JP2020511481A5 - - Google Patents

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JP2020511481A5
JP2020511481A5 JP2019551449A JP2019551449A JP2020511481A5 JP 2020511481 A5 JP2020511481 A5 JP 2020511481A5 JP 2019551449 A JP2019551449 A JP 2019551449A JP 2019551449 A JP2019551449 A JP 2019551449A JP 2020511481 A5 JP2020511481 A5 JP 2020511481A5
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amino acid
acid sequence
variable domain
heavy chain
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JP7170331B2 (en
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対象における癌の治療のための相乗的治療の組合わせであって、前記相乗的治療の組合わせが、ヒト腫瘍細胞の表面上のヒトＣＤ４７に結合するモノクローナル抗体又はその抗原結合断片と、第２の抗癌剤とを含み、これによって腫瘍細胞の免疫原性細胞死の増大を引き起こすことを特徴とする相乗的治療の組合わせ。A combination of synergistic treatments for the treatment of cancer in a subject, wherein the synergistic treatment combination comprises a monoclonal antibody or antigen-binding fragment thereof that binds to human CD47 on the surface of human tumor cells and a second. A combination of synergistic therapies comprising, and thereby causing an increase in immunogenic cell death of tumor cells. 請求項１に記載の相乗的治療の組合わせにおいて、前記モノクローナル抗体又はその抗原結合断片が、キメラ又はヒト化抗体であることを特徴とする相乗的治療の組合わせ。 In synergistic therapeutic combination of claim 1, wherein the monoclonal antibody or antigen-binding fragment thereof, synergistic therapeutic combination which is a chimeric or humanized antibody. 請求項１又は２に記載の相乗的治療の組合わせにおいて、前記モノクローナル抗体又はその抗原結合断片が、ヒトＣＤ４７に対するＳＩＲＰαの結合を阻止する、前記癌の腫瘍細胞の食作用を増大する、及び／又は前記癌の腫瘍細胞の死を誘導することを特徴とする相乗的治療の組合わせ。In the synergistic treatment combination according to claim 1 or 2, the monoclonal antibody or antigen-binding fragment thereof blocks the binding of SIRPα to human CD47, increases the phagocytosis of the tumor cells of the cancer, and / Alternatively, a combination of synergistic treatments characterized by inducing the death of tumor cells of the cancer. 請求項１乃至３の何れか１項に記載の相乗的治療の組合わせにおいて、前記モノクローナル抗体又はその抗原結合断片が、ヒト赤血球（ｈＲＢＣ）の検出可能な凝集を引き起こさないことを特徴とする相乗的治療の組合わせ。In the combination of synergistic therapies according to any one of claims 1 to 3, the monoclonal antibody or antigen-binding fragment thereof does not cause detectable aggregation of human red blood cells (hRBC). A combination of therapeutic treatments. 請求項１乃至４の何れか１項に記載の相乗的治療の組合わせにおいて、前記モノクローナル抗体又はその抗原結合断片が、最小限のｈＲＢＣ結合を有することを特徴とする相乗的治療の組合わせ。The synergistic treatment combination according to any one of claims 1 to 4, wherein the monoclonal antibody or an antigen-binding fragment thereof has a minimum hRBC binding. 請求項１乃至５の何れか１項に記載の相乗的治療の組合わせにおいて、前記モノクローナル抗体又はその抗原結合断片が、生理学的ｐＨと比較して、酸性ｐＨのヒトＣＤ４７に対して高い親和性を有することを特徴とする相乗的治療の組合わせ。 