JPWO2020035577A5 - - Google Patents

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JPWO2020035577A5
JPWO2020035577A5 JP2021507831A JP2021507831A JPWO2020035577A5 JP WO2020035577 A5 JPWO2020035577 A5 JP WO2020035577A5 JP 2021507831 A JP2021507831 A JP 2021507831A JP 2021507831 A JP2021507831 A JP 2021507831A JP WO2020035577 A5 JPWO2020035577 A5 JP WO2020035577A5
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Priority claimed from PCT/EP2019/071974 external-priority patent/WO2020035577A1/en
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インターロイキン－１受容体アクセサリータンパク質（ＩＬ１ＲＡＰ）に特異性を有する第１の結合剤およびＩＬ１ＲＡＰに特異性を有する第２の結合剤を少なくとも含む組成物であって、前記第１および第２の結合剤がＩＬ１ＲＡＰの少なくとも２つの異なる細胞外ドメインに結合する、前記組成物。 A composition comprising at least a first binding agent having specificity for interleukin-1 receptor accessory protein (IL1RAP) and a second binding agent having specificity for IL1RAP, wherein said first and second bindings are Said composition, wherein the agent binds to at least two different extracellular domains of IL1RAP. 前記第１および第２の結合剤のそれぞれが、抗ＩＬ１ＲＡＰ抗体または抗原結合断片である、請求項１に記載の組成物。 2. The composition of claim 1, wherein each of said first and second binding agents is an anti-IL1RAP antibody or antigen-binding fragment. ａ）第１の結合剤が：
ｉ）参照抗体「ＣＡＮ０４」；
ｉｉ）可変軽鎖（ＶL）アミノ酸配列：ＤＩＱＭＴＱＳＰＳＳＬＳＡＳＶＧＤＲＶＴＩＴＣＱＡＳＱＧＩＮＮＹＬＮＷＹＱＱＫＰＧＫＡＰＫＬＬＩＨＹＴＳＧＬＨＡＧＶＰＳＲＦＳＧＳＧＳＧＴＤＹＴＬＴＩＳＳＬＥＰＥＤＶＡＴＹＹＣＱＱＹＳＩＬＰＷＴＦＧＧＧＴＫＶＥＩＫＲ（配列番号１）、および可変重鎖（ＶH）アミノ酸配列：ＱＶＱＬＶＱＳＧＡＥＶＫＫＰＧＳＳＶＫＶＳＣＫＡＳＧＹＡＦＴＳＳＷＭＮＷＶＲＱＡＰＧＱＧＬＥＷＭＧＲＩＹＰＧＤＧＮＴＨＹＡＱＫＦＱＧＲＶＴＬＴＡＤＫＳＴＳＴＡＹＭＥＬＳＳＬＲＳＥＤＴＡＶＹＹＣＧＥＧＹＬＤＰＭＤＹＷＧＱＧＴＬＶＴＶＳＳ（配列番号４）を含む、抗体；
ｉｉｉ）下記の６つの相補性決定領域（ＣＤＲ）のうちの少なくとも１つを含む抗体：
軽鎖ＣＤＲ１：ＳＡＳＱＧＩＮＮＹＬＮ（配列番号８）またはＡＳＱＧＩＮＮＹＬＮ（配列番号２９）
軽鎖ＣＤＲ２：ＹＴＳＧＬＨＡＧＶ（配列番号９）またはＹＴＳＧＬＨＡ（配列番号２２）
軽鎖ＣＤＲ３：ＱＱＹＳＩＬＰＷＴ（配列番号１０）またはＱＹＳＩＬＰＷＴ（配列番号２３）
重鎖ＣＤＲ１：ＧＹＡＦＴＳＳＳＷＭＮ（配列番号１１）またはＧＹＡＦＴＳＳ（配列番号２４）
重鎖ＣＤＲ２：ＲＩＹＰＧＤＧＮＴＨＹＡＱＫＦＱＧ（配列番号１２）またはＹＰ
ＧＤＧＮ（配列番号２５）
重鎖ＣＤＲ３：ＧＹＬＤＰＭＤＹ（配列番号１３）；
ｉｖ）上記ｉ）の抗体と同じエピトープに結合する抗体；
ｖ）上記ｉ）の抗体のヒトＩＬ１ＲＡＰへの結合を阻害することができる抗体；
ｖｉ）ＩＬ１ＲＡＰの細胞外ドメイン２に結合することができる抗体；ならびに、
ｖｉｉ）上記ｉ）～ｖｉ）の抗体の抗原結合断片、
からなる群から選択される、抗ＩＬ１ＲＡＰ抗体またはその抗原結合断片であり；
ならびに、
ｂ）第２の結合剤が：
ｉ）参照抗体「ＣＡＮ０３」；
ｉｉ）可変軽鎖（ＶL）アミノ酸配列：ＤＩＬＬＴＱＳＰＡＩＬＳＶＳＰＧＥＲＶＳＦＳＣＲＡＳＱＳＩＧＴＳＩＨＷＹＱＲＲＴＮＧＳＰＲＬＬＩＫＳＡＳＥＳＩＳＧＩＰＳＲＦＳＧＳＧＳＧＴＤＦＴＬＳＩＮＳＶＥＳＥＤＩＡＤＹＹＣＱＱＳＮＳＷＰＴＴＦＧＡＧＴＫＬＥＬＫＲ（配列番号１４）、および可変重鎖（ＶH）アミノ酸配列：ＤＶＫＬＶＥＳＧＧＧＬＶＫＰＧＧＳＬＫＬＳＣＡＡＳＧＦＴＦＳＩＹＴＭＳＷＶＲＱＴＰＥＫＲＬＥＷＶＡＴＩＳＩＧＧＳＹＩＮＹＰＤＳＶＫＧＲＦＴＩＳＲＤＮＡＫＮＴＬＹＬＱＭＳＳＬＫＳＥＤＴＡＩＹＹＣＳＲＥＶＤＧＳＹＡＭＤＹＷＧＱＧＴＳＶＴＶＳＳ（配列番号１５）を含む、抗体；
ｉｉｉ）下記の６つの相補性決定領域（ＣＤＲ）のうちの少なくとも１つを含む抗体：
軽鎖ＣＤＲ１：ＲＡＳＱＳＩＧＴＳＩＨ（配列番号１６）またはＡＳＱＳＩＧＴＳＩＨ（配列番号３０）
軽鎖ＣＤＲ２：ＳＡＳＥＳＩＳ（配列番号１７）
軽鎖ＣＤＲ３：ＱＱＳＮＳＷＰＴＴ（配列番号１８）またはＱＳＮＳＷＰＴＴ（配列番号２６）
重鎖ＣＤＲ１：ＧＦＴＦＳＩＹＴＭＳ（配列番号１９）またはＧＦＴＦＳＩＹ（配列番号２７）
重鎖ＣＤＲ２：ＴＩＳＩＧＧＳＹＩＮＹＰＤＳＶＫＧ（配列番号２０）またはＳＩＧＧＳＹ（配列番号２８）
重鎖ＣＤＲ３：ＥＶＤＧＳＹＡＭＤＹ（配列番号２１）；
ｉｖ）上記ｉ）の抗体と同じエピトープに結合する抗体；
ｖ）上記ｉ）の抗体のヒトＩＬ１ＲＡＰへの結合を阻害することができる抗体；
ｖｉ）ＩＬ１ＲＡＰの細胞外ドメイン３に結合することができる抗体；ならびに、
ｖｉｉ）上記ｉ）～ｖｉ）の抗体の抗原結合断片、
からなる群から選択される、抗ＩＬ１ＲＡＰ抗体またはその抗原結合断片であり；
場合により：
前記（ａ）ｉｉｉ）の抗体が、前記ＣＤＲのうちの少なくとも１つ、例えば少なくとも２つ、例えば少なくとも３つ、例えば少なくとも４つ、例えば少なくとも５つ、例えば前記ＣＤＲのうちの６つすべてを含み、場合により、前記抗体が、３つすべての軽鎖ＣＤＲおよび／もしくは３つすべての重鎖ＣＤＲを含み；
ならびに／または、
前記（ｂ）ｉｉｉ）の抗体が、前記ＣＤＲのうちの少なくとも１つ、例えば少なくとも２つ、例えば少なくとも３つ、例えば少なくとも４つ、例えば少なくとも５つ、例えば前記ＣＤＲのうちの６つすべてを含み、場合により、前記抗体が、３つすべての軽鎖ＣＤＲおよび／もしくは３つすべての重鎖ＣＤＲを含む、
請求項１または２に記載の組成物。 a) the first binder is:
i) the reference antibody "CAN04";
ｉｉ）可変軽鎖（Ｖ L ）アミノ酸配列：ＤＩＱＭＴＱＳＰＳＳＬＳＡＳＶＧＤＲＶＴＩＴＣＱＡＳＱＧＩＮＮＹＬＮＷＹＱＱＫＰＧＫＡＰＫＬＬＩＨＹＴＳＧＬＨＡＧＶＰＳＲＦＳＧＳＧＳＧＴＤＹＴＬＴＩＳＳＬＥＰＥＤＶＡＴＹＹＣＱＱＹＳＩＬＰＷＴＦＧＧＧＴＫＶＥＩＫＲ（配列番号１）、および可変重鎖（Ｖ H ）アミノ酸配列：ＱＶＱＬＶＱＳＧＡＥＶＫＫＰＧＳＳＶＫＶＳＣＫＡＳＧＹＡＦＴＳＳＷＭＮＷＶＲＱＡＰＧＱＧＬＥＷＭＧＲＩＹＰＧＤＧＮＴＨＹＡＱＫＦＱＧＲＶＴＬＴＡＤＫＳＴＳＴＡＹＭＥＬＳＳＬＲＳＥＤＴＡＶＹＹＣＧＥＧＹＬＤＰＭＤＹＷＧＱＧＴＬＶＴＶＳＳ（配列番号４）を含む、抗体；
iii) an antibody comprising at least one of the following six complementarity determining regions (CDRs):
Light chain CDR1: SASQGINNYLN (SEQ ID NO:8) or ASQGINNYLN (SEQ ID NO:29)
Light chain CDR2: YTSGLHAGV (SEQ ID NO:9) or YTSGLHA (SEQ ID NO:22)
Light chain CDR3: QQYSILPWT (SEQ ID NO: 10) or QYSILPWT (SEQ ID NO: 23)
Heavy chain CDR1: GYAFTSSSWMN (SEQ ID NO: 11) or GYAFTSS (SEQ ID NO: 24)
Heavy chain CDR2: RIYPGDGNTHYAQKFQG (SEQ ID NO: 12) or YP
GDGN (SEQ ID NO: 25)
heavy chain CDR3: GYLDPMDY (SEQ ID NO: 13);
iv) an antibody that binds to the same epitope as the antibody in i) above;
v) an antibody capable of inhibiting the binding of the antibody of i) above to human IL1RAP;
vi) an antibody capable of binding to extracellular domain 2 of IL1RAP; and
vii) an antigen-binding fragment of the antibody of i) to vi) above;
An anti-IL1RAP antibody or antigen-binding fragment thereof selected from the group consisting of;
and
b) the second binder is:
i) reference antibody "CAN03";
ｉｉ）可変軽鎖（Ｖ L ）アミノ酸配列：ＤＩＬＬＴＱＳＰＡＩＬＳＶＳＰＧＥＲＶＳＦＳＣＲＡＳＱＳＩＧＴＳＩＨＷＹＱＲＲＴＮＧＳＰＲＬＬＩＫＳＡＳＥＳＩＳＧＩＰＳＲＦＳＧＳＧＳＧＴＤＦＴＬＳＩＮＳＶＥＳＥＤＩＡＤＹＹＣＱＱＳＮＳＷＰＴＴＦＧＡＧＴＫＬＥＬＫＲ（配列番号１４）、および可変重鎖（Ｖ H ）アミノ酸配列：ＤＶＫＬＶＥＳＧＧＧＬＶＫＰＧＧＳＬＫＬＳＣＡＡＳＧＦＴＦＳＩＹＴＭＳＷＶＲＱＴＰＥＫＲＬＥＷＶＡＴＩＳＩＧＧＳＹＩＮＹＰＤＳＶＫＧＲＦＴＩＳＲＤＮＡＫＮＴＬＹＬＱＭＳＳＬＫＳＥＤＴＡＩＹＹＣＳＲＥＶＤＧＳＹＡＭＤＹＷＧＱＧＴＳＶＴＶＳＳ（配列番号１５）を含む、抗体；
iii) an antibody comprising at least one of the following six complementarity determining regions (CDRs):
Light chain CDR1: RASQSIGTSIH (SEQ ID NO: 16) or ASQSIGTSIH (SEQ ID NO: 30)
Light chain CDR2: SASESIS (SEQ ID NO: 17)
Light chain CDR3: QQSNSWPTT (SEQ ID NO: 18) or QSNSWPTT (SEQ ID NO: 26)
Heavy chain CDR1: GFTFSIYTMS (SEQ ID NO: 19) or GFTFSIY (SEQ ID NO: 27)
Heavy chain CDR2: TISIGGSYINYPDSVKG (SEQ ID NO:20) or SIGGSY (SEQ ID NO:28)
Heavy chain CDR3: EVDGSYAMDY (SEQ ID NO: 21);
iv) an antibody that binds to the same epitope as the antibody in i) above;
v) an antibody capable of inhibiting the binding of the antibody of i) above to human IL1RAP;
vi) an antibody capable of binding to the extracellular domain 3 of IL1RAP; and
vii) an antigen-binding fragment of the antibody of i) to vi) above;
An anti-IL1RAP antibody or antigen-binding fragment thereof selected from the group consisting of;
Occasionally:
said antibody of (a)iii) comprises at least one, such as at least two, such as at least three, such as at least four, such as at least five, such as all six of said CDRs , optionally, said antibody comprises all three light chain CDRs and/or all three heavy chain CDRs;
and/or
said antibody of (b)iii) comprises at least one, such as at least two, such as at least three, such as at least four, such as at least five, such as all six of said CDRs , optionally, said antibody comprises all three light chain CDRs and/or all three heavy chain CDRs,
