP 7011764B2 JP 2018565261 A JP2018565261 A JP 2018565261A JP 2018565261 A JP2018565261 A JP 2018565261A JP 7011764 B2 JP7011764 B2 JP 7011764B2
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Description
本発明は、抗体依存性細胞傷害、抗体依存性細胞貪食作用を促進する抗体、及び、免疫チェックポイント分子として働く癌が産生するタンパク質の作用を阻害する抗体、樹状細胞活性化及びT細胞増殖を促進するアジュバント、並びに、抗腫瘍効果を促進する抗体とアジュバントとの間の共有結合などの、多くの利点を有する抗体-アジュバント免疫複合体を提供する。例えば、いくつかの場合において、ヒト単球は、本発明の免疫複合体による一晩刺激後にDC分化を受けるが、既知の刺激剤(例えば、GM-CSF及びIL-4)によるDC分化は、より長い時間を要する。免疫複合体活性化細胞は、既知の刺激剤で達成し得るものよりも、高い量(例えば、いくつかの場合では数倍量以上)の共刺激分子及び炎症性サイトカインを発現する。
定義
抗体アジュバント免疫複合体
Abは抗体であり、
Aは、抗体中の未改変アミノ酸側鎖、又は抗体中の改変アミノ酸側鎖であり、
Zは連結部分であり、
R1は、H及びC1~4アルキルから選択され、又は、
Z、R1、及び結合先である窒素原子は、5~8員複素環を含む連結部分を形成し、
各Yは、独立して、CHR2であり、式中、R2は、H、OH、及びNH2から選択され、
R3は、C1~6アルキル及び2~6員ヘテロアルキルから選択され、それぞれは、ハロ、ヒドロキシ、アミノ、オキソ(=O)、アルキルアミノ、アミド、アシル、ニトロ、シアノ、及びアルコキシからなる群から選択される、1つ又は2つ以上のメンバーで任意に置換され、
Xは、O及びCH2から選択され、
下付き文字nは、1~12の整数(すなわち、1、2、3、4、5、6、7、8、9、10、11、又は12)であり、下付き文字rは、1~10の整数(すなわち、1、2、3、4、5、6、7、8、9、又は10)である。
式Iaの免疫複合体の特定の実施形態では、下付き文字nは、1~6(すなわち、1、2、3、4、5、又は6)である。
Abは抗体であり、
Aは、抗体中の未改変アミノ酸側鎖、又は抗体中の改変アミノ酸側鎖であり、
Zは連結部分であり、
R1は、H及びC1~4アルキルから選択され、又は、
Z、R1、及び結合先である窒素原子は、5~8員複素環を含む連結部分を形成し、
各Yは、独立して、CHR2であり、式中、R2は、H、OH、及びNH2から選択され、
Xは、O及びCH2から選択され、
下付き文字nは、1~12の整数(すなわち、1、2、3、4、5、6、7、8、9、10、11、又は12)であり、
Wは、O、及びCH2からなる群から選択される。
Abは抗体であり、
下付き文字rは、1~10の整数(すなわち、1、2、3、4、5、6、7、8、9、又は10)であり、
Aは、抗体中の未改変アミノ酸側鎖、又は抗体中の改変アミノ酸側鎖であり、
Zは連結部分であり、
R1は、H及びC1~4アルキルから選択され、又は、
Z、R1、及び結合先である窒素原子は、5~8員複素環を含む連結部分を形成し、
R2は、H、OH、及びNH2から選択される。
Z1は、-C(O)-、-C(O)NH-、-CH2-から選択され、
Z2及びZ4は、独立して、結合、C1~30アルキレン、及び3~30員ヘテロアルキレンから選択され、このとき、
C1~30アルキレン及び3~30員ヘテロアルキレン中の隣接する原子のうち1つ又は2つ以上のグループは、任意にかつ独立して、-C(O)-、-NRaC(O)-、又は-C(O)NRa-で置換され、
C1~30アルキレン及び3~30員ヘテロアルキレン中の隣接する原子のうち1つ又は2つ以上のグループは、任意にかつ独立して、4~8員の二価炭素環で置換され、
C1~30アルキレン及び3~30員ヘテロアルキレン中の隣接する原子のうち1つ又は2つ以上のグループは、任意にかつ独立して、O、S、及びNから選択される1~4つのヘテロ原子を有する4~8員の二価複素環で置換され、
各Raは、H及びC1~6アルキルから独立して選択され、
Z3は、結合、二価ペプチド部分、二価ポリマー部分から選択され、
