JPWO2021139780A5 - - Google Patents

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JPWO2021139780A5
JPWO2021139780A5 JP2022542269A JP2022542269A JPWO2021139780A5 JP WO2021139780 A5 JPWO2021139780 A5 JP WO2021139780A5 JP 2022542269 A JP2022542269 A JP 2022542269A JP 2022542269 A JP2022542269 A JP 2022542269A JP WO2021139780 A5 JPWO2021139780 A5 JP WO2021139780A5
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amino acid
heavy chain
sequence shown
variable region
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Priority claimed from PCT/CN2021/070907 external-priority patent/WO2021139780A1/en
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ＴＩＧＩＴ及びＰＤ１に結合する多重特異性抗体であって、
ｉ）
以下：
ａ）配列番号９４に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ１、配列番号９５に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ２、及び配列番号９６に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ３、
ｂ）配列番号９８に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ１、配列番号９９に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ２、及び配列番号１００に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ３、
ｃ）配列番号１０２に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ１、配列番号１０３に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ２、及び配列番号１０４に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ３、
ｄ）配列番号１０６に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ１、配列番号１０７に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ２、及び配列番号１０８に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ３、
ｅ）配列番号１１０に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ１、配列番号１１１に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ２、及び配列番号１１２に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ３、
ｆ）配列番号１１４に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ１、配列番号１１５に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ２、及び配列番号１１６に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ３、
ｇ）配列番号１１８に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ１、配列番号１１９に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ２、及び配列番号１２０に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ３、
ｈ）配列番号１２２に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ１、配列番号１２３に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ２、及び配列番号１２４に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ３、
ｉ）配列番号１２６に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ１、配列番号１２７に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ２、及び配列番号１２８に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ３、
ｊ）配列番号１３０に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ１、配列番号１３１に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ２、及び配列番号１３２に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ３、
ｋ）配列番号１３４に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ１、配列番号１３５に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ２、及び配列番号１３６に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ３、
ｌ）配列番号１３８に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ１、配列番号１３９に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ２、及び配列番号１４０に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ３、
ｍ）配列番号１４２に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ１、配列番号１４３に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ２、及び配列番号１４４に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ３、
