JP7495489B2 - PD-1およびTGFβを標的化する組換えタンパク質 - Google Patents
PD-1およびTGFβを標的化する組換えタンパク質 Download PDFInfo
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Classifications
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- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/70596—Molecules with a "CD"-designation not provided for elsewhere
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- A61K31/713—Double-stranded nucleic acids or oligonucleotides
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- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/71—Receptors; Cell surface antigens; Cell surface determinants for growth factors; for growth regulators
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- 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
- C07K16/2818—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 CD28 or CD152
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- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
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- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
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- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
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- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/475—Growth factors; Growth regulators
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- C07K2317/524—CH2 domain
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- C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
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Description
PD-1
TGFβ
複数の分子を標的化する治療
a)ヒトTGFβR2断片と、
b)重鎖および軽鎖を含む抗体と、を含み、
ヒトTGFβR2断片が重鎖のC末端に連結されている、組換え融合タンパク質を提供する。
a)ヒトTGFβR2断片と、
b)重鎖可変領域および軽鎖可変領域を含む(Fab’)2と、を含み、
TGFβR2断片が前記重鎖可変領域のC末端に連結されている、組換え融合タンパク質を提供する。
1)配列番号10のアミノ酸配列、または、配列番号10と少なくとも80%の同一性を有し、同時に配列番号4の3CDRを有するアミノ酸配列と、配列番号5のアミノ酸配列、または、配列番号5と少なくとも80%の同一性を有し、同時に配列番号5の3CDRを有するアミノ酸配列と、を含む組換え融合タンパク質;
2)配列番号11のアミノ酸配列、または、配列番号11と少なくとも80%の同一性を有し、同時に配列番号4の3CDRを有するアミノ酸配列と、配列番号5のアミノ酸配列、または、配列番号5と少なくとも80%の同一性を有し、同時に配列番号5の3CDRを有するアミノ酸配列と、を含む組換え融合タンパク質;
3)配列番号12のアミノ酸配列、または、配列番号12と少なくとも80%の同一性を有し、同時に配列番号4の3CDRを有するアミノ酸配列と、配列番号5のアミノ酸配列、または、配列番号5と少なくとも80%の同一性を有し、同時に配列番号5の3CDRを有するアミノ酸配列と、を含む組換え融合タンパク質;または、
4)配列番号13のアミノ酸配列、または、配列番号13と少なくとも80%の同一性を有し、同時に配列番号4の3CDRを有するアミノ酸配列と、配列番号5のアミノ酸配列、または、配列番号5と少なくとも80%の同一性を有し、同時に配列番号5の3CDRを有するアミノ酸配列と、を含む組換え融合タンパク質。
ンから構成されるdAb断片(Wardet al.,(1989)Nature 341:544-546)、(vi)分離された相補性決定領域(CDR)、並びに(vii)単一の可変ドメイン及び2つの定常ドメインを含む重鎖可変領域であるナノボディを含む。さらに、Fv断片の2つのドメインであるVL及びVHは、別々の遺伝子によってコードされるが、組換え法により、それらを単一タンパク質鎖にすることができる合成リンカーを用いて結合することができる。前記単一タンパク質鎖において、VL及びVHがペアになって一価分子(一本鎖Fv(scFv)として知られている。例えば、Bird et al.(1988)Science 242:423-426;及びHuston et al.(1988)Proc.Natl.Acad.Sci.USA 85:5879-5883を参照)を形成する。このような一本鎖抗体も抗体の「抗原結合部分」との用語に含まれることが意図されている。これらの断片は、当業者に知られている従来の技術を使用して得られ、断片は、インタクト抗体と同じ方法で有用性についてスクリーニングされる。
実施例
実施例1.Trap-12、Trap-13、Trap-14およびTrap-15を発現させるベクターの構築
実施例2.タンパク質の発現と精製
実施例3.PD-1に結合した例示的な融合タンパク質
実施例4.TGFβ1に結合した例示的な融合タンパク質
実施例5.PD-1およびTGFβ1に対する例示的な融合タンパク質の結合親和性