Z5は、抗体中のアミノ酸側鎖の側鎖に結合される。
Z1は、-C(O)-、-C(O)NH-、-CH2-から選択され、
Z2及びZ4は、独立して、結合、C1~30アルキレン、及び3~30員ヘテロアルキレンから選択され、このとき、
C1~30アルキレン及び3~30員ヘテロアルキレン中の隣接する原子のうち1つ又は2つ以上のグループは、任意にかつ独立して、-C(O)-、
-NRaC(O)-又は-C(O)NRa-で置換され、
C1~30アルキレン及び3~30員ヘテロアルキレン中の隣接する原子のうち1つ又は2つ以上のグループは、任意にかつ独立して、4~8員の二価炭素環で置換され、
C1~30アルキレン及び3~30員ヘテロアルキレン中の隣接する原子のうち1つ又は2つ以上のグループは、任意にかつ独立して、O、S、及びNから選択される1~4つのヘテロ原子を有する4~8員の二価複素環で置換され、
各Raは、H及びC1~6アルキルから独立して選択され、
Z3は、結合、二価ペプチド部分、二価ポリマー部分から選択され、
Z5は、アミン結合部分及びチオール結合部分から選択される。
式中、Rは任意に存在し、1~8個(すなわち、1、2、3、4、5、6、7、又は8個)の炭素単位を含む、直鎖又は分岐鎖、環状又は直線状、飽和又は不飽和アルキル、ヘテロアルキル、アリール、又はヘテロアリール鎖であり、下付き文字cは、1~20の整数であり、破線
式中、Rは任意に存在し、1~8個(すなわち、1、2、3、4、5、6、7、又は8個)の炭素単位を含む、直鎖又は分岐鎖、環状又は直線状、飽和又は不飽和アルキル、ヘテロアルキル、アリール、又はヘテロアリール鎖であり、破線
アジュバント
いくつかの実施形態では、アジュバント(「Adj」)は次式のものであり、
抗体
B1I1、TGFB2、TGFB3、TGFBI、TGFBR1、TGFBR2、TGFBR3、THIL、THBS1(トロンボスポンジン-1)、THBS2、THBS4、THPO、TIE(Tie-1)、TIMP3、組織因子、TLR1、TLR2、TLR3、TLR4、TLR5、TLR6、TLR7、TLR8、TLR9、TLR10、TLR11、TNF、TNF-a、TNFAIP2(B94)、TNFAIP3、TNFRSFI1A、TNFRSF1A、TNFRSF1B、TNFRSF21、TNFRSF5、TNFRSF6(Fas)、TNFRSF7、TNFRSF8、TNFRSF9、TNFSF1O(TRAIL)、TNFSF1 1(TRANCE)、TNFSF12(APO3L)、TNFSF13(April)、TNFSF13B、TNFSF14(HVEM-L)、TNFRSF14(HVEM)、TNFSF15(VEGI)、TNFSF18、TNFSF4(OX40リガンド)、TNFSF5(CD40リガンド)、TNFSF6(FasL)、TNFSF7(CD27リガンド)、TNFSF8(CD30リガンド)、TNFSF9(4-1BBリガンド)、TOLLIP、Toll様受容体、TOP2A(トポイソメラーゼIia)、TP53、TPM1、TPM2、TRADD、TRAF1、TRAF2、TRAF3、TRAF4、TRAF5、TRAF6、TRKA、TREM1、TREM2、TRPC6、TSLP、TWEAK、チロシナーゼ、uPAR、VEGF、VEGFB、VEGFC、バーシカン、VHL C5、VLA-4、Wnt-1、XCL1(リンホタクチン)、XCL2(SCM-Ib)、XCRI(GPR5/CCXCR1)、YY1、ZFPM2、CLEC4C(BDCA-2、DLEC、CD303、CLECSF7)、CLEC4D(MCL、CLECSF8)、CLEC4E(Mincle)、CLEC6A(Dectin-2)、CLEC5A(MDL-1、CLECSF5)、CLEC1B(CLEC-2)、CLEC9A(DNGR-1)、CLEC7A(Dectin-1)、PDGFRa、SLAMF7、GP6(GPVI)、LILRA1(CD85I)、LILRA2(CD85H、ILT1)、LILRA4(CD85G、ILT7)、LILRA5(CD85F、ILT11)、LILRA6(CD85b、ILT8)、NCR1(CD335、LY94、NKp46)、NCR3(CD335、LY94、NKp46)、NCR3(CD337、NKp30)、OSCAR、TARM1、CD300C、CD300E、CD300LB(CD300B)、CD300LD(CD300D)、KIR2DL4(CD158D)、KIR2DS、KLRC2(CD159C、NKG2C)、KLRK1(CD314、NKG2D)、NCR2(CD336、NKp44)、PILRB、SIGLEC1(CD169、SN)、SIGLEC14、SIGLEC15(CD33L3)、SIGLEC16、SIRPB1(CD172B)、TREM1(CD354)、TREM2、及びKLRF1(NKp80)から選択される1つ又は2つ以上の標的に結合可能である(例えば、上記から選択される標的に特異的に結合する)。
