JPWO2020218951A5 - - Google Patents
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- JPWO2020218951A5 JPWO2020218951A5 JP2021563239A JP2021563239A JPWO2020218951A5 JP WO2020218951 A5 JPWO2020218951 A5 JP WO2020218951A5 JP 2021563239 A JP2021563239 A JP 2021563239A JP 2021563239 A JP2021563239 A JP 2021563239A JP WO2020218951 A5 JPWO2020218951 A5 JP WO2020218951A5
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実験から、ＢＣＤ－１６６－０１－０１４およびＢＣＤ－１６６－０２－０１生成物の高い抗腫瘍活性が解明されたが、それに対してＢＣＤ－１６６－０１－０１生成物は、有意な抗腫瘍活性を全く示さなかった。図３２および３３に結果を示す。
非限定的に、本発明は以下の態様を含む。
［態様１］
ＧＩＴＲに特異的に結合する単離されたモノクローナル抗体またはその抗原結合断片であって、
（ａ）（ｉ）以下の群：
ＮＹＧＭＨ（配列番号１）またはＹＹＷＭＹ（配列番号１２）
から選択されるアミノ酸配列を含むＣＤＲ１；
（ｉｉ）以下の群：
ＶＩＷＦＤＧＳＮＫＦＹＴＤＳＶＫＧ（配列番号２）またはＡＩＳＷＮＧＧＲＴＹＹＡＥＳＭＫＧ（配列番号１３）
から選択されるアミノ酸配列を含むＣＤＲ２；
（ｉｉｉ）以下の群：
ＥＬＧＧＹＹＹＤＳＳＧＦＲＰＹＹＹＧＭＤＶ（配列番号３）またはＮＲＹＹＳＤＰＮＹＧＭＮＬ（配列番号１４）
から選択されるアミノ酸配列を含むＣＤＲ３
を含む重鎖可変ドメイン、ならびに、
（ｂ）（ｉ）以下の群：
ＲＡＳＱＳＩＧＳＷＬＡ（配列番号７）またはＴＧＴＳＴＤＩＧＴＹＫＹＩＳ（配列番号１７）
から選択されるアミノ酸配列を含むＣＤＲ１；
（ｉｉ）以下の群：
ＡＡＳＴＬＱＲ（配列番号８）またはＧＶＳＨＲＰＳ（配列番号１８）
から選択されるアミノ酸配列を含むＣＤＲ２；
（ｉｉｉ）以下の群：
ＱＱＳＨＳＨＰＬＴ（配列番号９）またはＳＳＹＴＳＳＧＴＶＶ（配列番号１９）
から選択されるアミノ酸配列を含むＣＤＲ３
を含む軽鎖可変ドメイン
を含むモノクローナル抗体またはその抗原結合断片。
［態様２］
重鎖可変ドメインが、
（ｉ）それぞれ配列番号１、配列番号２および配列番号３の配列により表されるＣＤＲ１、ＣＤＲ２およびＣＤＲ３のアミノ酸配列、
（ｉｉ）それぞれ配列番号１２、配列番号１３および配列番号１４の配列により表されるＣＤＲ１、ＣＤＲ２およびＣＤＲ３アミノ酸配列
を含む、態様１に記載のモノクローナル抗体またはその抗原結合断片。
［態様３］
軽鎖可変ドメインが、
（ｉ）それぞれ配列番号７、配列番号８および配列番号９の配列により表されるアミノ酸配列を含むＣＤＲ１、ＣＤＲ２およびＣＤＲ３、
（ｉｉ）それぞれ配列番号１７、配列番号１８および配列番号１９の配列により表されるアミノ酸配列を含むＣＤＲ１、ＣＤＲ２およびＣＤＲ３
を含む、
態様１に記載のモノクローナル抗体またはその抗原結合断片。
［態様４］
－ 重鎖可変ドメインが、
それぞれ配列番号１、配列番号２および配列番号３の配列により表されるアミノ酸配列を含むＣＤＲ１、ＣＤＲ２およびＣＤＲ３を含み；
－ 軽鎖可変ドメインが、それぞれ配列番号７、配列番号８および配列番号９の配列により表されるアミノ酸配列を含むＣＤＲ１、ＣＤＲ２およびＣＤＲ３を含む、
態様１に記載のモノクローナル抗体またはその抗原結合断片。
［態様５］
－ 重鎖可変ドメインが、それぞれ配列番号１２、配列番号１３および配列番号１４の配列により表されるアミノ酸配列を含むＣＤＲ１、ＣＤＲ２およびＣＤＲ３を含む；
－ 軽鎖可変ドメインが、それぞれ配列番号１７、配列番号１８および配列番号１９の配列により表されるアミノ酸配列を含むＣＤＲ１、ＣＤＲ２およびＣＤＲ３を含む、
態様１に記載のモノクローナル抗体またはその抗原結合断片。
［態様６］
重鎖可変ドメインが、
（ｉ）配列番号４のアミノ酸配列に少なくとも９０％相同なアミノ酸配列；または
（ｉｉ）配列番号１５のアミノ酸配列に少なくとも９０％相同なアミノ酸配列
を含む、
態様１に記載のモノクローナル抗体またはその抗原結合断片。
［態様７］
（ｉ）重鎖可変ドメインが、配列番号４のアミノ酸配列を含むか、または
（ｉｉ）重鎖可変ドメインが、配列番号１５のアミノ酸配列を含む、
態様１に記載のモノクローナル抗体またはその抗原結合断片。
［態様８］
軽鎖可変ドメインが、
（ｉ）配列番号１０のアミノ酸配列に少なくとも９０％相同なアミノ酸配列；または
（ｉｉ）配列番号２０のアミノ酸配列に少なくとも９０％相同なアミノ酸配列
を含む、
態様１に記載のモノクローナル抗体またはその抗原結合断片。
［態様９］
（ｉ）軽鎖可変ドメインが、配列番号１０のアミノ酸配列を含むか；または
（ｉｉ）軽鎖可変ドメインが、配列番号２０のアミノ酸配列を含む、
態様１に記載のモノクローナル抗体またはその抗原結合断片。
［態様１０］
（ｉ）
－ 重鎖可変ドメインが、配列番号４のアミノ酸配列に少なくとも９０％相同なアミノ酸配列を含み；
－ 軽鎖可変ドメインが、配列番号１０のアミノ酸配列に少なくとも９０％相同なアミノ酸配列を含むか；または
（ｉｉ）
－ 重鎖可変ドメインが、配列番号１５のアミノ酸配列に少なくとも９０％相同なアミノ酸配列を含み；
－ 軽鎖可変ドメインが、配列番号２０のアミノ酸配列に少なくとも９０％相同なアミノ酸配列を含む、
態様１に記載のモノクローナル抗体またはその抗原結合断片。
［態様１１］
－ 重鎖可変ドメインが、配列番号４のアミノ酸配列を含み；