3. A composition according to claim 1 or 2. 前記第１の結合剤が：
ａ）配列番号４のアミノ酸配列を含む可変重鎖（ＶH）、および配列番号１のアミノ酸配列を含む可変軽鎖（ＶL）；
ｂ）配列番号５のアミノ酸配列を含む可変重鎖（ＶH）、および配列番号１のアミノ酸配列を含む可変軽鎖（ＶL）；
ｃ）配列番号６のアミノ酸配列を含む可変重鎖（ＶH）、および配列番号１のアミノ酸配列を含む可変軽鎖（ＶL）；
ｄ）配列番号７のアミノ酸配列を含む可変重鎖（ＶH）、および配列番号１のアミノ酸配列を含む可変軽鎖（ＶL）；
ｅ）配列番号４のアミノ酸配列を含む可変重鎖（ＶH）、および配列番号２のアミノ酸配列を含む可変軽鎖（ＶL）；
ｆ）配列番号５のアミノ酸配列を含む可変重鎖（ＶH）、および配列番号２のアミノ酸配列を含む可変軽鎖（ＶL）；
ｇ）配列番号６のアミノ酸配列を含む可変重鎖（ＶH）、および配列番号２のアミノ酸配列を含む可変軽鎖（ＶL）；
ｈ）配列番号７のアミノ酸配列を含む可変重鎖（ＶH）、および配列番号２のアミノ酸配列を含む可変軽鎖（ＶL）；
ｉ）配列番号４のアミノ酸配列を含む可変重鎖（ＶH）、および配列番号３のアミノ酸
配列を含む可変軽鎖（ＶL）；
ｊ）配列番号５のアミノ酸配列を含む可変重鎖（ＶH）、および配列番号３のアミノ酸配列を含む可変軽鎖（ＶL）；
ｋ）配列番号６のアミノ酸配列を含む可変重鎖（ＶH）、および配列番号３のアミノ酸配列を含む可変軽鎖（ＶL）；ならびに、
ｌ）配列番号７のアミノ酸配列を含む可変重鎖（ＶH）、および配列番号３のアミノ酸配列を含む可変軽鎖（ＶL）、
からなる群から選択される可変重鎖（ＶH）、および可変軽鎖（ＶL）を含む、抗ＩＬ１ＲＡＰ抗体またはその抗原結合断片である、請求項１～３のいずれか１項に記載の組成物。 The first binder is:
a) a variable heavy chain ( VH ) comprising the amino acid sequence of SEQ ID NO:4 and a variable light chain ( VL ) comprising the amino acid sequence of SEQ ID NO:1;
b) a variable heavy chain ( VH ) comprising the amino acid sequence of SEQ ID NO:5 and a variable light chain ( VL ) comprising the amino acid sequence of SEQ ID NO:1;
c) a variable heavy chain ( VH ) comprising the amino acid sequence of SEQ ID NO:6 and a variable light chain ( VL ) comprising the amino acid sequence of SEQ ID NO:1;
d) a variable heavy chain ( VH ) comprising the amino acid sequence of SEQ ID NO:7 and a variable light chain ( VL ) comprising the amino acid sequence of SEQ ID NO:1;
e) a variable heavy chain ( VH ) comprising the amino acid sequence of SEQ ID NO:4 and a variable light chain ( VL ) comprising the amino acid sequence of SEQ ID NO:2;
f) a variable heavy chain ( VH ) comprising the amino acid sequence of SEQ ID NO:5 and a variable light chain ( VL ) comprising the amino acid sequence of SEQ ID NO:2;
g) a variable heavy chain ( VH ) comprising the amino acid sequence of SEQ ID NO:6 and a variable light chain ( VL ) comprising the amino acid sequence of SEQ ID NO:2;
h) a variable heavy chain ( VH ) comprising the amino acid sequence of SEQ ID NO:7 and a variable light chain ( VL ) comprising the amino acid sequence of SEQ ID NO:2;
i) a variable heavy chain ( VH ) comprising the amino acid sequence of SEQ ID NO:4 and a variable light chain ( VL ) comprising the amino acid sequence of SEQ ID NO:3;
j) a variable heavy chain ( VH ) comprising the amino acid sequence of SEQ ID NO:5 and a variable light chain ( VL ) comprising the amino acid sequence of SEQ ID NO:3;
k) a variable heavy chain (V H ) comprising the amino acid sequence of SEQ ID NO: 6 and a variable light chain (V L ) comprising the amino acid sequence of SEQ ID NO: 3;
l) a variable heavy chain (V H ) comprising the amino acid sequence of SEQ ID NO:7 and a variable light chain (V L ) comprising the amino acid sequence of SEQ ID NO:3;
The anti-IL1RAP antibody or antigen-binding fragment thereof according to any one of claims 1 to 3, which comprises a variable heavy chain (V H ) and a variable light chain (V L ) selected from the group consisting of Composition. ａ）前記第１の結合剤が：
配列番号１、２、もしくは３のアミノ酸配列を含む、もしくはそれからなる軽鎖可変ドメイン（ＶL）；および、
配列番号４、５、６、もしくは７のアミノ酸配列を含む、もしくはそれからなる重鎖可変ドメイン（ＶH）を含む、抗ＩＬ１ＲＡＰ抗体もしくはその抗原結合断片であり；ならびに、
ｂ）前記第２の結合剤が：
配列番号１４のアミノ酸配列を含む、もしくはそれからなる軽鎖可変ドメイン（ＶL）；および、
配列番号１５のアミノ酸を含む、もしくはそれからなる重鎖可変ドメイン（ＶH）を含む、抗ＩＬ１ＲＡＰ抗体もしくはその抗原結合断片であり；
ならびに／または、
前記第１の結合剤が：
配列番号１のアミノ酸配列、もしくは配列番号１に対して少なくとも６０％の配列同一性、例えば少なくとも７０％の配列同一性、例えば少なくとも８０％の配列同一性、例えば少なくとも９０％の配列同一性、例えば少なくとも９５％の配列同一性、例えば少なくとも９７％の配列同一性、例えば少なくとも９８％の配列同一性、例えば少なくとも９９％の配列同一性を有するアミノ酸配列を含む、もしくはそれからなる可変軽鎖（ＶL）；
配列番号４のアミノ酸配列、もしくは配列番号４に対して少なくとも６０％の配列同一性、例えば少なくとも７０％の配列同一性、例えば少なくとも８０％の配列同一性、例えば少なくとも９０％の配列同一性、例えば少なくとも９５％の配列同一性、例えば少なくとも９７％の配列同一性、例えば少なくとも９８％の配列同一性、例えば少なくとも９９％の配列同一性を有するアミノ酸配列を含む、もしくはそれからなる可変重鎖（ＶH）；
配列番号８もしくは配列番号２９のアミノ酸配列、もしくは配列番号８もしくは配列番号２９に対して少なくとも８０％の配列同一性、例えば少なくとも９０％の配列同一性、例えば少なくとも９５％の配列同一性、例えば少なくとも９７％の配列同一性、例えば少なくとも９８％の配列同一性、例えば少なくとも９９％の配列同一性をそれぞれ有するアミノ酸配列を含む、もしくはそれからなる軽鎖ＣＤＲ１；
配列番号９もしくは配列番号２２のアミノ酸配列、もしくは配列番号９もしくは配列番号２２に対して少なくとも８０％の配列同一性、例えば少なくとも９０％の配列同一性、例えば少なくとも９５％の配列同一性、例えば少なくとも９７％の配列同一性、例えば少なくとも９８％の配列同一性、例えば少なくとも９９％の配列同一性をそれぞれ有するアミノ酸配列を含む、もしくはそれからなる軽鎖ＣＤＲ２；
配列番号１０もしくは配列番号２３のアミノ酸配列、もしくは配列番号１０もしくは配列番号２３に対して少なくとも８０％の配列同一性、例えば少なくとも９０％の配列同一性、例えば少なくとも９５％の配列同一性、例えば少なくとも９７％の配列同一性、例えば少なくとも９８％の配列同一性、例えば少なくとも９９％の配列同一性をそれぞれ有するアミノ酸配列を含む、もしくはそれからなる軽鎖ＣＤＲ３；
配列番号１１もしくは配列番号２４のアミノ酸配列、もしくは配列番号１１もしくは配列番号２４に対して少なくとも８０％の配列同一性、例えば少なくとも９０％の配列同一性、例えば少なくとも９５％の配列同一性、例えば少なくとも９７％の配列同一性、例えば少なくとも９８％の配列同一性、例えば少なくとも９９％の配列同一性をそれぞれ有するアミノ酸配列を含む、もしくはそれからなる重鎖ＣＤＲ１；
配列番号１２もしくは配列番号２５のアミノ酸配列、もしくは配列番号１２もしくは配列番号２５に対して少なくとも８０％の配列同一性、例えば少なくとも９０％の配列同一性、例えば少なくとも９５％の配列同一性、例えば少なくとも９７％の配列同一性、例えば少なくとも９８％の配列同一性、例えば少なくとも９９％の配列同一性をそれぞれ有するアミノ酸配列を含む、もしくはそれからなる重鎖ＣＤＲ２；および／もしくは、
配列番号１３のアミノ酸配列、もしくは配列番号１３に対して少なくとも８０％の配列同一性、例えば少なくとも９０％の配列同一性、例えば少なくとも９５％の配列同一性、例えば少なくとも９７％の配列同一性、例えば少なくとも９８％の配列同一性、例えば少なくとも９９％の配列同一性をそれぞれ有するアミノ酸配列を含む、もしくはそれからなる重鎖ＣＤＲ３、
を含む、抗ＩＬ１ＲＡＰ抗体またはその抗原結合断片であり；
ならびに／もしくは
前記第２の結合剤が：
配列番号１４のアミノ酸配列、もしくは配列番号１４に対して少なくとも８０％の配列同一性、例えば少なくとも９０％の配列同一性、例えば少なくとも９５％の配列同一性、例えば少なくとも９７％の配列同一性、例えば少なくとも９８％の配列同一性、例えば少なくとも９９％の配列同一性をそれぞれ有するアミノ酸配列を含む、もしくはそれからなる可変軽鎖（ＶL）；
配列番号１５のアミノ酸配列、もしくは配列番号１５に対して少なくとも８０％の配列同一性、例えば少なくとも９０％の配列同一性、例えば少なくとも９５％の配列同一性、例えば少なくとも９７％の配列同一性、例えば少なくとも９８％の配列同一性、例えば少なくとも９９％の配列同一性をそれぞれ有するアミノ酸配列を含む、もしくはそれからなる可変重鎖（ＶH）；
配列番号１６もしくは配列番号３０のアミノ酸配列、もしくは配列番号１６もしくは配列番号３０に対して少なくとも８０％の配列同一性、例えば少なくとも９０％の配列同一性、例えば少なくとも９５％の配列同一性、例えば少なくとも９７％の配列同一性、例えば少なくとも９８％の配列同一性、例えば少なくとも９９％の配列同一性をそれぞれ有するアミノ酸配列を含む、もしくはそれからなる軽鎖ＣＤＲ１；
配列番号１７のアミノ酸配列、もしくは配列番号１７に対して少なくとも８０％の配列同一性、例えば少なくとも９０％の配列同一性、例えば少なくとも９５％の配列同一性
、例えば少なくとも９７％の配列同一性、例えば少なくとも９８％の配列同一性、例えば少なくとも９９％の配列同一性をそれぞれ有するアミノ酸配列を含む、もしくはそれからなる軽鎖ＣＤＲ２；
配列番号１８もしくは配列番号２６のアミノ酸配列、もしくは配列番号１８もしくは配列番号２６に対して少なくとも８０％の配列同一性、例えば少なくとも９０％の配列同一性、例えば少なくとも９５％の配列同一性、例えば少なくとも９７％の配列同一性、例えば少なくとも９８％の配列同一性、例えば少なくとも９９％の配列同一性をそれぞれ有するアミノ酸配列を含む、もしくはそれからなる軽鎖ＣＤＲ３；
配列番号１９もしくは配列番号２７のアミノ酸配列、もしくは配列番号１９もしくは配列番号２７に対して少なくとも８０％の配列同一性、例えば少なくとも９０％の配列同一性、例えば少なくとも９５％の配列同一性、例えば少なくとも９７％の配列同一性、例えば少なくとも９８％の配列同一性、例えば少なくとも９９％の配列同一性をそれぞれ有するアミノ酸配列を含む、もしくはそれからなる重鎖ＣＤＲ１；
