JP7431394B2 - Her2、nkg2dおよびcd16に結合する多重特異性結合タンパク質ならびに使用方法 - Google Patents
Her2、nkg2dおよびcd16に結合する多重特異性結合タンパク質ならびに使用方法 Download PDFInfo
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Classifications
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- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
- C07K16/283—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against Fc-receptors, e.g. CD16, CD32, CD64
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2851—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the lectin superfamily, e.g. CD23, CD72
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/32—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
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- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
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- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
- C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/52—Constant or Fc region; Isotype
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- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
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- C07K2317/55—Fab or Fab'
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- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
- C07K2317/565—Complementarity determining region [CDR]
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- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
- C07K2317/62—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
- C07K2317/622—Single chain antibody (scFv)
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- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
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- Organic Chemistry (AREA)
- Immunology (AREA)
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- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
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- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Peptides Or Proteins (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
Description
本出願は、2018年8月8日出願の米国仮特許出願第62/716,259号の利益および優先権を主張し、当該出願の開示は、全ての目的についてその全体がこれにより参照により本明細書に組み込まれる。
配列表
発明の分野
HER2(ErbB2)は、上皮成長因子受容体ファミリーに属する膜貫通糖タンパク質である。それは、受容体チロシンキナーゼであり、細胞生存、増殖および成長を調節する。HER2は、ヒト悪性腫瘍において重要な役割を果たす。ERBB2遺伝子は、ヒト乳がんのおよそ30%において増幅または過剰発現される。HER2過剰発現乳がんを有する患者は、がんがHER2を過剰発現していない患者よりも実質的に低い全生存率および短い無病期間を有する。さらに、HER2の過剰発現は、乳がん転移の増大をもたらす。また、HER2の過剰発現は、乳がん、卵巣がん、食道がん、膀胱がんおよび胃がん、唾液腺導管癌、肺の腺癌、ならびに攻撃的形態の子宮がん、例えば、子宮漿液性子宮内膜癌を含む、多くの他のがんの種類において起こることが公知である。
(a)それぞれ、配列番号168、96および169のアミノ酸配列によって表される相補性決定領域1(CDR1)、相補性決定領域2(CDR2)および相補性決定領域3(CDR3)配列を含む重鎖可変ドメイン;ならびにそれぞれ、配列番号99、100および101のアミノ酸配列によって表されるCDR1、CDR2およびCDR3配列を含む軽鎖可変ドメイン;
(b)それぞれ、配列番号168、96および173のアミノ酸配列によって表されるCDR1、CDR2およびCDR3配列を含む重鎖可変ドメイン;ならびにそれぞれ、配列番号99、100および101のアミノ酸配列によって表されるCDR1、CDR2およびCDR3配列を含む軽鎖可変ドメイン;
(c)それぞれ、配列番号95、96および97のアミノ酸配列によって表されるCDR1、CDR2およびCDR3配列を含む重鎖可変ドメイン;ならびにそれぞれ、配列番号99、100および101のアミノ酸配列によって表されるCDR1、CDR2およびCDR3配列を含む軽鎖可変ドメイン;
(d)それぞれ、配列番号166、88および167のアミノ酸配列によって表されるCDR1、CDR2およびCDR3配列を含む重鎖可変ドメイン;ならびにそれぞれ、配列番号91、92および93のアミノ酸配列によって表されるCDR1、CDR2およびCDR3配列を含む軽鎖可変ドメイン;
(e)それぞれ、配列番号162、72および170のアミノ酸配列によって表されるCDR1、CDR2およびCDR3配列を含む重鎖可変ドメイン;ならびにそれぞれ、配列番号107、108および109のアミノ酸配列によって表されるCDR1、CDR2およびCDR3配列を含む軽鎖可変ドメイン;
(f)それぞれ、配列番号162、72および163のアミノ酸配列によって表されるCDR1、CDR2およびCDR3配列を含む重鎖可変ドメイン;ならびにそれぞれ、配列番号75、76および77のアミノ酸配列によって表されるCDR1、CDR2およびCDR3配列を含む軽鎖可変ドメイン;
(g)それぞれ、配列番号164、80および165のアミノ酸配列によって表されるCDR1、CDR2およびCDR3配列を含む重鎖可変ドメイン;ならびにそれぞれ、配列番号75、76および85のアミノ酸配列によって表されるCDR1、CDR2およびCDR3配列を含む軽鎖可変ドメイン;
(h)それぞれ、配列番号168、96および176のアミノ酸配列によって表されるCDR1、CDR2およびCDR3配列を含む重鎖可変ドメイン;ならびにそれぞれ、配列番号99、100および101のアミノ酸配列によって表されるCDR1、CDR2およびCDR3配列を含む軽鎖可変ドメイン;
(i)それぞれ、配列番号168、96および179のアミノ酸配列によって表されるCDR1、CDR2およびCDR3配列を含む重鎖可変ドメイン;ならびにそれぞれ、配列番号99、100および101のアミノ酸配列によって表されるCDR1、CDR2およびCDR3配列を含む軽鎖可変ドメイン;
(j)それぞれ、配列番号168、96および182のアミノ酸配列によって表されるCDR1、CDR2およびCDR3配列を含む重鎖可変ドメイン;ならびにそれぞれ、配列番号99、100および101のアミノ酸配列によって表されるCDR1、CDR2およびCDR3配列を含む軽鎖可変ドメイン;
(k)それぞれ、配列番号168、96および185のアミノ酸配列によって表されるCDR1、CDR2およびCDR3配列を含む重鎖可変ドメイン;ならびにそれぞれ、配列番号99、100および101のアミノ酸配列によって表されるCDR1、CDR2およびCDR3配列を含む軽鎖可変ドメイン;または
