JPWO2019173911A5 - - Google Patents
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- JPWO2019173911A5 JPWO2019173911A5 JP2020548783A JP2020548783A JPWO2019173911A5 JP WO2019173911 A5 JPWO2019173911 A5 JP WO2019173911A5 JP 2020548783 A JP2020548783 A JP 2020548783A JP 2020548783 A JP2020548783 A JP 2020548783A JP WO2019173911 A5 JPWO2019173911 A5 JP WO2019173911A5
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- 239000000611 antibody drug conjugate Substances 0.000 claims description 94
- 229940049595 antibody-drug conjugate Drugs 0.000 claims description 94
- 229920001184 polypeptide Polymers 0.000 claims description 64
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 64
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 64
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 claims description 56
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 claims description 56
- 239000000427 antigen Substances 0.000 claims description 40
- 102000036639 antigens Human genes 0.000 claims description 40
- 108091007433 antigens Proteins 0.000 claims description 40
- 150000001413 amino acids Chemical class 0.000 claims description 32
- 206010028980 Neoplasm Diseases 0.000 claims description 23
- 201000011510 cancer Diseases 0.000 claims description 23
- 108010044540 auristatin Proteins 0.000 claims description 20
- 239000000562 conjugate Substances 0.000 claims description 20
- 238000012986 modification Methods 0.000 claims description 12
- 230000004048 modification Effects 0.000 claims description 12
- 206010006187 Breast cancer Diseases 0.000 claims description 8
- 208000026310 Breast neoplasm Diseases 0.000 claims description 8
- 206010033128 Ovarian cancer Diseases 0.000 claims description 8
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 8
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 4
- 108091005804 Peptidases Proteins 0.000 claims description 4
- 239000004365 Protease Substances 0.000 claims description 4
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 claims description 4
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 4
- 206010017758 gastric cancer Diseases 0.000 claims description 4
- 201000005202 lung cancer Diseases 0.000 claims description 4
- 208000020816 lung neoplasm Diseases 0.000 claims description 4
- 201000011549 stomach cancer Diseases 0.000 claims description 4
- 101100330727 Arabidopsis thaliana DAR6 gene Proteins 0.000 claims description 3
- 239000000833 heterodimer Substances 0.000 claims description 3
- 238000003776 cleavage reaction Methods 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 229940079593 drug Drugs 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000000524 functional group Chemical group 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 229960002087 pertuzumab Drugs 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 230000007017 scission Effects 0.000 claims description 2