－ 軽鎖可変ドメインが、配列番号１０のアミノ酸配列を含む、
態様１０に記載のモノクローナル抗体またはその抗原結合断片。
［態様１２］
－ 重鎖可変ドメインが、配列番号１５のアミノ酸配列を含み；
－ 軽鎖可変ドメインが、配列番号２０のアミノ酸配列を含む、
態様１０に記載のモノクローナル抗体またはその抗原結合断片。
［態様１３］
ＧＩＴＲに特異的に結合する抗体が、全長ＩｇＧ抗体である、態様１に記載のモノクローナル抗体。
［態様１４］
全長ＩｇＧ抗体が、ヒトＩｇＧ１、ＩｇＧ２、ＩｇＧ３、ＩｇＧ４アイソタイプに関する、態様１３に記載のモノクローナル抗体。
［態様１５］
全長ＩｇＧ抗体が、ヒトＩｇＧ１アイソタイプに関する、態様１４に記載のモノクローナル抗体。
［態様１６］
ＧＩＴＲに特異的に結合する抗体が、アゴニスト特性、抗体依存性細胞傷害（ＡＤＣＣ）を増加させるが、補体依存性細胞傷害（ＣＤＣ）を増加させないように、Ｆｃ断片においてＥ３４５Ｒ突然変異を含む、態様１に記載のモノクローナル抗体。
［態様１７］
（ｉ）配列番号５の配列に少なくとも９０％相同なアミノ酸配列；または
（ｉｉ）配列番号６の配列に少なくとも９０％相同なアミノ酸配列
を含む重鎖を含む、態様１に記載のモノクローナル抗体。
［態様１８］
（ｉ）配列番号５のアミノ酸配列を含む重鎖；または
（ｉｉ）配列番号６のアミノ酸配列を含む重鎖
を含む、態様１に記載のモノクローナル抗体。
［態様１９］
配列番号１１の配列に少なくとも９０％相同なアミノ酸配列を含む軽鎖を含む、態様１に記載のモノクローナル抗体。
［態様２０］
配列番号１１のアミノ酸配列を含む軽鎖を含む、態様１に記載のモノクローナル抗体。
［態様２１］
（ｉ）
－ 配列番号５の配列に少なくとも９０％相同なアミノ酸配列を含む重鎖；
－ 配列番号１１の配列に少なくとも９０％相同なアミノ酸配列を含む軽鎖；または
（ｉｉ）
－ 配列番号６の配列に少なくとも９０％相同なアミノ酸配列を含む重鎖；
－ 配列番号１１の配列に少なくとも９０％相同なアミノ酸配列を含む軽鎖
を含む、態様１に記載のモノクローナル抗体。
［態様２２］
－ 配列番号５のアミノ酸配列を含む重鎖；
－ 配列番号１１のアミノ酸配列を含む軽鎖
を含む、態様１に記載のモノクローナル抗体。
［態様２３］
－ 配列番号６のアミノ酸配列を含む重鎖；
－ 配列番号１１のアミノ酸配列を含む軽鎖
を含む、態様１に記載のモノクローナル抗体。
［態様２４］
配列番号１６の配列に少なくとも９０％相同なアミノ酸配列を含む重鎖を含む、態様１に記載のモノクローナル抗体。
［態様２５］
配列番号１６のアミノ酸配列を含む重鎖を含む、態様１に記載のモノクローナル抗体。
［態様２６］
配列番号２１の配列に少なくとも９０％相同なアミノ酸配列を含む軽鎖を含む、態様１に記載のモノクローナル抗体。
［態様２７］
配列番号２１のアミノ酸配列を含む軽鎖を含む、態様１に記載のモノクローナル抗体。
［態様２８］
－ 配列番号１６の配列に少なくとも９０％相同なアミノ酸配列を含む重鎖；
－ 配列番号２１の配列に少なくとも９０％相同なアミノ酸配列を含む軽鎖
を含む、態様１に記載のモノクローナル抗体。
［態様２９］
－ 配列番号１６のアミノ酸配列を含む重鎖；
－ 配列番号２１のアミノ酸配列を含む軽鎖
を含む、態様１に記載のモノクローナル抗体。
［態様３０］
態様１～２９のいずれか一項に記載の抗体またはその抗原結合断片をコードする単離された核酸。
［態様３１］
ＤＮＡである、態様３０に記載の核酸。
［態様３２］
態様３０または３１に記載の核酸を含む発現ベクター。
［態様３３］
態様１～２９のいずれか一項に記載の抗体またはその抗原結合断片を得るための宿主細胞を得る方法であって、態様３２に記載のベクターで細胞を形質転換することを含む方法。
［態様３４］
態様３０または３１に記載の核酸を含む、態様１～２９のいずれか一項に記載の抗体またはその抗原結合断片を得るための宿主細胞。
［態様３５］
態様１～２９のいずれか一項に記載の抗体またはその抗原結合断片を得る方法であって、前記抗体を得るのに十分な条件下で、培養培地中で態様３４に記載の宿主細胞を培養するステップ、必要に応じて、それに続いて得られた抗体を単離および精製するステップを含む方法。
［態様３６］
治療有効量の態様１～２９のいずれか一項に記載の抗体またはその抗原結合断片を、１種または複数の医薬的に許容される賦形剤と組み合わせて含む、ＧＩＴＲによって媒介される疾患または障害を処置するための医薬組成物。
［態様３７］
以下の群：子宮頸がん、頭頸部がん、胃がん、乳がん、腎細胞がん、ＣＲＣ（結腸直腸がん）、（ＯＣ）卵巣がん、ＮＳＣＬＣ（非小細胞肺がん）から選択されるＧＩＴＲによって媒介される疾患または障害を処置することが意図された、態様３６に記載の医薬組成物。
［態様３８］
治療有効量の態様１～２９のいずれか一項に記載の抗体またはその抗原結合断片、および治療有効量の少なくとも１種の治療活性を有する抗腫瘍化合物を含む、ＧＩＴＲによって媒介される疾患または障害を処置するための医薬組成物。
［態様３９］
以下の群：子宮頸がん、頭頸部がん、胃がん、乳がん、腎細胞がん、ＣＲＣ（結腸直腸がん）、（ＯＣ）卵巣がん、ＮＳＣＬＣ（非小細胞肺がん）から選択されるＧＩＴＲによって媒介される疾患または障害を処置することが意図された、態様３８に記載の医薬組成物。
［態様４０］
治療活性を有する抗腫瘍化合物が、化学療法剤、抗体または抗ホルモン剤から選択される、態様３８に記載の医薬組成物。
［態様４１］
治療活性を有する抗腫瘍化合物が、
（ｉ）以下の群：抗ＰＤ１抗体、抗ＰＤ－Ｌ１抗体、抗ＣＴＬＡ４抗体、抗４－１ＢＢ抗体、抗ＯＸ４０抗体若しくはそれらの組合せから選択される抗体であるか、または
（ｉｉ）小分子であるか、または
（ｉｉｉ）自然または適応免疫の活性化剤の群から選択される、態様４０に記載の医薬組成物。
［態様４２］