配列番号２０もしくは配列番号２８のアミノ酸配列、もしくは配列番号２０もしくは配列番号２８に対して少なくとも８０％の配列同一性、例えば少なくとも９０％の配列同一性、例えば少なくとも９５％の配列同一性、例えば少なくとも９７％の配列同一性、例えば少なくとも９８％の配列同一性、例えば少なくとも９９％の配列同一性をそれぞれ有するアミノ酸配列を含む、もしくはそれからなる重鎖ＣＤＲ２；および／もしくは
配列番号２１のアミノ酸配列、もしくは配列番号２１に対して少なくとも８０％の配列同一性、例えば少なくとも９０％の配列同一性、例えば少なくとも９５％の配列同一性、例えば少なくとも９７％の配列同一性、例えば少なくとも９８％の配列同一性、例えば少なくとも９９％の配列同一性をそれぞれ有するアミノ酸配列を含む、もしくはそれからなる重鎖ＣＤＲ３、
を含む、抗ＩＬ１ＲＡＰ抗体またはその抗原結合断片である、
請求項１～４のいずれか１項に記載の組成物。 a) said first binder is:
a light chain variable domain ( VL ) comprising or consisting of the amino acid sequence of SEQ ID NO: 1, 2, or 3; and
an anti-IL1RAP antibody or antigen-binding fragment thereof comprising a heavy chain variable domain (V H ) comprising or consisting of the amino acid sequence of SEQ ID NOs: 4, 5, 6, or 7; and
b) said second binder is:
a light chain variable domain ( VL ) comprising or consisting of the amino acid sequence of SEQ ID NO: 14; and
an anti-IL1RAP antibody or antigen-binding fragment thereof comprising a heavy chain variable domain (V H ) comprising or consisting of the amino acids of SEQ ID NO: 15;
and/or
The first binder is:
The amino acid sequence of SEQ ID NO: 1, or at least 60% sequence identity, such as at least 70% sequence identity, such as at least 80% sequence identity, such as at least 90% sequence identity, such as at least 90% sequence identity, to SEQ ID NO: 1 A variable light chain (V L );
the amino acid sequence of SEQ ID NO:4, or at least 60% sequence identity, such as at least 70% sequence identity, such as at least 80% sequence identity, such as at least 90% sequence identity, such as at least 90% sequence identity, to SEQ ID NO:4 A variable heavy chain (V H );
The amino acid sequence of SEQ ID NO:8 or SEQ ID NO:29, or at least 80% sequence identity, such as at least 90% sequence identity, such as at least 95% sequence identity, such as at least a light chain CDR1 comprising or consisting of an amino acid sequence each having 97% sequence identity, such as at least 98% sequence identity, such as at least 99% sequence identity;
The amino acid sequence of SEQ ID NO:9 or SEQ ID NO:22, or at least 80% sequence identity, such as at least 90% sequence identity, such as at least 95% sequence identity, such as at least a light chain CDR2 comprising or consisting of an amino acid sequence each having 97% sequence identity, such as at least 98% sequence identity, such as at least 99% sequence identity;
The amino acid sequence of SEQ ID NO: 10 or SEQ ID NO: 23, or at least 80% sequence identity, such as at least 90% sequence identity, such as at least 95% sequence identity, such as at least a light chain CDR3 comprising or consisting of an amino acid sequence each having 97% sequence identity, such as at least 98% sequence identity, such as at least 99% sequence identity;
The amino acid sequence of SEQ ID NO: 11 or SEQ ID NO: 24, or at least 80% sequence identity, such as at least 90% sequence identity, such as at least 95% sequence identity, such as at least a heavy chain CDR1 comprising or consisting of an amino acid sequence each having 97% sequence identity, such as at least 98% sequence identity, such as at least 99% sequence identity;
The amino acid sequence of SEQ ID NO: 12 or SEQ ID NO: 25, or at least 80% sequence identity, such as at least 90% sequence identity, such as at least 95% sequence identity, such as at least a heavy chain CDR2 comprising or consisting of an amino acid sequence each having 97% sequence identity, such as at least 98% sequence identity, such as at least 99% sequence identity; and/or
the amino acid sequence of SEQ ID NO: 13, or at least 80% sequence identity, such as at least 90% sequence identity, such as at least 95% sequence identity, such as at least 97% sequence identity, to SEQ ID NO: 13, such as a heavy chain CDR3 comprising or consisting of an amino acid sequence each having at least 98% sequence identity, such as at least 99% sequence identity;
An anti-IL1RAP antibody or antigen-binding fragment thereof comprising
and/or wherein said second binding agent:
The amino acid sequence of SEQ ID NO: 14, or at least 80% sequence identity, such as at least 90% sequence identity, such as at least 95% sequence identity, such as at least 97% sequence identity, such as at least 97% sequence identity, to SEQ ID NO: 14 a variable light chain ( VL ) comprising or consisting of amino acid sequences each having at least 98% sequence identity, such as at least 99% sequence identity;
the amino acid sequence of SEQ ID NO: 15, or at least 80% sequence identity, such as at least 90% sequence identity, such as at least 95% sequence identity, such as at least 97% sequence identity, such as at least 97% sequence identity, to SEQ ID NO: 15; a variable heavy chain (V H ) comprising or consisting of amino acid sequences each having at least 98% sequence identity, such as at least 99% sequence identity;
The amino acid sequence of SEQ ID NO: 16 or SEQ ID NO: 30, or at least 80% sequence identity, such as at least 90% sequence identity, such as at least 95% sequence identity, such as at least a light chain CDR1 comprising or consisting of an amino acid sequence each having 97% sequence identity, such as at least 98% sequence identity, such as at least 99% sequence identity;
the amino acid sequence of SEQ ID NO: 17, or at least 80% sequence identity, such as at least 90% sequence identity, such as at least 95% sequence identity, such as at least 97% sequence identity, such as at least 97% sequence identity, to SEQ ID NO: 17 a light chain CDR2 comprising or consisting of an amino acid sequence each having at least 98% sequence identity, such as at least 99% sequence identity;
The amino acid sequence of SEQ ID NO: 18 or SEQ ID NO: 26, or at least 80% sequence identity, such as at least 90% sequence identity, such as at least 95% sequence identity, such as at least a light chain CDR3 comprising or consisting of an amino acid sequence each having 97% sequence identity, such as at least 98% sequence identity, such as at least 99% sequence identity;