- 229960000575 trastuzumab Drugs 0.000 claims description 2
- 238000000034 method Methods 0.000 description 7
- 239000000203 mixture Substances 0.000 description 5
- 238000003364 immunohistochemistry Methods 0.000 description 3
- 229940125644 antibody drug Drugs 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
Description
別の態様は、リンカー（Ｌ）を介してオーリスタチン類似体にコンジュゲートした抗ＨＥＲ２バイパラトピック抗体を含む抗体－薬物コンジュゲート組成物に関し、オーリスタチン類似体－リンカーは、一般式（ＩＩ）：
Ｘは存在せず；
Ｒ１は、
Ｌが、リンカーであり、
抗ＨＥＲ２バイパラトピック抗体は、ＨＥＲ２のＥＣＤ４の第１のＨＥＲ２エピトープに結合する第１の抗原結合ポリペプチド構築物及びＨＥＲ２のＥＣＤ２の第２のＨＥＲ２エピトープに結合する第２の抗原結合ポリペプチド構築物を含み、
抗体－薬物コンジュゲート組成物は、０．５～２．５の平均ＤＡＲを有し、かつＤＡＲ０の種を約１０％～約３０％およびＤＡＲ６以上の種を０％～約１５％有する。
[本発明1001]
低い平均薬物抗体比（ＤＡＲ）でリンカー（Ｌ）を介してオーリスタチン類似体にコンジュゲートした抗ＨＥＲ2バイパラトピック抗体を含む抗体－薬物コンジュゲートであって、
前記抗ＨＥＲ2バイパラトピック抗体は、第1のＨＥＲ2エピトープに結合する第1の抗原結合ポリペプチド構築物及び第2のＨＥＲ2エピトープに結合する第2の抗原結合ポリペプチド構築物を含み、前記第1及び第2のＨＥＲ2エピトープは異なるエピトープであり、
前記低い平均ＤＡＲは、3．9未満の平均ＤＡＲである、
前記抗体－薬物コンジュゲート。
[本発明1002]
前記オーリスタチン類似体リンカーが、一般式（ＩＩ）
式中、
Ｘは－Ｃ（Ｏ）ＮＨＣＨ（ＣＨ
2
Ｒ
2
）－であるか、またはＸは存在せず；
Ｒ
1
は、
Ｌが、リンカーであり、
本発明1001の抗体－薬物コンジュゲート。
[本発明1003]
Ｒ
1
が、
[本発明1004]
Ｘが存在しない、本発明1002の抗体－薬物コンジュゲート。
[本発明1005]
Ｒ
1
が、
[本発明1006]
Ｘが－Ｃ（Ｏ）ＮＨＣＨ（ＣＨ
2
Ｒ
2
）－である、本発明1002の抗体－薬物コンジュゲート。
[本発明1007]
Ｒ
1
が、
[本発明1008]
前記平均ＤＡＲが0．5～3．5である、本発明1001～1007のいずれかの抗体－薬物コンジュゲート。
[本発明1009]
前記平均ＤＡＲが0．5～2．5である、本発明1001～1007のいずれかの抗体－薬物コンジュゲート。
[本発明1010]
前記コンジュゲートが、ＤＡＲ0の種を5％以上含む、本発明1001～1009のいずれかの抗体－薬物コンジュゲート。
[本発明1011]
前記コンジュゲートが、ＤＡＲ0の種を15％以上含む、本発明1001～1009のいずれかの抗体－薬物コンジュゲート。
[本発明1012]
前記コンジュゲートが、ＤＡＲ0の種を約5％～約50％含む、本発明1001～1009のいずれかの抗体－薬物コンジュゲート。
[本発明1013]
前記コンジュゲートが、ＤＡＲ0の種を約10％～約30％含む、本発明1001～1009のいずれかの抗体－薬物コンジュゲート。
[本発明1014]
前記コンジュゲートが、ＤＡＲ0の種を約10％～約25％含む、本発明1001～1009のいずれかの抗体－薬物コンジュゲート。
[本発明1015]
前記コンジュゲートが、ＤＡＲ0の種を約15％～約25％含む、本発明1001～1009のいずれかの抗体－薬物コンジュゲート。
[本発明1016]
前記コンジュゲートが、ＤＡＲ6以上の種を25％以下含む、本発明1001～1015のいずれかの抗体－薬物コンジュゲート。
[本発明1017]
前記コンジュゲートが、ＤＡＲ6以上の種を15％以下含む、本発明1001～1015のいずれかの抗体－薬物コンジュゲート。
[本発明1018]
前記コンジュゲートが、ＤＡＲ6以上の種を0％～約15％含む、本発明1001～1015のいずれかの抗体－薬物コンジュゲート。
[本発明1019]
前記コンジュゲートが、ＤＡＲ6以上の種を約0％～約10％含む、本発明1001～1015のいずれかの抗体－薬物コンジュゲート。
[本発明1020]
Ｌが切断可能リンカーである、本発明1001～1019のいずれかの抗体－薬物コンジュゲート。
[本発明1021]
Ｌが、プロテアーゼ切断可能リンカーである、本発明1020の抗体－薬物コンジュゲート。
[本発明1022]
Ｌが、一般式（ＶＩ）
式中、
Ｚは、前記抗ＨＥＲ2バイパラトピック抗体上の標的基と反応できる官能基であり、
Ｓｔｒは、ストレッチャーであり；
ＡＡ
1
及びＡＡ
2
は、それぞれ独立してアミノ酸であり、ＡＡ
1
－［ＡＡ
2
］
ｍ
は、プロテアーゼ切断部位を形成し；
Ｘは、自壊性基であり；
Ｄは、前記オーリスタチン類似体への付着点であり；
ｓは、0または1であり；
ｍは、1～4の整数であり、
ｏは、0、1、または2である、
本発明1001～1021のいずれかの抗体－薬物コンジュゲート。
[本発明1023]
Ｌが、一般式（ＶＩＩＩ）：
式中、
Ａ－Ｓ－は、前記抗ＨＥＲ2バイパラトピック抗体への付着点であり；
Ｙは、1つ以上の追加のリンカー構成要素であるか、または存在せず、
Ｄは、前記オーリスタチン類似体への前記付着点である、
本発明1001～1021のいずれかの抗体－薬物コンジュゲート。
[本発明1024]
Ｌが、一般式（ＩＸ）
式中、
Ａ－Ｓ－は、前記抗ＨＥＲ2バイパラトピック抗体への前記付着点であり；
Ｙは、1つ以上の追加のリンカー構成要素であるか、または存在せず、
Ｄは、前記オーリスタチン類似体への前記付着点である、
本発明1001～1021のいずれかの抗体－薬物コンジュゲート。
[本発明1025]
前記オーリスタチン類似体リンカーが構造：
Ａ－Ｓ－は、前記抗ＨＥＲ2バイパラトピック抗体への前記付着点である、
本発明1001の抗体－薬物コンジュゲート。
[本発明1026]