態様２９に記載の抗体および少なくとも１種の治療活性を有する抗腫瘍化合物が、逐次的に投与される、態様４１に記載の医薬組成物。
［態様４３］
態様１～２９のいずれか一項に記載の抗体および少なくとも１種の治療活性を有する抗腫瘍化合物が、同時に投与される、態様４１に記載の医薬組成物。
［態様４４］
ＧＩＴＲの生物学的活性の阻害が必要な対象においてＧＩＴＲの生物学的活性を阻害するための方法であって、有効量の態様１～２９のいずれか一項に記載の抗体またはその抗原結合断片の投与を含む方法。
［態様４５］
ＧＩＴＲによって媒介される疾患または障害を処置するための方法であって、このような処置が必要な対象における、治療有効量の、態様１～２９のいずれか一項に記載の抗体もしくはその抗原結合断片または態様３６または３８に記載の医薬組成物の投与を含む方法。
［態様４６］
疾患または障害が、以下の群：子宮頸がん、頭頸部がん、胃がん、乳がん、腎細胞がん、ＣＲＣ（結腸直腸がん）、（ＯＣ）卵巣がん、ＮＳＣＬＣ（非小細胞肺がん）から選択される、態様４５に記載の疾患または障害を処置するための方法。
［態様４７］
態様１～２９のいずれか一項に記載の抗体もしくはその抗原結合断片または態様３６または３８に記載の医薬組成物の使用であって、ＧＩＴＲによって媒介される疾患または障害のこのような処置が必要な対象における処置のための使用。
［態様４８］
疾患または障害が、子宮頸がん、頭頸部がん、胃がん、乳がん、腎細胞がん、ＣＲＣ（結腸直腸がん）、（ＯＣ）卵巣がん、ＮＳＣＬＣ（非小細胞肺がん）を含む群から選択される、態様４７に記載の使用。
Experiments revealed high anti-tumor activity of the BCD-166-01-014 and BCD-166-02-01 products, whereas the BCD-166-01-01 product showed no significant anti-tumor activity. did not show any The results are shown in Figures 32 and 33.
Non-limiting, the present invention includes the following aspects.
[Aspect 1]
An isolated monoclonal antibody or antigen-binding fragment thereof that specifically binds to GITR, comprising:
(a)(i) the following groups:
NYGMH (SEQ ID NO: 1) or YYWMY (SEQ ID NO: 12)
a CDR1 comprising an amino acid sequence selected from;
(ii) the following groups:
VIWFDGSNKFYTDSVKG (SEQ ID NO: 2) or AISWNGGRTYYAESMKG (SEQ ID NO: 13)
a CDR2 comprising an amino acid sequence selected from;
(iii) the following groups:
ELGGYYYDSSGFRPYYYGMDV (SEQ ID NO: 3) or NRYYSDPNYGMNL (SEQ ID NO: 14)
a CDR3 comprising an amino acid sequence selected from
a heavy chain variable domain comprising, and
(b)(i) the following groups:
RASQSIGSWLA (SEQ ID NO: 7) or TGTSTDIGTYKYIS (SEQ ID NO: 17)
a CDR1 comprising an amino acid sequence selected from;
(ii) the following groups:
AASTLQR (SEQ ID NO:8) or GVSHRPS (SEQ ID NO:18)
a CDR2 comprising an amino acid sequence selected from;
(iii) the following groups:
QQSHSHPLT (SEQ ID NO:9) or SSYTSSGTVV (SEQ ID NO:19)
a CDR3 comprising an amino acid sequence selected from
A monoclonal antibody or antigen-binding fragment thereof comprising a light chain variable domain comprising:
[Aspect 2]
the heavy chain variable domain is
(i) the amino acid sequences of CDR1, CDR2 and CDR3 represented by the sequences SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3, respectively;
(ii) The monoclonal antibody or antigen-binding fragment thereof of aspect 1, comprising the CDR1, CDR2 and CDR3 amino acid sequences represented by the sequences SEQ ID NO: 12, SEQ ID NO: 13 and SEQ ID NO: 14, respectively.
