JPWO2021050554A5 - - Google Patents

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JPWO2021050554A5
JPWO2021050554A5 JP2022514675A JP2022514675A JPWO2021050554A5 JP WO2021050554 A5 JPWO2021050554 A5 JP WO2021050554A5 JP 2022514675 A JP2022514675 A JP 2022514675A JP 2022514675 A JP2022514675 A JP 2022514675A JP WO2021050554 A5 JPWO2021050554 A5 JP WO2021050554A5
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amino acid
formula
conjugate
acid sequence
acid residue
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Priority claimed from PCT/US2020/049954 external-priority patent/WO2021050554A1/en
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配列番号３のアミノ酸配列を含むＩＬ－２コンジュゲートであって、該ＩＬ－２コンジュゲートにおける少なくとも１つのアミノ酸残基は、式（Ｉ）の構造：
Figure 2021050554000001
 （式中：
ＺはＣＨ2であり、Ｙは
Figure 2021050554000002
 であり；
ＹはＣＨ2であり、Ｚは
Figure 2021050554000003
 であり；
ＺはＣＨ2であり、Ｙは
Figure 2021050554000004
 であり；または
ＹはＣＨ2であり、Ｚは
Figure 2021050554000005
 であり；
Ｗは、約５０ｋＤａの分子量を有するＰＥＧ基であり；
Ｘは構造：
Figure 2021050554000006
 を有し；
Ｘ－１は、先行するアミノ酸残基への結合点を示し；
Ｘ＋１は、後続のアミノ酸残基への結合点を示す）
に置き換えられており；
該ＩＬ－２コンジュゲートのアミノ酸配列における式（Ｉ）の構造の位置は、Ｋ８、Ｈ１５、Ｌ１８、Ｄ１９、Ｎ２５、Ｎ８７、Ｅ９９、およびＮ１１８から選択される、前記ＩＬ－２コンジュゲート。 An IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate has the structure of formula (I):
Figure 2021050554000001
 (In the formula:
Z is CH 2 and Y is
Figure 2021050554000002
 And;
Y is CH 2 and Z is
Figure 2021050554000003
 And;
Z is CH 2 and Y is
Figure 2021050554000004
 or Y is CH 2 and Z is
Figure 2021050554000005
 And;
W is a PEG group with a molecular weight of approximately 50 kDa;
X is structure:
Figure 2021050554000006
 has;
X-1 indicates the point of attachment to the preceding amino acid residue;
X+1 indicates the point of attachment to the subsequent amino acid residue)
has been replaced by;
Said IL-2 conjugate, wherein the position of the structure of formula (I) in the amino acid sequence of said IL-2 conjugate is selected from K8, H15, L18, D19, N25, N87, E99, and N118. 配列番号４のアミノ酸配列を含むＩＬ－２コンジュゲートであって、該ＩＬ－２コンジュゲートにおける少なくとも１つのアミノ酸残基は、式（Ｉ）の構造：
Figure 2021050554000007
 （式中：
ＺはＣＨ2であり、Ｙは
Figure 2021050554000008
 であり；
ＹはＣＨ2であり、Ｚは
Figure 2021050554000009
 であり；
ＺはＣＨ2であり、Ｙは
Figure 2021050554000010
 であり；または
ＹはＣＨ2であり、Ｚは
Figure 2021050554000011
 であり；
Ｗは、約５０ｋＤａの分子量を有するＰＥＧ基であり；
Ｘは構造：
Figure 2021050554000012
 を有し；
Ｘ－１は、先行するアミノ酸残基への結合点を示し；
Ｘ＋１は、後続のアミノ酸残基への結合点を示す）
に置き換えられており；
該ＩＬ－２コンジュゲートのアミノ酸配列における式（Ｉ）の構造の位置は、Ｋ９、Ｈ１６、Ｌ１９、Ｄ２０、Ｎ２６、Ｎ８８、Ｅ１００、およびＮ１１９から選択される、前記ＩＬ－２コンジュゲート。 An IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 4, wherein at least one amino acid residue in the IL-2 conjugate has the structure of formula (I):
Figure 2021050554000007
 (In the formula:
Z is CH 2 and Y is
Figure 2021050554000008
 And;
Y is CH 2 and Z is
Figure 2021050554000009
 And;
Z is CH 2 and Y is
Figure 2021050554000010
 or Y is CH 2 and Z is
Figure 2021050554000011
 And;
W is a PEG group with a molecular weight of approximately 50 kDa;
X is structure:
Figure 2021050554000012
 has;
X-1 indicates the point of attachment to the preceding amino acid residue;
X+1 indicates the point of attachment to the subsequent amino acid residue)
has been replaced by;
Said IL-2 conjugate, wherein the position of the structure of formula (I) in the amino acid sequence of said IL-2 conjugate is selected from K9, H16, L19, D20, N26, N88, E100, and N119. ＺはＣＨ2であり、Ｙは
Figure 2021050554000013
 である、請求項１または２に記載のＩＬ－２コンジュゲート。 Z is CH 2 and Y is
Figure 2021050554000013
 The IL-2 conjugate according to claim 1 or 2. ＹはＣＨ2であり、Ｚは
Figure 2021050554000014
 である、請求項１または２に記載のＩＬ－２コンジュゲート。 Y is CH 2 and Z is
Figure 2021050554000014
 The IL-2 conjugate according to claim 1 or 2. ＺはＣＨ2であり、Ｙは
Figure 2021050554000015
 である、請求項１または２に記載のＩＬ－２コンジュゲート。 Z is CH 2 and Y is
Figure 2021050554000015
 The IL-2 conjugate according to claim 1 or 2. ＹはＣＨ2であり、Ｚは
Figure 2021050554000016