(a)(i)抗原結合ドメイン及び(ii)Fcドメインを含む抗体構築物と、
(b)アジュバント部分と、
(c)リンカーと、を含み、
各アジュバント部分がリンカーを介して抗体構築物に共有結合している、免疫複合体。
Abは抗体であり、
Aは、抗体中の未改変アミノ酸側鎖、又は抗体中の改変アミノ酸側鎖であり、
Zは連結部分であり、
R1は、H及びC1~4アルキルから選択され、又は、
Z、R1、及び結合先である窒素原子は、5~8員複素環を含む連結部分を形成し、
各Yは、独立して、CHR2であり、式中、R2は、H、OH、及びNH2から選択され、
R3は、C1~6アルキル及び2~6員ヘテロアルキルから選択され、それぞれは、ハロ、ヒドロキシ、アミノ、オキソ(=O)、アルキルアミノ、アミド、アシル、ニトロ、シアノ、及びアルコキシからなる群から選択される、1つ又は2つ以上のメンバーで任意に置換され、
Xは、O及びCH2から選択され、
下付き文字nは、1~12の整数であり、
下付き文字rは、1~10の整数である、態様53に記載の免疫複合体。
Abは抗体であり、
Aは、抗体中の未改変アミノ酸側鎖、又は抗体中の改変アミノ酸側鎖であり、
Zは連結部分であり、
R1は、H及びC1~4アルキルから選択され、又は、
Z、R1、及び結合先である窒素原子は、5~8員複素環を含む連結部分を形成し、
各Yは、独立して、CHR2であり、式中、R2は、H、OH、及びNH2から選択され、
Xは、O及びCH2から選択され、
下付き文字nは、1~12の整数であり、
Wは、O、及びCH2からなる群から選択される、態様54に記載の免疫複合体。
Abは抗体であり、
下付き文字rは、1~10の整数であり、
Aは、抗体中の未改変アミノ酸側鎖、又は抗体中の改変アミノ酸側鎖であり、
Zは連結部分であり、
R1は、H及びC1~4アルキルから選択され、又は、
Z、R1、及び結合先である窒素原子は、5~8員複素環を含む連結部分を形成し、
R2は、H、OH、及びNH2から選択される、態様55に記載の免疫複合体。
Z1は、-C(O)-、-C(O)NH-、-CH2-から選択され、
Z2及びZ4は、独立して、結合、C1~30アルキレン、及び3~30員ヘテロアルキレンから選択され、このとき、
C1~30アルキレン及び3~30員ヘテロアルキレン中の隣接する原子のうち1つ又は2つ以上のグループは、任意にかつ独立して、-C(O)-、-NRaC(O)-、又は-C(O)NRa-で置換され、
C1~30アルキレン及び3~30員ヘテロアルキレン中の隣接する原子のうち1つ又は2つ以上のグループは、任意にかつ独立して、4~8員の二価炭素環で置換され、
C1~30アルキレン及び3~30員ヘテロアルキレン中の隣接する原子のうち1つ又は2つ以上のグループは、任意にかつ独立して、O、S、及びNから選択される1~4つのヘテロ原子を有する4~8員の二価複素環で置換され、
各Raは、H及びC1~6アルキルから独立して選択され、
Z3は、結合、二価ペプチド部分、二価ポリマー部分から選択され、
Z5は、抗体中のアミノ酸側鎖の側鎖に結合される、態様1~52のいずれか1つに記載の免疫複合体。
Z1は、-C(O)-、-C(O)NH-、-CH2-から選択され、
Z2及びZ4は、独立して、結合、C1~30アルキレン、及び3~30員ヘテロアルキレンから選択され、このとき、
C1~30アルキレン及び3~30員ヘテロアルキレン中の隣接する原子のうち1つ又は2つ以上のグループは、任意にかつ独立して、-C(O)-、
-NRaC(O)-又は-C(O)NRa-で置換され、
C1~30アルキレン及び3~30員ヘテロアルキレン中の隣接する原子のうち1つ又は2つ以上のグループは、任意にかつ独立して、4~8員の二価炭素環で置換され、
C1~30アルキレン及び3~30員ヘテロアルキレン中の隣接する原子のうち1つ又は2つ以上のグループは、任意にかつ独立して、O、S、及びNから選択される1~4つのヘテロ原子を有する4~8員の二価複素環で置換され、