前記平均ＤＡＲが0．5～2．5である、本発明1025の抗体－薬物コンジュゲート。
[本発明1027]
前記コンジュゲートが、ＤＡＲ0の種を5％以上含む、本発明1025または1026の抗体－薬物コンジュゲート。
[本発明1028]
前記コンジュゲートが、ＤＡＲ0の種を約5％～約50％含む、本発明1025または1026の抗体－薬物コンジュゲート。
[本発明1029]
前記コンジュゲートが、ＤＡＲ6以上の種を25％以下含む、本発明1025または1026の抗体－薬物コンジュゲート。
[本発明1030]
前記コンジュゲートが、ＤＡＲ6以上の種を0％～約15％含む、本発明1025または1026の抗体－薬物コンジュゲート。
[本発明1031]
前記抗ＨＥＲ2バイパラトピック抗体が、対応する二価の単一特異性抗体と比較してより高い親和性でＨＥＲ2に結合する、本発明1001～1030のいずれかの抗体－薬物コンジュゲート。
[本発明1032]
前記抗ＨＥＲ2バイパラトピック抗体が、対応する二価の単一特異性抗体と比較して、ＨＥＲ2発現細胞へのより高い内在化を示す、本発明1001～1031のいずれかの抗体－薬物コンジュゲート。
[本発明1033]
前記第1及び第2の抗原結合ポリペプチド構築物が独立して、ｓｃＦｖ、Ｆａｂ、Ｆａｂ’またはｓｄＡｂである、本発明1001～1032のいずれかの抗体－薬物コンジュゲート。
[本発明1034]
前記第1及び第2の抗原結合ポリペプチド構築物が独立して、ｓｃＦｖまたはＦａｂである、本発明1033の抗体－薬物コンジュゲート。
[本発明1035]
前記第1の抗原結合ポリペプチド構築物がｓｃＦｖであり、前記第2の抗原結合ポリペプチド構築物がＦａｂである、本発明1034の抗体－薬物コンジュゲート。
[本発明1036]
前記第1及び第2のＨＥＲ2エピトープが重複しないエピトープである、本発明1001～1035のいずれかの抗体－薬物コンジュゲート。
[本発明1037]
前記第1及び第2のＨＥＲ2エピトープがＨＥＲ2の異なるドメイン上にある、本発明1001～1036のいずれかの抗体－薬物コンジュゲート。
[本発明1038]
前記第1のＨＥＲ2エピトープがＨＥＲ2のＥＣＤ4にあり、前記第2のＨＥＲ2エピトープがＨＥＲ2のＥＣＤ2にある、本発明1037の抗体－薬物コンジュゲート。
[本発明1039]
前記第1の抗原結合ポリペプチド構築物が、ＨＥＲ2への結合についてトラスツズマブと競合する、本発明1001～1038のいずれかの抗体－薬物コンジュゲート。
[本発明1040]
前記第2の抗原結合ポリペプチド構築物が、ＨＥＲ2への結合についてペルツズマブと競合する、本発明1001～1039のいずれかの抗体－薬物コンジュゲート。
[本発明1041]
前記第1の抗原結合ポリペプチド構築物が、ｖ5019、ｖ5020、ｖ7091、ｖ10000、ｖ6902、ｖ6903またはｖ6717のいずれか1つのＥＣＤ4結合アームからのＣＤＲ配列を含む、本発明1001～1038のいずれかの抗体－薬物コンジュゲート。
[本発明1042]
前記第2の抗原結合ポリペプチド構築物が、ｖ5019、ｖ5020、ｖ7091、ｖ10000、ｖ6902、ｖ6903、ｖ6717、ｖ7133、ｖ15079、ｖ15080、ｖ15081、ｖ15082、ｖ15083、ｖ15084、またはｖ15085のいずれか1つのＥＣＤ2結合アームからのＣＤＲ配列を含む、本発明1001～1038および1041のいずれかの抗体－薬物コンジュゲート。
[本発明1043]
前記第2の抗原結合ポリペプチド構築物が、ｖ10000の前記ＥＣＤ2結合アームからの前記ＣＤＲ配列を含む、本発明1001～1038および1041のいずれかの抗体－薬物コンジュゲート。
[本発明1044]
前記第1の抗原結合ポリペプチド構築物が、ｖ10000の前記ＥＣＤ4結合アームからの前記ＣＤＲ配列を含み、前記第2の抗原結合ポリペプチド構築物が、ｖ10000の前記ＥＣＤ2結合アームからの前記ＣＤＲ配列を含む、本発明1001～1038のいずれかの抗体－薬物コンジュゲート。
[本発明1045]
前記第1の抗原結合ポリペプチド構築物が、ｖ10000の前記ＥＣＤ4結合アームからのＣＤＲのセットに対して90％以上の配列同一性を有する6つのＣＤＲのセットを含み、前記抗原結合ポリペプチド構築物が、ＥＣＤ4に結合する能力を保持している、本発明1001～1038のいずれかの抗体－薬物コンジュゲート。
[本発明1046]
前記第2の抗原結合ポリペプチド構築物が、ｖ10000の前記ＥＣＤ2結合アームからのＣＤＲのセットに対して90％以上の配列同一性を有する6つのＣＤＲのセットを含み、前記抗原結合ポリペプチド構築物が、ＥＣＤ2に結合する能力を保持している、本発明1001～1038および1045のいずれかの抗体－薬物コンジュゲート。
[本発明1047]
前記第1の抗原結合ポリペプチド構築物が、ＳＥＱ ＩＤ ＮＯ：27、28、29、39、40及び41に示されるＣＤＲ配列を含み、かつ第2の抗原結合ポリペプチド構築物が、ＳＥＱ ＩＤ ＮＯ：67、68、69、70、71及び72に示されるＣＤＲ配列を含む、本発明1001～1038のいずれかの抗体－薬物コンジュゲート。
[本発明1048]
前記抗ＨＥＲ2バイパラトピック抗体が足場をさらに含み、前記第1及び第2の抗原結合ポリペプチド構築物が、前記足場に作動可能に連結されている、本発明1001～1047のいずれかの抗体－薬物コンジュゲート。
[本発明1049]
前記足場が、ＩｇＧ Ｆｃ領域である、本発明1048の抗体－薬物コンジュゲート。
[本発明1050]
前記ＩｇＧ Ｆｃ領域が、修飾されたＣＨ3ドメインを含むヘテロ二量体Ｆｃ領域である、本発明1049の抗体－薬物コンジュゲート。
[本発明1051]
前記ＩｇＧ Ｆｃ領域は、
Ｆ405位及びＹ407位のアミノ酸修飾を含みかつ任意でＬ351位のアミノ酸修飾をさらに含む第1のポリペプチド配列と、
Ｔ366位及びＴ394位のアミノ酸修飾を含みかつ任意でＫ392位のアミノ酸修飾をさらに含む第2のポリペプチド配列と
を有する修飾ＣＨ3ドメインを含むヘテロ二量体Ｆｃ領域であり、
Ｆ405位の前記アミノ酸修飾は、Ｆ405Ａ、Ｆ405Ｓ、Ｆ405ＴまたはＦ405Ｖであり、Ｙ407位の前記アミノ酸修飾は、Ｙ407ＩまたはＹ407Ｖであり、Ｔ366位の前記アミノ酸修飾は、Ｔ366Ｉ、Ｔ366ＬまたはＴ366Ｍであり、Ｔ394位の前記アミノ酸修飾は、Ｔ394Ｗであり、Ｌ351位の前記アミノ酸修飾はＬ351Ｙであり、Ｋ392位の前記アミノ酸修飾はＫ392Ｆ、Ｋ392ＬまたはＫ392Ｍである、