ｎ）配列番号１４６に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ１、配列番号１４７に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ２、及び配列番号１４８に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ３、
ｏ）配列番号１５０に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ１、配列番号１５１に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ２、及び配列番号１５２に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ３、
ｐ）配列番号１５４に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ１、配列番号１５５に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ２、及び配列番号１５６に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ３、
ｑ）配列番号１５８に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ１、配列番号１５９に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ２、及び配列番号１６０に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ３、
ｒ）配列番号１６２に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ１、配列番号１６３に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ２、及び配列番号１６４に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ３、
ｓ）配列番号１６６に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ１、配列番号１６７に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ２、及び配列番号１６８に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ３、
ｔ）配列番号１７０に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ１、配列番号１７１に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ２、及び配列番号１７２に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ３、
ｕ）配列番号１７４に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ１、配列番号１７５に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ２、及び配列番号１７６に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ３、
ｖ）配列番号１７８に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ１、配列番号１７９に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ２、及び配列番号１８０に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ３、
ｗ）配列番号１８２に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ１、配列番号１８３に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ２、及び配列番号１８４に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ３、
ｘ）配列番号１８６に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ１、配列番号１８７に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ２、及び配列番号１８８に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ３、又は、
ｙ）配列番号１９０に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ１、配列番号１９１に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ２、及び配列番号１９２に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ３を含む、
重鎖可変領域を含むＴＩＧＩＴに結合する単一ドメイン抗体を含む抗ＴＩＧＩＴ抗体を含む第１の抗原結合部分と、
ｉｉ）
以下：
ａ）（１）アミノ酸配列ＦＴＦＳＮＹＧＭＳ（配列番号２２１）含むＣＤＲ－Ｈ１と、（２）アミノ酸配列ＴＩＳＧＧＧＳＮＩＹ（配列番号２２２）を含むＣＤＲ－Ｈ２と、（３）アミノ酸配列ＶＳＹＹＹＧＩＤＦ（配列番号２２３）を含むＣＤＲ－Ｈ３を含む重鎖可変ドメイン（ＶＨ）配列、及び（１）アミノ酸配列ＫＡＳＱＤＶＴＴＡＶＡ（配列番号２２４）を含むＣＤＲ－Ｌ１と、（２）アミノ酸配列ＷＡＳＴＲＨＴ（配列番号２２５）を含むＣＤＲ－Ｌ２と、（３）アミノ酸配列ＱＱＨＹＴＩＰＷＴ（配列番号２２６）を含むＣＤＲ－Ｌ３を含む軽鎖可変ドメイン（ＶＬ）配列、
ｂ）（１）アミノ酸配列ＦＲＦＳＮＹＧＭＳ（配列番号２２９）含むＣＤＲ－Ｈ１と、（２）アミノ酸配列ＴＩＳＧＧＧＳＮＡＹ（配列番号２３０）を含むＣＤＲ－Ｈ２と、（３）アミノ酸配列ＴＳＹＹＹＧＩＤＦ（配列番号２３１）を含むＣＤＲ－Ｈ３を含む重鎖可変ドメイン（ＶＨ）配列、及び（１）アミノ酸配列ＫＡＳＴＤＶＴＴＡＶＡ（配列番号２３２）を含むＣＤＲ－Ｌ１と、（２）アミノ酸配列ＷＡＳＬＲＨＴ（配列番号２３３）を含むＣＤＲ－Ｌ２と、（３）アミノ酸配列ＱＱＨＹＧＩＰＷＴ（配列番号２３４）を含むＣＤＲ－Ｌ３を含む軽鎖可変ドメイン（ＶＬ）配列、
ｃ）（１）アミノ酸配列ＦＴＦＳＮＹＧＭＳ（配列番号２３７）含むＣＤＲ－Ｈ１と、（２）アミノ酸配列ＴＩＳＧＧＧＳＮＩＹ（配列番号２３８）を含むＣＤＲ－Ｈ２と、（３）アミノ酸配列ＶＳＹＹＹＧＩＤＬ（配列番号２３９）を含むＣＤＲ－Ｈ３を含む重鎖可変ドメイン（ＶＨ）配列、及び（１）アミノ酸配列ＫＡＫＱＤＶＴＴＡＶＡ（配列番号２４０）を含むＣＤＲ－Ｌ１と、（２）アミノ酸配列ＷＡＳＴＲＨＴ（配列番号２４１）を含むＣＤＲ－Ｌ２と、（３）アミノ酸配列ＱＱＨＹＷＩＰＷＴ（配列番号２４２）を含むＣＤＲ－Ｌ３を含む軽鎖可変ドメイン（ＶＬ）配列、又は、