 である、請求項１または２に記載のＩＬ－２コンジュゲート。 Y is CH 2 and Z is
Figure 2021050554000016
 The IL-2 conjugate according to claim 1 or 2. ＩＬ－２コンジュゲートのアミノ酸配列における式（Ｉ）の構造の位置は、Ｋ９である、請求項２～６のいずれか１項に記載のＩＬ－２コンジュゲート。 IL-2 conjugate according to any one of claims 2 to 6, wherein the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate is K9. ＩＬ－２コンジュゲートのアミノ酸配列における式（Ｉ）の構造の位置は、Ｈ１６である、請求項２～６のいずれか１項に記載のＩＬ－２コンジュゲート。 The IL-2 conjugate according to any one of claims 2 to 6, wherein the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate is H16. ＩＬ－２コンジュゲートのアミノ酸配列における式（Ｉ）の構造の位置は、Ｌ１９である、請求項２～６のいずれか１項に記載のＩＬ－２コンジュゲート。 The IL-2 conjugate according to any one of claims 2 to 6, wherein the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate is L19. ＩＬ－２コンジュゲートのアミノ酸配列における式（Ｉ）の構造の位置は、Ｄ２０である、請求項２～６のいずれか１項に記載のＩＬ－２コンジュゲート。 The IL-2 conjugate according to any one of claims 2 to 6, wherein the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate is D20. ＩＬ－２コンジュゲートのアミノ酸配列における式（Ｉ）の構造の位置は、Ｎ２６である、請求項２～６のいずれか１項に記載のＩＬ－２コンジュゲート。 The IL-2 conjugate according to any one of claims 2 to 6, wherein the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate is N26. ＩＬ－２コンジュゲートのアミノ酸配列における式（Ｉ）の構造の位置は、Ｎ８８である、請求項２～６のいずれか１項に記載のＩＬ－２コンジュゲート。 The IL-2 conjugate according to any one of claims 2 to 6, wherein the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate is N88. ＩＬ－２コンジュゲートのアミノ酸配列における式（Ｉ）の構造の位置は、Ｅ１００である、請求項２～６のいずれか１項に記載のＩＬ－２コンジュゲート。 The IL-2 conjugate according to any one of claims 2 to 6, wherein the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate is E100. ＩＬ－２コンジュゲートのアミノ酸配列における式（Ｉ）の構造の位置は、Ｎ１１９である、請求項２～６のいずれか１項に記載のＩＬ－２コンジュゲート。 The IL-2 conjugate according to any one of claims 2 to 6, wherein the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate is N119. 配列番号３４～３７、３９～４２、１９９～２０２、および２０４～２０７のいずれか１つのアミノ酸配列を含むＩＬ－２コンジュゲートであって、［ＡｚＫ＿ＰＥＧ］は、式（ＩＩ）または式（ＩＩＩ）の構造：
Figure 2021050554000017
 （式中：
Ｗは、約５０ｋＤａの分子量を有するＰＥＧ基であり；
Ｘは構造：
Figure 2021050554000018
 を有し；
Ｘ－１は、先行するアミノ酸残基への結合点を示し；
Ｘ＋１は、後続のアミノ酸残基への結合点を示す）
を有する、前記ＩＬ－２コンジュゲート。 An IL-2 conjugate comprising the amino acid sequence of any one of SEQ ID NOs: 34-37, 39-42, 199-202, and 204-207, wherein [AzK_PEG] is a compound of formula (II) or formula (III) Structure of:
Figure 2021050554000017
 (In the formula:
W is a PEG group with a molecular weight of approximately 50 kDa;
X is structure:
Figure 2021050554000018
 has;
X-1 indicates the point of attachment to the preceding amino acid residue;
X+1 indicates the point of attachment to the subsequent amino acid residue)
The above IL-2 conjugate comprising: 配列番号４９～５２、５４～５７、２１４～２１７、および２１９～２２２のいずれか１つのアミノ酸配列を含むＩＬ－２コンジュゲートであって、［ＡｚＫ＿ＰＥＧ５０ｋＤａ］は、式（ＩＩ）または式（ＩＩＩ）の構造：
Figure 2021050554000019
 （式中：
Ｗは、約５０ｋＤａの分子量を有するＰＥＧ基であり；
Ｘは構造：
Figure 2021050554000020
 を有し；
Ｘ－１は、先行するアミノ酸残基への結合点を示し；
Ｘ＋１は、後続のアミノ酸残基への結合点を示す）
を有する、前記ＩＬ－２コンジュゲート。 An IL-2 conjugate comprising the amino acid sequence of any one of SEQ ID NOs: 49-52, 54-57, 214-217, and 219-222, wherein [AzK_PEG50kDa] is a compound of formula (II) or formula (III) Structure of:
Figure 2021050554000019
 (In the formula:
W is a PEG group with a molecular weight of approximately 50 kDa;
X is structure:
Figure 2021050554000020
 has;
X-1 indicates the point of attachment to the preceding amino acid residue;
X+1 indicates the point of attachment to the subsequent amino acid residue)
The above IL-2 conjugate comprising: ＩＬ－２コンジュゲートおよび薬学的に許容されるキャリアの混合物を含む医薬組成物であって、該混合物は、配列番号３４～３７、３９～４２、１９９～２０２、および２０４～２０７のいずれか１つのアミノ酸配列を含むＩＬ－２コンジュゲートであって、［ＡｚＫ＿ＰＥＧ］は、式（ＩＩ）の構造である、ＩＬ－２コンジュゲート、ならびに配列番号３４～３７、３９～４２、１９９～２０２、および２０４～２０７のいずれか１つのアミノ酸配列を含むＩＬ－２コンジュゲートであって、［ＡｚＫ＿ＰＥＧ］は、式（ＩＩＩ）の構造である、ＩＬ－２コンジュゲート：
Figure 2021050554000021
 （式中：
Ｗは、約５０ｋＤａの分子量を有するＰＥＧ基であり；
Ｘは構造：
Figure 2021050554000022
 を有し；
Ｘ－１は、先行するアミノ酸残基への結合点を示し；
Ｘ＋１は、後続のアミノ酸残基への結合点を示す）