本発明1049の抗体－薬物コンジュゲート。
[本発明1052]
（ａ）前記修飾ＣＨ3ドメインの前記第1のポリペプチド配列は、前記アミノ酸修飾Ｌ351Ｙ、Ｆ405Ａ及びＹ407Ｖを含み、前記修飾ＣＨ3ドメインの前記第2のポリペプチド配列は、前記アミノ酸修飾Ｔ366Ｌ、Ｋ392Ｍ及びＴ394Ｗを含む；または
（ｂ）前記修飾ＣＨ3ドメインの前記第1のポリペプチド配列は、前記アミノ酸修飾Ｌ351Ｙ、Ｆ405Ａ及びＹ407Ｖを含み、前記修飾ＣＨ3ドメインの前記第2のポリペプチド配列は、前記アミノ酸修飾Ｔ366Ｌ、Ｋ392Ｌ及びＴ394Ｗを含む；または
（ｃ）前記修飾ＣＨ3ドメインの前記第1のポリペプチド配列は、前記アミノ酸修飾Ｔ350Ｖ、Ｌ351Ｙ、Ｆ405Ａ及びＹ407Ｖを含み、前記修飾ＣＨ3ドメインの前記第2のポリペプチド配列は、前記アミノ酸修飾Ｔ350Ｖ、Ｔ366Ｌ、Ｋ392Ｍ及びＴ394Ｗを含む；
または
（ｄ）前記修飾ＣＨ3ドメインの前記第1のポリペプチド配列は、前記アミノ酸修飾Ｔ350Ｖ、Ｌ351Ｙ、Ｆ405Ａ及びＹ407Ｖを含み、前記修飾ＣＨ3ドメインの前記第2のポリペプチド配列は、前記アミノ酸修飾Ｔ350Ｖ、Ｔ366Ｌ、Ｋ392Ｌ及びＴ394Ｗを含む；
または
（ｅ）前記修飾ＣＨ3ドメインの前記第1のポリペプチド配列は、前記アミノ酸修飾Ｔ350Ｖ、Ｌ351Ｙ、Ｓ400Ｅ、Ｆ405Ａ及びＹ407Ｖを含み、前記修飾ＣＨ3ドメインの前記第2のポリペプチド配列は、前記アミノ酸修飾Ｔ350Ｖ、Ｔ366Ｌ、Ｎ390Ｒ、Ｋ392Ｍ及びＴ394Ｗを含む、
本発明1051の抗体－薬物コンジュゲート。
[本発明1053]
本発明1001～1052のいずれかの抗体－薬物コンジュゲート及び薬学的に許容される担体または希釈剤を含む、医薬組成物。
[本発明1054]
ＨＥＲ2発現癌細胞を有効量の本発明1001～1052のいずれかの抗体－薬物コンジュゲートと接触させることを含む、ＨＥＲ2発現癌細胞の成長を阻害する方法。
[本発明1055]
ＨＥＲ2発現癌を有する対象に、有効量の本発明1001～1052のいずれかの抗体－薬物コンジュゲートを投与することを含む、ＨＥＲ2発現癌を治療する方法。
[本発明1056]
前記ＨＥＲ2発現癌が、乳癌、卵巣癌、肺癌または胃癌である、本発明1055の方法。
[本発明1057]
前記ＨＥＲ2発現癌が乳癌である、本発明1055の方法。
[本発明1058]
前記ＨＥＲ2発現癌が卵巣癌である、本発明1055の方法。
[本発明1059]
前記ＨＥＲ2発現癌が免疫組織化学によりＨＥＲ2陰性としてスコア付けされる、本発明1055～1058のいずれかの方法。
[本発明1060]
治療に使用するための、本発明1001～1052のいずれかの抗体－薬物コンジュゲート。
[本発明1061]
ＨＥＲ2発現癌の治療を必要とする対象においてＨＥＲ2発現癌を治療するために使用するための、本発明1001～1052のいずれかの抗体－薬物コンジュゲート。
[本発明1062]
前記ＨＥＲ2発現癌が、乳癌、卵巣癌、肺癌または胃癌である、本発明1061の使用のための抗体－薬物コンジュゲート。
[本発明1063]
前記ＨＥＲ2発現癌が、乳癌である、本発明1061の使用のための抗体－薬物コンジュゲート。
[本発明1064]
前記ＨＥＲ2発現癌が、卵巣癌である、本発明1061の使用のための抗体－薬物コンジュゲート。
[本発明1065]
前記ＨＥＲ2発現癌が免疫組織化学によりＨＥＲ2陰性としてスコア付けされる、本発明1061～1064のいずれかの使用のための抗体－薬物コンジュゲート。
[本発明1066]
ＨＥＲ2発現癌の前記治療のための医薬の製造における、本発明1001～1052のいずれかの抗体－薬物コンジュゲートの使用。
[本発明1067]
前記ＨＥＲ2発現癌が、乳癌、卵巣癌、肺癌または胃癌である、本発明1066の使用。
[本発明1068]
前記ＨＥＲ2発現癌が乳癌である、本発明1066の使用。
[本発明1069]
前記ＨＥＲ2発現癌が卵巣癌である、本発明1066の使用。
[本発明1070]
前記ＨＥＲ2発現癌が免疫組織化学によりＨＥＲ2陰性としてスコア付けされる、本発明1066～1069のいずれかの方法。
[本発明1071]
リンカー（Ｌ）を介してオーリスタチン類似体にコンジュゲートした抗ＨＥＲ2バイパラトピック抗体を含む抗体－薬物コンジュゲート組成物であって、
前記オーリスタチン類似体－リンカーは、一般式（ＩＩ）：
式中、
Ｘは存在せず；
Ｒ
1
は、
Ｌが、リンカーであり、
前記抗ＨＥＲ2バイパラトピック抗体は、ＨＥＲ2のＥＣＤ4の第1のＨＥＲ2エピトープに結合する第1の抗原結合ポリペプチド構築物及びＨＥＲ2のＥＣＤ2の第2のＨＥＲ2エピトープに結合する第2の抗原結合ポリペプチド構築物を含み、
前記抗体－薬物コンジュゲート組成物は、0．5～2．5の平均ＤＡＲを有し、かつＤＡＲ0の種を約10％～約30％およびＤＡＲ6以上の種を0％～約15％有する、
前記抗体－薬物コンジュゲート組成物。
Another aspect relates to an antibody-drug conjugate composition comprising an anti-HER2 biparatopic antibody conjugated to an auristatin analog via a linker (L), wherein the auristatin analog-linker is the general formula (II). :
X does not exist;
R 1 is
L is the linker,
The anti-HER2 biparatopic antibody comprises a first antigen-binding polypeptide construct that binds to the first HER2 epitope of ECD4 in HER2 and a second antigen-binding polypeptide construct that binds to the second HER2 epitope of ECD2 in HER2. Including,
The antibody-drug conjugate composition has an average DA of 0.5-2.5 and has about 10% to about 30% of DA R0 seeds and 0% to about 15% of DA R6 and above seeds.