ｄ）（１）アミノ酸配列ＦＴＦＳＮＹＧＭＳ（配列番号２４５）含むＣＤＲ－Ｈ１と、（２）アミノ酸配列ＴＩＳＧＧＧＳＮＩＹ（配列番号２４６）を含むＣＤＲ－Ｈ２と、（３）アミノ酸配列ＳＳＹＹＹＧＩＤＬ（配列番号２４７）を含むＣＤＲ－Ｈ３を含む重鎖可変ドメイン（ＶＨ）配列、及び（１）アミノ酸配列ＫＡＳＱＤＶＴＮＡＶＡ（配列番号２４８）を含むＣＤＲ－Ｌ１と、（２）アミノ酸配列ＷＡＳＴＲＨＴ（配列番号２４９）を含むＣＤＲ－Ｌ２と、（３）アミノ酸配列ＱＱＨＹＴＩＰＷＴ（配列番号２５０）を含むＣＤＲ－Ｌ３を含む軽鎖可変ドメイン（ＶＬ）配列を含む、
ＰＤ１に結合する抗ＰＤ１抗体を含む第２の抗原結合部分を含む、多重特異性抗体。 A multispecific antibody that binds to TIGIT and PD1,
i)
below:
a) Heavy chain variable region CDR1 containing the amino acid having the sequence shown in SEQ ID NO: 94, heavy chain variable region CDR2 containing the amino acid having the sequence shown in SEQ ID NO: 95, and heavy chain containing the amino acid having the sequence shown in SEQ ID NO: 96. variable region CDR3,
b) Heavy chain variable region CDR1 comprising the amino acid having the sequence shown in SEQ ID NO: 98, heavy chain variable region CDR2 comprising the amino acid having the sequence shown in SEQ ID NO: 99, and heavy chain comprising the amino acid having the sequence shown in SEQ ID NO: 100. variable region CDR3,
c) Heavy chain variable region CDR1 comprising the amino acid having the sequence shown in SEQ ID NO: 102, heavy chain variable region CDR2 comprising the amino acid having the sequence shown in SEQ ID NO: 103, and heavy chain comprising the amino acid having the sequence shown in SEQ ID NO: 104. variable region CDR3,
d) A heavy chain variable region CDR1 comprising the amino acid having the sequence shown in SEQ ID NO: 106, a heavy chain variable region CDR2 comprising the amino acid having the sequence shown in SEQ ID NO: 107, and a heavy chain comprising the amino acid having the sequence shown in SEQ ID NO: 108. variable region CDR3,
e) A heavy chain variable region CDR1 comprising an amino acid having the sequence shown in SEQ ID NO: 110, a heavy chain variable region CDR2 comprising an amino acid having the sequence shown in SEQ ID NO: 111, and a heavy chain comprising an amino acid having the sequence shown in SEQ ID NO: 112. variable region CDR3,
f) A heavy chain variable region CDR1 comprising an amino acid having the sequence shown in SEQ ID NO: 114, a heavy chain variable region CDR2 comprising an amino acid having the sequence shown in SEQ ID NO: 115, and a heavy chain comprising an amino acid having the sequence shown in SEQ ID NO: 116. variable region CDR3,
g) A heavy chain variable region CDR1 comprising an amino acid having the sequence shown in SEQ ID NO: 118, a heavy chain variable region CDR2 comprising an amino acid having the sequence shown in SEQ ID NO: 119, and a heavy chain comprising an amino acid having the sequence shown in SEQ ID NO: 120. variable region CDR3,
h) Heavy chain variable region CDR1 comprising the amino acid having the sequence shown in SEQ ID NO: 122, heavy chain variable region CDR2 comprising the amino acid having the sequence shown in SEQ ID NO: 123, and heavy chain comprising the amino acid having the sequence shown in SEQ ID NO: 124. variable region CDR3,
i) Heavy chain variable region CDR1 comprising the amino acid having the sequence shown in SEQ ID NO: 126, heavy chain variable region CDR2 comprising the amino acid having the sequence shown in SEQ ID NO: 127, and heavy chain comprising the amino acid having the sequence shown in SEQ ID NO: 128. variable region CDR3,