各Raは、H及びC1~6アルキルから独立して選択され、
Z3は、結合、二価ペプチド部分、二価ポリマー部分から選択され、
Z5は、アミン結合部分及びチオール結合部分から選択される、態様59に記載の免疫複合体。
実施例1.抗体結合のためのイミダゾキノリン
実施例4.in vivoでの抗体アジュバント複合体効果の評価
実施例5.in vitroでの追加の抗体アジュバント複合体活性の調製及び評価
実施例6.in vitroでの抗Dectin-2アジュバント複合体活性の調製及び評価
実施例7.TLR7/8アジュバントの合成
実施例8.免疫複合体の合成
実施例9.ペンタフルオロフェニル(「PFP」)エステルを用いる免疫複合体BB-14の合成
実施例10.NHSエステルを用いる免疫複合体BB-15の合成
実施例11.TFPエステルを用いる免疫複合体の合成
実施例12.別のTLR7/TLR8アジュバントの合成
実施例13.TFPエステルを用いる免疫複合体BB-26の合成
実施例14.TFPエステルを用いる免疫複合体BB-27の合成
実施例15.TFPエステルを用いる免疫複合体BB-36の合成
実施例16.TFPエステルを用いる免疫複合体BB-45の合成
実施例17.TFPエステルを用いる免疫複合体BB-24の合成
実施例18.TFPエステルである免疫複合体BB-37の合成
実施例19.別のTLR7/8アジュバントの合成
実施例20.TFPエステルを用いる免疫複合体BB-42の合成
実施例21.TFPエステルを用いる免疫複合体BB-43及びBB-44の合成
実施例22.in vitroでの免疫複合体活性の評価
実施例23.BB-01の、比較複合体IRM1及び比較複合体IRM2に対する比較
実施例24.抗化合物1抗体の生成
実施例25.ELISAによる共役の検出
実施例26.ヒトIgGのヒトIg-Fcに結合した化合物1のELISAによる検出
実施例27.ラット抗Dectin2に結合した化合物1のELISAによる検出
実施例28.プロテインA結合活性の測定方法
実施例29.CD16aへの結合活性の測定方法
実施例30.CD64への結合活性の測定方法
項1
(a)(i)抗原結合ドメイン及び(ii)Fcドメインを含む抗体構築物と、
(b)アジュバント部分と、
(c)リンカーと、を含み、
各アジュバント部分がリンカーを介して抗体構築物に共有結合している、免疫複合体。
項2
前記抗体構築物が標的化結合ドメインを更に含む、項1に記載の免疫複合体。
項3
前記抗体構築物が抗体である、項1に記載の免疫複合体。
項4
前記抗原結合ドメインが癌細胞の抗原に結合する、項1~3のいずれか一項に記載の免疫複合体。
項5
前記抗原結合ドメインが、CDH1、CD19、CD20、CD29、CD30、CD38、CD40、CD47、EpCAM、MUC1、MUC16、EGFR、VEGF、HER2、SLAMF7、PDGFRa及びgp75からなる群から選択される抗原に結合する、項1~4のいずれか一項に記載の免疫複合体。
項6
前記抗体が、オララツマブ、オビヌツズマブ、トラスツズマブ、セツキシマブ、リツキシマブ、ペルツズマブ、ベバシズマブ、ダラツムマブ、エタネルセプト、及びエロツズマブからなる群から選択される、項3~4のいずれか一項に記載の免疫複合体。
項7
前記抗体が、免疫チェックポイント阻害剤の抗原に結合する、項3~4のいずれか一項に記載の免疫複合体。
項8
前記抗体が、CTLA4、PD-1、PD-L1、PD-L2、LAG-3、B7-H4、KIR、TNFRSF4、OX40L、IDO-1、IDO-2、CEACAM1、BTLA、TIM3、A2Ar、及びVISTAからなる群から選択される抗原に結合する、項3~4のいずれか一項に記載の免疫複合体。
項9
前記抗体が、ペンブロリズマブ、ニボルマブ、アテゾリズマブ、及びイピリムマブからなる群から選択される、項3~4のいずれか一項に記載の免疫複合体。
項10
前記抗体が、CLEC4C(BDCA-2、DLEC、CD303、CLECSF7)、CLEC4D(MCL、CLECSF8)、CLEC4E(Mincle)、CLEC6A(Dectin-2)、CLEC5A(MDL-1、CLECSF5)、CLEC1B(CLEC-2)、CLEC9A(DNGR-1)、及びCLEC7A(Dectin-1)からなる群から選択される抗原に結合する、項3~4のいずれか一項に記載の免疫複合体。