[Invention 1001]
An antibody-drug conjugate comprising an anti-HER2 biparatopic antibody conjugated to an auristatin analog via a linker (L) with a low average drug-antibody ratio (DAR).
The anti-HER2 biparatopic antibody comprises a first antigen-binding polypeptide construct that binds to a first HER2 epitope and a second antigen-binding polypeptide construct that binds to a second HER2 epitope, said first and first. The HER2 epitope of 2 is a different epitope,
The low average DA is an average DA less than 3.9,
The antibody-drug conjugate.
[Invention 1002]
The auristatin analog linker has the general formula (II).
During the ceremony
X is -C (O) NHCH (CH 2 R 2 )-or X is absent;
R 1 is
L is the linker,
The antibody-drug conjugate of the present invention 1001.
[Invention 1003]
R 1 is
[Invention 1004]
The antibody-drug conjugate of the invention 1002 in the absence of X.
[Invention 1005]
R 1 is
[Invention 1006]
The antibody-drug conjugate of the invention 1002, wherein X is —C (O) NHCH (CH 2 R 2 ) —.
[Invention 1007]
R 1 is
[Invention 1008]
The antibody-drug conjugate of any of 1001-1007 of the present invention, wherein the average DA is 0.5-3.5.
[Invention 1009]
The antibody-drug conjugate of any of 1001-1007 of the present invention, wherein the average DA is 0.5-2.5.
[Invention 1010]
The antibody-drug conjugate according to any one of the present inventions 1001 to 1009, wherein the conjugate contains 5% or more of the seeds of DAR0.
[Invention 1011]
The antibody-drug conjugate according to any one of the present inventions 1001 to 1009, wherein the conjugate contains 15% or more of the seeds of DAR0.
[Invention 1012]
The antibody-drug conjugate of any of 1001-1009 of the present invention, wherein the conjugate comprises from about 5% to about 50% of the seeds of DAR0.
[Invention 1013]
The antibody-drug conjugate of any of 1001-1009 of the present invention, wherein the conjugate comprises from about 10% to about 30% of the seeds of DAR0.
[Invention 1014]
The antibody-drug conjugate of any of 1001-1009 of the present invention, wherein the conjugate comprises from about 10% to about 25% of the seeds of DAR0.
[Invention 1015]
The antibody-drug conjugate of any of 1001-1009 of the present invention, wherein the conjugate comprises from about 15% to about 25% of the seeds of DAR0.
[Invention 1016]
The antibody-drug conjugate according to any one of the present inventions 1001 to 1015, wherein the conjugate contains 25% or less of a species of DA R6 or higher.
[Invention 1017]
The antibody-drug conjugate according to any one of the present inventions 1001 to 1015, wherein the conjugate contains 15% or less of a species of DA R6 or higher.
[Invention 1018]
The antibody-drug conjugate of any of 1001-1015 of the present invention, wherein the conjugate comprises 0% to about 15% of a species of DAR6 or higher.
[Invention 1019]
The antibody-drug conjugate of any of 1001-1015 of the present invention, wherein the conjugate comprises from about 0% to about 10% of a species of DAR6 or higher.
[Invention 1020]
The antibody-drug conjugate of any of 1001-1019 of the present invention, wherein L is a cleavable linker.
[Invention 1021]
The antibody-drug conjugate of the invention 1020, wherein L is a protease cleavable linker.
[Invention 1022]
L is the general formula (VI)
During the ceremony
Z is a functional group capable of reacting with a target group on the anti-HER2 biparatopic antibody.
Str is a stretcher;
AA 1 and AA 2 are independent amino acids, respectively, and AA 1- [AA 2 ] m forms a protease cleavage site;
X is a self-destructive group;
D is the point of attachment to the auristatin analog;
s is 0 or 1;
m is an integer from 1 to 4,
o is 0, 1, or 2,
The antibody-drug conjugate according to any one of the present inventions 1001 to 1021.
[Invention 1023]
L is the general formula (VIII):
During the ceremony
AS-is the point of attachment to the anti-HER2 biparatopic antibody;
Y is one or more additional linker components or does not exist,
D is the attachment point to the auristatin analog,
The antibody-drug conjugate according to any one of the present inventions 1001 to 1021.
[Invention 1024]
L is the general formula (IX)
During the ceremony
AS-is the point of attachment to the anti-HER2 biparatopic antibody;
Y is one or more additional linker components or does not exist,
D is the attachment point to the auristatin analog,
The antibody-drug conjugate according to any one of the present inventions 1001 to 1021.
[Invention 1025]
The structure of the auristatin analog linker:
AS-is the point of attachment to the anti-HER2 biparatopic antibody.
The antibody-drug conjugate of the present invention 1001.
[Invention 1026]
The antibody-drug conjugate of the invention 1025, wherein the average DA is 0.5-2.5.
[Invention 1027]
The antibody-drug conjugate of the invention 1025 or 1026, wherein said conjugate contains 5% or more of the seeds of DAR0.
[Invention 1028]
The antibody-drug conjugate of the invention 1025 or 1026, wherein the conjugate comprises from about 5% to about 50% of the seeds of DAR0.
