JPWO2021220218A5 - - Google Patents

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JPWO2021220218A5
JPWO2021220218A5 JP2022565970A JP2022565970A JPWO2021220218A5 JP WO2021220218 A5 JPWO2021220218 A5 JP WO2021220218A5 JP 2022565970 A JP2022565970 A JP 2022565970A JP 2022565970 A JP2022565970 A JP 2022565970A JP WO2021220218 A5 JPWO2021220218 A5 JP WO2021220218A5
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Prior art keywords
variant
antibody
polypeptide
cell
parental
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JP2022565970A
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JP2023523760A (en
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Priority claimed from PCT/IB2021/053585 external-priority patent/WO2021220218A1/en
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Claims (16)

ヒトＩｇＡ２内に含まれる親ＦｃポリペプチドのＦｃ変異体であって、前記Ｆｃ変異体
は、前記親Ｆｃポリペプチドと比較して変更されたＦｃαＲに対する結合又は変更された
抗体依存性細胞媒介性細胞毒性（ＡＤＣＣ）を示し、前記Ｆｃ変異体は、前記親Ｆｃポリ
ペプチドの前記Ｆｃ領域における少なくとも１つのアミノ酸改変を含み、前記少なくとも
１つのアミノ酸改変は：
Ｑ＿ＣＨ２．９４＿Ｅ、
Ｎ＿ＣＨ２．９７＿Ｙ、
Ｓ＿ＣＨ３．４５＿Ｄ、
Ｍ＿ＣＨ３．１０５＿Ｙ、
Ｑ＿ＣＨ３．１１８＿Ｙ、
Ｑ＿ＣＨ２．９４＿Ｅ／Ｎ＿ＣＨ２．９７＿Ｙ、
Ｑ＿ＣＨ２．９４＿Ｅ／Ｓ＿ＣＨ３．４５＿Ｄ、
Ｑ＿ＣＨ２．９４＿Ｅ／Ｍ＿ＣＨ３．１０５＿Ｙ、
Ｎ＿ＣＨ２．９７＿Ｙ／Ｓ＿ＣＨ３．４５＿Ｄ、
Ｎ＿ＣＨ２．９７＿Ｙ／Ｍ＿ＣＨ３．１０５＿Ｙ、
Ｓ＿ＣＨ３．４５＿Ｄ／Ｍ＿ＣＨ３．１０５＿Ｙ、
Ｍ＿ＣＨ３．１０５＿Ｙ／Ｑ＿ＣＨ３．１１８＿Ｙ、
Ｑ＿ＣＨ２．９４＿Ｅ／Ｎ＿ＣＨ２．９７＿Ｙ／Ｍ＿ＣＨ３．１０５＿Ｙ、
Ｎ＿ＣＨ２．９７＿Ｙ／Ｓ＿ＣＨ３．４５＿Ｄ／Ｍ＿ＣＨ３．１０５＿Ｙ、
Ｑ＿ＣＨ２．９４＿Ｅ／Ｓ＿ＣＨ３．４５＿Ｄ／Ｍ＿ＣＨ３．１０５＿Ｙ、
Ｍ＿ＣＨ３．１０５＿Ｙ／Ｑ＿ＣＨ３．１１８＿Ｙ／Ｓ＿ＣＨ３．４５＿Ｄ、
Ｑ＿ＣＨ２．９４＿Ｅ／Ｎ＿ＣＨ２．９７＿Ｙ／Ｓ＿ＣＨ３．４５＿Ｄ、
Ｑ＿ＣＨ２．９４＿Ｅ／Ｎ＿ＣＨ２．９７＿Ｙ／Ｓ＿ＣＨ３．４５＿Ｄ／Ｍ＿ＣＨ３．１
０５＿Ｙ、
Ｑ＿ＣＨ２．９４＿Ｅ／Ｎ＿ＣＨ２．９７＿Ｙ／Ｍ＿ＣＨ３．１０５＿Ｙ／Ｑ＿ＣＨ３．
１１８＿Ｙ、
Ｑ＿ＣＨ２．９４＿Ｅ／Ｎ＿ＣＨ２．９７＿Ｙ／Ｓ＿ＣＨ３．４５＿Ｄ／Ｍ＿ＣＨ３．１
０５＿Ｙ／Ｑ＿ＣＨ３．１１８＿Ｙ、
Ａ＿ＣＨ２．１０＿Ｓ、
Ｌ＿ＣＨ２．８９＿Ｉ、
Ｇ＿ＣＨ２．９１＿Ｖ、
Ｎ＿ＣＨ２．９７＿Ｈ、
Ｇ＿ＣＨ２．９９＿Ｗ、
Ｅ＿ＣＨ３．１０９＿Ｄ、
Ｌ＿ＣＨ３．１２４＿Ｆ、及び
Ｌ＿ＣＨ２．８９＿Ｉ／Ｇ＿ＣＨ２．９１＿Ｖ／Ｑ＿ＣＨ２．９４＿Ｅ／Ｎ＿ＣＨ２．９
７＿Ｙ／Ｇ＿ＣＨ２．９９＿Ｗ、
からなる群から選択され、
前記アミノ酸改変の番号付けは、Ｃ－ドメインについてのＩＭＧＴ番号付けに従う、Ｆｃ
変異体。 An Fc variant of a parent Fc polypeptide contained within human IgA2, wherein said Fc variant has altered binding to FcαR or altered antibody-dependent cell-mediated cell activation compared to said parent Fc polypeptide exhibiting toxicity (ADCC), said Fc variant comprises at least one amino acid alteration in said Fc region of said parent Fc polypeptide, said at least one amino acid alteration comprising:
Q_CH2.94_E,
N_CH2.97_Y,
S_CH3.45_D,
M_CH3.105_Y,
Q_CH3.118_Y,
Q_CH2.94_E/N_CH2.97_Y,
Q_CH2.94_E/S_CH3.45_D,
Q_CH2.94_E/M_CH3.105_Y,
N_CH2.97_Y/S_CH3.45_D,
N_CH2.97_Y/M_CH3.105_Y,
S_CH3.45_D/M_CH3.105_Y,
M_CH3.105_Y/Q_CH3.118_Y,
Q_CH2.94_E/N_CH2.97_Y/M_CH3.105_Y,
N_CH2.97_Y/S_CH3.45_D/M_CH3.105_Y,
Q_CH2.94_E/S_CH3.45_D/M_CH3.105_Y,
M_CH3.105_Y/Q_CH3.118_Y/S_CH3.45_D,
Q_CH2.94_E/N_CH2.97_Y/S_CH3.45_D,
Q_CH2.94_E/N_CH2.97_Y/S_CH3.45_D/M_CH3.1
05_Y,
Q_CH2.94_E/N_CH2.97_Y/M_CH3.105_Y/Q_CH3.