j) Heavy chain variable region CDR1 comprising the amino acid having the sequence shown in SEQ ID NO: 130, heavy chain variable region CDR2 comprising the amino acid having the sequence shown in SEQ ID NO: 131, and heavy chain comprising the amino acid having the sequence shown in SEQ ID NO: 132. variable region CDR3,
k) Heavy chain variable region CDR1 comprising the amino acid having the sequence shown in SEQ ID NO: 134, heavy chain variable region CDR2 comprising the amino acid having the sequence shown in SEQ ID NO: 135, and heavy chain comprising the amino acid having the sequence shown in SEQ ID NO: 136. variable region CDR3,
l) Heavy chain variable region CDR1 comprising the amino acid having the sequence shown in SEQ ID NO: 138, heavy chain variable region CDR2 comprising the amino acid having the sequence shown in SEQ ID NO: 139, and heavy chain comprising the amino acid having the sequence shown in SEQ ID NO: 140. variable region CDR3,
m) heavy chain variable region CDR1 comprising the amino acid having the sequence shown in SEQ ID NO: 142, heavy chain variable region CDR2 comprising the amino acid having the sequence shown in SEQ ID NO: 143, and heavy chain comprising the amino acid having the sequence shown in SEQ ID NO: 144. variable region CDR3,
n) Heavy chain variable region CDR1 comprising the amino acid having the sequence shown in SEQ ID NO: 146, heavy chain variable region CDR2 comprising the amino acid having the sequence shown in SEQ ID NO: 147, and heavy chain comprising the amino acid having the sequence shown in SEQ ID NO: 148. variable region CDR3,
o) Heavy chain variable region CDR1 comprising the amino acid having the sequence shown in SEQ ID NO: 150, heavy chain variable region CDR2 comprising the amino acid having the sequence shown in SEQ ID NO: 151, and heavy chain comprising the amino acid having the sequence shown in SEQ ID NO: 152. variable region CDR3,
p) Heavy chain variable region CDR1 comprising the amino acid having the sequence shown in SEQ ID NO: 154, heavy chain variable region CDR2 comprising the amino acid having the sequence shown in SEQ ID NO: 155, and heavy chain comprising the amino acid having the sequence shown in SEQ ID NO: 156. variable region CDR3,
q) Heavy chain variable region CDR1 comprising the amino acid having the sequence shown in SEQ ID NO: 158, heavy chain variable region CDR2 comprising the amino acid having the sequence shown in SEQ ID NO: 159, and heavy chain comprising the amino acid having the sequence shown in SEQ ID NO: 160. variable region CDR3,
r) Heavy chain variable region CDR1 comprising the amino acid having the sequence shown in SEQ ID NO: 162, heavy chain variable region CDR2 comprising the amino acid having the sequence shown in SEQ ID NO: 163, and heavy chain comprising the amino acid having the sequence shown in SEQ ID NO: 164. variable region CDR3,
s) A heavy chain variable region CDR1 comprising an amino acid having the sequence shown in SEQ ID NO: 166, a heavy chain variable region CDR2 comprising an amino acid having the sequence shown in SEQ ID NO: 167, and a heavy chain comprising an amino acid having the sequence shown in SEQ ID NO: 168. variable region CDR3,