[Aspect 3]
the light chain variable domain is
(i) CDR1, CDR2 and CDR3 comprising the amino acid sequences represented by the sequences of SEQ ID NO:7, SEQ ID NO:8 and SEQ ID NO:9, respectively;
(ii) CDR1, CDR2 and CDR3 comprising the amino acid sequences represented by the sequences of SEQ ID NO: 17, SEQ ID NO: 18 and SEQ ID NO: 19 respectively
including,
The monoclonal antibody or antigen-binding fragment thereof of aspect 1.
[Aspect 4]
- the heavy chain variable domain is
comprising CDR1, CDR2 and CDR3 comprising amino acid sequences represented by the sequences of SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3, respectively;
- the light chain variable domain comprises CDR1, CDR2 and CDR3 comprising the amino acid sequences represented by the sequences of SEQ ID NO:7, SEQ ID NO:8 and SEQ ID NO:9, respectively;
The monoclonal antibody or antigen-binding fragment thereof of aspect 1.
[Aspect 5]
- the heavy chain variable domain comprises CDR1, CDR2 and CDR3 comprising the amino acid sequences represented by the sequences of SEQ ID NO: 12, SEQ ID NO: 13 and SEQ ID NO: 14 respectively;
- the light chain variable domain comprises CDR1, CDR2 and CDR3 comprising the amino acid sequences represented by the sequences of SEQ ID NO: 17, SEQ ID NO: 18 and SEQ ID NO: 19, respectively;
The monoclonal antibody or antigen-binding fragment thereof of aspect 1.
[Aspect 6]
the heavy chain variable domain is
(i) an amino acid sequence that is at least 90% homologous to the amino acid sequence of SEQ ID NO:4; or (ii) an amino acid sequence that is at least 90% homologous to the amino acid sequence of SEQ ID NO:15.
The monoclonal antibody or antigen-binding fragment thereof of aspect 1.
[Aspect 7]
(i) the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO:4, or (ii) the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO:15,
The monoclonal antibody or antigen-binding fragment thereof of aspect 1.
[Aspect 8]
the light chain variable domain is
(i) an amino acid sequence that is at least 90% homologous to the amino acid sequence of SEQ ID NO:10; or (ii) an amino acid sequence that is at least 90% homologous to the amino acid sequence of SEQ ID NO:20.
The monoclonal antibody or antigen-binding fragment thereof of aspect 1.
[Aspect 9]
(i) the light chain variable domain comprises the amino acid sequence of SEQ ID NO:10; or (ii) the light chain variable domain comprises the amino acid sequence of SEQ ID NO:20.
The monoclonal antibody or antigen-binding fragment thereof of aspect 1.
[Aspect 10]
(i)
- the heavy chain variable domain comprises an amino acid sequence that is at least 90% homologous to the amino acid sequence of SEQ ID NO:4;
- the light chain variable domain comprises an amino acid sequence that is at least 90% homologous to the amino acid sequence of SEQ ID NO: 10; or (ii)
- the heavy chain variable domain comprises an amino acid sequence that is at least 90% homologous to the amino acid sequence of SEQ ID NO: 15;
- the light chain variable domain comprises an amino acid sequence that is at least 90% homologous to the amino acid sequence of SEQ ID NO:20;
The monoclonal antibody or antigen-binding fragment thereof of aspect 1.
[Aspect 11]
- the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO:4;
- the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 10,
A monoclonal antibody or antigen-binding fragment thereof according to aspect 10.
[Aspect 12]
- the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 15;
- the light chain variable domain comprises the amino acid sequence of SEQ ID NO:20,
A monoclonal antibody or antigen-binding fragment thereof according to aspect 10.
[Aspect 13]
A monoclonal antibody according to aspect 1, wherein the antibody that specifically binds to GITR is a full-length IgG antibody.
[Aspect 14]
14. A monoclonal antibody according to aspect 13, wherein the full length IgG antibody is of human IgG1, IgG2, IgG3, IgG4 isotypes.
[Aspect 15]
15. A monoclonal antibody according to aspect 14, wherein the full length IgG antibody is of the human IgGl isotype.
[Aspect 16]
containing the E345R mutation in the Fc fragment so that antibodies that specifically bind to GITR have increased agonist properties, antibody dependent cellular cytotoxicity (ADCC) but not complement dependent cytotoxicity (CDC); A monoclonal antibody according to aspect 1.
[Aspect 17]
(i) an amino acid sequence that is at least 90% homologous to the sequence of SEQ ID NO:5; or (ii) an amino acid sequence that is at least 90% homologous to the sequence of SEQ ID NO:6.
[Aspect 18]
(i) a heavy chain comprising the amino acid sequence of SEQ ID NO:5; or (ii) a heavy chain comprising the amino acid sequence of SEQ ID NO:6.
[Aspect 19]
A monoclonal antibody according to aspect 1, comprising a light chain comprising an amino acid sequence that is at least 90% homologous to the sequence of SEQ ID NO:11.
[Aspect 20]
A monoclonal antibody according to aspect 1, comprising a light chain comprising the amino acid sequence of SEQ ID NO:11.