を含む、前記医薬組成物。 A pharmaceutical composition comprising a mixture of an IL-2 conjugate and a pharmaceutically acceptable carrier, the mixture comprising any one of SEQ ID NOs: 34-37, 39-42, 199-202, and 204-207. an IL-2 conjugate comprising three amino acid sequences, [AzK_PEG] having the structure of formula (II), and SEQ ID NOs: 34-37, 39-42, 199-202, and An IL-2 conjugate comprising any one amino acid sequence of 204 to 207, wherein [AzK_PEG] is a structure of formula (III):
Figure 2021050554000021
 (In the formula:
W is a PEG group with a molecular weight of approximately 50 kDa;
X is structure:
Figure 2021050554000022
 has;
X-1 indicates the point of attachment to the preceding amino acid residue;
X+1 indicates the point of attachment to the subsequent amino acid residue)
The above pharmaceutical composition comprising: ＩＬ－２コンジュゲートおよび薬学的に許容されるキャリアの混合物を含む医薬組成物であって、該混合物は、配列番号４９～５２、５４～５７、２１４～２１７、および２１９～２２２のいずれか１つのアミノ酸配列を含むＩＬ－２コンジュゲートであって、［ＡｚＫ＿ＰＥＧ５０ｋＤａ］は、式（ＩＩ）の構造である、ＩＬ－２コンジュゲート、ならびに配列番号４９～５２、５４～５７、２１４～２１７、および２１９～２２２のいずれか１つのアミノ酸配列を含むＩＬ－２コンジュゲートであって、［ＡｚＫ＿ＰＥＧ５０ｋＤａ］は、式（ＩＩＩ）の構造である、ＩＬ－２コンジュゲート：
Figure 2021050554000023
 （式中：
Ｗは、約５０ｋＤａの分子量を有するＰＥＧ基であり；
Ｘは構造：
Figure 2021050554000024
 を有し；
Ｘ－１は、先行するアミノ酸残基への結合点を示し；
Ｘ＋１は、後続のアミノ酸残基への結合点を示す）
を含む、前記医薬組成物。 A pharmaceutical composition comprising a mixture of an IL-2 conjugate and a pharmaceutically acceptable carrier, the mixture comprising any one of SEQ ID NOs: 49-52, 54-57, 214-217, and 219-222. [AzK_PEG50kDa] is an IL-2 conjugate having the structure of formula (II), and SEQ ID NOs: 49-52, 54-57, 214-217, and An IL-2 conjugate comprising any one amino acid sequence of 219 to 222, wherein [AzK_PEG50kDa] is a structure of formula (III):
Figure 2021050554000023
 (In the formula:
W is a PEG group with a molecular weight of approximately 50 kDa;
X is structure:
Figure 2021050554000024
 has;
X-1 indicates the point of attachment to the preceding amino acid residue;
X+1 indicates the point of attachment to the subsequent amino acid residue)
The above pharmaceutical composition comprising: 配列番号１０９～１１２、１１４～１１７、１５４～１５７、および１５９～１６２のいずれか１つのアミノ酸配列を含むＩＬ－２コンジュゲートであって、［ＡｚＫ＿Ｌ１＿ＰＥＧ］は、式（ＩＶ）または式（Ｖ）の構造：
Figure 2021050554000025
 （式中：
Ｗは、約５０ｋＤａの分子量を有するＰＥＧ基であり；
Ｘは構造：
Figure 2021050554000026
 を有し；
Ｘ－１は、先行するアミノ酸残基への結合点を示し；
Ｘ＋１は、後続のアミノ酸残基への結合点を示す）
を有する、前記ＩＬ－２コンジュゲート。 An IL-2 conjugate comprising the amino acid sequence of any one of SEQ ID NOs: 109-112, 114-117, 154-157, and 159-162, wherein [AzK_L1_PEG] is a compound of formula (IV) or formula (V) Structure of:
Figure 2021050554000025
 (In the formula:
W is a PEG group with a molecular weight of approximately 50 kDa;
X is structure:
Figure 2021050554000026
 has;
X-1 indicates the point of attachment to the preceding amino acid residue;
X+1 indicates the point of attachment to the subsequent amino acid residue)
The above IL-2 conjugate comprising: 配列番号１２４～１２７、１２９～１３２、１６９～１７２、および１７４～１７７のいずれか１つのアミノ酸配列を含むＩＬ－２コンジュゲートであって、［ＡｚＫ＿Ｌ１＿ＰＥＧ５０ｋＤａ］は、式（ＩＶ）または式（Ｖ）の構造：
Figure 2021050554000027
 （式中：
Ｗは、約５０ｋＤａの分子量を有するＰＥＧ基であり；
Ｘは構造：
Figure 2021050554000028
 を有し；
Ｘ－１は、先行するアミノ酸残基への結合点を示し；
Ｘ＋１は、後続のアミノ酸残基への結合点を示す）
を有する、前記ＩＬ－２コンジュゲート。 An IL-2 conjugate comprising any one amino acid sequence of SEQ ID NOs: 124-127, 129-132, 169-172, and 174-177, wherein [AzK_L1_PEG50kDa] is a compound of formula (IV) or formula (V) Structure of:
Figure 2021050554000027
 (In the formula:
W is a PEG group with a molecular weight of approximately 50 kDa;
X is structure:
Figure 2021050554000028
 has;
X-1 indicates the point of attachment to the preceding amino acid residue;
X+1 indicates the point of attachment to the subsequent amino acid residue)
The above IL-2 conjugate comprising: 配列番号１７０のアミノ酸配列を有する、請求項２０に記載のＩＬ－２コンジュゲート。 The IL-2 conjugate according to claim 20, having the amino acid sequence of SEQ ID NO: 170. ＩＬ－２コンジュゲートおよび薬学的に許容されるキャリアの混合物を含む医薬組成物であって、該混合物は、配列番号１０９～１１２、１１４～１１７、１５４～１５７、および１５９～１６２のいずれか１つのアミノ酸配列を含むＩＬ－２コンジュゲートであって、［Ａｚｋ＿Ｌ１＿ＰＥＧ］は、式（ＩＶ）の構造である、ＩＬ－２コンジュゲート、ならびに配列番号１０９～１１２、１１４～１１７、１５４～１５７、および１５９～１６２のいずれか１つのアミノ酸配列を含むＩＬ－２コンジュゲートであって、［Ａｚｋ＿Ｌ１＿ＰＥＧ］は、式（Ｖ）の構造である、ＩＬ－２コンジュゲート：