t) Heavy chain variable region CDR1 comprising the amino acid having the sequence shown in SEQ ID NO: 170, heavy chain variable region CDR2 comprising the amino acid having the sequence shown in SEQ ID NO: 171, and heavy chain comprising the amino acid having the sequence shown in SEQ ID NO: 172. variable region CDR3,
u) Heavy chain variable region CDR1 comprising the amino acid having the sequence shown in SEQ ID NO: 174, heavy chain variable region CDR2 comprising the amino acid having the sequence shown in SEQ ID NO: 175, and heavy chain comprising the amino acid having the sequence shown in SEQ ID NO: 176. variable region CDR3,
v) Heavy chain variable region CDR1 comprising the amino acid having the sequence shown in SEQ ID NO: 178, heavy chain variable region CDR2 comprising the amino acid having the sequence shown in SEQ ID NO: 179, and heavy chain comprising the amino acid having the sequence shown in SEQ ID NO: 180. variable region CDR3,
w) Heavy chain variable region CDR1 comprising the amino acid having the sequence shown in SEQ ID NO: 182, heavy chain variable region CDR2 comprising the amino acid having the sequence shown in SEQ ID NO: 183, and heavy chain comprising the amino acid having the sequence shown in SEQ ID NO: 184. variable region CDR3,
x) A heavy chain variable region CDR1 comprising an amino acid having the sequence shown in SEQ ID NO: 186, a heavy chain variable region CDR2 comprising an amino acid having the sequence shown in SEQ ID NO: 187, and a heavy chain comprising an amino acid having the sequence shown in SEQ ID NO: 188. variable region CDR3, or
y) Heavy chain variable region CDR1 comprising the amino acid having the sequence shown in SEQ ID NO: 190, heavy chain variable region CDR2 comprising the amino acid having the sequence shown in SEQ ID NO: 191, and heavy chain comprising the amino acid having the sequence shown in SEQ ID NO: 192. Contains variable region CDR3,
a first antigen-binding portion comprising an anti-TIGIT antibody comprising a single domain antibody that binds TIGIT comprising a heavy chain variable region ;
ii)
below:
a) (1) CDR-H1 containing the amino acid sequence FTFSNYGMS (SEQ ID NO: 221), (2) CDR-H2 containing the amino acid sequence TISGGGSNIY (SEQ ID NO: 222), and (3) containing the amino acid sequence VSYYYGIDF (SEQ ID NO: 223) A heavy chain variable domain (VH) sequence comprising CDR-H3, and (1) CDR-L1 comprising the amino acid sequence KASQDVTTAVA (SEQ ID NO: 224), and (2) CDR-L2 comprising the amino acid sequence WASTRHT (SEQ ID NO: 225). , (3) a light chain variable domain (VL) sequence comprising a CDR-L3 comprising the amino acid sequence QQHYTIPWT (SEQ ID NO: 226);
b) (1) CDR-H1 containing the amino acid sequence FRFSNYGMS (SEQ ID NO: 229), (2) CDR-H2 containing the amino acid sequence TISGGGSNAY (SEQ ID NO: 230), and (3) containing the amino acid sequence TSYYYGIDF (SEQ ID NO: 231) A heavy chain variable domain (VH) sequence comprising CDR-H3, and (1) CDR-L1 comprising the amino acid sequence KASTDVTTAVA (SEQ ID NO: 232), and (2) CDR-L2 comprising the amino acid sequence WASLRHT (SEQ ID NO: 233). , (3) a light chain variable domain (VL) sequence comprising a CDR-L3 comprising the amino acid sequence QQHYGIPWT (SEQ ID NO: 234);