In synergistic therapeutic combination according to any one of claims 1 to 5, wherein said monoclonal antibody or antigen-binding fragment, as compared to the physiological pH, higher than the human CD47 acidic pH A combination of synergistic treatments characterized by having an affinity. 請求項１乃至６の何れか１項に記載の相乗的治療の組合わせにおいて、前記抗体又はその抗原結合断片が、可変重鎖ＣＤＲ１（ＨＣＤＲ１）、可変重鎖ＣＤＲ２（ＨＣＤＲ２）、及び可変重鎖ＣＤＲ３（ＨＣＤＲ３）、可変軽鎖ＣＤＲ１（ＬＣＤＲ１）、可変軽鎖ＣＤＲ２（ＬＣＤＲ２）、及び可変軽鎖ＣＤＲ３（ＬＣＤＲ３）の組合せを含み、ここで、前記組合せが、以下：
（ｉ）配列番号１を含むＨＣＤＲ１、配列番号４を含むＨＣＤＲ２、配列番号７を含むＨＣＤＲ３、配列番号１１を含むＬＣＤＲ１、配列番号１５を含むＬＣＤＲ２、配列番号１８を含むＬＣＤＲ３；
（ｉｉ）配列番号１を含むＨＣＤＲ１、配列番号４を含むＨＣＤＲ２、配列番号８を含むＨＣＤＲ３、配列番号１１を含むＬＣＤＲ１、配列番号１５を含むＬＣＤＲ２、配列番号１８を含むＬＣＤＲ３；
（ｉｉｉ）配列番号２を含むＨＣＤＲ１、配列番号５を含むＨＣＤＲ２、配列番号９を含むＨＣＤＲ３、配列番号１２を含むＬＣＤＲ１、配列番号１６を含むＬＣＤＲ２、配列番号１９を含むＬＣＤＲ３；
（ｉｖ）配列番号３を含むＨＣＤＲ１、配列番号６を含むＨＣＤＲ２、配列番号１０を含むＨＣＤＲ３、配列番号１４を含むＬＣＤＲ１、配列番号１７を含むＬＣＤＲ２、配列番号１９を含むＬＣＤＲ３；
（ｖ）配列番号３を含むＨＣＤＲ１、配列番号６を含むＨＣＤＲ２、配列番号１０を含むＨＣＤＲ３、配列番号１４を含むＬＣＤＲ１、配列番号１７を含むＬＣＤＲ２、配列番号１８を含むＬＣＤＲ３
からなる群から選択されることを特徴とする相乗的治療の組合わせ。 In the combination of synergistic treatments according to any one of claims 1 to 6, the antibody or antigen-binding fragment thereof is a variable heavy chain CDR1 (HCDR1), a variable heavy chain CDR2 (HCDR2), and a variable heavy chain. Includes combinations of CDR3 (HCDR3), variable light chain CDR1 (LCDR1), variable light chain CDR2 (LCDR2), and variable light chain CDR3 (LCDR3), wherein the combination is:
(I) HCDR1 containing SEQ ID NO: 1, HCDR2 containing SEQ ID NO: 4, HCDR3 containing SEQ ID NO: 7, LCDR1 containing SEQ ID NO: 11, LCDR2 containing SEQ ID NO: 15, LCDR3 containing SEQ ID NO: 18;
(Ii) HCDR1 containing SEQ ID NO: 1, HCDR2 containing SEQ ID NO: 4, HCDR3 containing SEQ ID NO: 8, LCDR1 containing SEQ ID NO: 11, LCDR2 containing SEQ ID NO: 15, LCDR3 containing SEQ ID NO: 18;
(Iii) HCDR1 including SEQ ID NO: 2, HCDR2 including SEQ ID NO: 5, HCDR3 including SEQ ID NO: 9, LCDR1 including SEQ ID NO: 12, LCDR2 including SEQ ID NO: 16, LCDR3 including SEQ ID NO: 19;
(Iv) SEQ ID NO: 3 including HCDR1, HCDR2 comprising SEQ ID NO: 6, HCDR3 comprising SEQ ID NO: 10, LCDR1 comprising SEQ ID NO: 14, LCDR2 comprising SEQ ID NO: 17, LCDR3 comprising SEQ ID NO: 19;
(V) HCDR1 containing SEQ ID NO: 3, HCDR2 containing SEQ ID NO: 6, HCDR3 containing SEQ ID NO: 10, LCDR1 containing SEQ ID NO: 14, LCDR2 containing SEQ ID NO: 17, LCDR3 containing SEQ ID NO: 18.