Figure 2021050554000029
 （式中：
Ｗは、約５０ｋＤａの分子量を有するＰＥＧ基であり；
Ｘは構造：
Figure 2021050554000030
 を有し；
Ｘ－１は、先行するアミノ酸残基への結合点を示し；
Ｘ＋１は、後続のアミノ酸残基への結合点を示す）
を含む、前記医薬組成物。 A pharmaceutical composition comprising a mixture of an IL-2 conjugate and a pharmaceutically acceptable carrier, the mixture comprising any one of SEQ ID NOs: 109-112, 114-117, 154-157, and 159-162. an IL-2 conjugate comprising three amino acid sequences, [Azk_L1_PEG] having the structure of formula (IV), and SEQ ID NOs: 109-112, 114-117, 154-157, and An IL-2 conjugate comprising any one amino acid sequence of 159 to 162, wherein [Azk_L1_PEG] is a structure of formula (V):
Figure 2021050554000029
 (In the formula:
W is a PEG group with a molecular weight of approximately 50 kDa;
X is structure:
Figure 2021050554000030
 has;
X-1 indicates the point of attachment to the preceding amino acid residue;
X+1 indicates the point of attachment to the subsequent amino acid residue)
The above pharmaceutical composition comprising: ＩＬ－２コンジュゲートおよび薬学的に許容されるキャリアの混合物を含む医薬組成物であって、該混合物は、配列番号１２４～１２７、１２９～１３２、１６９～１７２、および１７４～１７７のいずれか１つのアミノ酸配列を含むＩＬ－２コンジュゲートであって、［ＡｚＫ＿Ｌ１＿ＰＥＧ５０ｋＤａ］は、式（ＩＶ）の構造である、ＩＬ－２コンジュゲート、ならびに配列番号１２４～１２７、１２９～１３２、１６９～１７２、および１７４～１７７のいずれか１つのアミノ酸配列を含むＩＬ－２コンジュゲートであって、［ＡｚＫ＿Ｌ１＿ＰＥＧ５０ｋＤａ］は、式（Ｖ）の構造である、ＩＬ－２コンジュゲート：
Figure 2021050554000031
 （式中：
Ｗは、約５０ｋＤａの分子量を有するＰＥＧ基であり；
Ｘは構造：
Figure 2021050554000032
 を有し；
Ｘ－１は、先行するアミノ酸残基への結合点を示し；
Ｘ＋１は、後続のアミノ酸残基への結合点を示す）
を含む、前記医薬組成物。 A pharmaceutical composition comprising a mixture of an IL-2 conjugate and a pharmaceutically acceptable carrier, the mixture comprising any one of SEQ ID NOs: 124-127, 129-132, 169-172, and 174-177. [AzK_L1_PEG50kDa] is an IL-2 conjugate having the structure of formula (IV), and SEQ ID NOs: 124-127, 129-132, 169-172, and An IL-2 conjugate comprising any one amino acid sequence of 174 to 177, wherein [AzK_L1_PEG50kDa] has the structure of formula (V):
Figure 2021050554000031
 (In the formula:
W is a PEG group with a molecular weight of approximately 50 kDa;
X is structure:
Figure 2021050554000032
 has;
X-1 indicates the point of attachment to the preceding amino acid residue;
X+1 indicates the point of attachment to the subsequent amino acid residue)
The above pharmaceutical composition comprising: 配列番号３のアミノ酸配列を含むＩＬ－２コンジュゲートであって、該ＩＬ－２コンジュゲートにおける少なくとも１つのアミノ酸残基は、式（ＶＩ）または式（ＶＩＩ）の構造：
Figure 2021050554000033
 （式中：
ｎは、ＰＥＧ部分の分子量が約５０ｋＤａであるような整数であり；
Ｘは構造：
Figure 2021050554000034
 を有し、
Ｘ－１は、先行するアミノ酸残基への結合点を示し；
Ｘ＋１は、後続のアミノ酸残基への結合点を示す）
に置き換えられており、
ＩＬ－２コンジュゲートのアミノ酸配列における式（ＶＩ）または式（ＶＩＩ）の構造の位置は、Ｋ８、Ｈ１５、Ｌ１８、Ｄ１９、Ｎ２５、Ｎ８７、Ｅ９９、およびＮ１１８から選択される、前記ＩＬ－２コンジュゲート。 An IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate has a structure of formula (VI) or formula (VII):
Figure 2021050554000033
 (In the formula:
n is an integer such that the molecular weight of the PEG moiety is approximately 50 kDa;
X is structure:
Figure 2021050554000034
 has
X-1 indicates the point of attachment to the preceding amino acid residue;
X+1 indicates the point of attachment to the subsequent amino acid residue)
has been replaced by
The position of the structure of formula (VI) or formula (VII) in the amino acid sequence of the IL-2 conjugate is selected from K8, H15, L18, D19, N25, N87, E99, and N118. Gate. 配列番号３のアミノ酸配列を含むＩＬ－２コンジュゲートであって、該ＩＬ－２コンジュゲートにおける少なくとも１つのアミノ酸残基は、式（ＶＩＩＩ）または式（ＩＸ）の構造：
Figure 2021050554000035
 （式中：
ｎは、ＰＥＧ部分の分子量が約５０ｋＤａであるような整数であり；
Ｘは構造：
Figure 2021050554000036
 を有し、
Ｘ－１は、先行するアミノ酸残基への結合点を示し；
Ｘ＋１は、後続のアミノ酸残基への結合点を示す）
に置き換えられており、
ＩＬ－２コンジュゲートのアミノ酸配列における式（ＶＩＩＩ）または式（ＩＸ）の構造の位置は、Ｋ８、Ｈ１５、Ｌ１８、Ｄ１９、Ｎ２５、Ｎ８７、Ｅ９９、およびＮ１１８から選択される、前記ＩＬ－２コンジュゲート。 An IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate has a structure of formula (VIII) or formula (IX):