c) (1) CDR-H1 containing the amino acid sequence FTFSNYGMS (SEQ ID NO: 237), (2) CDR-H2 containing the amino acid sequence TISGGGSNIY (SEQ ID NO: 238), and (3) containing the amino acid sequence VSYYYGIDL (SEQ ID NO: 239). A heavy chain variable domain (VH) sequence comprising CDR-H3, and (1) CDR-L1 comprising the amino acid sequence KAKQDVTTAVA (SEQ ID NO: 240), and (2) CDR-L2 comprising the amino acid sequence WASTRHT (SEQ ID NO: 241). , (3) a light chain variable domain (VL) sequence comprising a CDR-L3 comprising the amino acid sequence QQHYWIPWT (SEQ ID NO: 242), or
d) (1) CDR-H1 containing the amino acid sequence FTFSNYGMS (SEQ ID NO: 245), (2) CDR-H2 containing the amino acid sequence TISGGGSNIY (SEQ ID NO: 246), and (3) containing the amino acid sequence SSYYYGIDL (SEQ ID NO: 247) A heavy chain variable domain (VH) sequence comprising CDR-H3, and (1) CDR-L1 comprising the amino acid sequence KASQDVTNAVA (SEQ ID NO: 248), and (2) CDR-L2 comprising the amino acid sequence WASTRHT (SEQ ID NO: 249). , (3) comprising a light chain variable domain (VL) sequence comprising a CDR-L3 comprising the amino acid sequence QQHYTIPWT (SEQ ID NO: 250);
A multispecific antibody comprising a second antigen binding portion comprising an anti-PD1 antibody that binds to PD1. 該単一ドメイン抗体が、配列番号１８６に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ１と、配列番号１８７に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ２と、配列番号１８８に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ３を含む、請求項１に記載の多重特異性抗体。 The single domain antibody has a heavy chain variable region CDR1 comprising an amino acid having the sequence shown in SEQ ID NO: 186, a heavy chain variable region CDR2 comprising an amino acid having the sequence shown in SEQ ID NO: 187, and a sequence shown in SEQ ID NO: 188. 2. The multispecific antibody of claim 1 , comprising a heavy chain variable region CDR3 comprising amino acids having the following amino acids. 該単一ドメイン抗体が、配列番号９７、１０１、１０５、１０９、１１３、１１７、１２１、１２５、１２９、１３３、１３７、１４１、１４５、１４９、１５３、１５７、１６１、１６５、１６９、１７３、１７７、１８１、１８５、１８９及び１９３からなる群から選ばれるアミノ酸配列を含む重鎖可変領域を含む、請求項１または２に記載の多重特異性抗体。 The single domain antibody is SEQ ID NO. 3. The multispecific antibody of claim 1 or 2 , comprising a heavy chain variable region comprising an amino acid sequence selected from the group consisting of , 181, 185, 189 and 193. 該単一ドメイン抗体が、配列番号１８９に示すアミノ酸配列を含む重鎖可変領域を含む、請求項１～３のいずれか一項に記載の多重特異性抗体。 Multispecific antibody according to any one of claims 1 to 3 , wherein the single domain antibody comprises a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 189. 該第２の抗原結合部分が、（１）アミノ酸配列ＦＴＦＳＮＹＧＭＳ（配列番号２２１）含むＣＤＲ－Ｈ１と、（２）アミノ酸配列ＴＩＳＧＧＧＳＮＩＹ（配列番号２２２）を含むＣＤＲ－Ｈ２と、（３）アミノ酸配列ＶＳＹＹＹＧＩＤＦ（配列番号２２３）を含むＣＤＲ－Ｈ３を含む重鎖可変ドメイン（ＶＨ）配列、及び（１）アミノ酸配列ＫＡＳＱＤＶＴＴＡＶＡ（配列番号２２４）を含むＣＤＲ－Ｌ１と、（２）アミノ酸配列ＷＡＳＴＲＨＴ（配列番号２２５）を含むＣＤＲ－Ｌ２と、（３）アミノ酸配列ＱＱＨＹＴＩＰＷＴ（配列番号２２６）を含むＣＤＲ－Ｌ３を含む軽鎖可変ドメイン（ＶＬ）配列を含む、請求項１～４のいずれか一項に記載の多重特異性抗体。 The second antigen-binding portion comprises (1) CDR-H1 containing the amino acid sequence FTFSNYGMS (SEQ ID NO: 221), (2) CDR-H2 containing the amino acid sequence TISGGGSNIY (SEQ ID NO: 222), and (3) the amino acid sequence VSYYYGIDF. (SEQ ID NO: 223); and (1) CDR-L1, which includes the amino acid sequence KASQDVTTAVA (SEQ ID NO: 224); and (2) the amino acid sequence WASTRHT (SEQ ID NO: 225). ) and (3) a light chain variable domain (VL) sequence comprising a CDR-L3 comprising the amino acid sequence QQHYTIPWT (SEQ ID NO: 226 ). Multispecific antibodies. 