Synergistic therapeutic combination which is characterized and selected Turkey from the group consisting of. 請求項７に記載の相乗的治療の組合わせにおいて、ＨＣＤＲ１が配列番号３を含み、ＨＣＤＲ２が配列番号６を含み、ＨＣＤＲ３が配列番号１０を含み、ＬＣＤＲ１が配列番号１４を含み、ＬＣＤＲ２が配列番号１７を含み、ＬＣＤＲ３が配列番号１８を含むことを特徴とする相乗的治療の組合わせ。In the combination of synergistic treatments of claim 7, HCDR1 comprises SEQ ID NO: 3, HCDR2 comprises SEQ ID NO: 6, HCDR3 comprises SEQ ID NO: 10, LCDR1 comprises SEQ ID NO: 14, and LCDR2 comprises SEQ ID NO: A combination of synergistic treatments comprising 17, wherein LCDR3 comprises SEQ ID NO: 18. 請求項１乃至７の何れか１項に記載の相乗的治療の組合わせにおいて、前記モノクローナル抗体又はその抗原結合断片が、以下：
（ｉ）配列番号２１のアミノ酸配列を含む重鎖可変ドメインと、アミノ酸配列配列番号４１を含む軽鎖可変ドメイン；
（ｉｉ）配列番号２３のアミノ酸配列を含む重鎖可変ドメインと、アミノ酸配列配列番号４３を含む軽鎖可変ドメイン；
（ｉｉｉ）配列番号３４のアミノ酸配列を含む重鎖可変ドメインと、アミノ酸配列配列番号４９を含む軽鎖可変ドメイン；
（ｉｖ）配列番号３６のアミノ酸配列を含む重鎖可変ドメインと、アミノ酸配列配列番号５２を含む軽鎖可変ドメイン；
（ｖ）配列番号３８のアミノ酸配列を含む重鎖可変ドメインと、アミノ酸配列配列番号５２を含む軽鎖可変ドメイン；
（ｖｉ）配列番号３９のアミノ酸配列を含む重鎖可変ドメインと、アミノ酸配列配列番号５２を含む軽鎖可変ドメイン；
（ｖｉｉ）配列番号２４のアミノ酸配列を含む重鎖可変ドメインと、アミノ酸配列配列番号４３を含む軽鎖可変ドメイン；
（ｖｉｉｉ）配列番号３７のアミノ酸配列を含む重鎖可変ドメインと、アミノ酸配列配列番号５２を含む軽鎖可変ドメイン；
（ｉｘ）配列番号３３のアミノ酸配列を含む重鎖可変ドメインと、アミノ酸配列配列番号４８を含む軽鎖可変ドメイン；
（ｘ）配列番号２６のアミノ酸配列を含む重鎖可変ドメインと、アミノ酸配列配列番号４４を含む軽鎖可変ドメイン；
（ｘｉ）配列番号２７のアミノ酸配列を含む重鎖可変ドメインと、アミノ酸配列配列番号４４を含む軽鎖可変ドメイン；
（ｘｉｉ）配列番号３８のアミノ酸配列を含む重鎖可変ドメインと、アミノ酸配列配列番号５１を含む軽鎖可変ドメイン；
（ｘｉｉｉ）配列番号３９のアミノ酸配列を含む重鎖可変ドメインと、アミノ酸配列配列番号５１を含む軽鎖可変ドメイン；
（ｘｉｖ）配列番号４０のアミノ酸配列を含む重鎖可変ドメインと、アミノ酸配列配列番号５２を含む軽鎖可変ドメイン；
（ｘｖ）配列番号３６のアミノ酸配列を含む重鎖可変ドメインと、アミノ酸配列配列番号５１を含む軽鎖可変ドメイン；
（ｘｖｉ）配列番号２９のアミノ酸配列を含む重鎖可変ドメインと、アミノ酸配列配列番号４７を含む軽鎖可変ドメイン；
（ｘｖｉｉ）配列番号３０のアミノ酸配列を含む重鎖可変ドメインと、アミノ酸配列配列番号４７を含む軽鎖可変ドメイン；
（ｘｖｉｉｉ）配列番号３１のアミノ酸配列を含む重鎖可変ドメインと、アミノ酸配列配列番号４７を含む軽鎖可変ドメイン；
（ｘｉｘ）配列番号３２のアミノ酸配列を含む重鎖可変ドメインと、アミノ酸配列配列番号４７を含む軽鎖可変ドメイン；
（ｘｘ）配列番号３３のアミノ酸配列を含む重鎖可変ドメインと、アミノ酸配列配列番号４７を含む軽鎖可変ドメイン；
（ｘｘｉ）配列番号２９のアミノ酸配列を含む重鎖可変ドメインと、アミノ酸配列配列番号４８を含む軽鎖可変ドメイン；
（ｘｘｉｉ）配列番号３０のアミノ酸配列を含む重鎖可変ドメインと、アミノ酸配列配列番号４８を含む軽鎖可変ドメイン；
（ｘｘｉｉｉ）配列番号３１のアミノ酸配列を含む重鎖可変ドメインと、アミノ酸配列配列番号４８を含む軽鎖可変ドメイン；
（ｘｘｉｖ）配列番号３２のアミノ酸配列を含む重鎖可変ドメインと、アミノ酸配列配列番号４８を含む軽鎖可変ドメイン；
（ｘｘｖ）配列番号２６のアミノ酸配列を含む重鎖可変ドメインと、アミノ酸配列配列番号４３を含む軽鎖可変ドメイン；
（ｘｘｖｉ）配列番号２７のアミノ酸配列を含む重鎖可変ドメインと、アミノ酸配列配列番号４３を含む軽鎖可変ドメイン；
（ｘｘｖｉｉ）配列番号２８のアミノ酸配列を含む重鎖可変ドメインと、アミノ酸配列配列番号４６を含む軽鎖可変ドメイン；
（ｘｘｖｉｉｉ）配列番号３５のアミノ酸配列を含む重鎖可変ドメインと、アミノ酸配列配列番号５０を含む軽鎖可変ドメイン；
（ｘｘｉｘ）配列番号２９のアミノ酸配列を含む重鎖可変ドメインと、アミノ酸配列配列番号４８を含む軽鎖可変ドメイン；
（ｘｘｘ）配列番号３０のアミノ酸配列を含む重鎖可変ドメインと、アミノ酸配列配列番号４８を含む軽鎖可変ドメイン；
（ｘｘｘｉ）配列番号３１のアミノ酸配列を含む重鎖可変ドメインと、アミノ酸配列配列番号４８を含む軽鎖可変ドメイン；
（ｘｘｘｉｉ）配列番号３２のアミノ酸配列を含む重鎖可変ドメインと、アミノ酸配列配列番号４８を含む軽鎖可変ドメイン；
（ｘｘｘｉｉｉ）配列番号３７のアミノ酸配列を含む重鎖可変ドメインと、アミノ酸配列配列番号５１を含む軽鎖可変ドメイン；及び
（ｘｘｘｉｖ）配列番号４０のアミノ酸配列を含む重鎖可変ドメインと、アミノ酸配列配列番号５１を含む軽鎖可変ドメイン
からなる群から選択される重鎖可変ドメイン（ＶＨ）と軽鎖可変ドメイン（ＶＬ）の組合せを含むことを特徴とする相乗的治療の組合わせ。 In the combination of synergistic treatments according to any one of claims 1 to 7, the monoclonal antibody or the antigen-binding fragment thereof is described below.