(l)それぞれ、配列番号168、96および188のアミノ酸配列によって表されるCDR1、CDR2およびCDR3配列を含む重鎖可変ドメイン;ならびにそれぞれ、配列番号99、100および101のアミノ酸配列によって表されるCDR1、CDR2およびCDR3配列を含む軽鎖可変ドメイン
を含む、NKG2Dに結合する第1の抗原結合部位;ならびに
(a)それぞれ、配列番号115、116および117のアミノ酸配列によって表されるCDR1、CDR2およびCDR3配列を含む重鎖可変ドメイン;ならびにそれぞれ、配列番号119、120および121のアミノ酸配列によって表されるCDR1、CDR2およびCDR3配列を含む軽鎖可変ドメイン;
(b)それぞれ、配列番号123、124および125のアミノ酸配列によって表されるCDR1、CDR2およびCDR3配列を含む重鎖可変ドメイン;ならびにそれぞれ、配列番号127、128および129のアミノ酸配列によって表されるCDR1、CDR2およびCDR3配列を含む軽鎖可変ドメイン;または
(c)それぞれ、配列番号131、132および133のアミノ酸配列によって表されるCDR1、CDR2およびCDR3配列を含む重鎖可変ドメイン;ならびにそれぞれ、配列番号135、136および137のアミノ酸配列によって表されるCDR1、CDR2およびCDR3配列を含む軽鎖可変ドメイン
を含む、HER2に結合するscFvを含む第2の抗原結合部位
を含む。
I.タンパク質
NKG2D結合部位
配列番号110
配列番号112
HER2結合部位
例示的な多重特異性結合タンパク質
N末端~C末端:NKG2D結合FabのVH、CH1、およびFcを含む、鎖A;
N末端~C末端:HER2結合scFvのVL、(G4S)4リンカー(配列番号203)、HER2結合scFvのVH、Ala-Serリンカー、およびFcを含む、鎖B;ならびに
N末端~C末端:NKG2D結合FabのVL、およびCLを含む、鎖C
を含む。
トラスツズマブscFv
トラスツズマブscFv-Fc(RVT)
A49 VH
A49 VH-CH1-Fc(EW)
A49 VL
A49 VL-LC
A49MI VH
A49MI VH-CH1-Fc(EW)
トラスツズマブscFv-Fc(KiH)
A49 VH-CH1-Fc(KiH)
A49MI VH-CH1-Fc(KiH)
A44 VH
A44 VH-CH1-Fc(EW)
A44 VL
A44 VL-CL
A44 VH-CH1-Fc(KiH)
ペルツズマブscFv
ペルツズマブscFv-Fc
ペルツズマブscFv-Fc(KiH)
MGAH22 scFv
MGAH22 scFv-Fc
MGAH22 scFv-Fc(KiH)
II.多重特異性タンパク質の特徴
MGAH22重鎖
MGAH22軽鎖
III.治療適用
IV.併用療法
V.医薬組成物
(実施例1)
初代ヒトNK細胞の細胞傷害性アッセイ:
DELFIA細胞傷害性アッセイ:
長期ヒトPBMC細胞傷害性アッセイ:
(実施例2)
ヒト全血におけるTriNKETの結合
(実施例3)
ヒト心筋細胞対さまざまなレベルのHER2を発現するヒトがん細胞へのA49-F3’-TriNKET-トラスツズマブ結合の評価
ヒトPBMC細胞傷害性アッセイ
初代ヒトPBMC細胞傷害性アッセイ
(実施例4)
TriNKETは、TAA+腫瘍細胞のCD8+T細胞溶解を誘発する
初代ヒトCD8T細胞の細胞傷害性アッセイ:初代ヒトCD8エフェクターT細胞生成
初代ヒトCD8エフェクターT細胞の特徴付け
短期CD8エフェクターT細胞DELFIA細胞傷害性アッセイ
長期CD8エフェクターT細胞Incucyte細胞傷害性アッセイ
細胞傷害性アッセイにおいて使用されるCD8Tエフェクター細胞の特徴付け
短期CD8エフェクターT細胞DELFIA細胞傷害性アッセイ
長期CD8エフェクターT細胞Incucyte細胞傷害性アッセイ
(実施例5)
ヒトがん抗原を発現した細胞へのTriNKET結合の評価
TriNKET結合アッセイ
初代ヒトNK細胞の細胞傷害性アッセイ
DELFIA細胞傷害性アッセイ
scFv-Fc
(L234A、L235AおよびP329G(LALAPG)置換(第3の括弧[]内に示される)を含む)
鎖全体VH-CH1-Fc
(L234A、L235AおよびP329G(LALAPG)置換(第3の括弧[]内に示される)を含む)
(実施例6)
ADI-27749のバリアントおよびバリアントを含有するTriNKET
番号付き実施形態
参照による組込み
均等物
本発明は、例えば以下の項目を提供する。
(項目1)
(a)NKG2Dに結合するFab断片を含む第1の抗原結合部位と;