Figure 2021050554000035
 (In the formula:
n is an integer such that the molecular weight of the PEG moiety is approximately 50 kDa;
X is structure:
Figure 2021050554000036
 has
X-1 indicates the point of attachment to the preceding amino acid residue;
X+1 indicates the point of attachment to the subsequent amino acid residue)
has been replaced by
The position of the structure of formula (VIII) or formula (IX) in the amino acid sequence of the IL-2 conjugate is selected from K8, H15, L18, D19, N25, N87, E99, and N118. Gate. 配列番号３のアミノ酸配列を含むＩＬ－２コンジュゲートであって、該ＩＬ－２コンジュゲートにおける少なくとも１つのアミノ酸残基は、式（Ｘ）または式（ＸＩ）の構造：
Figure 2021050554000037
 （式中：
ｎは、ＰＥＧ部分の分子量が約５０ｋＤａであるような整数であり；
波線は、置き換えられていない配列番号３内のアミノ酸残基への共有結合を示す）
に置き換えられており、
ＩＬ－２コンジュゲートのアミノ酸配列における式（Ｘ）または式（ＸＩ）の構造の位置は、Ｋ８、Ｈ１５、Ｌ１８、Ｄ１９、Ｎ２５、Ｎ８７、Ｅ９９、およびＮ１１８から選択される、前記ＩＬ－２コンジュゲート。 An IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate has a structure of formula (X) or formula (XI):
Figure 2021050554000037
 (In the formula:
n is an integer such that the molecular weight of the PEG moiety is approximately 50 kDa;
Wavy lines indicate covalent bonds to amino acid residues within SEQ ID NO: 3 that are not replaced)
has been replaced by
The position of the structure of formula (X) or formula (XI) in the amino acid sequence of the IL-2 conjugate is selected from K8, H15, L18, D19, N25, N87, E99, and N118. Gate. 配列番号３のアミノ酸配列を含むＩＬ－２コンジュゲートであって、該ＩＬ－２コンジュゲートにおける少なくとも１つのアミノ酸残基は、式（ＸＩＩ）または式（ＸＩＩＩ）の構造：
Figure 2021050554000038
 （式中：
ｎは、ＰＥＧ部分の分子量が約５０ｋＤａであるような整数であり；
波線は、置き換えられていない配列番号３内のアミノ酸残基への共有結合を示す）
に置き換えられており、
ＩＬ－２コンジュゲートのアミノ酸配列における式（ＸＩＩ）または式（ＸＩＩ）の構造の位置は、Ｋ８、Ｈ１５、Ｌ１８、Ｄ１９、Ｎ２５、Ｎ８７、Ｅ９９、およびＮ１１８から選択される、前記ＩＬ－２コンジュゲート。 An IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate has a structure of formula (XII) or formula (XIII):
Figure 2021050554000038
 (In the formula:
n is an integer such that the molecular weight of the PEG moiety is approximately 50 kDa;
Wavy lines indicate covalent bonds to amino acid residues within SEQ ID NO: 3 that are not replaced)
has been replaced by
The position of formula (XII) or the structure of formula (XII) in the amino acid sequence of the IL-2 conjugate is selected from K8, H15, L18, D19, N25, N87, E99, and N118. Gate. 配列番号４のアミノ酸配列を含むＩＬ－２コンジュゲートであって、該ＩＬ－２コンジュゲートにおける少なくとも１つのアミノ酸残基は、式（ＶＩ）または式（ＶＩＩ）の構造：
Figure 2021050554000039
 （式中：
ｎは、ＰＥＧ部分の分子量が約５０ｋＤａであるような整数であり；
Ｘは構造：
Figure 2021050554000040
 を有し、
Ｘ－１は、先行するアミノ酸残基への結合点を示し；
Ｘ＋１は、後続のアミノ酸残基への結合点を示す）
に置き換えられており、
ＩＬ－２コンジュゲートのアミノ酸配列における式（ＶＩ）または式（ＶＩＩ）の構造の位置は、Ｋ９、Ｈ１６、Ｌ１９、Ｄ２０、Ｎ２６、Ｎ８８、Ｅ１００、およびＮ１１９から選択される、前記ＩＬ－２コンジュゲート。 An IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 4, wherein at least one amino acid residue in the IL-2 conjugate has a structure of formula (VI) or formula (VII):
Figure 2021050554000039
 (In the formula:
n is an integer such that the molecular weight of the PEG moiety is approximately 50 kDa;
X is structure:
Figure 2021050554000040
 has
X-1 indicates the point of attachment to the preceding amino acid residue;
X+1 indicates the point of attachment to the subsequent amino acid residue)
has been replaced by
The position of the structure of formula (VI) or formula (VII) in the amino acid sequence of the IL-2 conjugate is selected from K9, H16, L19, D20, N26, N88, E100, and N119. Gate. 配列番号４のアミノ酸配列を含むＩＬ－２コンジュゲートであって、該ＩＬ－２コンジュゲートにおける少なくとも１つのアミノ酸残基は、式（ＶＩＩＩ）または式（ＩＸ）の構造：
Figure 2021050554000041
 （式中：
ｎは、ＰＥＧ部分の分子量が約５０ｋＤａであるような整数であり；
Ｘは構造：
Figure 2021050554000042
 を有し、
Ｘ－１は、先行するアミノ酸残基への結合点を示し；
Ｘ＋１は、後続のアミノ酸残基への結合点を示す）
に置き換えられており、
ＩＬ－２コンジュゲートのアミノ酸配列における式（ＶＩＩＩ）または式（ＩＸ）の構造の位置は、Ｋ９、Ｈ１６、Ｌ１９、Ｄ２０、Ｎ２６、Ｎ８８、Ｅ１００、およびＮ１１９から選択される、前記ＩＬ－２コンジュゲート。 An IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 4, wherein at least one amino acid residue in the IL-2 conjugate has a structure of formula (VIII) or formula (IX):