The amino acid sequence of SEQ ID NO: 19 or SEQ ID NO: 27, or at least 80% sequence identity, such as at least 90% sequence identity, such as at least 95% sequence identity, such as at least a heavy chain CDR1 comprising or consisting of an amino acid sequence each having 97% sequence identity, such as at least 98% sequence identity, such as at least 99% sequence identity;
The amino acid sequence of SEQ ID NO:20 or SEQ ID NO:28, or at least 80% sequence identity, such as at least 90% sequence identity, such as at least 95% sequence identity, such as at least a heavy chain CDR2 comprising or consisting of an amino acid sequence having 97% sequence identity, such as at least 98% sequence identity, such as at least 99% sequence identity, respectively; and/or the amino acid sequence of SEQ ID NO:21, or at least 80% sequence identity, such as at least 90% sequence identity, such as at least 95% sequence identity, such as at least 97% sequence identity, such as at least 98% sequence identity, to SEQ ID NO:21; a heavy chain CDR3 comprising or consisting of, for example, an amino acid sequence each having at least 99% sequence identity;
An anti-IL1RAP antibody or antigen-binding fragment thereof comprising
A composition according to any one of claims 1-4. 前記組成物中の前記第２の結合剤に対する前記第１の結合剤の比率が、１０：１～１：１０、例えば５：１～１：５、例えば２：１～１：２、例えば３：２～２：３、例えば１１：９～９：１１、例えば１：１であり；
前記第１および第２の結合剤が、アイソタイプサブタイプＩｇＧ１、ＩｇＧ２、ＩｇＧ３もしくはＩｇＧ４の抗体分子であり；
前記組成物が、細胞膜に結合したＩＬ１ＲＡＰの内在化を誘導することができ；および／または、
前記第１および／もしくは前記第２の結合剤が、抗体依存性細胞媒介性細胞傷害（ＡＤＣＣ）を誘導する能力を欠いている、
請求項１～５のいずれか１項に記載の組成物。 The ratio of said first binder to said second binder in said composition is from 10:1 to 1:10, such as from 5:1 to 1:5, such as from 2:1 to 1:2, such as 3 : 2 to 2:3, such as 11:9 to 9:11, such as 1:1;
said first and second binding agents are antibody molecules of isotype subtype IgG1, IgG2, IgG3 or IgG4;
said composition is capable of inducing internalization of cell membrane bound IL1RAP; and/or
said first and/or said second binding agent lacks the ability to induce antibody-dependent cell-mediated cytotoxicity (ADCC);
A composition according to any one of claims 1-5. 第１の抗原結合領域、および
第２の抗原結合領域、
を含む、２エピトープ結合剤であって、
前記第１の抗原結合領域および前記第２の抗原結合領域が、ヒトインターロイキン受容体アクセサリータンパク質（ＩＬ１ＲＡＰ）の異なる細胞外ドメインに結合する、前記２エピトープ結合剤。 a first antigen binding region, and a second antigen binding region,
A two-epitope binding agent comprising
Said two-epitope binding agent, wherein said first antigen binding region and said second antigen binding region bind to different extracellular domains of human interleukin receptor accessory protein (IL1RAP). 前記２エピトープ結合剤が、ポリペプチド、および／または、抗体である、請求項７に記載の２エピトープ結合剤。 8. The bi-epitope binding agent of claim 7, wherein said bi-epitope binding agent is a polypeptide and/or an antibody. ａ）前記第１の抗原結合領域が：
ｉ）参照抗体「ＣＡＮ０４」と同じ抗原に結合する抗原結合領域；
ｉｉ）抗体ＣＡＮ０４と同じエピトープに結合する抗原結合領域；
ｉｉｉ）抗体ＣＡＮ０４のヒトＩＬ１ＲＡＰへの結合を阻害することができる抗原結合領域；
ｉｖ）ＩＬ１ＲＡＰのドメイン２に結合することができる抗原結合領域；
ｖ）抗体ＣＡＮ０４の、可変軽鎖（ＶL）アミノ酸配列：ＤＩＱＭＴＱＳＰＳＳＬＳＡＳＶＧＤＲＶＴＩＴＣＱＡＳＱＧＩＮＮＹＬＮＷＹＱＱＫＰＧＫＡＰＫＬＬＩＨＹＴＳＧＬＨＡＧＶＰＳＲＦＳＧＳＧＳＧＴＤＹＴＬＴＩＳＳＬＥＰＥＤＶＡＴＹＹＣＱＱＹＳＩＬＰＷＴＦＧＧＧＴＫＶＥＩＫＲ（配列番号１）、および可変重鎖（ＶH）アミノ酸配列：ＤＶＫＬＶＥＳＧＧＧＬＶＫＰＧＧＳＬＫＬＳＣＡＡＳＧＦＴＦＳＩＹＴＭＳＷＶＲＱＴＰＥＫＲＬＥＷＶＡＴＩＳＩＧＧＳＹＩＮＹＰＤＳＶＫＧＲＦＴＩＳＲＤＮＡＫＮＴＬＹＬＱＭＳＳＬＫＳＥＤＴＡＩＹＹＣＳＲＥＶＤＧＳＹＡＭＤＹＷＧＱＧＴＳＶＴＶＳＳ（配列番号４）を含む、またはそれからなるアミノ酸配列；
ｖｉ）配列番号３５の重鎖アミノ酸配列および配列番号３６の軽鎖アミノ酸配列を含む、またはそれからなるアミノ酸配列；
ｖｉｉ）下記の６つの相補性決定領域（ＣＤＲ）のうちの少なくとも１つを含む、またはそれからなるアミノ酸配列：
軽鎖ＣＤＲ１：ＳＡＳＱＧＩＮＮＹＬＮ（配列番号８）またはＡＳＱＧＩＮＮＹＬＮ（配列番号２９）
軽鎖ＣＤＲ２：ＹＴＳＧＬＨＡＧＶ（配列番号９）またはＹＴＳＧＬＨＡ（配列番号２２）
軽鎖ＣＤＲ３：ＱＱＹＳＩＬＰＷＴ（配列番号１０）またはＱＹＳＩＬＰＷＴ（配列番号２３）
重鎖ＣＤＲ１：ＧＹＡＦＴＳＳＳＷＭＮ（配列番号１１）またはＧＹＡＦＴＳＳ（配列番号２４）
重鎖ＣＤＲ２：ＲＩＹＰＧＤＧＮＴＨＹＡＱＫＦＱＧ（配列番号１２）またはＹＰＧＤＧＮ（配列番号２５）
重鎖ＣＤＲ３：ＧＹＬＤＰＭＤＹ（配列番号１３）；ならびに、
ｖｉｉｉ）上記ｉ）～ｖｉ）の抗体の抗原結合断片、
からなる群から選択され；
ならびに、
ｂ）前記第２の抗原結合領域が：
ｉ）参照抗体「ＣＡＮ０３」と同じ抗原に結合する抗原結合領域；
ｉｉ）抗体ＣＡＮ０３と同じエピトープに結合する抗原結合領域；
ｉｉｉ）抗体ＣＡＮ０３のヒトＩＬ１ＲＡＰへの結合を阻害することができる抗原結合領域；
ｉｖ）ＩＬ１ＲＡＰの細胞外ドメイン３に結合することができる抗原結合領域；
ｖ）抗体ＣＡＮ０３の、可変軽鎖（ＶL）アミノ酸配列：ＤＩＬＬＴＱＳＰＡＩＬＳＶＳＰＧＥＲＶＳＦＳＣＲＡＳＱＳＩＧＴＳＩＨＷＹＱＲＲＴＮＧＳＰＲＬＬＩＫＳＡＳＥＳＩＳＧＩＰＳＲＦＳＧＳＧＳＧＴＤＦＴＬＳＩＮＳＶＥＳＥＤＩＡＤＹＹＣＱＱＳＮＳＷＰＴＴＦＧＡＧＴＫＬＥＬＫＲ（配列番号１４）、および可変重鎖（ＶH）アミノ酸配列：ＤＶＫＬＶＥＳＧＧＧＬＶＫＰＧＧＳＬＫＬＳＣＡＡＳＧＦＴＦＳＩＹＴＭＳＷＶＲＱＴＰＥＫＲＬＥＷＶＡＴＩＳＩＧＧＳＹＩＮＹＰＤＳＶＫＧＲＦＴＩＳＲＤＮＡＫＮＴＬＹＬＱＭＳＳＬＫＳＥＤＴＡＩＹＹＣＳＲＥＶＤＧＳＹＡＭＤＹＷＧＱＧＴＳＶＴＶＳＳ（配列番号１５）を含む、またはそれからなるアミノ酸配列；
ｖｉ）配列番号３７の重鎖アミノ酸配列および配列番号３８の軽鎖アミノ酸配列を含む、またはそれからなるアミノ酸配列；
ｖｉｉ）下記の６つの相補性決定領域（ＣＤＲ）のうちの少なくとも１つを含む抗原結合領域：
軽鎖ＣＤＲ１：ＲＡＳＱＳＩＧＴＳＩＨ（配列番号１６）またはＡＳＱＳＩＧＴＳＩＨ（配列番号３０）
軽鎖ＣＤＲ２：ＳＡＳＥＳＩＳ（配列番号１７）
軽鎖ＣＤＲ３：ＱＱＳＮＳＷＰＴＴ（配列番号１８）またはＱＳＮＳＷＰＴＴ（配列番号２６）
重鎖ＣＤＲ１：ＧＦＴＦＳＩＹＴＭＳ（配列番号１９）またはＧＦＴＦＳＩＹ（配列番号２７）
重鎖ＣＤＲ２：ＴＩＳＩＧＧＳＹＩＮＹＰＤＳＶＫＧ（配列番号２０）またはＳＩＧＧＳＹ（配列番号２８）
重鎖ＣＤＲ３：ＥＶＤＧＳＹＡＭＤＹ（配列番号２１）；ならびに、
ｖｉｉｉ）上記ｉ）～ｖｉ）の抗体の抗原結合断片、
からなる群から選択される、請求項７または８に記載の２エピトープ結合剤。 a) said first antigen binding region comprises:
i) an antigen-binding region that binds to the same antigen as the reference antibody "CAN04";
ii) an antigen binding region that binds to the same epitope as antibody CAN04;
iii) an antigen binding region capable of inhibiting the binding of antibody CAN04 to human IL1RAP;
iv) an antigen binding region capable of binding to domain 2 of IL1RAP;
ｖ）抗体ＣＡＮ０４の、可変軽鎖（Ｖ L ）アミノ酸配列：ＤＩＱＭＴＱＳＰＳＳＬＳＡＳＶＧＤＲＶＴＩＴＣＱＡＳＱＧＩＮＮＹＬＮＷＹＱＱＫＰＧＫＡＰＫＬＬＩＨＹＴＳＧＬＨＡＧＶＰＳＲＦＳＧＳＧＳＧＴＤＹＴＬＴＩＳＳＬＥＰＥＤＶＡＴＹＹＣＱＱＹＳＩＬＰＷＴＦＧＧＧＴＫＶＥＩＫＲ（配列番号１）、および可変重鎖（Ｖ H ）アミノ酸配列：ＤＶＫＬＶＥＳＧＧＧＬＶＫＰＧＧＳＬＫＬＳＣＡＡＳＧＦＴＦＳＩＹＴＭＳＷＶＲＱＴＰＥＫＲＬＥＷＶＡＴＩＳＩＧＧＳＹＩＮＹＰＤＳＶＫＧＲＦＴＩＳＲＤＮＡＫＮＴＬＹＬＱＭＳＳＬＫＳＥＤＴＡＩＹＹＣＳＲＥＶＤＧＳＹＡＭＤＹＷＧＱＧＴＳＶＴＶＳＳ（配列番号４）を含む、またはそれからなるアミノ酸配列；
vi) an amino acid sequence comprising or consisting of the heavy chain amino acid sequence of SEQ ID NO:35 and the light chain amino acid sequence of SEQ ID NO:36;
vii) an amino acid sequence comprising or consisting of at least one of the following six complementarity determining regions (CDRs):
Light chain CDR1: SASQGINNYLN (SEQ ID NO:8) or ASQGINNYLN (SEQ ID NO:29)
Light chain CDR2: YTSGLHAGV (SEQ ID NO:9) or YTSGLHA (SEQ ID NO:22)
Light chain CDR3: QQYSILPWT (SEQ ID NO: 10) or QYSILPWT (SEQ ID NO: 23)
Heavy chain CDR1: GYAFTSSSWMN (SEQ ID NO: 11) or GYAFTSS (SEQ ID NO: 24)
Heavy chain CDR2: RIYPGDGNTHYAQKFQG (SEQ ID NO: 12) or YPGDGN (SEQ ID NO: 25)
Heavy chain CDR3: GYLDPMDY (SEQ ID NO: 13); and
viii) an antigen-binding fragment of the antibody of i) to vi) above;
selected from the group consisting of;
and
b) said second antigen binding region is:
i) an antigen binding region that binds to the same antigen as the reference antibody "CAN03";
ii) an antigen binding region that binds to the same epitope as antibody CAN03;
iii) an antigen-binding region capable of inhibiting the binding of antibody CAN03 to human IL1RAP;
iv) an antigen-binding region capable of binding to the extracellular domain 3 of IL1RAP;
ｖ）抗体ＣＡＮ０３の、可変軽鎖（Ｖ L ）アミノ酸配列：ＤＩＬＬＴＱＳＰＡＩＬＳＶＳＰＧＥＲＶＳＦＳＣＲＡＳＱＳＩＧＴＳＩＨＷＹＱＲＲＴＮＧＳＰＲＬＬＩＫＳＡＳＥＳＩＳＧＩＰＳＲＦＳＧＳＧＳＧＴＤＦＴＬＳＩＮＳＶＥＳＥＤＩＡＤＹＹＣＱＱＳＮＳＷＰＴＴＦＧＡＧＴＫＬＥＬＫＲ（配列番号１４）、および可変重鎖（Ｖ H ）アミノ酸配列：ＤＶＫＬＶＥＳＧＧＧＬＶＫＰＧＧＳＬＫＬＳＣＡＡＳＧＦＴＦＳＩＹＴＭＳＷＶＲＱＴＰＥＫＲＬＥＷＶＡＴＩＳＩＧＧＳＹＩＮＹＰＤＳＶＫＧＲＦＴＩＳＲＤＮＡＫＮＴＬＹＬＱＭＳＳＬＫＳＥＤＴＡＩＹＹＣＳＲＥＶＤＧＳＹＡＭＤＹＷＧＱＧＴＳＶＴＶＳＳ（配列番号１５）を含む、またはそれからなるアミノ酸配列；
vi) an amino acid sequence comprising or consisting of the heavy chain amino acid sequence of SEQ ID NO:37 and the light chain amino acid sequence of SEQ ID NO:38;
vii) an antigen binding region comprising at least one of the following six complementarity determining regions (CDRs):
Light chain CDR1: RASQSIGTSIH (SEQ ID NO: 16) or ASQSIGTSIH (SEQ ID NO: 30)
Light chain CDR2: SASESIS (SEQ ID NO: 17)
Light chain CDR3: QQSNSWPTT (SEQ ID NO: 18) or QSNSWPTT (SEQ ID NO: 26)
Heavy chain CDR1: GFTFSIYTMS (SEQ ID NO: 19) or GFTFSIY (SEQ ID NO: 27)
Heavy chain CDR2: TISIGGSYINYPDSVKG (SEQ ID NO:20) or SIGGSY (SEQ ID NO:28)
Heavy chain CDR3: EVDGSYAMDY (SEQ ID NO: 21); and
viii) an antigen-binding fragment of the antibody of i) to vi) above;
9. A two-epitope binding agent according to claim 7 or 8, selected from the group consisting of: 前記第１の抗原結合領域が：
ａ）配列番号４のアミノ酸配列を含む可変重鎖（ＶH）、および配列番号１のアミノ酸配列を含む可変軽鎖（ＶL）；
ｂ）配列番号５のアミノ酸配列を含む可変重鎖（ＶH）、および配列番号１のアミノ酸配列を含む可変軽鎖（ＶL）；
ｃ）配列番号６のアミノ酸配列を含む可変重鎖（ＶH）、および配列番号１のアミノ酸配列を含む可変軽鎖（ＶL）；
ｄ）配列番号７のアミノ酸配列を含む可変重鎖（ＶH）、および配列番号１のアミノ酸配列を含む可変軽鎖（ＶL）；
ｅ）配列番号４のアミノ酸配列を含む可変重鎖（ＶH）、および配列番号２のアミノ酸配列を含む可変軽鎖（ＶL）；
ｆ）配列番号５のアミノ酸配列を含む可変重鎖（ＶH）、および配列番号２のアミノ酸配列を含む可変軽鎖（ＶL）；
ｇ）配列番号６のアミノ酸配列を含む可変重鎖（ＶH）、および配列番号２のアミノ酸配列を含む可変軽鎖（ＶL）；
ｈ）配列番号７のアミノ酸配列を含む可変重鎖（ＶH）、および配列番号２のアミノ酸配列を含む可変軽鎖（ＶL）；
ｉ）配列番号４のアミノ酸配列を含む可変重鎖（ＶH）、および配列番号３のアミノ酸配列を含む可変軽鎖（ＶL）；
ｊ）配列番号５のアミノ酸配列を含む可変重鎖（ＶH）、および配列番号３のアミノ酸配列を含む可変軽鎖（ＶL）；
ｋ）配列番号６のアミノ酸配列を含む可変重鎖（ＶH）、および配列番号３のアミノ酸配列を含む可変軽鎖（ＶL）；ならびに、
ｌ）配列番号７のアミノ酸配列を含む可変重鎖（ＶH）、および配列番号３のアミノ酸配列を含む可変軽鎖（ＶL）、
からなる群から選択される、可変重鎖（ＶH）および可変軽鎖（ＶL）を含む、
請求項７～９のいずれか１項に記載の２エピトープ結合剤。 wherein said first antigen binding region:
a) a variable heavy chain ( VH ) comprising the amino acid sequence of SEQ ID NO:4 and a variable light chain ( VL ) comprising the amino acid sequence of SEQ ID NO:1;
b) a variable heavy chain ( VH ) comprising the amino acid sequence of SEQ ID NO:5 and a variable light chain ( VL ) comprising the amino acid sequence of SEQ ID NO:1;
c) a variable heavy chain ( VH ) comprising the amino acid sequence of SEQ ID NO:6 and a variable light chain ( VL ) comprising the amino acid sequence of SEQ ID NO:1;
d) a variable heavy chain ( VH ) comprising the amino acid sequence of SEQ ID NO:7 and a variable light chain ( VL ) comprising the amino acid sequence of SEQ ID NO:1;
e) a variable heavy chain ( VH ) comprising the amino acid sequence of SEQ ID NO:4 and a variable light chain ( VL ) comprising the amino acid sequence of SEQ ID NO:2;
f) a variable heavy chain ( VH ) comprising the amino acid sequence of SEQ ID NO:5 and a variable light chain ( VL ) comprising the amino acid sequence of SEQ ID NO:2;
g) a variable heavy chain ( VH ) comprising the amino acid sequence of SEQ ID NO:6 and a variable light chain ( VL ) comprising the amino acid sequence of SEQ ID NO:2;
h) a variable heavy chain ( VH ) comprising the amino acid sequence of SEQ ID NO:7 and a variable light chain ( VL ) comprising the amino acid sequence of SEQ ID NO:2;
i) a variable heavy chain ( VH ) comprising the amino acid sequence of SEQ ID NO:4 and a variable light chain ( VL ) comprising the amino acid sequence of SEQ ID NO:3;
j) a variable heavy chain ( VH ) comprising the amino acid sequence of SEQ ID NO:5 and a variable light chain ( VL ) comprising the amino acid sequence of SEQ ID NO:3;
k) a variable heavy chain (V H ) comprising the amino acid sequence of SEQ ID NO: 6 and a variable light chain (V L ) comprising the amino acid sequence of SEQ ID NO: 3;
l) a variable heavy chain (V H ) comprising the amino acid sequence of SEQ ID NO:7 and a variable light chain (V L ) comprising the amino acid sequence of SEQ ID NO:3;
a variable heavy chain (V H ) and a variable light chain (V L ) selected from the group consisting of
A two-epitope binding agent according to any one of claims 7-9. ａ）前記第１の抗原結合領域が：
配列番号１、２、もしくは３のアミノ酸配列を含む、もしくはそれからなる軽鎖可変ドメイン（ＶL）；および、
配列番号４、５、６、もしくは７のアミノ酸配列を含む、もしくはそれからなる重鎖可変ドメイン（ＶH）を含み；ならびに、
ｂ）前記第２の抗原結合領域が：
配列番号１４のアミノ酸配列を含む、もしくはそれからなる軽鎖可変ドメイン（ＶL）；および、
配列番号１５のアミノ酸を含む、もしくはそれからなる重鎖可変ドメイン（ＶH）を含み；
ならびに／または、
前記第１の抗原結合領域が：
配列番号１のアミノ酸配列、もしくは配列番号１に対して少なくとも６０％の配列同一性、例えば少なくとも７０％の配列同一性、例えば少なくとも８０％の配列同一性、例えば少なくとも９０％の配列同一性、例えば少なくとも９５％の配列同一性、例えば少なくとも９７％の配列同一性、例えば少なくとも９８％の配列同一性、例えば少なくとも９９％の配列同一性を有するアミノ酸配列を含む、もしくはそれからなる可変軽鎖（ＶL）；
配列番号４のアミノ酸配列、もしくは配列番号４に対して少なくとも６０％の配列同一性、例えば少なくとも７０％の配列同一性、例えば少なくとも８０％の配列同一性、例えば少なくとも９０％の配列同一性、例えば少なくとも９５％の配列同一性、例えば少なくとも９７％の配列同一性、例えば少なくとも９８％の配列同一性、例えば少なくとも９９％の配列同一性を有するアミノ酸配列を含む、もしくはそれからなる可変重鎖（ＶH）；
配列番号８もしくは配列番号２９のアミノ酸配列、もしくは配列番号８もしくは配列番号２９に対して少なくとも８０％の配列同一性、例えば少なくとも９０％の配列同一性、例えば少なくとも９５％の配列同一性、例えば少なくとも９７％の配列同一性、例えば少なくとも９８％の配列同一性、例えば少なくとも９９％の配列同一性をそれぞれ有するアミノ酸配列を含む、もしくはそれからなる軽鎖ＣＤＲ１；
配列番号９もしくは配列番号２２のアミノ酸配列、もしくは配列番号９もしくは配列番号２２に対して少なくとも８０％の配列同一性、例えば少なくとも９０％の配列同一性、例えば少なくとも９５％の配列同一性、例えば少なくとも９７％の配列同一性、例えば少なくとも９８％の配列同一性、例えば少なくとも９９％の配列同一性をそれぞれ有するアミノ酸配列を含む、もしくはそれからなる軽鎖ＣＤＲ２；
配列番号１０もしくは配列番号２３のアミノ酸配列、もしくは配列番号１０もしくは配列番号２３に対して少なくとも８０％の配列同一性、例えば少なくとも９０％の配列同一性、例えば少なくとも９５％の配列同一性、例えば少なくとも９７％の配列同一性、例えば少なくとも９８％の配列同一性、例えば少なくとも９９％の配列同一性をそれぞれ有するアミノ酸配列を含む、もしくはそれからなる軽鎖ＣＤＲ３；
配列番号１１もしくは配列番号２４のアミノ酸配列、もしくは配列番号１１もしくは配列番号２４に対して少なくとも８０％の配列同一性、例えば少なくとも９０％の配列同一性、例えば少なくとも９５％の配列同一性、例えば少なくとも９７％の配列同一性、例えば少なくとも９８％の配列同一性、例えば少なくとも９９％の配列同一性をそれぞれ有するアミノ酸配列を含む、もしくはそれからなる重鎖ＣＤＲ１；
配列番号１２もしくは配列番号２５のアミノ酸配列、もしくは配列番号１２もしくは配列番号２５に対して少なくとも８０％の配列同一性、例えば少なくとも９０％の配列同一性、例えば少なくとも９５％の配列同一性、例えば少なくとも９７％の配列同一性、例えば少なくとも９８％の配列同一性、例えば少なくとも９９％の配列同一性をそれぞれ有するアミノ酸配列を含む、もしくはそれからなる重鎖ＣＤＲ２；および／もしくは、