項11
前記抗体が、IgG1抗体である、項3~4のいずれか一項に記載の免疫複合体。
項12
前記抗体が、ペンブロリズマブ、ニボルマブ、アテゾリズマブ、イピリムマブ、オビヌツズマブ、トラスツズマブ、セツキシマブ、リツキシマブ、ペルツズマブ、ベバシズマブ、ダラツムマブ、エタネルセプト、オララツマブ、及びエロツズマブからなる群から選択される抗体のバイオシミラーである、項3~4のいずれか一項に記載の免疫複合体。
項13
前記抗体が、修飾されたFc領域を含む、項3~4のいずれか一項に記載の免疫複合体。
項14
前記免疫複合体が、式Iの構造体、
又はその薬学的に許容される塩を有し、式中、Abは抗体であり、Aは、前記抗体中の未修飾アミノ酸側鎖、又は前記抗体中の修飾アミノ酸側鎖であり、Zは連結部分であり、Adjはアジュバント部分であり、下付き文字rは、1~10の整数である、項1~13のいずれか一項に記載の免疫複合体。
項15
前記免疫複合体が、式Iaの構造体、
又はその薬学的に許容される塩を有し、式中、
Abは抗体であり、
Aは、前記抗体中の未改変アミノ酸側鎖、又は前記抗体中の改変アミノ酸側鎖であり、
Zは連結部分であり、
R 1 は、H及びC 1~4 アルキルから選択され、又は、
Z、R 1 、及び結合先である窒素原子は、5~8員複素環を含む連結部分を形成し、
各Yは、独立して、CHR 2 であり、式中、R 2 は、H、OH、及びNH 2 から選択され、
R 3 は、C 1~6 アルキル及び2~6員ヘテロアルキルから選択され、それぞれは、ハロ、ヒドロキシ、アミノ、オキソ(=O)、アルキルアミノ、アミド、アシル、ニトロ、シアノ、及びアルコキシからなる群から選択される、1つ又は2つ以上のメンバーで任意に置換され、
Xは、O及びCH 2 から選択され、
下付き文字nは、1~12の整数であり、
下付き文字rは、1~10の整数である、項14に記載の免疫複合体。
項16
前記免疫複合体が、式Ibの構造体、
又はその薬学的に許容される塩を有し、式中、
Abは抗体であり、
Aは、前記抗体中の未改変アミノ酸側鎖、又は前記抗体中の改変アミノ酸側鎖であり、
Zは連結部分であり、
R 1 は、H及びC 1~4 アルキルから選択され、又は、
Z、R 1 、及び結合先である窒素原子は、5~8員複素環を含む連結部分を形成し、
各Yは、独立して、CHR 2 であり、式中、R 2 は、H、OH、及びNH 2 から選択され、
Xは、O及びCH 2 から選択され、
下付き文字nは、1~12の整数であり、
Wは、O、及びCH 2 からなる群から選択される、項15に記載の免疫複合体。
項17
前記免疫複合体が、式Icの構造体、
又はその薬学的に許容される塩を有し、式中、
Abは抗体であり、
下付き文字rは、1~10の整数であり、
Aは、前記抗体中の未改変アミノ酸側鎖、又は前記抗体中の改変アミノ酸側鎖であり、
Zは連結部分であり、
R 1 は、H及びC 1~4 アルキルから選択され、又は、
Z、R 1 、及び結合先である窒素原子は、5~8員複素環を含む連結部分を形成し、
R 2 は、H、OH、及びNH 2 から選択される、項16に記載の免疫複合体。
項18
前記免疫複合体が、式Idの構造体、
又はその薬学的に許容される塩を有し、式中、Abは抗体であり、Aは、前記抗体中の未修飾アミノ酸側鎖、又は前記抗体中の修飾アミノ酸側鎖であり、R 2 は、H、OH、及びNH 2 から選択され、下付き文字rは、1~10の整数である、項17に記載の免疫複合体。
項19
前記免疫複合体が、式IIの構造体、
又はその薬学的に許容される塩を有し、式中、Abは抗体であり、Aは、前記抗体中の未修飾アミノ酸側鎖、又は前記抗体中の修飾アミノ酸側鎖であり、Adjはアジュバント部分であり、下付き文字rは、1~10の整数であり、
Z 1 は、-C(O)-、-C(O)NH-、-CH 2 -から選択され、
Z 2 及びZ 4 は、独立して、結合、C 1~30 アルキレン、及び3~30員ヘテロアルキレンから選択され、このとき、
C 1~30 アルキレン及び3~30員ヘテロアルキレン中の隣接する原子のうち1つ又は2つ以上のグループは、任意にかつ独立して、-C(O)-、-NR a C(O)-、又は-C(O)NR a -で置換され、
C 1~30 アルキレン及び3~30員ヘテロアルキレン中の隣接する原子のうち1つ又は2つ以上のグループは、任意にかつ独立して、4~8員の二価炭素環で置換され、