該第２の抗原結合部分の抗ＰＤ１抗体が、ＩｇＧ１、ＩｇＧ２、ＩｇＧ３及びＩｇＧ４のＦｃ領域からなる群から選ばれるＦｃ領域を含む、請求項１～５のいずれか一項に記載の多重特異性抗体。 The multispecific antibody according to any one of claims 1 to 5 , wherein the anti-PD1 antibody of the second antigen-binding portion comprises an Fc region selected from the group consisting of IgG1, IgG2, IgG3 and IgG4 Fc regions. antibody. 該Ｆｃ領域は、ＩｇＧ４ Ｆｃ領域を含む、請求項６に記載の多重特異性抗体。 7. The multispecific antibody of claim 6 , wherein the Fc region comprises an IgG4 Fc region. 該ＩｇＧ４ Ｆｃ領域は、Ｓ２２８Ｐ突然変異を含む、請求項７に記載の多重特異性抗体。 8. The multispecific antibody of claim 7 , wherein the IgG4 Fc region comprises the S228P mutation. 該多重特異性抗体は、二重特異性抗体である、請求項１～８のいずれか一項に記載の多重特異性抗体。 The multispecific antibody according to any one of claims 1 to 8 , wherein the multispecific antibody is a bispecific antibody. 該多重特異性抗体が、
ｉ）配列番号１８６に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ１と、配列番号１８７に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ２と、配列番号１８８に示す配列を有するアミノ酸を含む重鎖可変領域ＣＤＲ３を含む単一ドメイン抗ＴＩＧＩＴ抗体を含む第１の抗原結合部分と、
ｉｉ）（１）配列番号２２１に示すアミノ酸配列を含むＣＤＲ－Ｈ１と、（２）配列番号２２２に示すアミノ酸配列を含むＣＤＲ－Ｈ２と、（３）配列番号２２３に示すアミノ酸配列を含むＣＤＲ－Ｈ３を含む重鎖可変ドメイン（ＶＨ）配列と、（１）配列番号２２４に示すアミノ酸配列を含むＣＤＲ－Ｌ１と、（２）配列番号２２５に示すアミノ酸配列を含むＣＤＲ－Ｌ２と、（３）配列番号２２６に示すアミノ酸配列を含むＣＤＲ－Ｌ３を含む軽鎖可変ドメイン（ＶＬ）配列を含む抗ＰＤ１抗体を含む第２の抗原結合部分を含む、請求項１～９のいずれか一項に記載の多重特異性抗体。 The multispecific antibody is
i) A heavy chain variable region CDR1 containing the amino acid having the sequence shown in SEQ ID NO: 186, a heavy chain variable region CDR2 containing the amino acid having the sequence shown in SEQ ID NO: 187, and a heavy chain variable region CDR2 containing the amino acid having the sequence shown in SEQ ID NO: 188. a first antigen binding portion comprising a single domain anti-TIGIT antibody comprising chain variable region CDR3;
ii) (1) CDR-H1 containing the amino acid sequence shown in SEQ ID NO: 221, (2) CDR-H2 containing the amino acid sequence shown in SEQ ID NO: 222, and (3) CDR- containing the amino acid sequence shown in SEQ ID NO: 223. A heavy chain variable domain (VH) sequence containing H3, (1) CDR-L1 containing the amino acid sequence shown in SEQ ID NO: 224, (2) CDR-L2 containing the amino acid sequence shown in SEQ ID NO: 225, (3) 10. A second antigen-binding portion comprising an anti-PD1 antibody comprising a light chain variable domain (VL) sequence comprising a CDR-L3 comprising the amino acid sequence shown in SEQ ID NO: 226. multispecific antibodies. 該多重特異性抗体が、配列番号２５３に示すアミノ酸配列を含む、抗ＴＩＧＩＴ抗体に連結される抗ＰＤ１抗体重鎖と、配列番号２５４に示すアミノ酸配列を含む抗ＰＤ１抗体軽鎖を含む、請求項１～１０のいずれか一項に記載の多重特異性抗体。 Claim wherein the multispecific antibody comprises an anti-PD1 antibody heavy chain linked to an anti-TIGIT antibody comprising the amino acid sequence shown in SEQ ID NO: 253, and an anti-PD1 antibody light chain comprising the amino acid sequence shown in SEQ ID NO: 254. The multispecific antibody according to any one of 1 to 10 . 該多重特異性抗体が、配列番号２５７に示すアミノ酸配列を含む、抗ＴＩＧＩＴ抗体に連結される抗ＰＤ１抗体重鎖と、配列番号２５８に示すアミノ酸配列を含む抗ＰＤ１抗体軽鎖を含む、請求項１～１０のいずれか一項に記載の多重特異性抗体。 