配列番号１３のアミノ酸配列、もしくは配列番号１３に対して少なくとも８０％の配列同一性、例えば少なくとも９０％の配列同一性、例えば少なくとも９５％の配列同一性、例えば少なくとも９７％の配列同一性、例えば少なくとも９８％の配列同一性、例えば少なくとも９９％の配列同一性をそれぞれ有するアミノ酸配列を含む、もしくはそれからなる重鎖ＣＤＲ３、
を含み；
ならびに／もしくは
前記第２の抗原結合領域が：
配列番号１４のアミノ酸配列、もしくは配列番号１４に対して少なくとも８０％の配列同一性、例えば少なくとも９０％の配列同一性、例えば少なくとも９５％の配列同一性、例えば少なくとも９７％の配列同一性、例えば少なくとも９８％の配列同一性、例えば少なくとも９９％の配列同一性をそれぞれ有するアミノ酸配列を含む、もしくはそれからなる可変軽鎖（ＶL）；
配列番号１５のアミノ酸配列、もしくは配列番号１５に対して少なくとも８０％の配列同一性、例えば少なくとも９０％の配列同一性、例えば少なくとも９５％の配列同一性、例えば少なくとも９７％の配列同一性、例えば少なくとも９８％の配列同一性、例えば少なくとも９９％の配列同一性をそれぞれ有するアミノ酸配列を含む、もしくはそれからなる可変重鎖（ＶH）；
配列番号１６もしくは配列番号３０のアミノ酸配列、もしくは配列番号１６もしくは配列番号３０に対して少なくとも８０％の配列同一性、例えば少なくとも９０％の配列同一性、例えば少なくとも９５％の配列同一性、例えば少なくとも９７％の配列同一性、例えば少なくとも９８％の配列同一性、例えば少なくとも９９％の配列同一性をそれぞれ有するアミノ酸配列を含む、もしくはそれからなる軽鎖ＣＤＲ１；
配列番号１７のアミノ酸配列、もしくは配列番号１７に対して少なくとも８０％の配列同一性、例えば少なくとも９０％の配列同一性、例えば少なくとも９５％の配列同一性、例えば少なくとも９７％の配列同一性、例えば少なくとも９８％の配列同一性、例えば少なくとも９９％の配列同一性をそれぞれ有するアミノ酸配列を含む、もしくはそれからなる軽鎖ＣＤＲ２；
配列番号１８もしくは配列番号２６のアミノ酸配列、もしくは配列番号１８もしくは配列番号２６に対して少なくとも８０％の配列同一性、例えば少なくとも９０％の配列同一性、例えば少なくとも９５％の配列同一性、例えば少なくとも９７％の配列同一性、例えば少なくとも９８％の配列同一性、例えば少なくとも９９％の配列同一性をそれぞれ有するアミノ酸配列を含む、もしくはそれからなる軽鎖ＣＤＲ３；
配列番号１９もしくは配列番号２７のアミノ酸配列、もしくは配列番号１９もしくは配列番号２７に対して少なくとも８０％の配列同一性、例えば少なくとも９０％の配列同一性、例えば少なくとも９５％の配列同一性、例えば少なくとも９７％の配列同一性、例えば少なくとも９８％の配列同一性、例えば少なくとも９９％の配列同一性をそれぞれ有するアミノ酸配列を含む、もしくはそれからなる重鎖ＣＤＲ１；
配列番号２０もしくは配列番号２８のアミノ酸配列、もしくは配列番号２０もしくは配列番号２８に対して少なくとも８０％の配列同一性、例えば少なくとも９０％の配列同一性、例えば少なくとも９５％の配列同一性、例えば少なくとも９７％の配列同一性、例えば少なくとも９８％の配列同一性、例えば少なくとも９９％の配列同一性をそれぞれ有するアミノ酸配列を含む、もしくはそれからなる重鎖ＣＤＲ２；および／もしくは、
配列番号２１のアミノ酸配列、もしくは配列番号２１に対して少なくとも８０％の配列同一性、例えば少なくとも９０％の配列同一性、例えば少なくとも９５％の配列同一性、例えば少なくとも９７％の配列同一性、例えば少なくとも９８％の配列同一性、例えば少なくとも９９％の配列同一性をそれぞれ有するアミノ酸配列を含む、もしくはそれからなる重鎖ＣＤＲ３、
を含む、
請求項７～１０のいずれか１項に記載の２エピトープ結合剤。 a) said first antigen binding region comprises:
a light chain variable domain ( VL ) comprising or consisting of the amino acid sequence of SEQ ID NO: 1, 2, or 3; and
a heavy chain variable domain (V H ) comprising or consisting of the amino acid sequence of SEQ ID NO: 4, 5, 6, or 7; and
b) said second antigen binding region is:
a light chain variable domain ( VL ) comprising or consisting of the amino acid sequence of SEQ ID NO: 14; and
comprising a heavy chain variable domain (V H ) comprising or consisting of amino acids of SEQ ID NO: 15;
and/or
wherein said first antigen binding region:
The amino acid sequence of SEQ ID NO: 1, or at least 60% sequence identity, such as at least 70% sequence identity, such as at least 80% sequence identity, such as at least 90% sequence identity, such as at least 90% sequence identity, to SEQ ID NO: 1 A variable light chain (V L );
the amino acid sequence of SEQ ID NO:4, or at least 60% sequence identity, such as at least 70% sequence identity, such as at least 80% sequence identity, such as at least 90% sequence identity, such as at least 90% sequence identity, to SEQ ID NO:4 A variable heavy chain (V H );
The amino acid sequence of SEQ ID NO:8 or SEQ ID NO:29, or at least 80% sequence identity, such as at least 90% sequence identity, such as at least 95% sequence identity, such as at least a light chain CDR1 comprising or consisting of an amino acid sequence each having 97% sequence identity, such as at least 98% sequence identity, such as at least 99% sequence identity;
The amino acid sequence of SEQ ID NO:9 or SEQ ID NO:22, or at least 80% sequence identity, such as at least 90% sequence identity, such as at least 95% sequence identity, such as at least a light chain CDR2 comprising or consisting of an amino acid sequence each having 97% sequence identity, such as at least 98% sequence identity, such as at least 99% sequence identity;
The amino acid sequence of SEQ ID NO: 10 or SEQ ID NO: 23, or at least 80% sequence identity, such as at least 90% sequence identity, such as at least 95% sequence identity, such as at least a light chain CDR3 comprising or consisting of an amino acid sequence each having 97% sequence identity, such as at least 98% sequence identity, such as at least 99% sequence identity;
The amino acid sequence of SEQ ID NO: 11 or SEQ ID NO: 24, or at least 80% sequence identity, such as at least 90% sequence identity, such as at least 95% sequence identity, such as at least a heavy chain CDR1 comprising or consisting of an amino acid sequence each having 97% sequence identity, such as at least 98% sequence identity, such as at least 99% sequence identity;
The amino acid sequence of SEQ ID NO: 12 or SEQ ID NO: 25, or at least 80% sequence identity, such as at least 90% sequence identity, such as at least 95% sequence identity, such as at least a heavy chain CDR2 comprising or consisting of an amino acid sequence each having 97% sequence identity, such as at least 98% sequence identity, such as at least 99% sequence identity; and/or
the amino acid sequence of SEQ ID NO: 13, or at least 80% sequence identity, such as at least 90% sequence identity, such as at least 95% sequence identity, such as at least 97% sequence identity, to SEQ ID NO: 13, such as a heavy chain CDR3 comprising or consisting of an amino acid sequence each having at least 98% sequence identity, such as at least 99% sequence identity;
includes;
and/or wherein said second antigen binding region is:
The amino acid sequence of SEQ ID NO: 14, or at least 80% sequence identity, such as at least 90% sequence identity, such as at least 95% sequence identity, such as at least 97% sequence identity, such as at least 97% sequence identity, to SEQ ID NO: 14 a variable light chain ( VL ) comprising or consisting of amino acid sequences each having at least 98% sequence identity, such as at least 99% sequence identity;
the amino acid sequence of SEQ ID NO: 15, or at least 80% sequence identity, such as at least 90% sequence identity, such as at least 95% sequence identity, such as at least 97% sequence identity, such as at least 97% sequence identity, to SEQ ID NO: 15; a variable heavy chain (V H ) comprising or consisting of amino acid sequences each having at least 98% sequence identity, such as at least 99% sequence identity;