C 1~30 アルキレン及び3~30員ヘテロアルキレン中の隣接する原子のうち1つ又は2つ以上のグループは、任意にかつ独立して、O、S、及びNから選択される1~4つのヘテロ原子を有する4~8員の二価複素環で置換され、
各R a は、H及びC 1~6 アルキルから独立して選択され、
Z 3 は、結合、二価ペプチド部分、二価ポリマー部分から選択され、
Z 5 は、前記抗体中のアミノ酸側鎖の側鎖に結合される、項1~13のいずれか一項に記載の免疫複合体。
項20
前記免疫複合体が、式IIIの構造体、
又は薬学的に許容されるその塩を有し、式中、Abは、少なくとも1つのリジン側鎖を有する抗体であり、Adjはアジュバントであり、Gは、CH 2 、C=O、又は結合であり、Lはリンカーであり、下付き文字rは、1~10の整数である、項1~13のいずれか一項に記載の免疫複合体。
項21
前記アジュバント部分が、パターン認識受容体(PRR)アゴニストである、項1~20のいずれか一項に記載の免疫複合体。
項22
前記アジュバント部分が、次式のものであり、
式中、各Jは、独立して、水素、OR 4 、又はR 4 であり、各R 4 は、独立して、水素、又は、1~8個の炭素単位を含むアルキル、ヘテロアルキル、シクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリール、アリールアルキル、若しくはヘテロアリールアルキル基であり、Qは任意に存在し、1~8個の炭素単位を含むアルキル、ヘテロアルキル、シクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリール、アリールアルキル、又はヘテロアリールアルキル基であり、破線
は、アジュバントに結合する点を表す、項1~20のいずれか一項に記載の免疫複合体。
項23
前記アジュバント部分が、次式のものであり、
式中、Jは、水素、OR 4 、又はR 4 であり、各R 4 は、独立して、水素、又は、1~8個の炭素単位を含むアルキル、ヘテロアルキル、シクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリール、アリールアルキル、若しくはヘテロアリールアルキル基であり、Qは、1~8個の炭素単位を含むアルキル、ヘテロアルキル、シクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリール、アリールアルキル、又はヘテロアリールアルキル基からなる群から選択され、破線
は、アジュバントに結合する点を表す、項1~20のいずれか一項に記載の免疫複合体。
項24
前記アジュバント部分が、次式のものであり、
式中、各R 4 は、独立して、水素、又は、1~8個の炭素単位を含むアルキル、ヘテロアルキル、シクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリール、アリールアルキル、若しくはヘテロアリールアルキル基であり、Qは、1~8個の炭素単位を含むアルキル、ヘテロアルキル、シクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリール、アリールアルキル、又はヘテロアリールアルキル基であり、破線
は、アジュバントに結合する点を表す、項1~20のいずれか一項に記載の免疫複合体。
項25
前記アジュバント部分が、次式のものであり、
式中、各Jは、独立して、水素、OR 4 、又はR 4 であり、各R 4 は、独立して、水素、又は1~8個の炭素単位を含むアルキル、ヘテロアルキル、シクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリール、アリールアルキル、若しくはヘテロアリールアルキル基であり、各Uは、独立して、CH又はNであり、このとき少なくとも1つのUがNであり、各下付き文字tは、1~3の整数であり、Qは任意に存在し、1~8個の炭素単位を含むアルキル、ヘテロアルキル、シクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリール、アリールアルキル、又はヘテロアリールアルキル基であり、破線
は、アジュバントに結合する点を表す、項1~20のいずれか一項に記載の免疫複合体。
項26