Figure 2021050554000041
 (In the formula:
n is an integer such that the molecular weight of the PEG moiety is approximately 50 kDa;
X is structure:
Figure 2021050554000042
 has
X-1 indicates the point of attachment to the preceding amino acid residue;
X+1 indicates the point of attachment to the subsequent amino acid residue)
has been replaced by
The position of the structure of formula (VIII) or formula (IX) in the amino acid sequence of the IL-2 conjugate is selected from K9, H16, L19, D20, N26, N88, E100, and N119. Gate. 配列番号４のアミノ酸配列を含むＩＬ－２コンジュゲートであって、該ＩＬ－２コンジュゲートにおける少なくとも１つのアミノ酸残基は、式（Ｘ）または式（ＸＩ）の構造：
Figure 2021050554000043
 （式中：
ｎは、ＰＥＧ部分の分子量が約５０ｋＤａであるような整数であり；
波線は、置き換えられていない配列番号４内のアミノ酸残基への共有結合を示す）
に置き換えられており、
ＩＬ－２コンジュゲートのアミノ酸配列における式（Ｘ）または式（ＸＩ）の構造の位置は、Ｋ９、Ｈ１６、Ｌ１９、Ｄ２０、Ｎ２６、Ｎ８８、Ｅ１００、およびＮ１１９から選択される、前記ＩＬ－２コンジュゲート。 An IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 4, wherein at least one amino acid residue in the IL-2 conjugate has a structure of formula (X) or formula (XI):
Figure 2021050554000043
 (In the formula:
n is an integer such that the molecular weight of the PEG moiety is approximately 50 kDa;
Wavy lines indicate covalent bonds to amino acid residues within SEQ ID NO: 4 that are not replaced)
has been replaced by
The position of the structure of formula (X) or formula (XI) in the amino acid sequence of the IL-2 conjugate is selected from K9, H16, L19, D20, N26, N88, E100, and N119. Gate. 配列番号４のアミノ酸配列を含むＩＬ－２コンジュゲートであって、該ＩＬ－２コンジュゲートにおける少なくとも１つのアミノ酸残基は、式（ＸＩＩ）または式（ＸＩＩＩ）の構造：
Figure 2021050554000044
 （式中：
ｎは、ＰＥＧ部分の分子量が約５０ｋＤａであるような整数であり；
波線は、置き換えられていない配列番号４内のアミノ酸残基への共有結合を示す）
に置き換えられており、
ＩＬ－２コンジュゲートのアミノ酸配列における式（ＸＩＩ）または式（ＸＩＩＩ）の構造の位置は、Ｋ９、Ｈ１６、Ｌ１９、Ｄ２０、Ｎ２６、Ｎ８８、Ｅ１００、およびＮ１１９から選択される、前記ＩＬ－２コンジュゲート。 An IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 4, wherein at least one amino acid residue in the IL-2 conjugate has a structure of formula (XII) or formula (XIII):
Figure 2021050554000044
 (In the formula:
n is an integer such that the molecular weight of the PEG moiety is approximately 50 kDa;
Wavy lines indicate covalent bonds to amino acid residues within SEQ ID NO: 4 that are not replaced)
has been replaced by
The position of the structure of formula (XII) or formula (XIII) in the amino acid sequence of the IL-2 conjugate is selected from K9, H16, L19, D20, N26, N88, E100, and N119. Gate. それを必要とする対象における自己免疫疾患を治療する方法に使用するための請求項１～１６、１９～２１、および２４～３１のいずれか1項に記載の治療有効量のＩＬ－２コンジュゲートを含む医薬組成物。 A therapeutically effective amount of an IL-2 conjugate according to any one of claims 1-16, 19-21, and 24-31 for use in a method of treating an autoimmune disease in a subject in need thereof. A pharmaceutical composition comprising. 自己免疫疾患は、移植片対宿主病（ＧＶＨＤ）、アトピー性皮膚炎、クローン病、円形脱毛症、自己免疫性溶血性貧血、自己免疫性肝炎、皮膚筋炎、１型糖尿病、若年性／小児１型糖尿病、若年性特発性関節炎、糸球体腎炎、グレーブス病、ギラン－バレー症候群、特発性血小板減少性紫斑病、重症筋無力症、多発性硬化症、天疱瘡／類天疱瘡、悪性貧血、結節性多発性動脈炎、多発性筋炎、原発性胆汁胆管炎、原発性胆汁肝硬変、非アルコール性脂肪性肝炎（ＮＡＳＨ）、乾癬、関節リウマチ、強皮症、ＣＲＥＳＴ症候群、シェーグレン症候群、全身性ループスエリテマトーデス、甲状腺炎、ブドウ膜炎、白斑、ウェゲナー肉芽腫症、アジソン病（副腎不全症）、橋本甲状腺炎、自己免疫性肝炎、不妊症、ＡＮＣＡ関連血管炎、乾癬性関節炎、セリアック病、潰瘍性大腸炎、硬化性苔癬、およびベーチェット病から選択される、請求項３２に記載の医薬組成物。 Autoimmune diseases include graft-versus-host disease (GVHD), atopic dermatitis, Crohn's disease, alopecia areata, autoimmune hemolytic anemia, autoimmune hepatitis, dermatomyositis, type 1 diabetes, and juvenile/childhood 1. type diabetes, juvenile idiopathic arthritis, glomerulonephritis, Graves' disease, Guillain-Barré syndrome, idiopathic thrombocytopenic purpura, myasthenia gravis, multiple sclerosis, pemphigus/pemphigoid, pernicious anemia, nodules Polyarteritis polyarteritis, polymyositis, primary biliary cholangitis, primary biliary cirrhosis, nonalcoholic steatohepatitis (NASH), psoriasis, rheumatoid arthritis, scleroderma, CREST syndrome, Sjogren's syndrome, systemic lupus erythematosus , thyroiditis, uveitis, vitiligo, Wegener's granulomatosis, Addison's disease (adrenal insufficiency), Hashimoto's thyroiditis, autoimmune hepatitis, infertility, ANCA-related vasculitis, psoriatic arthritis, celiac disease, ulcerative colon 33. The pharmaceutical composition according to claim 32, selected from lichen sclerosus, lichen sclerosus, and Behcet's disease. 