(b)HER2に結合する一本鎖可変領域断片(scFv)を含む第2の抗原結合部位と;
(c)CD16に結合するのに十分な抗体Fcドメインもしくはその部分、またはCD16に結合する第3の抗原結合部位と
を含むタンパク質。
(項目2)
前記scFvが、Ala-Serを含むヒンジを介して、CD16に結合するのに十分な前記抗体Fcドメインもしくはその部分、またはCD16に結合する前記第3の抗原結合部位に連結している、項目1に記載のタンパク質。
(項目3)
前記scFvが、前記抗体Fcドメインに連結している、項目2に記載のタンパク質。
(項目4)
前記scFvが、重鎖可変ドメインおよび軽鎖可変ドメインを含む、項目1から3のいずれか一項に記載のタンパク質。
(項目5)
前記scFvの前記重鎖可変ドメインが、前記scFvの前記軽鎖可変ドメインとジスルフィド架橋を形成する、項目4に記載のタンパク質。
(項目6)
前記ジスルフィド架橋が、前記重鎖可変ドメインのC44と前記軽鎖可変ドメインのC100との間に形成される、項目5に記載のタンパク質。
(項目7)
前記scFvの前記軽鎖可変ドメインが、フレキシブルリンカーを介して前記scFvの前記重鎖可変ドメインに連結している、項目4から6のいずれか一項に記載のタンパク質。
(項目8)
前記フレキシブルリンカーが、配列番号143のアミノ酸配列を含む、項目7に記載のタンパク質。
(項目9)
前記フレキシブルリンカーが、配列番号143のアミノ酸配列からなる、項目8に記載のタンパク質。
(項目10)
前記軽鎖可変ドメインが、前記重鎖可変ドメインのN末端またはC末端に位置する、項目4から9のいずれか一項に記載のタンパク質。
(項目11)
前記軽鎖可変ドメインが、前記重鎖可変ドメインのN末端に位置する、項目10に記載のタンパク質。
(項目12)
前記Fab断片が、CD16に結合するのに十分な前記抗体Fcドメインもしくはその部分、またはCD16に結合する前記第3の抗原結合部位に連結している、項目1から11のいずれか一項に記載のタンパク質。
(項目13)
NKG2Dに結合する前記第1の抗原結合部位が、
(a)それぞれ、配列番号168、96および169のアミノ酸配列によって表される相補性決定領域1(CDR1)、相補性決定領域2(CDR2)および相補性決定領域3(CDR3)配列を含む重鎖可変ドメイン;ならびにそれぞれ、配列番号99、100および101のアミノ酸配列によって表されるCDR1、CDR2およびCDR3配列を含む軽鎖可変ドメイン;
(b)それぞれ、配列番号168、96および173のアミノ酸配列によって表されるCDR1、CDR2およびCDR3配列を含む重鎖可変ドメイン;ならびにそれぞれ、配列番号99、100および101のアミノ酸配列によって表されるCDR1、CDR2およびCDR3配列を含む軽鎖可変ドメイン;
(c)それぞれ、配列番号95、96および97のアミノ酸配列によって表されるCDR1、CDR2およびCDR3配列を含む重鎖可変ドメイン;ならびにそれぞれ、配列番号99、100および101のアミノ酸配列によって表されるCDR1、CDR2およびCDR3配列を含む軽鎖可変ドメイン;
(d)それぞれ、配列番号166、88および167のアミノ酸配列によって表されるCDR1、CDR2およびCDR3配列を含む重鎖可変ドメイン;ならびにそれぞれ、配列番号91、92および93のアミノ酸配列によって表されるCDR1、CDR2およびCDR3配列を含む軽鎖可変ドメイン;
(e)それぞれ、配列番号162、72および170のアミノ酸配列によって表されるCDR1、CDR2およびCDR3配列を含む重鎖可変ドメイン;ならびにそれぞれ、配列番号107、108および109のアミノ酸配列によって表されるCDR1、CDR2およびCDR3配列を含む軽鎖可変ドメイン;
(f)それぞれ、配列番号162、72および163のアミノ酸配列によって表されるCDR1、CDR2およびCDR3配列を含む重鎖可変ドメイン;ならびにそれぞれ、配列番号75、76および77のアミノ酸配列によって表されるCDR1、CDR2およびCDR3配列を含む軽鎖可変ドメイン;
(g)それぞれ、配列番号164、80および165のアミノ酸配列によって表されるCDR1、CDR2およびCDR3配列を含む重鎖可変ドメイン;ならびにそれぞれ、配列番号75、76および85のアミノ酸配列によって表されるCDR1、CDR2およびCDR3配列を含む軽鎖可変ドメイン;
(h)それぞれ、配列番号168、96および176のアミノ酸配列によって表されるCDR1、CDR2およびCDR3配列を含む重鎖可変ドメイン;ならびにそれぞれ、配列番号99、100および101のアミノ酸配列によって表されるCDR1、CDR2およびCDR3配列を含む軽鎖可変ドメイン;