前記アジュバント部分が、次式のものであり、
式中、Jは、水素、OR 4 、又はR 4 であり、各R 4 は、独立して、水素、又は1~8個の炭素単位を含むアルキル、ヘテロアルキル、シクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリール、アリールアルキル、若しくはヘテロアリールアルキル基であり、R 5 は、水素、又は、1~10個の炭素単位を含むアルキル、ヘテロアルキル、シクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリール、アリールアルキル、若しくはヘテロアリールアルキル基であり、Qは、1~8個の炭素単位を含むアルキル、ヘテロアルキル、シクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリール、アリールアルキル、若しくはヘテロアリールアルキル基であり、破線
は、アジュバントに結合する点を表す、項1~20のいずれか一項に記載の免疫複合体。
項27
前記アジュバント部分が、次式のものであり、
式中、R 1 は、H及びC 1~4 アルキルから選択され、R 3 は、C 1~6 アルキル及び2~6員ヘテロアルキルから選択され、これらはそれぞれ、ハロ、ヒドロキシ、アミノ、オキソ(=O)、アルキルアミノ、アミド、アシル、ニトロ、シアノ、及びアルコキシからなる群から選択される1つ又は2つ以上のメンバーで任意に置換され、Xは、O及びCH 2 から選択され、各Yは、独立して、CHR 2 であり、このとき、R 2 は、H、OH、及びNH 2 から選択され、下付き文字nは、1~12の整数であり、破線
は、アジュバントに結合する点を表す、項1~20のいずれか一項に記載の免疫複合体。
項28
前記アジュバント部分が、次のものであり、
式中、破線
は、アジュバントに結合する点を表す、項1~20のいずれか一項に記載の免疫複合体。
項29
複数の、項11~28のいずれか一項に記載の免疫複合体を含む、組成物。
項30
治療有効量の、項1~28のいずれか一項に記載の免疫複合体、又は、項29に記載の組成物をこれらが必要な被検体に投与することを含む、癌の治療方法。
Claims (30)
- (a)(i)抗原結合ドメイン、及び(ii)Fcドメイン、を含む抗体構築物と、
(b)式:
(式中、各Jは、独立して、水素、OR4、又はR4であり、各R4は、独立して、水素、又は1~8個の炭素単位を含むアルキル、ヘテロアルキル、シクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリール、アリールアルキル、若しくはヘテロアリールアルキル基であり、各Uは、独立して、CH又はNであり、このとき少なくとも1つのUがNであり、各下付き文字tは、独立して、1~3の整数であり、Qは任意に存在し、1~8個の炭素単位を含むアルキル、ヘテロアルキル、シクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリール、アリールアルキル、又はヘテロアリールアルキル基であり、破線
は、(c)リンカーに結合するアジュバントの点を表す)
のアジュバント部分と、
(c)リンカーと、
を含み、
アジュバント部分が前記リンカーを介して抗体構築物に共有結合している、
免疫複合体。 - 各Jが水素である、請求項1に記載の免疫複合体。
- Qが存在しない、請求項1又は2に記載の免疫複合体。
- 各UがNであり、各下付き文字tは2である、請求項1~3のいずれかに記載の免疫複合体。
- 各R4が1~8個の炭素単位を含むヘテロアルキル基である、請求項1~4のいずれかnい記載の免疫複合体。
- 各R4が1~8個の炭素単位を含むアルキル基である、請求項1~4のいずれかに記載の免疫複合体。
- 各R4がブチルである、請求項1~4のいずれかに記載の免疫複合体。
- 前記抗原結合ドメインが、CDH1、CD19、CD20、CD29、CD30、CD38、CD40、CD47、EpCAM、MUC1、MUC16、EGFR、VEGF、HER2、SLAMF7、PDGFRa、gp75、CTLA4、PD-1、PD-L1、PD-L2、LAG-3、B7-H4、KIR、TNFRSF4、OX40L、IDO-1、IDO-2、CEACAM1、BTLA、TIM3、A2Ar、VISTA、CLEC4C(BDCA-2、DLEC、CD303、CLECSF7)、CLEC4D(MCL、CLECSF8)、CLEC4E(Mincle)、CLEC6A(Dectin-2)、CLEC5A(MDL-1、CLECSF5)、CLEC1B(CLEC-2)、CLEC9A(DNGR-1)、及びCLEC7A(Dectin-1)からなる群から選択される抗原に結合する、請求項1~8のいずれかに記載の免疫複合体。