(I) A heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 21 and a light chain variable domain containing the amino acid SEQ ID NO: 41;
(Ii) A heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 23 and a light chain variable domain containing the amino acid SEQ ID NO: 43;
(Iii) A heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 34 and a light chain variable domain containing the amino acid SEQ ID NO: 49;
(Iv) A heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 36 and a light chain variable domain comprising the amino acid SEQ ID NO: 52;
(V) A heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 38 and a light chain variable domain containing the amino acid SEQ ID NO: 52;
(Vi) A heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 39 and a light chain variable domain containing the amino acid SEQ ID NO: 52;
(Vii) A heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 24 and a light chain variable domain containing the amino acid SEQ ID NO: 43;
(Viii) A heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 37 and a light chain variable domain containing the amino acid sequence No. 52;
(Ix) A heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 33 and a light chain variable domain containing the amino acid SEQ ID NO: 48;
(X) A heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 26 and a light chain variable domain containing the amino acid SEQ ID NO: 44;
(Xi) A heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 27 and a light chain variable domain containing the amino acid SEQ ID NO: 44;
(Xii) A heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 38 and a light chain variable domain containing the amino acid SEQ ID NO: 51;
(Xiii) A heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 39 and a light chain variable domain containing the amino acid sequence No. 51;
(Xiv) A heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 40 and a light chain variable domain comprising the amino acid SEQ ID NO: 52;
(Xv) A heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 36 and a light chain variable domain containing the amino acid SEQ ID NO: 51;
(Xvi) A heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 29 and a light chain variable domain containing the amino acid SEQ ID NO: 47;
(Xvii) A heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 30 and a light chain variable domain containing the amino acid sequence No. 47;
(Xviii) A heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 31 and a light chain variable domain containing the amino acid sequence No. 47;
(Xix) A heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 32 and a light chain variable domain containing the amino acid SEQ ID NO: 47;
(Xx) A heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 33 and a light chain variable domain containing the amino acid SEQ ID NO: 47;
(Xxi) A heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 29 and a light chain variable domain containing the amino acid SEQ ID NO: 48;
(Xxii) A heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 30 and a light chain variable domain containing the amino acid SEQ ID NO: 48;
(Xxiii) A heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 31 and a light chain variable domain containing the amino acid sequence No. 48;
(Xxiv) A heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 32 and a light chain variable domain containing the amino acid SEQ ID NO: 48;
(Xxv) A heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 26 and a light chain variable domain containing the amino acid SEQ ID NO: 43;
(Xxvi) A heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 27 and a light chain variable domain containing the amino acid sequence No. 43;