[Aspect 21]
(i)
- a heavy chain comprising an amino acid sequence that is at least 90% homologous to the sequence of SEQ ID NO:5;
- a light chain comprising an amino acid sequence that is at least 90% homologous to the sequence of SEQ ID NO: 11; or (ii)
- a heavy chain comprising an amino acid sequence that is at least 90% homologous to the sequence of SEQ ID NO:6;
- A monoclonal antibody according to aspect 1, comprising a light chain comprising an amino acid sequence that is at least 90% homologous to the sequence of SEQ ID NO:11.
[Aspect 22]
- a heavy chain comprising the amino acid sequence of SEQ ID NO:5;
- a monoclonal antibody according to aspect 1, comprising a light chain comprising the amino acid sequence of SEQ ID NO:11.
[Aspect 23]
- a heavy chain comprising the amino acid sequence of SEQ ID NO:6;
- a monoclonal antibody according to aspect 1, comprising a light chain comprising the amino acid sequence of SEQ ID NO:11.
[Aspect 24]
A monoclonal antibody according to aspect 1, comprising a heavy chain comprising an amino acid sequence that is at least 90% homologous to the sequence of SEQ ID NO:16.
[Aspect 25]
A monoclonal antibody according to aspect 1, comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:16.
[Aspect 26]
A monoclonal antibody according to aspect 1, comprising a light chain comprising an amino acid sequence that is at least 90% homologous to the sequence of SEQ ID NO:21.
[Aspect 27]
A monoclonal antibody according to aspect 1, comprising a light chain comprising the amino acid sequence of SEQ ID NO:21.
[Aspect 28]
- a heavy chain comprising an amino acid sequence that is at least 90% homologous to the sequence of SEQ ID NO: 16;
- A monoclonal antibody according to aspect 1, comprising a light chain comprising an amino acid sequence that is at least 90% homologous to the sequence of SEQ ID NO:21.
[Aspect 29]
- a heavy chain comprising the amino acid sequence of SEQ ID NO: 16;
- a monoclonal antibody according to aspect 1, comprising a light chain comprising the amino acid sequence of SEQ ID NO:21.
[Aspect 30]
An isolated nucleic acid encoding the antibody or antigen-binding fragment thereof of any one of aspects 1-29.
[Aspect 31]
31. A nucleic acid according to aspect 30, which is DNA.
[Aspect 32]
32. An expression vector comprising a nucleic acid according to aspect 30 or 31.
[Aspect 33]
A method of obtaining a host cell for obtaining an antibody or antigen-binding fragment thereof according to any one of aspects 1-29, comprising transforming the cell with a vector according to aspect 32.
[Aspect 34]
A host cell for obtaining an antibody or antigen-binding fragment thereof according to any one of aspects 1-29, comprising a nucleic acid according to aspects 30 or 31.
[Aspect 35]
A method of obtaining an antibody or antigen-binding fragment thereof according to any one of aspects 1-29, comprising culturing a host cell according to aspect 34 in a culture medium under conditions sufficient to obtain said antibody. optionally followed by isolating and purifying the resulting antibody.
[Aspect 36]
A disease mediated by GITR comprising a therapeutically effective amount of an antibody or antigen-binding fragment thereof according to any one of aspects 1-29 in combination with one or more pharmaceutically acceptable excipients or A pharmaceutical composition for treating disorders.
[Aspect 37]
GITR selected from the following groups: cervical cancer, head and neck cancer, gastric cancer, breast cancer, renal cell carcinoma, CRC (colorectal cancer), (OC) ovarian cancer, NSCLC (non-small cell lung cancer) 37. A pharmaceutical composition according to aspect 36, intended for treating a disease or disorder mediated by
[Aspect 38]
A disease or disorder mediated by GITR comprising a therapeutically effective amount of the antibody or antigen-binding fragment thereof of any one of aspects 1-29, and a therapeutically effective amount of at least one therapeutically active anti-tumor compound. A pharmaceutical composition for treating
[Aspect 39]
GITR selected from the following groups: cervical cancer, head and neck cancer, gastric cancer, breast cancer, renal cell carcinoma, CRC (colorectal cancer), (OC) ovarian cancer, NSCLC (non-small cell lung cancer) 39. A pharmaceutical composition according to aspect 38, intended for treating a disease or disorder mediated by
[Aspect 40]
39. A pharmaceutical composition according to aspect 38, wherein the therapeutically active anti-tumor compound is selected from chemotherapeutic agents, antibodies or anti-hormonal agents.
[Aspect 41]
anti-tumor compounds with therapeutic activity
(i) an antibody selected from the following group: anti-PD1 antibody, anti-PD-L1 antibody, anti-CTLA4 antibody, anti-4-1BB antibody, anti-OX40 antibody, or combinations thereof, or (ii) a small molecule or (iii) selected from the group of activators of innate or adaptive immunity.
[Aspect 42]
42. A pharmaceutical composition according to aspect 41, wherein the antibody according to aspect 29 and the at least one therapeutically active anti-tumor compound are administered sequentially.
[Aspect 43]
42. A pharmaceutical composition according to aspect 41, wherein the antibody according to any one of aspects 1-29 and at least one therapeutically active anti-tumor compound are administered simultaneously.
[Aspect 44]
30. A method for inhibiting GITR biological activity in a subject in need thereof, comprising an effective amount of the antibody or antigen-binding fragment thereof of any one of aspects 1-29 A method comprising the administration of
[Aspect 45]
30. A method for treating a disease or disorder mediated by GITR, comprising a therapeutically effective amount of the antibody of any one of aspects 1-29, or antigen binding thereof, in a subject in need of such treatment. A method comprising administering a fragment or a pharmaceutical composition according to aspects 36 or 38.