The amino acid sequence of SEQ ID NO: 16 or SEQ ID NO: 30, or at least 80% sequence identity, such as at least 90% sequence identity, such as at least 95% sequence identity, such as at least a light chain CDR1 comprising or consisting of an amino acid sequence each having 97% sequence identity, such as at least 98% sequence identity, such as at least 99% sequence identity;
the amino acid sequence of SEQ ID NO: 17, or at least 80% sequence identity, such as at least 90% sequence identity, such as at least 95% sequence identity, such as at least 97% sequence identity, such as at least 97% sequence identity, to SEQ ID NO: 17 a light chain CDR2 comprising or consisting of an amino acid sequence each having at least 98% sequence identity, such as at least 99% sequence identity;
The amino acid sequence of SEQ ID NO: 18 or SEQ ID NO: 26, or at least 80% sequence identity, such as at least 90% sequence identity, such as at least 95% sequence identity, such as at least a light chain CDR3 comprising or consisting of an amino acid sequence each having 97% sequence identity, such as at least 98% sequence identity, such as at least 99% sequence identity;
The amino acid sequence of SEQ ID NO: 19 or SEQ ID NO: 27, or at least 80% sequence identity, such as at least 90% sequence identity, such as at least 95% sequence identity, such as at least a heavy chain CDR1 comprising or consisting of an amino acid sequence each having 97% sequence identity, such as at least 98% sequence identity, such as at least 99% sequence identity;
The amino acid sequence of SEQ ID NO:20 or SEQ ID NO:28, or at least 80% sequence identity, such as at least 90% sequence identity, such as at least 95% sequence identity, such as at least a heavy chain CDR2 comprising or consisting of an amino acid sequence each having 97% sequence identity, such as at least 98% sequence identity, such as at least 99% sequence identity; and/or
the amino acid sequence of SEQ ID NO:21, or at least 80% sequence identity, such as at least 90% sequence identity, such as at least 95% sequence identity, such as at least 97% sequence identity, such as at least 97% sequence identity, to SEQ ID NO:21 a heavy chain CDR3 comprising or consisting of an amino acid sequence each having at least 98% sequence identity, such as at least 99% sequence identity;
including,
A two-epitope binding agent according to any one of claims 7-10. 前記２エピトープ結合剤が、二重可変ドメイン抗体、２エピトープＦａｂ断片、２エピトープｓｃＦｖ、二価二重特異性抗体、一価二重特異性抗体、「ノブインホール」二重特異性抗体、ｓｃＦｖ２＿Ｆｃ二重特異性抗体、ＢｉＴＥ／ｓｃＦｖ２二重特異性抗体、ＤＶＤ－Ｉｇ二重特異性抗体、ＩｇＧ－Ｆａｂ二重特異性抗体、ＦＡｂ－ＩｇＧ二重特異性抗体、ＤＡＲＴ系二重特異性抗体、ＤＮＬ－Ｆａｂ３二重特異性抗体またはｓｃＦｖ－ＨＡＳ－ｓｃＦｖ二重特異性抗体である、請求項７～１１のいずれか１項記載の２エピトープ結合剤。 The bi-epitope binding agent is a dual variable domain antibody, a bi-epitope Fab fragment, a bi-epitope scFv, a bivalent bispecific antibody, a monovalent bispecific antibody, a "knob-in-hole" bispecific antibody, scFv2_Fc bispecific antibodies, BiTE/scFv2 bispecific antibodies, DVD-Ig bispecific antibodies, IgG-Fab bispecific antibodies, FAb-IgG bispecific antibodies, DART-based bispecific antibodies, A two-epitope binding agent according to any one of claims 7 to 11, which is a DNL-Fab3 bispecific antibody or a scFv-HAS-scFv bispecific antibody. （ｉ）請求項１に記載の第１および第２の結合剤、または（ｉｉ）請求項７に記載の２ピトープ結合剤のいずれかをコードする、単離ポリヌクレオチド。 8. An isolated polynucleotide encoding either (i) the first and second binding agents of claim 1 or (ii) the two-pitope binding agent of claim 7. （ｉ）請求項１に記載の第１および第２の結合剤、もしくは（ｉｉ）請求項７に記載の
２エピトープ結合剤のいずれかを集合的もしくは個別にコードする１つ以上のポリヌクレオチドを含む発現ベクター、組成物、もしくは宿主細胞、
または、
（ｉｉ）それぞれ、請求項１に記載の第１および第２の結合剤、もしくは（ｉｉ）請求項７に記載の２エピトープ結合剤のいずれかを集合的もしくは個別にコードする１つ以上のポリヌクレオチドを含む１つ以上の発現ベクターを含む、宿主細胞であって、場合により、前記宿主細胞が、真核生物または原核生物の宿主細胞である、前記宿主細胞。 one or more polynucleotides that collectively or individually encode either (i) the first and second binding agents of claim 1 or (ii) the two-epitope binding agents of claim 7; an expression vector, composition, or host cell comprising
or,
(ii) the first and second binding agents of claim 1, respectively; or (ii) the two-epitope binding agents of claim 7; A host cell comprising one or more expression vectors comprising nucleotides, optionally said host cell being a eukaryotic or prokaryotic host cell. 請求項１～６および１４のいずれか１項に記載の組成物、請求項７～１２のいずれか１項に記載の２エピトープ結合剤、請求項１３に記載のポリヌクレオチド、請求項１４に記載のベクター、または請求項１４に記載の宿主細胞；ならびに、薬学的に許容される賦形剤を含む、医薬組成物。 A composition according to any one of claims 1-6 and 14, a two-epitope binding agent according to any one of claims 7-12, a polynucleotide according to claim 13, a polynucleotide according to claim 14. or the host cell of claim 14; and a pharmaceutically acceptable excipient. 以下の使用：
（ｉ）医薬品として、もしくは診断および／もしくは予後の薬剤として；または、
（ｉｉ）哺乳動物におけるＩＬ１ＲＡＰ関連の疾患または障害の治療、改善、予防、診断もしくは予後における、
場合により、前記ＩＬ１ＲＡＰ関連の疾患または障害は、増殖性障害、自己免疫障害、および自己炎症性障害などの炎症性障害からなる群から選択され、
場合により、前記疾患もしくは障害は：
ａ）関節リウマチ、骨関節炎、多発性硬化症、関節硬化症、強皮症（全身性硬化症）、狼瘡、全身性紅斑性狼瘡（ＳＬＥ）、（急性）糸球体腎炎、喘息、慢性閉塞性肺疾患（ＣＯＰＤ）、呼吸困難症候群（ＡＲＤＳ）、炎症性腸疾患、大腸炎、血管炎、ブドウ膜炎、皮膚炎、アトピー性皮膚炎、脱毛症、鼻炎（アレルギー）、アレルギー性結膜炎、重症筋無力症、強皮症、サルコイドーシス、乾癬性関節炎、乾癬、強直性脊椎炎、若年性特発性関節炎、グレーブス病、シェーグレン症候群、子宮内膜症、クローン病、ベーチェット病、セリアック病、１型真性糖尿病、グレーブス病、炎症性腸疾患、多発性硬化症、乾癬、関節リウマチ、全身性紅斑性狼瘡、家族性地中海熱（ＦＭＦ）、高免疫グロブリンＤ血症および周期熱症候群（ＨＩＤＳ）、ＴＮＦ受容体関連周期症候群（ＴＲＡＰＳ）、クリオピリン関連周期性症候群（ＣＡＰＳ、マックルウェルズ症候群、家族性寒冷蕁麻疹、新生児期発症など）、多系統炎症性疾患（ＮＯＭＩＤ）、周期性発熱、アフタ性口内炎、咽頭炎および腺炎（ＰＦＡＰＡ症候群）、ブラウ症候群、化膿性無菌性関節炎、壊疽性膿皮症、にきび（ＰＡＰＡ）、インターロイキン１受容体拮抗薬（ＤＩＲＡ）の欠乏、成人－発症スティル病および全身発症若年性特発性関節炎、心血管疾患からなる群から選択され；もしくは、
ｂ）腫瘍性障害であって；場合により、前記腫瘍性障害が、前立腺がん、乳がん、肺がん、結腸直腸がん、黒色腫、膀胱がん、脳／ＣＮＳがん、子宮頸がん、食道がん、胃がん、頭頸部がん、腎臓がん、肝がん、リンパ腫、卵巣がん、膵臓がん、肉腫、慢性骨髄性白血病（ＣＭＬ）、骨髄増殖性疾患（ＭＰＤ）、骨髄異形成症候群（ＭＤＳ）、急性リンパ芽球性白血病（ＡＬＬ）および急性骨髄性白血病（ＡＭＬ）からなる群から選択される；
（ｉｉｉ）増殖性障害、自己免疫障害、および自己炎症性障害などの炎症性障害からなる群から選択される疾患または障害の治療における、
場合により、前記疾患もしくは障害は：
ａ）関節リウマチ、骨関節炎、多発性硬化症、関節硬化症、強皮症（全身性硬化症）、狼瘡、全身性紅斑性狼瘡（ＳＬＥ）、（急性）糸球体腎炎、喘息、慢性閉塞性肺疾患（ＣＯＰＤ）、呼吸困難症候群（ＡＲＤＳ）、炎症性腸疾患、大腸炎、血管炎、ブドウ膜炎、皮膚炎、アトピー性皮膚炎、脱毛症、鼻炎（アレルギー）、アレルギー性結膜炎、重症筋無力症、強皮症、サルコイドーシス、乾癬性関節炎、乾癬、強直性脊椎炎、若年性特発性関節炎、グレーブス病、シェーグレン症候群、子宮内膜症、クローン病、ベーチェッ
ト病、セリアック病、１型真性糖尿病、グレーブス病、炎症性腸疾患、多発性硬化症、乾癬、関節リウマチ、全身性紅斑性狼瘡、家族性地中海熱（ＦＭＦ）、高免疫グロブリンＤ血症および周期熱症候群（ＨＩＤＳ）、ＴＮＦ受容体関連周期症候群（ＴＲＡＰＳ）、クリオピリン関連周期性症候群（ＣＡＰＳ、マックルウェルズ症候群、家族性寒冷蕁麻疹、新生児期発症など）、多系統炎症性疾患（ＮＯＭＩＤ）、周期性発熱、アフタ性口内炎、咽頭炎および腺炎（ＰＦＡＰＡ症候群）、ブラウ症候群、化膿性無菌性関節炎、壊疽性膿皮症、にきび（ＰＡＰＡ）、インターロイキン１受容体拮抗薬（ＤＩＲＡ）の欠乏、成人－発症スティル病および全身発症若年性特発性関節炎、心血管疾患からなる群から選択され；もしくは