[Invention 1029]
The antibody-drug conjugate of the invention 1025 or 1026, wherein the conjugate comprises 25% or less of a species of DA R6 or higher.
[Invention 1030]
The antibody-drug conjugate of the invention 1025 or 1026, wherein the conjugate comprises 0% to about 15% of a species of DA R6 or higher.
[Invention 1031]
The antibody-drug conjugate of any of the inventions 1001-1030, wherein the anti-HER2 biparatopic antibody binds HER2 with higher affinity as compared to the corresponding divalent monospecific antibody.
[Invention 1032]
The antibody-drug conjugate of any of the inventions 1001-1031, wherein the anti-HER2 biparatopic antibody exhibits higher internalization into HER2-expressing cells as compared to the corresponding bivalent monospecific antibody. ..
[Invention 1033]
The antibody-drug conjugate of any of the inventions 1001-1032, wherein the first and second antigen-binding polypeptide constructs are independently scFv, Fab, Fab'or sdAb.
[Invention 1034]
The antibody-drug conjugate of the invention 1033, wherein the first and second antigen-binding polypeptide constructs are independently scFv or Fab.
[Invention 1035]
The antibody-drug conjugate of the invention 1034, wherein the first antigen-binding polypeptide construct is scFv and the second antigen-binding polypeptide construct is Fab.
[Invention 1036]
The antibody-drug conjugate of any of 1001-1035 of the present invention, wherein the first and second HER2 epitopes are non-overlapping epitopes.
[Invention 1037]
The antibody-drug conjugate of any of the inventions 1001-1036, wherein the first and second HER2 epitopes are on different domains of HER2.
[Invention 1038]
The antibody-drug conjugate of the invention 1037, wherein the first HER2 epitope is in ECD4 of HER2 and the second HER2 epitope is in ECD2 of HER2.
[Invention 1039]
The antibody-drug conjugate of any of the present inventions 1001-1038, wherein the first antigen-binding polypeptide construct competes with trastuzumab for binding to HER2.
[Invention 1040]
The antibody-drug conjugate of any of the present inventions 1001-1039, wherein the second antigen-binding polypeptide construct competes with pertuzumab for binding to HER2.
[Invention 1041]
The antibody of any of the invention 1001-1038, wherein the first antigen-binding polypeptide construct comprises a CDR sequence from any one of the ECD4 binding arms of v5019, v5020, v7091, v10000, v6902, v6903 or v6717-. Drug conjugate.
[Invention 1042]
The second antigen-binding polypeptide construct is from any one of the ECD2 binding arms of v5019, v5020, v7091, v10000, v6902, v6903, v6717, v7133, v15079, v15080, v15081, v15082, v15083, v15084, or v15085. An antibody-drug conjugate of any of 1001-1038 and 1041 of the present invention comprising the CDR sequence of.
[Invention 1043]
The antibody-drug conjugate of any of the inventions 1001-1038 and 1041, wherein the second antigen-binding polypeptide construct comprises the CDR sequence from the ECD2 binding arm of v10000.
[Invention 1044]
The first antigen-binding polypeptide construct comprises the CDR sequences from the ECD4 binding arm of v10000 and the second antigen-binding polypeptide construct comprises the CDR sequences from the ECD2 binding arm of v10000. The antibody-drug conjugate of any of 1001 to 1038 of the present invention.
[Invention 1045]
The first antigen-binding polypeptide construct comprises a set of 6 CDRs having 90% or more sequence identity to the set of CDRs from the ECD4 binding arm of v10000, said antigen-binding polypeptide construct. An antibody-drug conjugate of any of the inventions 1001-1038 that retains the ability to bind ECD4.
[Invention 1046]
The second antigen-binding polypeptide construct comprises a set of 6 CDRs having 90% or more sequence identity to the set of CDRs from the ECD2 binding arm of v10000, said antigen-binding polypeptide construct. An antibody-drug conjugate of any of the inventions 1001-1038 and 1045 that retains the ability to bind ECD2.
[Invention 1047]
The first antigen-binding polypeptide construct comprises the CDR sequences shown in SEQ ID NOs: 27, 28, 29, 39, 40 and 41, and the second antigen-binding polypeptide construct comprises SEQ ID NO: 67. , 68, 69, 70, 71 and 72, the antibody-drug conjugate of any of the present inventions 1001-1038 comprising the CDR sequences shown.
[Invention 1048]
The antibody-drug of any of the present inventions 1001-1047, wherein the anti-HER2 biparatopic antibody further comprises a scaffold, and the first and second antigen-binding polypeptide constructs are operably linked to the scaffold. Conjugate.
[Invention 1049]
The antibody-drug conjugate of the invention 1048, wherein the scaffold is an IgG Fc region.
[Invention 1050]
The antibody-drug conjugate of the invention 1049, wherein the IgG Fc region is a heterodimer Fc region containing a modified CH3 domain.
[Invention 1051]
The IgG Fc region is
A first polypeptide sequence containing an amino acid modification at positions F405 and Y407 and optionally further an amino acid modification at position L351.
With a second polypeptide sequence containing amino acid modifications at positions T366 and T394 and optionally further amino acid modification at position K392.
A heterodimer Fc region containing a modified CH3 domain with
The amino acid modification at position F405 is F405A, F405S, F405T or F405V, the amino acid modification at position Y407 is Y407I or Y407V, and the amino acid modification at position T366 is T366I, T366L or T366M, position T394. The amino acid modification of the above is T394W, the amino acid modification of the L351 position is L351Y, and the amino acid modification of the K392 position is K392F, K392L or K392M.
The antibody-drug conjugate of the invention 1049.