(i)それぞれ、配列番号168、96および179のアミノ酸配列によって表されるCDR1、CDR2およびCDR3配列を含む重鎖可変ドメイン;ならびにそれぞれ、配列番号99、100および101のアミノ酸配列によって表されるCDR1、CDR2およびCDR3配列を含む軽鎖可変ドメイン;
(j)それぞれ、配列番号168、96および182のアミノ酸配列によって表されるCDR1、CDR2およびCDR3配列を含む重鎖可変ドメイン;ならびにそれぞれ、配列番号99、100および101のアミノ酸配列によって表されるCDR1、CDR2およびCDR3配列を含む軽鎖可変ドメイン;
(k)それぞれ、配列番号168、96および185のアミノ酸配列によって表されるCDR1、CDR2およびCDR3配列を含む重鎖可変ドメイン;ならびにそれぞれ、配列番号99、100および101のアミノ酸配列によって表されるCDR1、CDR2およびCDR3配列を含む軽鎖可変ドメイン;または
(l)それぞれ、配列番号168、96および188のアミノ酸配列によって表されるCDR1、CDR2およびCDR3配列を含む重鎖可変ドメイン;ならびにそれぞれ、配列番号99、100および101のアミノ酸配列によって表されるCDR1、CDR2およびCDR3配列を含む軽鎖可変ドメイン
を含む、項目1から12のいずれか一項に記載のタンパク質。
(項目14)
NKG2Dに結合する前記第1の抗原結合部位が、配列番号86および配列番号94から選択されるアミノ酸配列と少なくとも90%同一の重鎖可変ドメインを含む、項目1から13のいずれか一項に記載のタンパク質。
(項目15)
NKG2Dに結合する前記第1の抗原結合部位が、
(a)配列番号94と少なくとも90%同一の重鎖可変ドメイン、および配列番号98と少なくとも90%同一の軽鎖可変ドメイン;
(b)配列番号144と少なくとも90%同一の重鎖可変ドメイン、および配列番号98と少なくとも90%同一の軽鎖可変ドメイン;または
(c)配列番号86と少なくとも90%同一の重鎖可変ドメイン、および配列番号90と少なくとも90%同一の軽鎖可変ドメイン
を含む、項目1から14のいずれか一項に記載のタンパク質。
(項目16)
NKG2Dに結合する前記第1の抗原結合部位が、
(a)配列番号94と少なくとも95%同一の重鎖可変ドメイン、および配列番号98と少なくとも95%同一の軽鎖可変ドメイン;
(b)配列番号144と少なくとも95%同一の重鎖可変ドメイン、および配列番号98と少なくとも95%同一の軽鎖可変ドメイン;または
(c)配列番号86と少なくとも95%同一の重鎖可変ドメイン、および配列番号90と少なくとも95%同一の軽鎖可変ドメイン
を含む、項目1から15のいずれか一項に記載のタンパク質。
(項目17)
NKG2Dに結合する前記第1の抗原結合部位が、
(a)配列番号94と同一の重鎖可変ドメイン、および配列番号98と同一の軽鎖可変ドメイン;
(b)配列番号144と同一の重鎖可変ドメイン、および配列番号98と同一の軽鎖可変ドメイン;または
(c)配列番号86と同一の重鎖可変ドメイン、および配列番号90と同一の軽鎖可変ドメイン
を含む、項目1から16のいずれか一項に記載のタンパク質。
(項目18)
表面プラズモン共鳴によって測定して、2nM~120nMのK D でNKG2Dに結合する、項目1から17のいずれか一項に記載のタンパク質。
(項目19)
HER2に結合する前記第2の抗原結合部位が、
(a)それぞれ、配列番号115、116および117のアミノ酸配列によって表されるCDR1、CDR2およびCDR3配列を含む重鎖可変ドメイン;ならびにそれぞれ、配列番号119、120および121のアミノ酸配列によって表されるCDR1、CDR2およびCDR3配列を含む軽鎖可変ドメイン;
(b)それぞれ、配列番号123、124および125のアミノ酸配列によって表されるCDR1、CDR2およびCDR3配列を含む重鎖可変ドメイン;ならびにそれぞれ、配列番号127、128および129のアミノ酸配列によって表されるCDR1、CDR2およびCDR3配列を含む軽鎖可変ドメイン;または
(c)それぞれ、配列番号131、132および133のアミノ酸配列によって表されるCDR1、CDR2およびCDR3配列を含む重鎖可変ドメイン;ならびにそれぞれ、配列番号135、136および137のアミノ酸配列によって表されるCDR1、CDR2およびCDR3配列を含む軽鎖可変ドメイン
を含む、項目1から18のいずれか一項に記載のタンパク質。
(項目20)
HER2に結合する前記第2の抗原結合部位が、