ｂ）腫瘍性障害であって；場合により、前記腫瘍性障害が、前立腺がん、乳がん、肺がん、結腸直腸がん、黒色腫、膀胱がん、脳／ＣＮＳがん、子宮頸がん、食道がん、胃がん、頭頸部がん、腎臓がん、肝がん、リンパ腫、卵巣がん、膵臓がん、肉腫、慢性骨髄性白血病（ＣＭＬ）、骨髄増殖性疾患（ＭＰＤ）、骨髄異形成症候群（ＭＤＳ）、急性リンパ芽球性白血病（ＡＬＬ）および急性骨髄性白血病（ＡＭＬ）からなる群から選択される；
のための、請求項１～６および１４のいずれか１項に記載の組成物、請求項７～１２のいずれか１項に記載の２エピトープ結合剤、請求項１３に記載のポリヌクレオチド、請求項１４に記載のベクター、請求項１４に記載の宿主細胞、または請求項１５に記載の医薬組成物。 Using the following:
(i) as a pharmaceutical or as a diagnostic and/or prognostic agent; or
(ii) in the treatment, amelioration, prevention, diagnosis or prognosis of an IL1RAP-related disease or disorder in a mammal,
optionally, said IL1RAP-associated disease or disorder is selected from the group consisting of proliferative disorders, autoimmune disorders, and inflammatory disorders such as autoinflammatory disorders;
Optionally, said disease or disorder is:
a) Rheumatoid arthritis, osteoarthritis, multiple sclerosis, arthrosis, scleroderma (systemic sclerosis), lupus, systemic lupus erythematosus (SLE), (acute) glomerulonephritis, asthma, chronic obstructive Pulmonary disease (COPD), respiratory distress syndrome (ARDS), inflammatory bowel disease, colitis, vasculitis, uveitis, dermatitis, atopic dermatitis, alopecia, rhinitis (allergy), allergic conjunctivitis, muscle gravis Asthenia, scleroderma, sarcoidosis, psoriatic arthritis, psoriasis, ankylosing spondylitis, juvenile idiopathic arthritis, Graves' disease, Sjogren's syndrome, endometriosis, Crohn's disease, Behcet's disease, celiac disease, type 1 diabetes mellitus , Graves' disease, inflammatory bowel disease, multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, familial Mediterranean fever (FMF), hyperimmunoglobulinemia and periodic fever syndrome (HIDS), TNF receptors associated periodic syndrome (TRAPS), cryopyrin-associated periodic syndrome (CAPS, Muckle-Wells syndrome, familial cold urticaria, neonatal onset, etc.), multisystem inflammatory disease (NOMID), periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA syndrome), Blau syndrome, aseptic pyogenic arthritis, pyoderma gangrenosum, acne (PAPA), interleukin-1 receptor antagonist (DIRA) deficiency, adult-onset Still's disease and systemic onset juvenile is selected from the group consisting of idiopathic arthritis, cardiovascular disease; or
b) a neoplastic disorder; optionally said neoplastic disorder is prostate cancer, breast cancer, lung cancer, colorectal cancer, melanoma, bladder cancer, brain/CNS cancer, cervical cancer, esophagus Cancer, gastric cancer, head and neck cancer, kidney cancer, liver cancer, lymphoma, ovarian cancer, pancreatic cancer, sarcoma, chronic myelogenous leukemia (CML), myeloproliferative disease (MPD), myelodysplastic syndrome (MDS), acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML);
(iii) in the treatment of a disease or disorder selected from the group consisting of proliferative disorders, autoimmune disorders, and inflammatory disorders such as autoinflammatory disorders;
Optionally, said disease or disorder is:
a) Rheumatoid arthritis, osteoarthritis, multiple sclerosis, arthrosis, scleroderma (systemic sclerosis), lupus, systemic lupus erythematosus (SLE), (acute) glomerulonephritis, asthma, chronic obstructive Pulmonary disease (COPD), respiratory distress syndrome (ARDS), inflammatory bowel disease, colitis, vasculitis, uveitis, dermatitis, atopic dermatitis, alopecia, rhinitis (allergy), allergic conjunctivitis, muscle gravis Asthenia, scleroderma, sarcoidosis, psoriatic arthritis, psoriasis, ankylosing spondylitis, juvenile idiopathic arthritis, Graves' disease, Sjogren's syndrome, endometriosis, Crohn's disease, Behcet's disease, celiac disease, type 1 diabetes mellitus , Graves' disease, inflammatory bowel disease, multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, familial Mediterranean fever (FMF), hyperimmunoglobulinemia and periodic fever syndrome (HIDS), TNF receptors associated periodic syndrome (TRAPS), cryopyrin-associated periodic syndrome (CAPS, Muckle-Wells syndrome, familial cold urticaria, neonatal onset, etc.), multisystem inflammatory disease (NOMID), periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA syndrome), Blau syndrome, aseptic pyogenic arthritis, pyoderma gangrenosum, acne (PAPA), interleukin-1 receptor antagonist (DIRA) deficiency, adult-onset Still's disease and systemic onset juvenile or b) a neoplastic disorder; optionally said neoplastic disorder is prostate cancer, breast cancer, lung cancer, colorectal cancer, melanoma, Bladder cancer, brain/CNS cancer, cervical cancer, esophageal cancer, gastric cancer, head and neck cancer, kidney cancer, liver cancer, lymphoma, ovarian cancer, pancreatic cancer, sarcoma, chronic myelogenous leukemia (CML), myeloproliferative disease (MPD), myelodysplastic syndrome (MDS), acute lymphoblastic leukemia (ALL) and acute myelogenous leukemia (AML);
for, the composition of any one of claims 1-6 and 14, the two-epitope binding agent of any one of claims 7-12, the polynucleotide of claim 13, claim 15. The vector of claim 14, the host cell of claim 14, or the pharmaceutical composition of claim 15. 哺乳動物におけるＩＬ１ＲＡＰ関連の疾患または障害の治療、改善、予防、診断または予後の使用のための請求項１～６のいずれか１項に記載のＩＬ１ＲＡＰに特異性を有する第１の結合剤であって、前記第１の結合剤が、ＩＬ１ＲＡＰに特異性を有する１つ以上のさらなる結合剤と組み合わせて使用するためのものであり、前記第１の結合剤およびさらなる結合剤が、ＩＬ１ＲＡＰの少なくとも２つの異なる細胞外ドメインに結合する、前記第１の結合剤。 A first binding agent having specificity for IL1RAP according to any one of claims 1-6 for use in the treatment, amelioration, prevention, diagnosis or prognosis of an IL1RAP-associated disease or disorder in a mammal. wherein said first binding agent is for use in combination with one or more additional binding agents having specificity for IL1RAP, wherein said first binding agent and additional binding agents are for at least two binding agents of IL1RAP. Said first binding agent that binds to two different extracellular domains.
JP2021507831A 2018-08-16 2019-08-15 Anti-IL1RAP antibody composition Pending JP2022532812A (en)

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