118_Y,
Q_CH2.94_E/N_CH2.97_Y/S_CH3.45_D/M_CH3.1
05_Y/Q_CH3.118_Y,
A_CH2.10_S,
L_CH2.89_I,
G_CH2.91_V,
N_CH2.97_H,
G_CH2.99_W,
E_CH3.109_D,
L_CH3.124_F, and L_CH2.89_I/G_CH2.91_V/Q_CH2.94_E/N_CH2.9
7_Y/G_CH2.99_W,
is selected from the group consisting of
The numbering of said amino acid modifications follows IMGT numbering for the C-domain, Fc
Mutant. 前記Ｆｃ変異体が、表面プラズモン共鳴により測定して、前記親Ｆｃポリペプチドの少
なくとも約５０倍の、ヒトＦｃαＲＩに対する増加した親和性を有する、請求項１に記載
のＦｃ変異体。 2. The Fc variant of claim 1, wherein said Fc variant has an increased affinity for human Fc[alpha]RI that is at least about 50-fold that of said parental Fc polypeptide as measured by surface plasmon resonance. 前記親ＦｃポリペプチドがヒトＩｇＧ１を含む、請求項１又は請求項２に記載のＦｃ変
異体。 3. The Fc variant of claim 1 or claim 2, wherein said parental Fc polypeptide comprises human IgG1. 前記Ｆｃ変異体が、表面プラズモン共鳴により測定して、前記親Ｆｃポリペプチドの少
なくとも約３００倍の、ヒトＦｃαＲＩに対する増加した親和性を有する、請求項３に記
載のＦｃ変異体。 4. The Fc variant of claim 3, wherein said Fc variant has an increased affinity for human Fc[alpha]RI of at least about 300-fold over said parental Fc polypeptide as measured by surface plasmon resonance. 前記Ｆｃ変異体が、ＭＤＡ－ＭＢ－４５３細胞殺傷アッセイにおいて測定して、抗体依
存性細胞媒介性細胞毒性を前記親Ｆｃポリペプチドの少なくとも約５倍増加させる、請求
項１～４のいずれか１項に記載のＦｃ変異体。 5. Any one of claims 1-4, wherein said Fc variant increases antibody-dependent cell-mediated cytotoxicity by at least about 5-fold over said parental Fc polypeptide, as measured in the MDA-MB-453 cell killing assay. 3. Fc variant according to paragraph. 前記Ｆｃ変異体が、前記親Ｆｃポリペプチドの少なくとも約２倍の、Ｃａｌｕ－３細胞
殺傷アッセイにおける増加した有効性を有する、請求項１～５のいずれか１項に記載のＦ
ｃ変異体。 6. The F of any one of claims 1-5, wherein said Fc variant has increased efficacy in a Calu-3 cell killing assay that is at least about twice that of said parental Fc polypeptide.
c mutant. Ｆｃ変異体を含むｌｇＡ２抗体であって、前記抗体が、親Ｆｃポリペプチドを含むＩｇ
Ａ２抗体と比較して増加したＦｃαＲ親和性、又は増加した抗体依存性細胞媒介性細胞毒
性を有し、前記抗体が：ＣＨ２．１０、ＣＨ２．８９、ＣＨ２．９１、ＣＨ２．９４、Ｃ
Ｈ２．９７、ＣＨ２．９９、ＣＨ３．４５、ＣＨ３．１０５、ＣＨ３．１０９、ＣＨ３．
１１８及びＣＨ３．１２４からなる群から選択される位置におけるアミノ酸改変を含み、
前記アミノ酸改変の番号付けは、Ｃ－ドメインについてのＩＭＧＴ番号付けに従う、ｌｇ
Ａ２抗体。 lgA2 antibody comprising an Fc variant, said antibody comprising an Ig comprising a parent Fc polypeptide
having increased FcαR affinity or increased antibody-dependent cell-mediated cytotoxicity compared to the A2 antibody, wherein said antibody is: CH2.10, CH2.89, CH2.91, CH2.94, C
H2.97, CH2.99, CH3.45, CH3.105, CH3.109, CH3.
comprising an amino acid modification at a position selected from the group consisting of 118 and CH3.124;
The numbering of said amino acid modifications follows IMGT numbering for the C-domain, lg
A2 antibody. 前記抗体が腫瘍抗原に結合する、請求項７に記載のＩｇＡ抗体。 8. The IgA antibody of claim 7, wherein said antibody binds to a tumor antigen. 請求項１～６のいずれか１項に記載のＦｃ変異体又は請求項７又は請求項８に記載の抗