(Xxvii) A heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 28 and a light chain variable domain containing the amino acid sequence No. 46;
(Xxxviii) A heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 35 and a light chain variable domain containing the amino acid sequence No. 50;
(Xxix) A heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 29 and a light chain variable domain containing the amino acid SEQ ID NO: 48;
(Xxxx) A heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 30 and a light chain variable domain containing the amino acid SEQ ID NO: 48;
(Xxxxi) A heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 31 and a light chain variable domain containing the amino acid SEQ ID NO: 48;
(Xxxxi) A heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 32 and a light chain variable domain containing the amino acid sequence No. 48;
(Xxxxiii) Heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 37, light chain variable domain containing amino acid SEQ ID NO: 51; and (xxxx) Heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 40, and amino acid sequence sequence. synergistic therapeutic combination, characterized in combinations including that the heavy chain variable domain selected from the group consisting of a light chain variable domain (VH) and light chain variable domain (VL) including the number 51. 請求項１乃至８の何れか１項に記載の相乗的治療の組合わせにおいて、前記モノクローナル抗体又はその抗原結合断片が、配列番号３６のアミノ酸配列を含む重鎖可変ドメイン、及び、配列番号５２のアミノ酸配列を含む軽鎖可変ドメインを含むことを特徴とする相乗的治療の組合わせ。In the combination of synergistic therapies according to any one of claims 1 to 8, the monoclonal antibody or antigen-binding fragment thereof is a heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 36, and SEQ ID NO: 52. A combination of synergistic therapies characterized by containing a light chain variable domain comprising an amino acid sequence. 請求項１乃至７、及び９の何れか１項に記載のモノクローナル抗体又はその抗原結合断片において、
（ｉ）配列番号７８のアミノ酸配列を含む重鎖と、アミノ酸配列配列番号６７を含む軽鎖；
（ｉｉ）配列番号７９のアミノ酸配列を含む重鎖と、アミノ酸配列配列番号６９を含む軽鎖；
（ｉｉｉ）配列番号８０のアミノ酸配列を含む重鎖と、アミノ酸配列配列番号７０を含む軽鎖；
（ｉｖ）配列番号８１のアミノ酸配列を含む重鎖と、アミノ酸配列配列番号７１を含む軽鎖；
（ｖ）配列番号８２のアミノ酸配列を含む重鎖と、アミノ酸配列配列番号７１を含む軽鎖；
（ｖｉ）配列番号８３のアミノ酸配列を含む重鎖と、アミノ酸配列配列番号７１を含む軽鎖；
（ｖｉｉ）配列番号８４のアミノ酸配列を含む重鎖と、アミノ酸配列配列番号６９を含む軽鎖；
（ｖｉｉｉ）配列番号８５のアミノ酸配列を含む重鎖と、アミノ酸配列配列番号７１を含む軽鎖；
（ｉｘ）配列番号８６のアミノ酸配列を含む重鎖と、アミノ酸配列配列番号７２を含む軽鎖；
（ｘ）配列番号８７のアミノ酸配列を含む重鎖と、アミノ酸配列配列番号７３を含む軽鎖；
（ｘｉ）配列番号８８のアミノ酸配列を含む重鎖と、アミノ酸配列配列番号７３を含む軽鎖；
（ｘｉｉ）配列番号８２のアミノ酸配列を含む重鎖と、アミノ酸配列配列番号７４を含む軽鎖；
（ｘｉｉｉ）配列番号８３のアミノ酸配列を含む重鎖と、アミノ酸配列配列番号７４を含む軽鎖；
（ｘｉｖ）配列番号８９のアミノ酸配列を含む重鎖と、アミノ酸配列配列番号７１を含む軽鎖；
（ｘｖ）配列番号８１のアミノ酸配列を含む重鎖と、アミノ酸配列配列番号７４を含む軽鎖；
（ｘｖｉ）配列番号９０のアミノ酸配列を含む重鎖と、アミノ酸配列配列番号７５を含む軽鎖；
（ｘｖｉｉ）配列番号９１のアミノ酸配列を含む重鎖と、アミノ酸配列配列番号７５を含む軽鎖；
（ｘｖｉｉｉ）配列番号９２のアミノ酸配列を含む重鎖と、アミノ酸配列配列番号７５を含む軽鎖；
（ｘｉｘ）配列番号９３のアミノ酸配列を含む重鎖と、アミノ酸配列配列番号７５を含む軽鎖；
（ｘｘ）配列番号８６のアミノ酸配列を含む重鎖と、アミノ酸配列配列番号７５を含む軽鎖；
（ｘｘｉ）配列番号９４のアミノ酸配列を含む重鎖と、アミノ酸配列配列番号７２を含む軽鎖；
（ｘｘｉｉ）配列番号９１のアミノ酸配列を含む重鎖と、アミノ酸配列配列番号７２を含む軽鎖；
（ｘｘｉｉｉ）配列番号９２のアミノ酸配列を含む重鎖と、アミノ酸配列配列番号７２を含む軽鎖；
（ｘｘｉｖ）配列番号９３のアミノ酸配列を含む重鎖と、アミノ酸配列配列番号７２を含む軽鎖；
（ｘｘｖ）配列番号８７のアミノ酸配列を含む重鎖と、アミノ酸配列配列番号６９を含む軽鎖；
（ｘｘｖｉ）配列番号８８のアミノ酸配列を含む重鎖と、アミノ酸配列配列番号６９を含む軽鎖；
（ｘｘｖｉｉ）配列番号９５のアミノ酸配列を含む重鎖と、アミノ酸配列配列番号７６を含む軽鎖；
（ｘｘｖｉｉｉ）配列番号９６のアミノ酸配列を含む重鎖と、アミノ酸配列配列番号７７を含む軽鎖；
（ｘｘｉｘ）配列番号９７のアミノ酸配列を含む重鎖と、アミノ酸配列配列番号７２を含む軽鎖；
（ｘｘｘ）配列番号９８のアミノ酸配列を含む重鎖と、アミノ酸配列配列番号７２を含む軽鎖；
（ｘｘｘｉ）配列番号９９のアミノ酸配列を含む重鎖と、アミノ酸配列配列番号７２を含む軽鎖；
（ｘｘｘｉｉ）配列番号１００のアミノ酸配列を含む重鎖と、アミノ酸配列配列番号７２を含む軽鎖；
（ｘｘｘｉｉｉ）配列番号８５のアミノ酸配列を含む重鎖と、アミノ酸配列配列番号７４を含む軽鎖；
（ｘｘｘｉｖ）配列番号８９のアミノ酸配列を含む重鎖と、アミノ酸配列配列番号７４を含む軽鎖
からなる群から選択される少なくとも１つの重鎖及び少なくとも１つの軽鎖を含むことを特徴とする、モノクローナル抗体又はその抗原結合断片。 The monoclonal antibody according to any one of claims 1 to 7 and 9 or an antigen-binding fragment thereof.
