JPWO2019005640A5 - - Google Patents

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JPWO2019005640A5
JPWO2019005640A5 JP2020520430A JP2020520430A JPWO2019005640A5 JP WO2019005640 A5 JPWO2019005640 A5 JP WO2019005640A5 JP 2020520430 A JP2020520430 A JP 2020520430A JP 2020520430 A JP2020520430 A JP 2020520430A JP WO2019005640 A5 JPWO2019005640 A5 JP WO2019005640A5
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scfv domain
specific antibody
acid sequence
percentage homology
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JP2020530306A (en
JP7474193B2 (en
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Priority claimed from PCT/US2018/039157 external-priority patent/WO2019005640A2/en
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Claims (26)

N末端及びC末端を有する四重特異性抗体モノマーであって、
N末端からC末端まで直列に、
N末端に第一のscFvドメイン、
第二のscFvドメイン、
Fabドメイン、
Fcドメイン、及び
C末端に第三のscFv、
を含み、
前記第一のscFvドメイン、第二のscFvドメイン、Fabドメイン、及び第三のscFvドメインは、異なる抗原に対して結合特異性をそれぞれ有し、且つ
前記抗原は、腫瘍抗原、免疫シグナル伝達抗原、又はそれらの組み合わせである、
四重特異性抗体モノマー。 A quadrispecific antibody monomer having an N-terminal and a C-terminal.
In series from the N-terminus to the C-terminus,
First scFv domain at the N-terminus,
Second scFv domain,
Fab domain,
Fc domain, and
Third scFv at the C-terminus,
Including
The first scFv domain, the second scFv domain, the Fab domain, and the third scFv domain have binding specificity for different antigens, respectively, and the antigens are tumor antigen, immune signaling antigen, and the like. Or a combination of them,
Quadruple specific antibody monomer. 前記第一のscFvドメイン、第二のscFvドメイン、Fabドメイン、及び第三のscFvドメインがそれぞれ独立して、ROR1、PD-L1、CD3、CD28、41BB、CEA、HER2、EGFRvIII、EGFR、LMP1、LMP2A、メソセリン、PSMA、EpCAM、glypimay-3、gpA33、GD2、TROP2、NKG2D、BCMA、CD19、CD20、CD33、CD123、CD22、CD30、PD1、OX40、4-1BB、GITR、TIGIT、TIM-3、LAG-3、CTLA4、CD40、VISTA、ICOS、BTLA、LIGHT、HVEM、CSF1R、CD73、及びCD39から選択される抗原に対する結合特異性を有し、且つ前記FcドメインがヒトIgG Fcドメインを含む、請求項1に記載の四重特異性抗体モノマー。 The first scFv domain, the second scFv domain, the Fab domain, and the third scFv domain are independent of each other, ROR1, PD-L1, CD3, CD28, 41BB, CEA, HER2, EGFRvIII, EGFR, LMP1, LMP2A, Mesocerin, PSMA, EpCAM, glypimay-3, gpA33, GD2, TROP2, NKG2D, BCMA, CD19, CD20, CD33, CD123, CD22, CD30, PD1, OX40, 4-1BB, GITR, TIGIT, TIM-3, Claimed to have binding specificity for an antigen selected from LAG-3, CTLA4, CD40, VISTA, ICOS, BTLA, LIGHT, HVEM, CSF1R, CD73, and CD39, and said Fc domain comprising human IgG Fc domain. Item 1. The quadruspecific antibody monomer according to Item 1. 前記第一のscFvドメイン、第二のscFvドメイン、Fabドメイン、及び第三のscFvドメインがそれぞれ独立して、CD19、CD3、CD137、4-1BB、及びPD-L1.から選択される抗原に対する結合特異性を有する、請求項1に記載の四重特異性抗体モノマー。 The first scFv domain, the second scFv domain, the Fab domain, and the third scFv domain independently bind to an antigen selected from CD19, CD3, CD137, 4-1BB, and PD-L1. The tetraspecific antibody monomer according to claim 1, which has specificity. 前記第一のscFvドメインがCD19に対する結合特異性を有する、請求項1に記載の四重特異性抗体モノマー。 The quartet-specific antibody monomer according to claim 1, wherein the first scFv domain has binding specificity for CD19. 前記第二のscFvドメインがCD3に対する結合特異性を有する、請求項1記載の四重特異性抗体モノマー。 The quadruplex specific antibody monomer according to claim 1, wherein the second scFv domain has binding specificity for CD3. 