[Aspect 46]
The disease or disorder is in the following groups: cervical cancer, head and neck cancer, gastric cancer, breast cancer, renal cell carcinoma, CRC (colorectal cancer), (OC) ovarian cancer, NSCLC (non-small cell lung cancer) 46. A method for treating a disease or disorder according to aspect 45, selected from:
[Aspect 47]
Use of an antibody or antigen-binding fragment thereof according to any one of aspects 1 to 29 or a pharmaceutical composition according to aspects 36 or 38 in need of such treatment of a disease or disorder mediated by GITR use for treatment in a subject.
[Aspect 48]
from the group wherein the disease or disorder comprises cervical cancer, head and neck cancer, gastric cancer, breast cancer, renal cell carcinoma, CRC (colorectal cancer), (OC) ovarian cancer, NSCLC (non-small cell lung cancer) 48. Use according to aspect 47, selected.
Claims (45)
（ａ）（ｉ）以下の群：
ＮＹＧＭＨ（配列番号１）またはＹＹＷＭＹ（配列番号１２）
から選択されるアミノ酸配列を含むＣＤＲ１；
（ｉｉ）以下の群：
ＶＩＷＦＤＧＳＮＫＦＹＴＤＳＶＫＧ（配列番号２）またはＡＩＳＷＮＧＧＲＴＹＹＡＥＳＭＫＧ（配列番号１３）
から選択されるアミノ酸配列を含むＣＤＲ２；
（ｉｉｉ）以下の群：
ＥＬＧＧＹＹＹＤＳＳＧＦＲＰＹＹＹＧＭＤＶ（配列番号３）またはＮＲＹＹＳＤＰＮＹＧＭＮＬ（配列番号１４）
から選択されるアミノ酸配列を含むＣＤＲ３
を含む重鎖可変ドメイン、ならびに、
（ｂ）（ｉ）以下の群：
ＲＡＳＱＳＩＧＳＷＬＡ（配列番号７）またはＴＧＴＳＴＤＩＧＴＹＫＹＩＳ（配列番号１７）
から選択されるアミノ酸配列を含むＣＤＲ１；
（ｉｉ）以下の群：
ＡＡＳＴＬＱＲ（配列番号８）またはＧＶＳＨＲＰＳ（配列番号１８）
から選択されるアミノ酸配列を含むＣＤＲ２；
（ｉｉｉ）以下の群：
ＱＱＳＨＳＨＰＬＴ（配列番号９）またはＳＳＹＴＳＳＧＴＶＶ（配列番号１９）
から選択されるアミノ酸配列を含むＣＤＲ３
を含む軽鎖可変ドメイン
を含むモノクローナル抗体またはその抗原結合断片。 An isolated monoclonal antibody or antigen-binding fragment thereof that specifically binds to GITR, comprising:
(a)(i) the following groups:
NYGMH (SEQ ID NO: 1) or YYWMY (SEQ ID NO: 12)
a CDR1 comprising an amino acid sequence selected from;
(ii) the following groups:
VIWFDGSNKFYTDSVKG (SEQ ID NO: 2) or AISWNGGRTYYAESMKG (SEQ ID NO: 13)
a CDR2 comprising an amino acid sequence selected from;
(iii) the following groups:
ELGGYYYDSSGFRPYYYGMDV (SEQ ID NO: 3) or NRYYSDPNYGMNL (SEQ ID NO: 14)
a CDR3 comprising an amino acid sequence selected from
a heavy chain variable domain comprising, and
(b)(i) the following groups:
RASQSIGSWLA (SEQ ID NO: 7) or TGTSTDIGTYKYIS (SEQ ID NO: 17)
a CDR1 comprising an amino acid sequence selected from;
(ii) the following groups:
AASTLQR (SEQ ID NO:8) or GVSHRPS (SEQ ID NO:18)
a CDR2 comprising an amino acid sequence selected from;
(iii) the following groups:
QQSHSHPLT (SEQ ID NO:9) or SSYTSSGTVV (SEQ ID NO:19)
a CDR3 comprising an amino acid sequence selected from
A monoclonal antibody or antigen-binding fragment thereof comprising a light chain variable domain comprising:
（ｉ）それぞれ配列番号１、配列番号２および配列番号３の配列により表されるＣＤＲ１、ＣＤＲ２およびＣＤＲ３のアミノ酸配列、
（ｉｉ）それぞれ配列番号１２、配列番号１３および配列番号１４の配列により表されるＣＤＲ１、ＣＤＲ２およびＣＤＲ３アミノ酸配列
を含む、請求項１に記載のモノクローナル抗体またはその抗原結合断片。 the heavy chain variable domain is
(i) the amino acid sequences of CDR1, CDR2 and CDR3 represented by the sequences SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3, respectively;
2. The monoclonal antibody or antigen-binding fragment thereof of claim 1, comprising (ii) the CDR1, CDR2 and CDR3 amino acid sequences represented by the sequences SEQ ID NO: 12, SEQ ID NO: 13 and SEQ ID NO: 14, respectively.
（ｉ）それぞれ配列番号７、配列番号８および配列番号９の配列により表されるアミノ酸配列を含むＣＤＲ１、ＣＤＲ２およびＣＤＲ３、
（ｉｉ）それぞれ配列番号１７、配列番号１８および配列番号１９の配列により表されるアミノ酸配列を含むＣＤＲ１、ＣＤＲ２およびＣＤＲ３
を含む、
請求項１に記載のモノクローナル抗体またはその抗原結合断片。 the light chain variable domain is
(i) CDR1, CDR2 and CDR3 comprising the amino acid sequences represented by the sequences of SEQ ID NO:7, SEQ ID NO:8 and SEQ ID NO:9, respectively;
(ii) CDR1, CDR2 and CDR3 comprising the amino acid sequences represented by the sequences of SEQ ID NO: 17, SEQ ID NO: 18 and SEQ ID NO: 19 respectively
including,
The monoclonal antibody or antigen-binding fragment thereof according to claim 1.