258. The multispecific antibody comprises an anti-PD1 antibody heavy chain linked to an anti-TIGIT antibody comprising the amino acid sequence shown in SEQ ID NO: 257, and an anti-PD1 antibody light chain comprising the amino acid sequence shown in SEQ ID NO: 258. The multispecific antibody according to any one of 1 to 10. 治療剤に連結される請求項１～１２のいずれか一項に記載の多重特異性抗体を含む、免疫コンジュゲート。 An immunoconjugate comprising a multispecific antibody according to any one of claims 1 to 12 linked to a therapeutic agent. 該治療剤が、細胞毒素であるかまたは放射性同位体である、請求項１３に記載の免疫コンジュゲート。 14. The immunoconjugate of claim 13 , wherein the therapeutic agent is a cytotoxin or a radioisotope. ａ）請求項１～１２のいずれか一項に記載の多重特異性抗体又は請求項１３もしくは１４に記載の免疫コンジュゲートと、ｂ）薬学的に許容される担体を含む、薬物組成物。 A pharmaceutical composition comprising a) a multispecific antibody according to any one of claims 1 to 12 or an immunoconjugate according to claims 13 or 14 , and b) a pharmaceutically acceptable carrier . 請求項１～１２のいずれか一項に記載の多重特異性抗体をコードする、核酸。 A nucleic acid encoding a multispecific antibody according to any one of claims 1 to 12 . 請求項１６に記載の核酸を含む、ベクター。 A vector comprising the nucleic acid according to claim 16 . 請求項１６に記載の核酸又は請求項１７に記載のベクターを含む、宿主細胞。 A host cell comprising a nucleic acid according to claim 16 or a vector according to claim 17 . 請求項１～１２のいずれか一項に記載の多重特異性抗体を調製する方法であって、請求項１８に記載の宿主細胞において該多重特異性抗体を発現し、該宿主細胞から該多重特異性抗体を単離することを含む、方法。 19. A method for preparing a multispecific antibody according to any one of claims 1 to 12 , comprising expressing the multispecific antibody in a host cell according to claim 18 , and obtaining the multispecific antibody from the host cell. 1. A method comprising isolating a sex antibody. 薬物として用いられる、請求項１～１２のいずれか一項に記載の多重特異性抗体。 The multispecific antibody according to any one of claims 1 to 12 , which is used as a drug. 癌の治療に用いられる、請求項１～１２のいずれか一項に記載の多重特異性抗体。 The multispecific antibody according to any one of claims 1 to 12 , which is used for the treatment of cancer. 薬物として用いられる、請求項１５に記載の薬物組成物。 The drug composition according to claim 15 , which is used as a drug. 癌の治療に用いられる、請求項１５に記載の薬物組成物。 The pharmaceutical composition according to claim 15 , which is used for the treatment of cancer. 該癌が、中皮腫、肺癌、膵臓癌、卵巣癌、乳癌、結腸癌、胸膜腫瘍、膠芽細胞腫、食道癌、胃癌、滑膜肉腫、胸腺癌、子宮内膜癌、胃腫瘍、胆管癌、頭頸癌、血液癌及びそれらの組み合わせからなる群から選ばれる、請求項２１に記載の多重特異性抗体又は請求項２３に記載の薬物組成物。 The cancer is mesothelioma, lung cancer, pancreatic cancer, ovarian cancer, breast cancer, colon cancer, pleural tumor, glioblastoma, esophageal cancer, gastric cancer, synovial sarcoma, thymic cancer, endometrial cancer, gastric tumor, bile duct cancer. 24. The multispecific antibody of claim 21 or the pharmaceutical composition of claim 23 selected from the group consisting of cancer, head and neck cancer, hematological cancer, and combinations thereof. 請求項１～１２のいずれか一項に記載の多重特異性抗体、請求項１３または１４に記載の免疫コンジュゲート、請求項１５に記載の薬物組成物、請求項１６に記載の核酸、請求項１７に記載のベクター、又は請求項１８に記載の宿主細胞を含む、キット。 Multispecific antibody according to any one of claims 1 to 12 , immunoconjugate according to claim 13 or 14 , pharmaceutical composition according to claim 15 , nucleic acid according to claim 16 , claim 19. A kit comprising the vector according to claim 17 or the host cell according to claim 18 . 新生物を治療及び／又は予防するためのマニュアルをさらに含む、請求項２５に記載のキット。 26. Kit according to claim 25 , further comprising a manual for treating and/or preventing neoplasms.
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