体を、１つ以上の薬学的に許容され得る賦形剤、希釈剤又は担体と組み合わせて含む医薬
組成物。 combining the Fc variant of any one of claims 1-6 or the antibody of claim 7 or claim 8 with one or more pharmaceutically acceptable excipients, diluents or carriers A pharmaceutical composition comprising さらに１つ以上の追加の活性剤を含む、請求項９に記載の医薬組成物。 10. The pharmaceutical composition of Claim 9, further comprising one or more additional active agents. 細胞増殖性疾患又は状態の治療における使用のための、請求項１～６のいずれか１項に
記載のＦｃ変異体又は請求項７又は請求項８に記載の抗体。 An Fc variant according to any one of claims 1-6 or an antibody according to claim 7 or claim 8 for use in the treatment of a cell proliferative disease or condition. 前記細胞増殖性疾患又は状態が：乳癌、神経芽腫、リンパ腫、膵膵管腺癌、黒色腫、腎
細胞癌、膀胱癌、結腸直腸癌、非小細胞肺癌、非ホジキンリンパ腫及び多発性骨髄腫から
なる群から選択される、請求項１１に記載の使用のためのＦｃ変異体又は抗体。 said cell proliferative disease or condition is from: breast cancer, neuroblastoma, lymphoma, pancreatic ductal adenocarcinoma, melanoma, renal cell carcinoma, bladder cancer, colorectal cancer, non-small cell lung cancer, non-Hodgkin's lymphoma and multiple myeloma 12. An Fc variant or antibody for use according to claim 11, selected from the group consisting of: 請求項１～６のいずれか１項に記載のＦｃ変異体又は請求項７又は請求項８に記載の抗
体をコードする単離された核酸分子。 An isolated nucleic acid molecule encoding the Fc variant of any one of claims 1-6 or the antibody of claim 7 or claim 8. １つ以上の請求項１３に記載の核酸配列を含むクローニング又は発現ベクターであって
、請求項１～６のいずれか１項に記載のＦｃ変異体又は請求項７又は請求項８に記載の抗
体の組換え産生に適している、ベクター。 A cloning or expression vector comprising one or more nucleic acid sequences according to claim 13, the Fc variant according to any one of claims 1 to 6 or the antibody according to claim 7 or claim 8. vector, which is suitable for recombinant production of １つ以上の請求項１４に記載のクローニング又は発現ベクターを含む宿主細胞。 A host cell comprising one or more cloning or expression vectors according to claim 14. 請求項１～６のいずれか１項に記載のＦｃ変異体又は請求項７又は請求項８に記載の抗
体を調製する方法であって、請求項１５に記載の宿主細胞を培養することと、前記宿主細
胞培養物から前記Ｆｃ変異体又は抗体を精製することと、前記宿主細胞培養物から前記Ｆ
ｃ変異体又は抗体を回収することと、を含む、方法。 A method for preparing the Fc variant of any one of claims 1 to 6 or the antibody of claim 7 or claim 8, comprising culturing the host cell of claim 15, purifying said Fc variant or antibody from said host cell culture;
retrieving the c variant or antibody.
JP2022565970A 2020-05-01 2021-04-29 immunoglobulin variant Pending JP2023523760A (en)

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US202063018698P 2020-05-01 2020-05-01
US63/018,698 2020-05-01
PCT/IB2021/053585 WO2021220218A1 (en) 2020-05-01 2021-04-29 Immunoglobulin variants

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JPWO2021220218A5 true JPWO2021220218A5 (en) 2023-06-14

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