対象は、医薬組成物の対象への投与の前に、対象の血液中のリウマトイド因子の増加した濃度を呈するように決定される、請求項３２または３３に記載の医薬組成物。 34. The pharmaceutical composition of claim 32 or 33, wherein the subject is determined to exhibit an increased concentration of rheumatoid factor in the subject's blood prior to administration of the pharmaceutical composition to the subject. それを必要とする対象における関節リウマチを治療する方法に使用するための、請求項１～１６、１９～２１、および２４～３１のいずれか１項に記載の治療有効量のＩＬ－２コンジュゲートを含む医薬組成物であって、該方法は、
（ａ）対象の血液中のリウマトイド因子の濃度を決定する工程；および
（ｂ）対象の血液中のリウマトイド因子の濃度が約１４ＩＵ／ｍＬよりも高い場合に、対象に、該医薬組成物を投与する工程
を含む、前記医薬組成物。 A therapeutically effective amount of an IL-2 conjugate according to any one of claims 1-16, 19-21, and 24-31 for use in a method of treating rheumatoid arthritis in a subject in need thereof. A pharmaceutical composition comprising:
(a) determining the concentration of rheumatoid factor in the subject's blood; and (b) administering the pharmaceutical composition to the subject if the concentration of rheumatoid factor in the subject's blood is greater than about 14 IU/mL. The pharmaceutical composition, comprising the step of: 対象は、医薬組成物の対象への投与の前に、場合によりウェスターグレン速度法またはウィントローブ速度法を使用して、異常な赤血球沈降速度（ＥＳＲ）試験を呈するように決定される、請求項３２または３３に記載の医薬組成物。 The subject is determined to exhibit an abnormal erythrocyte sedimentation rate (ESR) test, optionally using the Westergren velocity method or the Wintrobe velocity method, prior to administration of the pharmaceutical composition to the subject. The pharmaceutical composition according to item 32 or 33. それを必要とする対象における自己免疫疾患を治療する方法に使用するための、請求項１～１６、１９～２１、および２４～３１のいずれか１項に記載の治療有効量のＩＬ－２コンジュゲートを含む医薬組成物であって、該方法は、
（ａ）対象において赤血球沈降速度（ＥＳＲ）を決定する工程；および
（ｂ）ＥＳＲが異常であると決定された場合に、対象に、該医薬組成物を投与する工程を含む、前記医薬組成物。 A therapeutically effective amount of an IL-2 conjugate according to any one of claims 1-16, 19-21, and 24-31 for use in a method of treating an autoimmune disease in a subject in need thereof. A pharmaceutical composition comprising a gate, the method comprising:
(a) determining the erythrocyte sedimentation rate (ESR) in the subject; and (b) administering the pharmaceutical composition to the subject if the ESR is determined to be abnormal. . それを必要とする対象における自己免疫疾患を治療する方法に使用するための、請求項１～１６、１９～２１、および２４～３１のいずれか１項に記載の治療有効量のＩＬ－２コンジュゲートを含む医薬組成物であって、該方法は、
（ａ）対象の血液中のＣ反応性タンパク質（ＣＲＰ）の濃度を決定する工程；および
（ｂ）対象の血液中のＣ反応性タンパク質（ＣＲＰ）の濃度が異常であると決定された場合に、対象に、該医薬組成物を投与する工程
を含む、前記医薬組成物。 A therapeutically effective amount of an IL-2 conjugate according to any one of claims 1-16, 19-21, and 24-31 for use in a method of treating an autoimmune disease in a subject in need thereof. A pharmaceutical composition comprising a gate, the method comprising:
(a) determining the concentration of C-reactive protein (CRP) in the subject's blood; and (b) if the concentration of C-reactive protein (CRP) in the subject's blood is determined to be abnormal; , the pharmaceutical composition comprising the step of administering the pharmaceutical composition to a subject. 対象は、医薬組成物の対象への投与の前に、１０ｍｇ／Ｌよりも高い血液中のＣ反応性タンパク質（ＣＲＰ）の濃度を呈するように決定される、請求項３８に記載の医薬組成物。 39. The pharmaceutical composition of claim 38, wherein the subject is determined to exhibit a concentration of C-reactive protein (CRP) in the blood greater than 10 mg/L prior to administration of the pharmaceutical composition to the subject. . それを必要とする対象における関節リウマチを治療する方法に使用するための、請求項１～１６、１９～２１、および２４～３１のいずれか１項に記載の治療有効量のＩＬ－２コンジュゲートを含む医薬組成物であって、該方法は、対象の血液中の抗環状シトルリン化ペプチド（抗ＣＣＰ）の濃度が異常であると決定された場合に、対象に、該医薬組成物を投与する工程を含む、前記医薬組成物。 