(I) A heavy chain containing the amino acid sequence of SEQ ID NO: 78 and a light chain containing the amino acid SEQ ID NO: 67;
(Ii) A heavy chain containing the amino acid sequence of SEQ ID NO: 79 and a light chain containing the amino acid SEQ ID NO: 69;
(Iii) A heavy chain containing the amino acid sequence of SEQ ID NO: 80 and a light chain containing the amino acid SEQ ID NO: 70;
(Iv) A heavy chain containing the amino acid sequence of SEQ ID NO: 81 and a light chain containing the amino acid SEQ ID NO: 71;
(V) A heavy chain containing the amino acid sequence of SEQ ID NO: 82 and a light chain containing the amino acid SEQ ID NO: 71;
(Vi) A heavy chain containing the amino acid sequence of SEQ ID NO: 83 and a light chain containing the amino acid SEQ ID NO: 71;
(Vii) A heavy chain containing the amino acid sequence of SEQ ID NO: 84 and a light chain containing the amino acid SEQ ID NO: 69;
(Viii) A heavy chain containing the amino acid sequence of SEQ ID NO: 85 and a light chain containing the amino acid SEQ ID NO: 71;
(Ix) A heavy chain containing the amino acid sequence of SEQ ID NO: 86 and a light chain containing the amino acid SEQ ID NO: 72;
(X) A heavy chain containing the amino acid sequence of SEQ ID NO: 87 and a light chain containing the amino acid SEQ ID NO: 73;
(Xi) A heavy chain containing the amino acid sequence of SEQ ID NO: 88 and a light chain containing the amino acid SEQ ID NO: 73;
(Xii) A heavy chain containing the amino acid sequence of SEQ ID NO: 82 and a light chain containing the amino acid SEQ ID NO: 74;
(Xiii) A heavy chain containing the amino acid sequence of SEQ ID NO: 83 and a light chain containing the amino acid SEQ ID NO: 74;
(Xiv) A heavy chain containing the amino acid sequence of SEQ ID NO: 89 and a light chain containing the amino acid SEQ ID NO: 71;
(Xv) A heavy chain containing the amino acid sequence of SEQ ID NO: 81 and a light chain containing the amino acid SEQ ID NO: 74;
(Xvi) A heavy chain containing the amino acid sequence of SEQ ID NO: 90 and a light chain containing the amino acid SEQ ID NO: 75;
(Xvii) A heavy chain containing the amino acid sequence of SEQ ID NO: 91 and a light chain containing the amino acid SEQ ID NO: 75;
(Xviii) A heavy chain containing the amino acid sequence of SEQ ID NO: 92 and a light chain containing the amino acid sequence No. 75;
(Xix) A heavy chain containing the amino acid sequence of SEQ ID NO: 93 and a light chain containing the amino acid SEQ ID NO: 75;
(Xx) A heavy chain containing the amino acid sequence of SEQ ID NO: 86 and a light chain containing the amino acid SEQ ID NO: 75;
(Xxi) A heavy chain containing the amino acid sequence of SEQ ID NO: 94 and a light chain containing the amino acid SEQ ID NO: 72;
(Xxii) A heavy chain containing the amino acid sequence of SEQ ID NO: 91 and a light chain containing the amino acid sequence No. 72;
(Xxiii) A heavy chain containing the amino acid sequence of SEQ ID NO: 92 and a light chain containing the amino acid sequence No. 72;
(Xxiv) A heavy chain containing the amino acid sequence of SEQ ID NO: 93 and a light chain containing the amino acid SEQ ID NO: 72;
(Xxv) A heavy chain containing the amino acid sequence of SEQ ID NO: 87 and a light chain containing the amino acid SEQ ID NO: 69;