前記Fabドメインが4-1BB又はCD137に対する結合特異性を有する、請求項1記載の四重特異性抗体モノマー。 The quadruspecific antibody monomer according to claim 1, wherein the Fab domain has binding specificity for 4-1BB or CD137. 前記第三のscFvドメインがPD-L1に対する結合特異性を有する、請求項1に記載の四重特異性抗体モノマー。 The quadruplex specific antibody monomer according to claim 1, wherein the third scFv domain has binding specificity for PD-L1. 前記第一のscFvドメインがCD19に対する結合特異性を有し、前記第二のscFvドメインがCD3に対する結合特異性を有し、前記Fabドメインが4-1BB又はCD137に対する結合特異性を有し、且つ前記第三のscFvドメインがPD-L1に対する結合特異性を有する、請求項1に記載の四重特異性抗体モノマー。 The first scFv domain has binding specificity for CD19, the second scFv domain has binding specificity for CD3, the Fab domain has binding specificity for 4-1BB or CD137, and The tetraspecific antibody monomer according to claim 1, wherein the third scFv domain has binding specificity for PD-L1. 前記第一のscFvドメイン、第二のscFvドメイン、又は第三のscFvドメインがgly-gly-gly-gly-ser (G4S)nリンカーを含み、前記nは2、3、又は4である、請求項1に記載の四重特異性抗体モノマー。 Claim that the first scFv domain, the second scFv domain, or the third scFv domain comprises a gly-gly-gly-gly-ser (G4S) n linker, wherein n is 2, 3, or 4. Item 1. The quadruspecific antibody monomer according to Item 1. 配列番号37～40とパーセンテージ相同性を有するアミノ酸配列を含み、前記パーセンテージ相同性が98％以上である、請求項1に記載の四重特異性抗体モノマー。 The quartet-specific antibody monomer according to claim 1, which comprises an amino acid sequence having a percentage homology with SEQ ID NOs: 37 to 40 and having the percentage homology of 98% or more. 配列番号2、4、6、8、10、12、26、28、30、32とパーセンテージ相同性を有するアミノ酸配列を含み、前記パーセンテージ相同性が98％以上である、scFvドメイン。 A scFv domain comprising an amino acid sequence having a percentage homology with SEQ ID NOs: 2, 4, 6, 8, 10, 12, 26, 28, 30, 32, wherein the percentage homology is 98% or greater. 配列番号1～12、26～32とパーセンテージ相同性を有するアミノ酸配列を含み、前記パーセンテージ相同性が90％以上である、請求項1に記載の四重特異性抗体モノマーのFabドメイン。 The Fab domain of the quaternary specific antibody monomer according to claim 1, which comprises an amino acid sequence having a percentage homology with SEQ ID NOs: 1 to 12 and 26 to 32, and the percentage homology is 90% or more. 請求項1に記載の四重特異性抗体モノマーを含む四重特異性抗体。 A quadruplex specific antibody comprising the quadruspecific antibody monomer according to claim 1. 配列番号38及び40とパーセンテージ相同性を有するアミノ酸配列を含み、前記パーセンテージ相同性は98％以上である、請求項13に記載の四重特異性抗体。 The quadruplex specific antibody according to claim 13, which comprises an amino acid sequence having a percentage homology with SEQ ID NOs: 38 and 40, wherein the percentage homology is 98% or more. 配列番号37及び39とパーセンテージ相同性を有するアミノ酸配列をコードし、前記パーセンテージ相同性が98％以上である、単離された核酸配列。 An isolated nucleic acid sequence encoding an amino acid sequence having a percentage homology with SEQ ID NOs: 37 and 39, wherein the percentage homology is 98% or more. 請求項15に記載の単離された核酸配列を含む発現ベクター。 An expression vector comprising the isolated nucleic acid sequence according to claim 15. 前記宿主細胞が原核細胞又は真核細胞である、請求項15記載の単離された核酸配列を含む宿主細胞。 The host cell comprising the isolated nucleic acid sequence according to claim 15, wherein the host cell is a prokaryotic cell or an eukaryotic cell. 四重特異性抗体又はモノマーの生産方法であって、
四重特異性抗体又は単量体をコードするDNA配列が発現されるように、単離された核酸配列を含む宿主細胞を培養する工程、及び
前記四重特異性抗体を精製する工程を含み、
前記単離された核酸配列は、配列番号37～40とパーセンテージ相同性を有するアミノ酸をコードし、
前記パーセンテージ相同性は98％以上である、
生産方法。 A method for producing a quadruplex specific antibody or monomer.