A therapeutically effective amount of an IL-2 conjugate according to any one of claims 1-16, 19-21, and 24-31 for use in a method of treating rheumatoid arthritis in a subject in need thereof. The method comprises administering the pharmaceutical composition to a subject when the concentration of anti-cyclic citrullinated peptide (anti-CCP) in the subject's blood is determined to be abnormal. The pharmaceutical composition, comprising the steps. それを必要とする対象における関節リウマチを治療する方法に使用するための、請求項１～１６、１９～２１、および２４～３１にのいずれか１項記載の治療有効量のＩＬ－２コンジュゲートを含む医薬組成物であって、該方法は、対象の血液中の抗環状シトルリン化ペプチド（抗ＣＣＰ）の濃度が約２０ＩＵ／ｍＬよりも高いと決定された場合に、対象に、該医薬組成物を投与する工程を含む、前記医薬組成物。 A therapeutically effective amount of an IL-2 conjugate according to any one of claims 1-16, 19-21, and 24-31 for use in a method of treating rheumatoid arthritis in a subject in need thereof. The method comprises administering the pharmaceutical composition to a subject when the concentration of anti-cyclic citrullinated peptide (anti-CCP) in the subject's blood is determined to be greater than about 20 IU/mL. The pharmaceutical composition, comprising the step of administering the product. ＩＬ－２コンジュゲートを製造する方法であって、
式
Figure 2021050554000045
 の非天然アミノ酸を含むＩＬ－２ポリペプチドであって、ＩＬ－２ポリペプチドは配列番号３または４のアミノ酸配列を含み、ＩＬ－２ポリペプチドにおける少なくとも１つのアミノ酸残基は非天然アミノ酸に置き換えられており、位置Ｘ－１は、先行するアミノ酸残基への結合点を示し、位置Ｘ＋１は、後続のアミノ酸残基への結合点を示し、位置Ｘは、非天然アミノ酸に置換されるアミノ酸の位置を示す、ＩＬ－２ポリペプチドを、式
Figure 2021050554000046
 （式中、ｎは、ｍＰＥＧ－ＤＢＣＯが、約５０ｋＤａの分子量を有するＰＥＧを含むようなものである）のｍＰＥＧ－ＤＢＣＯと反応させ、それにより、ＩＬ－２コンジュゲートを製造することを含み、
ＩＬ－２コンジュゲートのアミノ酸配列における位置Ｘは、配列番号３内のアミノ酸位置を基準にして、Ｋ８、Ｈ１５、Ｌ１８、Ｄ１９、Ｎ２５、Ｎ８７、Ｅ９９、およびＮ１１８から選択され、またはＩＬ－２コンジュゲートのアミノ酸配列における位置Ｘは、配列番号４内のアミノ酸位置を基準にして、Ｋ９、Ｈ１６、Ｌ１９、Ｄ２０、Ｎ２６、Ｎ８８、Ｅ１００、およびＮ１１９から選択される、
前記方法。 1. A method of producing an IL-2 conjugate, the method comprising:
formula
Figure 2021050554000045
 an IL-2 polypeptide comprising an unnatural amino acid, the IL-2 polypeptide comprising the amino acid sequence of SEQ ID NO: 3 or 4, wherein at least one amino acid residue in the IL-2 polypeptide is replaced with the unnatural amino acid. position X-1 indicates the point of attachment to the preceding amino acid residue, position X+1 indicates the point of attachment to the subsequent amino acid residue, and position An IL-2 polypeptide with the formula
Figure 2021050554000046
 wherein n is such that the mPEG-DBCO comprises PEG having a molecular weight of about 50 kDa, thereby producing an IL-2 conjugate;
Position X in the amino acid sequence of the IL-2 conjugate is selected from K8, H15, L18, D19, N25, N87, E99, and N118, or Position X in the amino acid sequence of the gate is selected from K9, H16, L19, D20, N26, N88, E100, and N119, based on the amino acid position in SEQ ID NO: 4.
Said method. 位置Ｘは、配列番号３内のアミノ酸位置を基準にして、Ｋ８、Ｈ１５、Ｌ１８、Ｄ１９、Ｎ２５、Ｎ８７、Ｅ９９、またはＮ１１８である、請求項４２に記載の方法。 43. The method of claim 42, wherein position X is K8, H15, L18, D19, N25, N87, E99, or N118, relative to the amino acid position within SEQ ID NO:3. 位置Ｘは、配列番号４内のアミノ酸位置を基準にして、Ｋ９、Ｈ１６、Ｌ１９、Ｄ２０、Ｎ２６、Ｎ８８、Ｅ１００、またはＮ１１９である、請求項４２に記載の方法。 43. The method of claim 42, wherein position X is K9, H16, L19, D20, N26, N88, E100, or N119, relative to the amino acid position within SEQ ID NO:4. ＩＬ－２コンジュゲートは、請求項１～１６、１９～２１、および２１～３１のいずれか１項に記載のＩＬ－２コンジュゲートである、請求項４２に記載の方法。 43. The method of claim 42, wherein the IL-2 conjugate is an IL-2 conjugate according to any one of claims 1-16, 19-21, and 21-31. ＺはＣＨ2であり、Ｙは
Figure 2021050554000047
 であり；または
ＹはＣＨ2であり、Ｚは
Figure 2021050554000048
 である、請求項８に記載のＩＬ－２コンジュゲート。 Z is CH 2 and Y is
Figure 2021050554000047
 or Y is CH 2 and Z is
Figure 2021050554000048
 The IL-2 conjugate according to claim 8. ＩＬ－２コンジュゲートは、配列番号１７０のアミノ酸配列を含む、請求項２３に記載の医薬組成物。 24. The pharmaceutical composition of claim 23, wherein the IL-2 conjugate comprises the amino acid sequence of SEQ ID NO: 170.
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