(Xxvi) A heavy chain containing the amino acid sequence of SEQ ID NO: 88 and a light chain containing the amino acid SEQ ID NO: 69;
(Xxvii) A heavy chain containing the amino acid sequence of SEQ ID NO: 95 and a light chain containing the amino acid sequence No. 76;
(Xxxviii) A heavy chain containing the amino acid sequence of SEQ ID NO: 96 and a light chain containing the amino acid sequence No. 77;
(Xxix) A heavy chain containing the amino acid sequence of SEQ ID NO: 97 and a light chain containing the amino acid sequence No. 72;
(Xxxx) A heavy chain containing the amino acid sequence of SEQ ID NO: 98 and a light chain containing the amino acid SEQ ID NO: 72;
(Xxxxi) A heavy chain containing the amino acid sequence of SEQ ID NO: 99 and a light chain containing the amino acid sequence No. 72;
(Xxxxi) A heavy chain containing the amino acid sequence of SEQ ID NO: 100 and a light chain containing the amino acid sequence No. 72;
(Xxxxiii) A heavy chain containing the amino acid sequence of SEQ ID NO: 85 and a light chain containing the amino acid sequence No. 74;
To a heavy chain comprising the amino acid sequence of (xxxiv) SEQ ID NO: 89, and at least one heavy chain and wherein including that at least one light chain are selected from the group consisting of a light chain comprising the amino acid sequence SEQ ID NO: 74 , Monoclonal antibody or antigen-binding fragment thereof. 請求項１乃至１１の何れか１項に記載の相乗的治療の組合わせにおいて、前記重鎖が配列番号７９のアミノ酸配列を含み、前記軽鎖が配列番号７０のアミノ酸配列を含むことを特徴とする相乗的治療の組合わせ。In the combination of synergistic treatments according to any one of claims 1 to 11, the heavy chain comprises the amino acid sequence of SEQ ID NO: 79 and the light chain comprises the amino acid sequence of SEQ ID NO: 70. A combination of synergistic treatments. 請求項１乃至１２の何れか１項に記載の相乗的治療の組合わせにおいて、前記第２の抗癌剤が、アントラサイクリン、白金、タキソール、トポイソメラーゼ阻害剤、代謝拮抗剤、抗腫瘍抗生物質、有糸分裂阻害剤、及びアルキル化剤からなる群から選択される化学療法薬であることを特徴とする相乗的治療の組合わせ。 In the combination of synergistic treatments according to any one of claims 1 to 12, the second anticancer agent is anthracycline, platinum, taxol, topoisomerase inhibitor, antimetabolite, antitumor antibiotic, threaded. A combination of synergistic treatments characterized by being a chemotherapeutic agent selected from the group consisting of mitotic inhibitors and alkylating agents . 請求項１３に記載の相乗的治療の組合わせにおいて、前記化学療法薬が、ドキソルビシン、エピルビシン、ダウノルビシン、イダルビシン、オキサリプラチン、シスプラチン、カルボプラチン、パクリタキセル、ドセタキセル、イリノテカン、トポテカン、エトポシド、ミトキサントロン、５−ＦＵ、カペシタビン、シタラビン、ゲムシタビン、ペルメトレキセド、ビノレルビン、ビンブラスチン、ビンクリスチン、及びテムゾロミドから選択されることを特徴とする相乗的治療の組合わせ。 In the synergistic treatment combination according to claim 13 , the chemotherapeutic agent is doxorubicin, epirubicin, daunorubicin, idarubicin , oxaliplatin, cisplatin, carboplatin , paclitaxel, docetaxel , irinotecan, topotecan, etoposide, mitoxantrone , 5 -A combination of synergistic treatments characterized by being selected from FU, capecitabin, citarabin, gemcitabine, permetrexed, binorerbin , vinblastin, vincristine , and temzolomid. 請求項１乃至１２の何れか１項に記載の相乗的治療の組合わせにおいて、前記第２の抗癌剤が、ボルテゾミブ又はカルフィルゾミブであることを特徴とする相乗的治療の組合わせ。 In synergistic therapeutic combination according to any one of claims 1 to 12, wherein the second anticancer agent, a synergistic therapeutic combination which is a bortezomib or carfilzomib. 