[Invention 1052]
(A) The first polypeptide sequence of the modified CH3 domain comprises the amino acid modified L351Y, F405A and Y407V, and the second polypeptide sequence of the modified CH3 domain is the amino acid modified T366L, K392M and T394W. Including; or
(B) The first polypeptide sequence of the modified CH3 domain comprises the amino acid modified L351Y, F405A and Y407V, and the second polypeptide sequence of the modified CH3 domain is the amino acid modified T366L, K392L and T394W. Including; or
(C) The first polypeptide sequence of the modified CH3 domain comprises the amino acid modified T350V, L351Y, F405A and Y407V, and the second polypeptide sequence of the modified CH3 domain is the amino acid modified T350V, T366L. , K392M and T394W;
or
(D) The first polypeptide sequence of the modified CH3 domain comprises the amino acid modified T350V, L351Y, F405A and Y407V, and the second polypeptide sequence of the modified CH3 domain is the amino acid modified T350V, T366L. , K392L and T394W;
or
(E) The first polypeptide sequence of the modified CH3 domain comprises the amino acid modified T350V, L351Y, S400E, F405A and Y407V, and the second polypeptide sequence of the modified CH3 domain is the amino acid modified T350V. , T366L, N390R, K392M and T394W,
The antibody-drug conjugate of the 1051 invention.
[Invention 1053]
A pharmaceutical composition comprising an antibody-drug conjugate of any of 1001 to 1052 of the present invention and a pharmaceutically acceptable carrier or diluent.
[Invention 1054]
A method of inhibiting the growth of HER2-expressing cancer cells, comprising contacting the HER2-expressing cancer cells with an effective amount of any antibody-drug conjugate of the present invention.
[Invention 1055]
A method for treating a HER2-expressing cancer, which comprises administering an effective amount of an antibody-drug conjugate of any of 1001 to 1052 of the present invention to a subject having a HER2-expressing cancer.
[Invention 1056]
The method of the present invention 1055, wherein the HER2-expressing cancer is breast cancer, ovarian cancer, lung cancer or gastric cancer.
[Invention 1057]
The method of the present invention 1055, wherein the HER2-expressing cancer is breast cancer.
[Invention 1058]
The method of the present invention 1055, wherein the HER2-expressing cancer is ovarian cancer.
[Invention 1059]
The method of any of 1055-1058 of the present invention, wherein the HER2-expressing cancer is scored as HER2-negative by immunohistochemistry.
[Invention 1060]
An antibody-drug conjugate of any of the inventions 1001 to 1052 for use in treatment.
[Invention 1061]
The antibody-drug conjugate of any of the present inventions 1001 to 1052 for use in treating HER2-expressing cancer in a subject in need of treatment for HER2-expressing cancer.
[Invention 1062]
An antibody-drug conjugate for use of the present invention 1061, wherein the HER2-expressing cancer is breast cancer, ovarian cancer, lung cancer or gastric cancer.
[Invention 1063]
The antibody-drug conjugate for use of the present invention 1061, wherein the HER2-expressing cancer is breast cancer.
[Invention 1064]
An antibody-drug conjugate for use of the present invention 1061, wherein the HER2-expressing cancer is ovarian cancer.
[Invention 1065]
An antibody-drug conjugate for use in any of 1061-1064 of the invention, wherein the HER2-expressing cancer is scored as HER2-negative by immunohistochemistry.
[Invention 1066]
Use of an antibody-drug conjugate of any of 1001 to 1052 of the present invention in the manufacture of a pharmaceutical for said treatment of HER2-expressing cancer.
[Invention 1067]
Use of the present invention 1066, wherein the HER2-expressing cancer is breast cancer, ovarian cancer, lung cancer or gastric cancer.
[Invention 1068]
Use of the present invention 1066, wherein the HER2-expressing cancer is breast cancer.
[Invention 1069]
Use of the present invention 1066, wherein the HER2-expressing cancer is ovarian cancer.
[Invention 1070]
The method of any of 1066-1069 of the present invention, wherein the HER2-expressing cancer is scored as HER2-negative by immunohistochemistry.
[Invention 1071]
An antibody-drug conjugate composition comprising an anti-HER2 biparatopic antibody conjugated to an auristatin analog via a linker (L).
The auristatin analog-linker is a general formula (II) :.
During the ceremony
X does not exist;
R 1 is
L is the linker,
The anti-HER2 biparatopic antibody is a first antigen-binding polypeptide construct that binds to the first HER2 epitope of ECD4 of HER2 and a second antigen-binding polypeptide construct that binds to the second HER2 epitope of ECD2 of HER2. Including
The antibody-drug conjugate composition has an average DA of 0.5 to 2.5 and has about 10% to about 30% of DA R0 seeds and 0% to about 15% of DA R6 and above seeds.
The antibody-drug conjugate composition.
Claims (30)
前記抗ＨＥＲ２バイパラトピック抗体は、第１のＨＥＲ２エピトープに結合する第１の抗原結合ポリペプチド構築物及び第２のＨＥＲ２エピトープに結合する第２の抗原結合ポリペプチド構築物を含み、前記第１及び第２のＨＥＲ２エピトープはＨＥＲ２の異なるドメイン上にあり、
オーリスタチン類似体およびリンカーは、一般式（Ｘ）：
Ｒ １ は、
Ｌは、リンカーであり、
前記低い平均ＤＡＲは、１．５～２．５である、
前記抗体－薬物コンジュゲート。 An antibody-drug conjugate comprising an anti-HER2 biparatopic antibody conjugated to an auristatin analog via a linker (L) with a low average drug-antibody ratio (DAR).
The anti-HER2 biparatopic antibody comprises a first antigen-binding polypeptide construct that binds to a first HER2 epitope and a second antigen-binding polypeptide construct that binds to a second HER2 epitope, said first and first. The 2 HER2 epitopes are on different domains of HER2 and
Auristatin analogs and linkers are represented by the general formula (X) :.
R 1 is
L is a linker and
The low average DA is 1.5-2.5 ,
The antibody-drug conjugate.