(a)配列番号195と少なくとも90%同一のアミノ酸配列を含む重鎖可変ドメイン、および配列番号196と少なくとも90%同一のアミノ酸配列を含む軽鎖可変ドメイン;
(b)配列番号197と少なくとも90%同一のアミノ酸配列を含む重鎖可変ドメイン、および配列番号198と少なくとも90%同一のアミノ酸配列を含む軽鎖可変ドメイン;または
(c)配列番号199と少なくとも90%同一のアミノ酸配列を含む重鎖可変ドメイン、および配列番号200と少なくとも90%同一のアミノ酸配列を含む軽鎖可変ドメインを含む、項目1から19のいずれか一項に記載のタンパク質。
(項目21)
HER2に結合する前記第2の抗原結合部位が、
(a)配列番号195と少なくとも95%同一のアミノ酸配列を含む重鎖可変ドメイン、および配列番号196と少なくとも95%同一のアミノ酸配列を含む軽鎖可変ドメイン;
(b)配列番号197と少なくとも95%同一のアミノ酸配列を含む重鎖可変ドメイン、および配列番号198と少なくとも95%同一のアミノ酸配列を含む軽鎖可変ドメイン;または
(c)配列番号199と少なくとも95%同一のアミノ酸配列を含む重鎖可変ドメイン、および配列番号200と少なくとも95%同一のアミノ酸配列を含む軽鎖可変ドメインを含む、項目1から20のいずれか一項に記載のタンパク質。
(項目22)
HER2に結合する前記第2の抗原結合部位が、
(a)配列番号195と同一のアミノ酸配列を含む重鎖可変ドメイン、および配列番号196と同一のアミノ酸配列を含む軽鎖可変ドメイン;
(b)配列番号197と同一のアミノ酸配列を含む重鎖可変ドメイン、および配列番号198と同一のアミノ酸配列を含む軽鎖可変ドメイン;または
(c)配列番号199と同一のアミノ酸配列を含む重鎖可変ドメイン、および配列番号200と同一のアミノ酸配列を含む軽鎖可変ドメイン
を含む、項目1から21のいずれか一項に記載のタンパク質。
(項目23)
HER2に結合する前記第2の抗原結合部位が、配列番号139、配列番号189または配列番号171のアミノ酸配列を含む、項目1から22のいずれか一項に記載のタンパク質。
(項目24)
HER2に結合する前記第2の抗原結合部位が、配列番号139のアミノ酸配列を含む、項目23に記載のタンパク質。
(項目25)
前記抗体Fcドメインが、ヒトIgG1抗体のヒンジおよびCH2ドメインを含む、項目1から24のいずれか一項に記載のタンパク質。
(項目26)
前記抗体Fcドメインが、ヒトIgG1抗体のアミノ酸234~332と少なくとも90%同一のアミノ酸配列を含む、項目25に記載のタンパク質。
(項目27)
前記抗体Fcドメインが、ヒトIgG1のFcドメインと少なくとも90%同一のアミノ酸配列を含み、Q347、Y349、T350、L351、S354、E356、E357、K360、Q362、S364、T366、L368、K370、N390、K392、T394、D399、S400、D401、F405、Y407、K409、T411、K439からなる群から選択される1つまたは複数の位置で異なる、項目25または26に記載のタンパク質。
(項目28)
前記抗体Fcドメインが、Q347R、D399VおよびF405T置換を含むヒトIgG1のFcドメインである、項目1から27のいずれか一項に記載のタンパク質。
(項目29)
前記置換を含む前記抗体Fcドメインが、前記scFvに連結している、項目28に記載のタンパク質。
(項目30)
前記抗体Fcドメインが、K360EおよびK409W置換を含むヒトIgG1のFcドメインである、項目1から29のいずれか一項に記載のタンパク質。
(項目31)
前記置換を含む前記抗体Fcドメインが、前記Fab断片に連結している、項目30に記載のタンパク質。
(項目32)
前記抗体Fcドメインが、T366W置換を含むヒトIgG1のFcドメインである、項目1から27のいずれか一項に記載のタンパク質。
(項目33)
前記置換を含む前記抗体Fcドメインが、前記Fab断片に連結している、項目32に記載のタンパク質。
(項目34)
前記抗体Fcドメインが、T366S、L368AおよびY407V置換を含むヒトIgG1のFcドメインである、項目1から27および32から33のいずれか一項に記載のタンパク質。
(項目35)
前記置換を含む前記抗体Fcドメインが、前記scFvに連結している、項目34に記載のタンパク質。
(項目36)
配列番号141、配列番号145、配列番号147、配列番号194、配列番号155または配列番号148の配列を含む、項目1から35のいずれかに記載のタンパク質。
(項目37)
前記抗体Fcドメインに連結した前記scFvが、配列番号140または配列番号146のアミノ酸配列によって表される、項目1から36のいずれか一項に記載のタンパク質。