請求項１乃至１５の何れか１項に記載の相乗的治療の組合わせにおいて、前記癌が、白血病、リンパ腫、卵巣癌、乳癌、子宮内膜癌、結腸癌（結腸直腸癌）、直腸癌、膀胱癌、尿路上皮癌、肺癌（非小細胞肺癌、肺の腺癌、肺の扁平上皮癌）、気管支癌、骨癌、前立腺癌、膵臓癌、胃癌、肝細胞癌、膀胱癌、胆管癌、食道癌、腎細胞癌、甲状腺癌、頭部及び頚部の扁平上皮癌（頭部及び頚部癌）、精巣癌、内分泌腺癌、副腎腺癌、脳下垂体癌、皮膚癌、軟組織の癌、血管の癌、脳腫瘍、神経癌、眼の癌、髄膜癌、中咽頭癌、下咽頭癌、子宮頸癌、及び子宮癌、膠芽腫、髄芽腫、星細胞腫、神経膠腫、髄膜腫、ガストリノーマ、神経芽細胞腫、黒色腫、骨髄異形成症候群、並びに肉腫からなる群から選択され、前記白血病が、全身性肥満細胞症、急性リンパ性（リンパ芽球性）白血病（ＡＬＬ）、Ｔ細胞ＡＬＬ、急性骨髄性白血病（ＡＭＬ）、骨髄性白血病、慢性リンパ性白血病（ＣＬＬ）、多発性骨髄腫（ＭＭ）、慢性骨髄性白血病（ＣＭＬ）、骨髄増殖性疾患／腫瘍、骨髄異形成症候群、単球性白血病、及びプラズマ細胞白血病病からなる群から選択され；前記リンパ腫が、ホジキンリンパ腫、並びに例えば、低悪性度／濾胞性非ホジキンリンパ腫（ＮＨＬ）、細胞リンパ腫（ＦＣＣ）、マントル細胞リンパ腫（ＭＣＬ）、びまん性大細胞リンパ腫（ＤＬＣＬ）、小リンパ球性（ＳＬ）ＮＨＬ、中悪性度／濾胞性ＮＨＬ、中悪性度びまん性ＮＨＬ、高悪性度免疫芽球性ＮＨＬ、高悪性度リンパ球性ＮＨＬ、高悪性度小型非切れ込み核細胞性ＮＨＬ、巨大病変（ｂｕｌｋｙ ｄｉｓｅａｓｅ）ＮＨＬ、及びワルデンシュトレーム型マクログロブリン血症（Ｗａｌｄｅｎｓｔｒｏｍ’ｓ Ｍａｃｒｏｇｌｏｂｕｌｉｎｅｍｉａ）などの非ホジキンリンパ腫を含む、組織球性リンパ腫及びＴ細胞リンパ腫、Ｂ細胞リンパ腫からなる群から選択され；前記肉腫が、骨肉腫、ユーイング肉腫、平滑筋肉腫、滑膜肉腫、胞巣状軟部肉腫、血管肉腫、脂肪肉腫、繊維肉腫、横紋筋肉腫、及び軟骨肉腫からなる群から選択されることを特徴とする相乗的治療の組合わせ。
In the combination of synergistic treatments according to any one of claims 1 to 15, the cancer is leukemia, lymphoma, ovarian cancer, breast cancer, endometrial cancer, colon cancer ( colon-rectal cancer), rectal cancer, and the like. Bladgkin cancer, urinary tract epithelial cancer, lung cancer (non-small cell lung cancer, lung adenocarcinoma, squamous epithelial cancer of the lung), bronchial cancer, bone cancer, prostate cancer, pancreatic cancer, gastric cancer, hepatocellular cancer, bladder cancer, bile duct cancer , Esophageal cancer, renal cell cancer, thyroid cancer, flat epithelial cancer of the head and neck (head and neck cancer), testicular cancer, endocrine adenocarcinoma, adrenal adenocarcinoma, pituitary gland cancer, skin cancer, soft tissue cancer, Vascular cancer, brain tumor, nerve cancer, eye cancer, mening membrane cancer, mesopharyngeal cancer, hypopharyngeal cancer, cervical cancer, and uterine cancer, glioblastoma, myelblastoma, astrocyte tumor, glioma, spinal cord Selected from the group consisting of membrane tumor, gastrinoma, neuroblastoma, melanoma, myelodysplastic syndrome, and sarcoma , the leukemia is systemic obeskinosis, acute lymphocytic leukemia (ALL). , T cell ALL, acute myeloid leukemia (AML), myeloid leukemia, chronic lymphocytic leukemia (CLL), multiple myeloma (MM), chronic myeloid leukemia (CML), myelloid proliferative disease / tumor, myelodyskinosis Selected from the group consisting of formation syndrome, monocytic leukemia, and plasma cell leukemia; the lymphomas are Hodgkin's lymphoma and, for example, low-grade / non-Hodgkin's non-Hodgkin's lymphoma (NHL), cell lymphoma (FCC), mantle. Cellular lymphoma (MCL), diffuse large cell lymphoma (DLCL), small lymphocytic (SL) NHL, medium-grade / follicular NHL, medium-grade diffuse NHL, high-grade immunoblastic NHL, high-grade Tissues containing non-Hodgkin's lymphoma such as degree lymphocytic NHL, high-grade small non-notgkinous nuclear cell NHL, bulky disease NHL, and Waldenstrom's Macroglobulinemia Selected from the group consisting of globular lymphoma, T-cell lymphoma, and B-cell lymphoma; the sarcoma is osteosarcoma, Ewing sarcoma, smooth muscle muscular tumor, synovial sarcoma, fodgkin soft sarcoma, angiosarcoma, liposkinoma, fibrosarcoma , A combination of synergistic treatments characterized by being selected from the group consisting of rhombic myoma, and chondroskinoma .
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