- 前記抗原結合ドメインが、EGFR、HER2、PD-L1、又はCD20に結合する、請求項1~9のいずれかに記載の免疫複合体。
- 前記抗体構築物が抗体である、請求項1~10のいずれかに記載の免疫複合体。
- 前記抗体が、ペンブロリズマブ、ニボルマブ、アテゾリズマブ、アベルマブ、イピリムマブ、オビヌツズマブ、トラスツズマブ、セツキシマブ、リツキシマブ、ペルツズマブ、ベバシズマブ、ダラツムマブ、エタネルセプト、オララツマブ、エロツズマブ、マルジェツキシマブ、及びこれらのバイオシミラーからなる群から選択される、請求項11に記載の免疫複合体。
- 前記抗体が、トラスツズマブ又はそのバイオシミラーである、請求項11又は12に記載の免疫複合体。
- 前記抗体が、修飾されたFcドメインを含む、請求項11~13のいずれかに記載の免疫複合体。
- (i)前記修飾されたFcドメインが、少なくとも1つのアミノ酸の挿入、欠失、又は置換を含むか、及び/又は
(ii)前記修飾されたFcドメインが、脱グリコシル化又は非フコシル化されている、請求項14に記載の免疫複合体。 - 式II:
(式中、Abは
が、前記抗体構築物のアミノ酸残基である抗体構築物であり、
Aは、前記アミノ酸残基のリジン側鎖、チオール修飾リジン側鎖、又はシステイン側鎖であり、
Adjはアジュバント部分であり、
下付き文字rは、1~10の整数であり、
Z1は、-C(O)-、-C(O)NH-、及び-CH2-から選択され、
Z2及びZ4は、各々独立して、結合、C1~30アルキレン、及び3~30員ヘテロアルキレンから選択され、ここで、
C1~30アルキレン及び3~30員ヘテロアルキレン中の隣接する原子の1つ以上の群は、任意にかつ独立して、-C(O)-、-NRaC(O)-、又は-C(O)NRa-で置換され、各Raは、H及びC1~6アルキルから独立して選択され、
C1~30アルキレン及び3~30員ヘテロアルキレン中の隣接する原子の1つ以上の群は、任意にかつ独立して、4~8員の二価炭素環で置換され、
C1~30アルキレン及び3~30員ヘテロアルキレン中の隣接する原子の1つ以上の群は、任意にかつ独立して、O、S、及びNから選択される1~4つのヘテロ原子を有する4~8員の二価複素環で置換され、
Z3は、結合、二価ペプチド部分、又は二価ポリマー部分であり、
Z5は、アミン結合部分、及びチオール結合部分から選択される)の構造を有する免疫複合体又はその薬学的に許容可能な塩である、請求項1~15のいずれかに記載の免疫複合体。 - Gは結合である、請求項18~20のいずれかに記載の免疫複合体。
- aは1~10である、請求項19~21のいずれかに記載の免疫複合体。
- 下付文字rは1~5の整数である、請求項16~22のいずれかに記載の免疫複合体。
- aは1~20の整数である、請求項24に記載の免疫複合体。
- aは、1~10の整数である、請求項24又は25に記載の免疫複合体。
- 請求項1~26のいずれかに記載の免疫複合体又はその薬学的に許容可能な塩を複数含む組成物。
- 免疫複合体又はその薬学的に許容可能な塩当たりのアジュバント部分の平均値が約1~約4である、請求項27に記載の組成物。
- 1種以上の薬学的に許容可能な賦形剤をさらに含む、請求項27又は28に記載の組成物。
- 癌を治療するための、請求項1~26のいずれかに記載の免疫複合体又は請求項27~29のいずれかに記載の組成物。
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US10675358B2 (en) | 2020-06-09 |
US20200206357A1 (en) | 2020-07-02 |
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AU2017292934A1 (en) | 2019-01-17 |
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