It comprises a step of culturing a host cell containing an isolated nucleic acid sequence and a step of purifying the quadruplex specific antibody so that a DNA sequence encoding a quadruple specific antibody or monomer is expressed.
The isolated nucleic acid sequence encodes an amino acid having a percentage homology with SEQ ID NOs: 37-40.
The percentage homology is 98% or more,
Production method. 請求項13に記載の精製された四重特異性抗体を含む、がんの治療又は予防用の医薬組成物。 A pharmaceutical composition for treating or preventing cancer , which comprises the purified quadruspecific antibody according to claim 13. リンカーを介して請求項13に記載の四重特異性抗体に連結された細胞毒性剤又は造影剤を含み、
前記リンカーが、エステル結合、エーテル結合、アミド結合、ジスルフィド結合、イミド結合、スルホン結合、リン酸結合、リンエステル結合、ペプチド結合、疎水性ポリ（エチレングリコール）リンカー、又はそれらの組み合わせを含む、
免疫複合体。 It comprises a cytotoxic agent or a contrast agent linked to the quadruplex specific antibody according to claim 13 via a linker.
The linker comprises an ester bond, an ether bond, an amide bond, a disulfide bond, an imide bond, a sulfone bond, a phosphate bond, a phosphate bond, a peptide bond, a hydrophobic poly (ethylene glycol) linker, or a combination thereof.
Immune complex. 前記細胞毒性剤が、カリケアマイシン、有糸分裂阻害剤、毒素、放射性同位体、毒素、治療薬、又はそれらの組み合わせの一群から選ばれる、化学療法剤、増殖阻害剤、又は細胞毒性剤を含む、請求項20に記載の免疫複合体。 The cytotoxic agent is a chemotherapeutic agent, a growth inhibitor, or a cytotoxic agent selected from a group of calikeamycin, a thread division inhibitor, a toxin, a radioactive isotope, a toxin, a therapeutic agent, or a combination thereof. 20. The immunoconjugate according to claim 20. 薬学的に許容される担体と、請求項13に記載の四重特異性抗体、請求項20に記載の免疫複合体の1つ又はその両方とを含む、医薬組成物。 A pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or both of the tetraspecific antibodies of claim 13 and one or both of the immune complexes of claim 20. 放射性同位体、放射性核種、毒素、抗体、酵素、化学療法剤又はそれらの組み合わせから選択される治療薬をさらに含む、請求項22に記載の医薬組成物。 22. The pharmaceutical composition of claim 22, further comprising a therapeutic agent selected from radioisotopes, radionuclides, toxins, antibodies, enzymes, chemotherapeutic agents or combinations thereof. がんを有するヒト対象の治療用の医薬組成物であって、請求項13に記載の有効量の四重特異性抗体を含む、医薬組成物。 A pharmaceutical composition for the treatment of a human subject having cancer, comprising the effective amount of the quadruspecific antibody according to claim 13. 前記治療が、有効量の治療薬を共投与する工程を含み、前記治療薬が、抗体、化学療法剤、酵素、抗エストロゲン剤、受容体チロシンキナーゼ阻害剤、キナーゼ阻害剤、細胞周期阻害剤、チェックポイント阻害剤、DNA、RNA又は、蛋白質合成阻害剤、RAS阻害剤、PD1阻害剤、PD-L1、CTLA4、4-1BB、OX40、GITR、ICOS、LIGHT、TIM3、LAG3、TIGIT、CD40、CD27、HVEM、BTLA、VISTA、B7H4、CSF1R、NKG2D、CD73、CD3、CD19、又はそれらの組み合わせを含む、請求項24に記載の医薬組成物。 The treatment comprises the step of co-administering an effective amount of the therapeutic agent, wherein the therapeutic agent is an antibody, a chemotherapeutic agent, an enzyme, an anti-estrogen agent, a receptor tyrosine kinase inhibitor, a kinase inhibitor, a cell cycle inhibitor, Checkpoint inhibitor, DNA, RNA or protein synthesis inhibitor, RAS inhibitor, PD1 inhibitor, PD-L1, CTLA4, 4-1BB, OX40, GITR, ICOS, LIGHT, TIM3, LAG3, TIGIT, CD40, CD27 , HVEM, BTLA, VISTA, B7H4, CSF1R, NKG2D, CD73, CD3, CD19, or a combination thereof , according to claim 24. 有効濃度の請求項13に記載の四重特異性抗体を含む溶液であって、前記溶液が、ヒト対象の血漿である、溶液。 A solution comprising the quadruspecific antibody according to claim 13 having an effective concentration, wherein the solution is plasma for a human subject.
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