それぞれ配列番号１、配列番号２および配列番号３の配列により表されるアミノ酸配列を含むＣＤＲ１、ＣＤＲ２およびＣＤＲ３を含み；
－ 軽鎖可変ドメインが、それぞれ配列番号７、配列番号８および配列番号９の配列により表されるアミノ酸配列を含むＣＤＲ１、ＣＤＲ２およびＣＤＲ３を含む、
請求項１に記載のモノクローナル抗体またはその抗原結合断片。 - the heavy chain variable domain is
comprising CDR1, CDR2 and CDR3 comprising amino acid sequences represented by the sequences of SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3, respectively;
- the light chain variable domain comprises CDR1, CDR2 and CDR3 comprising the amino acid sequences represented by the sequences of SEQ ID NO:7, SEQ ID NO:8 and SEQ ID NO:9, respectively;
The monoclonal antibody or antigen-binding fragment thereof according to claim 1.
－ 軽鎖可変ドメインが、それぞれ配列番号１７、配列番号１８および配列番号１９の配列により表されるアミノ酸配列を含むＣＤＲ１、ＣＤＲ２およびＣＤＲ３を含む、
請求項１に記載のモノクローナル抗体またはその抗原結合断片。 - the heavy chain variable domain comprises CDR1, CDR2 and CDR3 comprising the amino acid sequences represented by the sequences of SEQ ID NO: 12, SEQ ID NO: 13 and SEQ ID NO: 14 respectively;
- the light chain variable domain comprises CDR1, CDR2 and CDR3 comprising the amino acid sequences represented by the sequences of SEQ ID NO: 17, SEQ ID NO: 18 and SEQ ID NO: 19, respectively;
The monoclonal antibody or antigen-binding fragment thereof according to claim 1.
（ｉ）配列番号４のアミノ酸配列に少なくとも９０％相同なアミノ酸配列；または
（ｉｉ）配列番号１５のアミノ酸配列に少なくとも９０％相同なアミノ酸配列
を含む、
請求項１に記載のモノクローナル抗体またはその抗原結合断片。 the heavy chain variable domain is
(i) an amino acid sequence that is at least 90% homologous to the amino acid sequence of SEQ ID NO:4; or (ii) an amino acid sequence that is at least 90% homologous to the amino acid sequence of SEQ ID NO:15.
The monoclonal antibody or antigen-binding fragment thereof according to claim 1.
（ｉｉ）重鎖可変ドメインが、配列番号１５のアミノ酸配列を含む、
請求項１に記載のモノクローナル抗体またはその抗原結合断片。 (i) the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO:4, or (ii) the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO:15,
The monoclonal antibody or antigen-binding fragment thereof according to claim 1.
（ｉ）配列番号１０のアミノ酸配列に少なくとも９０％相同なアミノ酸配列；または
（ｉｉ）配列番号２０のアミノ酸配列に少なくとも９０％相同なアミノ酸配列
を含む、
請求項１に記載のモノクローナル抗体またはその抗原結合断片。 the light chain variable domain is
(i) an amino acid sequence that is at least 90% homologous to the amino acid sequence of SEQ ID NO:10; or (ii) an amino acid sequence that is at least 90% homologous to the amino acid sequence of SEQ ID NO:20.
The monoclonal antibody or antigen-binding fragment thereof according to claim 1.
（ｉｉ）軽鎖可変ドメインが、配列番号２０のアミノ酸配列を含む、
請求項１に記載のモノクローナル抗体またはその抗原結合断片。 (i) the light chain variable domain comprises the amino acid sequence of SEQ ID NO:10; or (ii) the light chain variable domain comprises the amino acid sequence of SEQ ID NO:20.
The monoclonal antibody or antigen-binding fragment thereof according to claim 1.
－ 重鎖可変ドメインが、配列番号４のアミノ酸配列に少なくとも９０％相同なアミノ酸配列を含み；
－ 軽鎖可変ドメインが、配列番号１０のアミノ酸配列に少なくとも９０％相同なアミノ酸配列を含むか；または
（ｉｉ）
－ 重鎖可変ドメインが、配列番号１５のアミノ酸配列に少なくとも９０％相同なアミノ酸配列を含み；
－ 軽鎖可変ドメインが、配列番号２０のアミノ酸配列に少なくとも９０％相同なアミノ酸配列を含む、
請求項１に記載のモノクローナル抗体またはその抗原結合断片。 (i)
- the heavy chain variable domain comprises an amino acid sequence that is at least 90% homologous to the amino acid sequence of SEQ ID NO:4;
- the light chain variable domain comprises an amino acid sequence that is at least 90% homologous to the amino acid sequence of SEQ ID NO: 10; or (ii)
- the heavy chain variable domain comprises an amino acid sequence that is at least 90% homologous to the amino acid sequence of SEQ ID NO: 15;
- the light chain variable domain comprises an amino acid sequence that is at least 90% homologous to the amino acid sequence of SEQ ID NO:20;
The monoclonal antibody or antigen-binding fragment thereof according to claim 1.
－ 軽鎖可変ドメインが、配列番号１０のアミノ酸配列を含む、
請求項１０に記載のモノクローナル抗体またはその抗原結合断片。 - the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO:4;
- the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 10,
11. The monoclonal antibody or antigen-binding fragment thereof according to claim 10.
－ 軽鎖可変ドメインが、配列番号２０のアミノ酸配列を含む、
請求項１０に記載のモノクローナル抗体またはその抗原結合断片。 - the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 15;
- the light chain variable domain comprises the amino acid sequence of SEQ ID NO:20,
11. The monoclonal antibody or antigen-binding fragment thereof according to claim 10.
（ｉｉ）配列番号６の配列に少なくとも９０％相同なアミノ酸配列
を含む重鎖を含む、請求項１に記載のモノクローナル抗体またはその抗原結合断片。 2. The monoclonal antibody of claim 1, comprising a heavy chain comprising (i) an amino acid sequence that is at least 90% homologous to the sequence of SEQ ID NO:5; or (ii) an amino acid sequence that is at least 90% homologous to the sequence of SEQ ID NO:6; or an antigen-binding fragment thereof .