(項目38)
(a)配列番号141と少なくとも90%同一のアミノ酸配列を含む第1のポリペプチド;
(b)配列番号140、配列番号190または配列番号192と少なくとも90%同一のアミノ酸配列を含む第2のポリペプチド;および
(c)配列番号142と少なくとも90%同一のアミノ酸配列を含む第3のポリペプチド
を含むタンパク質。
(項目39)
前記第2のポリペプチドが、配列番号140と少なくとも90%同一のアミノ酸配列を含む、項目38に記載のタンパク質。
(項目40)
(a)配列番号141と少なくとも95%同一のアミノ酸配列を含む第1のポリペプチド;
(b)配列番号140、配列番号190または配列番号192と少なくとも95%同一のアミノ酸配列を含む第2のポリペプチド;および
(c)配列番号142と少なくとも95%同一のアミノ酸配列を含む第3のポリペプチド
を含むタンパク質。
(項目41)
前記第2のポリペプチドが、配列番号140と少なくとも95%同一のアミノ酸配列を含む、項目40に記載のタンパク質。
(項目42)
(a)配列番号141のアミノ酸配列を含む第1のポリペプチド;
(b)配列番号140、配列番号190または配列番号192のアミノ酸配列を含む第2のポリペプチド;および
(c)配列番号142のアミノ酸配列を含む第3のポリペプチド
を含むタンパク質。
(項目43)
前記第2のポリペプチドが、配列番号140のアミノ酸配列を含む、項目42に記載のタンパク質。
(項目44)
前記項目のいずれか一項に記載のタンパク質と、薬学的に許容される担体とを含む製剤。
(項目45)
項目1から43のいずれか一項に記載のタンパク質を発現する1つまたは複数の核酸を含む細胞。
(項目46)
腫瘍細胞死を直接的および/または間接的に増強する方法であって、腫瘍およびナチュラルキラー細胞を、項目1から43のいずれか一項に記載のタンパク質に曝露するステップを含む方法。
(項目47)
がんを処置する方法であって、項目1から43のいずれか一項に記載のタンパク質または項目44に記載の製剤を、患者に投与するステップを含む方法。
(項目48)
前記がんが、乳がん、甲状腺がん、胃がん、腎細胞癌、肺の腺癌、前立腺がん、胆管癌、子宮がん、膵臓がん、結腸直腸がん、卵巣がん、子宮頸がん、頭頸部がん、肺扁平上皮がん、中皮腫、肝臓がん、中皮腫、肉腫および胆嚢がんからなる群から選択される、項目47に記載の方法。
Claims (15)
- NKG2Dに結合するFab断片、HER2に結合する一本鎖可変領域断片(scFv)およびCD16に結合するのに十分な抗体Fcドメインもしくはその部分を含む、多重特異性結合タンパク質であって、
(a)配列番号141のアミノ酸配列を含む第1のポリペプチド;
(b)配列番号140のアミノ酸配列を含む第2のポリペプチド;および
(c)配列番号142のアミノ酸配列を含む第3のポリペプチド
を含む、多重特異性結合タンパク質。 - 請求項1に記載のタンパク質と、薬学的に許容される担体とを含む製剤。
- 請求項1に記載のタンパク質を発現する1つまたは複数の核酸を含む細胞。
- がんを処置する方法における使用のための組成物であって、請求項1に記載のタンパク質を含み、前記方法が、前記組成物を患者に投与するステップを含む、組成物。
- 前記がんが、乳がん、甲状腺がん、胃がん、腎細胞癌、肺の腺癌、前立腺がん、胆管癌、子宮がん、膵臓がん、結腸直腸がん、卵巣がん、子宮頸がん、頭頸部がん、肺扁平上皮がん、中皮腫、肝臓がん、中皮腫、肉腫および胆嚢がんからなる群から選択される、請求項4に記載の組成物。
- 前記がんが、胃がんである、請求項4に記載の組成物。
- 前記がんが、食道がんである、請求項4に記載の組成物。
- 前記がんが、乳がんである、請求項4に記載の組成物。
- 前記がんが、膀胱がんである、請求項4に記載の組成物。
- 前記がんが、肺がんである、請求項4に記載の組成物。
- 前記がんが、肺の腺癌である、請求項4に記載の組成物。
- 前記がんが、肺扁平上皮がんである、請求項4に記載の組成物。
- 前記方法が、プログラム細胞死タンパク質1(PD1)を阻害する免疫チェックポイント阻害剤を投与することをさらに含む、請求項4に記載の組成物。
- 前記方法が、PDL1を阻害する免疫チェックポイント阻害剤を投与することをさらに含む、請求項4に記載の組成物。
- 前記方法が、LAG3を阻害する免疫チェックポイント阻害剤を投与することをさらに含む、請求項4に記載の組成物。
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