実施例7.PD-1-PD-L1相互作用を遮断した例示的な融合タンパク質
実施例8.Trap-15はヒトTGFβ1に拮抗し、PBMC機能を再活性化した
実施例9.Trap-15は抗体依存性細胞傷害(ADCC)を誘導しなかった
細胞溶解%=100×(ODサンプル-OD標的細胞+エフェクター細胞)/(OD最大放出-OD最小放出)。
データをGraphpad Prismによって分析した。
実施例10.Trap-15は補体依存性細胞傷害(CDC)を誘導しなかった
細胞溶解%=100×(1-(RLUサンプル-RLUバックグラウンド)/(RLU細胞+正常なヒト血漿-RLUバックグラウンド))。
実施例11.MC38-OVAモデルに対するTrap-15の抗腫瘍効果
本発明の態様の一部を以下に記載する。
1.a)TGFβに結合する、ヒトTGFβR2細胞外ドメインまたはその断片と、
b)PD-1に結合し、かつ、配列番号2を含む重鎖可変領域の3CDRと配列番号3を含む軽鎖可変領域の3CDRとを含む、抗体またはその抗原結合断片と、を含む、組換え融合タンパク質であって、前記ヒトTGFβR2細胞外ドメインが、リンカーを介して、前記抗体の重鎖のC末端に連結され、重鎖-リンカー-TGFβR2融合タンパク質を形成し、前記TGFβR2細胞外ドメインが、配列番号1のアミノ酸配列を含み、配列番号2を含む前記重鎖可変領域の3CDRが、SYYIH、VINPSGGSTTYAQKFQGおよびGSYSSGWDYYYYYGMDVであり、配列番号3を含む前記軽鎖可変領域の3CDRが、RSSQSLLHSQGYNYLD、LGSNRASおよびMQALQTPWTであり、そして前記リンカーが、配列番号6、7、8または9のアミノ酸配列を含む、組換え融合タンパク質。
Claims (14)
- a)TGFβに結合する、ヒトTGFβR2細胞外ドメインと、
b)PD-1に結合する、重鎖と軽鎖とを含む抗体と、を含む、組換え融合タンパク質であって、前記重鎖が、配列番号4のアミノ酸配列、または、配列番号4と少なくとも90%の同一性を有し、同時に配列番号4の3CDRを有するアミノ酸配列を含み、前記軽鎖が、配列番号5のアミノ酸配列、または、配列番号5と少なくとも90%の同一性を有し、同時に配列番号5の3CDRを有するアミノ酸配列を含み、前記ヒトTGFβR2細胞外ドメインのN末端が、リンカーを介して、前記抗体の重鎖のC末端に連結され、重鎖-リンカー-TGFβR2融合タンパク質を形成する、組換え融合タンパク質。 - 前記TGFβR2細胞外ドメインが、配列番号1のアミノ酸配列、または配列番号1と少なくとも90%の同一性を有するアミノ酸配列を含む、請求項1に記載の組換え融合タンパク質。
- 前記リンカーが、配列番号6、7、8または9のアミノ酸配列を含む、請求項1または2に記載の組換え融合タンパク質。
- 前記重鎖-リンカー-TGFβR2融合タンパク質が、配列番号10、11、12または13のいずれか1つから選択されるアミノ酸配列、または、それぞれ配列番号10、11、12または13と少なくとも90%の同一性を有し、同時にそれぞれ対応する配列番号10、11、12または13の3CDRを有するアミノ酸配列を含む、請求項1~3のいずれか一項に記載の組換え融合タンパク質。
- 配列番号5のアミノ酸配列、または、配列番号5と少なくとも90%の同一性を有し、同時に配列番号5の3CDRを有するアミノ酸配列を含む、軽鎖を含む、請求項4に記載の組換え融合タンパク質。
- 1)配列番号10のアミノ酸配列、または、配列番号10と少なくとも90%の同一性を有し、同時に配列番号4の3CDRを有するアミノ酸配列と、配列番号5のアミノ酸配列、または、配列番号5と少なくとも90%の同一性を有し、同時に配列番号5の3CDRを有するアミノ酸配列と、を含む組換え融合タンパク質;
2)配列番号11のアミノ酸配列、または、配列番号11と少なくとも90%の同一性を有し、同時に配列番号4の3CDRを有するアミノ酸配列と、配列番号5のアミノ酸配列、または、配列番号5と少なくとも90%の同一性を有し、同時に配列番号5の3CDRを有するアミノ酸配列と、を含む組換え融合タンパク質;
3)配列番号12のアミノ酸配列、または、配列番号12と少なくとも90%の同一性を有し、同時に配列番号4の3CDRを有するアミノ酸配列と、配列番号5のアミノ酸配列、または、配列番号5と少なくとも90%の同一性を有し、同時に配列番号5の3CDRを有するアミノ酸配列と、を含む組換え融合タンパク質;または、
4)配列番号13のアミノ酸配列、または、配列番号13と少なくとも90%の同一性を有し、同時に配列番号4の3CDRを有するアミノ酸配列と、配列番号5のアミノ酸配列、または、配列番号5と少なくとも90%の同一性を有し、同時に配列番号5の3CDRを有するアミノ酸配列と、を含む組換え融合タンパク質;
から選択される、請求項1~5のいずれか一項に記載の組換え融合タンパク質。 - 請求項1~6のいずれか一項に記載の組換え融合タンパク質をコードする核酸。
- 請求項7に記載の核酸を含むベクター。
- 請求項7に記載の核酸または請求項8に記載のベクターを含む宿主細胞。
- 適切な条件下で請求項9に記載の宿主細胞を培養するステップを含む、組換え融合タンパク質の製造方法。
- 請求項10に記載の方法によって製造される組換え融合タンパク質。
- 前記組換え融合タンパク質が、
配列番号13のアミノ酸配列、または、配列番号13と少なくとも90%の同一性を有し、同時に配列番号4の3CDRを有するアミノ酸配列と、
配列番号5のアミノ酸配列、または、配列番号5と少なくとも90%の同一性を有し、同時に配列番号5の3CDRを有するアミノ酸配列と、を含む、
請求項6に記載の組換え融合タンパク質と、少なくとも1つの薬学的に許容される担体と、を含む医薬組成物。 - 前記組換え融合タンパク質が、
配列番号13のアミノ酸配列、または、配列番号13と少なくとも90%の同一性を有し、同時に配列番号4の3CDRを有するアミノ酸配列と、
配列番号5のアミノ酸配列、または、配列番号5と少なくとも90%の同一性を有し、同時に配列番号5の3CDRを有するアミノ酸配列と、を含む、
TGFβおよび/またはPD-L1を過剰発現する疾患を治療するための薬剤の製造における、請求項1~6若しくは11のいずれか一項に記載の組換え融合タンパク質または請求項12に記載の医薬組成物の使用。 - 前記疾患が、結腸直腸(大腸)、乳房、卵巣、膵臓、胃、前立腺、腎臓、頸部、骨髄腫、リンパ腫、白血病、甲状腺、子宮内膜、子宮、膀胱、神経内分泌、頭頸部、肝臓、鼻咽頭、精巣、小細胞肺癌、非小細胞肺癌、黒色腫、基底細胞皮膚癌、扁平上皮癌、隆起性皮膚線維肉腫、メルケル細胞癌、膠芽腫、神経膠腫、肉腫、中皮腫、および骨髄異形成症候群からなる群より選択される癌/腫瘍である、請求項13に記載の使用。
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