（ｉｉ）配列番号６のアミノ酸配列を含む重鎖
を含む、請求項１に記載のモノクローナル抗体またはその抗原結合断片。 2. The monoclonal antibody or antigen-binding fragment thereof of claim 1, comprising (i) a heavy chain comprising the amino acid sequence of SEQ ID NO:5; or (ii) a heavy chain comprising the amino acid sequence of SEQ ID NO:6.
－ 配列番号５の配列に少なくとも９０％相同なアミノ酸配列を含む重鎖；
－ 配列番号１１の配列に少なくとも９０％相同なアミノ酸配列を含む軽鎖；または
（ｉｉ）
－ 配列番号６の配列に少なくとも９０％相同なアミノ酸配列を含む重鎖；
－ 配列番号１１の配列に少なくとも９０％相同なアミノ酸配列を含む軽鎖
を含む、請求項１に記載のモノクローナル抗体またはその抗原結合断片。 (i)
- a heavy chain comprising an amino acid sequence that is at least 90% homologous to the sequence of SEQ ID NO:5;
- a light chain comprising an amino acid sequence that is at least 90% homologous to the sequence of SEQ ID NO: 11; or (ii)
- a heavy chain comprising an amino acid sequence that is at least 90% homologous to the sequence of SEQ ID NO:6;
- a monoclonal antibody or antigen-binding fragment thereof according to claim 1, comprising a light chain comprising an amino acid sequence that is at least 90% homologous to the sequence of SEQ ID NO:11.
－ 配列番号１１のアミノ酸配列を含む軽鎖
を含む、請求項１に記載のモノクローナル抗体またはその抗原結合断片。 - a heavy chain comprising the amino acid sequence of SEQ ID NO:5;
- a monoclonal antibody or antigen-binding fragment thereof according to claim 1, comprising a light chain comprising the amino acid sequence of SEQ ID NO:11.
－ 配列番号１１のアミノ酸配列を含む軽鎖
を含む、請求項１に記載のモノクローナル抗体またはその抗原結合断片。 - a heavy chain comprising the amino acid sequence of SEQ ID NO:6;
- a monoclonal antibody or antigen-binding fragment thereof according to claim 1, comprising a light chain comprising the amino acid sequence of SEQ ID NO:11.
－ 配列番号２１の配列に少なくとも９０％相同なアミノ酸配列を含む軽鎖
を含む、請求項１に記載のモノクローナル抗体またはその抗原結合断片。 - a heavy chain comprising an amino acid sequence that is at least 90% homologous to the sequence of SEQ ID NO: 16;
- A monoclonal antibody or antigen-binding fragment thereof according to claim 1, comprising a light chain comprising an amino acid sequence that is at least 90% homologous to the sequence of SEQ ID NO:21.
－ 配列番号２１のアミノ酸配列を含む軽鎖
を含む、請求項１に記載のモノクローナル抗体またはその抗原結合断片。 - a heavy chain comprising the amino acid sequence of SEQ ID NO: 16;
- a monoclonal antibody or antigen-binding fragment thereof according to claim 1, comprising a light chain comprising the amino acid sequence of SEQ ID NO:21.
（ｉ）以下の群：抗ＰＤ１抗体、抗ＰＤ－Ｌ１抗体、抗ＣＴＬＡ４抗体、抗４－１ＢＢ抗体、抗ＯＸ４０抗体若しくはそれらの組合せから選択される抗体であるか、または
（ｉｉ）小分子であるか、または
（ｉｉｉ）自然または適応免疫の活性化剤の群から選択される、
請求項３８に記載の医薬組成物。 anti-tumor compounds with therapeutic activity
(i) an antibody selected from the following group: anti-PD1 antibody, anti-PD-L1 antibody, anti-CTLA4 antibody, anti-4-1BB antibody, anti-OX40 antibody, or combinations thereof, or (ii) a small molecule or (iii) selected from the group of activators of natural or adaptive immunity,
39. A pharmaceutical composition according to claim 38 .
あるいは、
請求項１～２９のいずれか一項に記載の抗体またはその抗原結合断片、および少なくとも１種の治療活性を有する抗腫瘍化合物が、同時に投与される、
請求項３７に記載の医薬組成物。 The antibody or antigen-binding fragment thereof of any one of claims 1-29 and at least one therapeutically active anti-tumor compound are administered sequentially,
or,
The antibody or antigen-binding fragment thereof of any one of claims 1-29 and at least one therapeutically active anti-tumor compound are administered simultaneously,
38. A pharmaceutical composition according to claim 37 .
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| RU2019112296A RU2734432C1 (en) | 2019-04-23 | 2019-04-23 | Monoclonal antibody which specifically binds gitr |
| RU2019112296 | 2019-04-23 | ||
| PCT/RU2020/050080 WO2020218951A2 (en) | 2019-04-23 | 2020-04-23 | Monoclonal antibody that binds specifically to gitr |
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| JP2022532991A JP2022532991A (en) | 2022-07-21 |
| JPWO2020218951A5 true JPWO2020218951A5 (en) | 2023-05-02 |
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| US (1) | US20220213209A1 (en) |
| EP (1) | EP3964525A4 (en) |
| JP (1) | JP2022532991A (en) |
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| CN112362876B (en) * | 2020-08-06 | 2023-12-15 | 武汉天德生物科技有限公司 | Colloidal gold test strip for detecting early senile dementia and preparation method thereof |
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| CN114920845A (en) * | 2020-12-31 | 2022-08-19 | 中元汇吉生物技术股份有限公司 | Protein capable of specifically binding to human IgG4 and application thereof |
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