式中、
Ｚは、前記抗ＨＥＲ２バイパラトピック抗体上の標的基と反応できる官能基であり、
Ｓｔｒは、ストレッチャーであり；
ＡＡ１及びＡＡ２は、それぞれ独立してアミノ酸であり、ＡＡ１－［ＡＡ２］ｍは、プロテアーゼ切断部位を形成し；
Ｘは、自壊性基であり；
Ｄは、前記オーリスタチン類似体への付着点であり；
ｓは、０または１であり；
ｍは、１～４の整数であり、
ｏは、０、１、または２である、
請求項１～９のいずれか１項に記載の抗体－薬物コンジュゲート。 L is the general formula (VI):
During the ceremony
Z is a functional group capable of reacting with a target group on the anti-HER2 biparatopic antibody.
Str is a stretcher;
AA 1 and AA 2 are independent amino acids, respectively, and AA 1- [AA 2 ] m forms a protease cleavage site;
X is a self-destructive group;
D is the point of attachment to the auristatin analog;
s is 0 or 1;
m is an integer of 1 to 4,
o is 0, 1, or 2,
The antibody-drug conjugate according to any one of claims 1 to 9 .
式中、
Ａ－Ｓ－は、前記抗ＨＥＲ２バイパラトピック抗体への前記付着点であり；
Ｙは、１つ以上の追加のリンカー構成要素であるか、または存在せず、
Ｄは、前記オーリスタチン類似体への前記付着点である、
請求項１～９のいずれか１項に記載の抗体－薬物コンジュゲート。 L is the general formula (IX):
During the ceremony
AS-is the point of attachment to the anti-HER2 biparatopic antibody;
Y is one or more additional linker components or does not exist,
D is the attachment point to the auristatin analog,
The antibody-drug conjugate according to any one of claims 1 to 9 .
Ａ－Ｓ－は、前記抗ＨＥＲ２バイパラトピック抗体への前記付着点である、
請求項１～７のいずれか一項に記載の抗体－薬物コンジュゲート。 The structure of the auristatin analog and linker:
AS-is the point of attachment to the anti-HER2 biparatopic antibody.
The antibody-drug conjugate according to any one of claims 1 to 7 .
Ｈ１が第１の抗原結合ポリペプチド構築物を含み、Ｈ２およびＬ１が第２の抗原結合ポリペプチド構築物を含み、
Ｈ１がＳＥＱ ＩＤ ＮＯ：３６に示される配列を含み、Ｈ２がＳＥＱ ＩＤ ＮＯ：６３に示される配列を含み、Ｌ１がＳＥＱ ＩＤ ＮＯ：２４に示される配列を含む、請求項１～１７のいずれか一項に記載の抗体－薬物コンジュゲート。 The anti-HER2 biparatopic antibody comprises a first heavy chain (H1), a second heavy chain (H2) and a light chain (L1).
H1 contains a first antigen-binding polypeptide construct, H2 and L1 contain a second antigen-binding polypeptide construct.
Any of claims 1-17, wherein H1 comprises the sequence set forth in SEQ ID NO: 36, H2 comprises the sequence set forth in SEQ ID NO: 63, and L1 comprises the sequence set forth in SEQ ID NO: 24. The antibody-drug conjugate according to paragraph 1 .
（ａ）前記修飾ＣＨ３ドメインの前記第１のポリペプチド配列は、前記アミノ酸修飾Ｌ３５１Ｙ、Ｆ４０５Ａ及びＹ４０７Ｖを含み、前記修飾ＣＨ３ドメインの前記第２のポリペプチド配列は、前記アミノ酸修飾Ｔ３６６Ｌ、Ｋ３９２Ｍ及びＴ３９４Ｗを含む；または
（ｂ）前記修飾ＣＨ３ドメインの前記第１のポリペプチド配列は、前記アミノ酸修飾Ｌ３５１Ｙ、Ｆ４０５Ａ及びＹ４０７Ｖを含み、前記修飾ＣＨ３ドメインの前記第２のポリペプチド配列は、前記アミノ酸修飾Ｔ３６６Ｌ、Ｋ３９２Ｌ及びＴ３９４Ｗを含む；または
（ｃ）前記修飾ＣＨ３ドメインの前記第１のポリペプチド配列は、前記アミノ酸修飾Ｔ３５０Ｖ、Ｌ３５１Ｙ、Ｆ４０５Ａ及びＹ４０７Ｖを含み、前記修飾ＣＨ３ドメインの前記第２のポリペプチド配列は、前記アミノ酸修飾Ｔ３５０Ｖ、Ｔ３６６Ｌ、Ｋ３９２Ｍ及びＴ３９４Ｗを含む；
または
（ｄ）前記修飾ＣＨ３ドメインの前記第１のポリペプチド配列は、前記アミノ酸修飾Ｔ３５０Ｖ、Ｌ３５１Ｙ、Ｆ４０５Ａ及びＹ４０７Ｖを含み、前記修飾ＣＨ３ドメインの前記第２のポリペプチド配列は、前記アミノ酸修飾Ｔ３５０Ｖ、Ｔ３６６Ｌ、Ｋ３９２Ｌ及びＴ３９４Ｗを含む；
または
（ｅ）前記修飾ＣＨ３ドメインの前記第１のポリペプチド配列は、前記アミノ酸修飾Ｔ３５０Ｖ、Ｌ３５１Ｙ、Ｓ４００Ｅ、Ｆ４０５Ａ及びＹ４０７Ｖを含み、前記修飾ＣＨ３ドメインの前記第２のポリペプチド配列は、前記アミノ酸修飾Ｔ３５０Ｖ、Ｔ３６６Ｌ、Ｎ３９０Ｒ、Ｋ３９２Ｍ及びＴ３９４Ｗを含む、
請求項２３に記載の抗体－薬物コンジュゲート。 The IgG Fc region is a heterodimer Fc region comprising a modified CH3 domain, wherein the modified CH3 domain comprises a first polypeptide sequence and a second polypeptide sequence.
(A) The first polypeptide sequence of the modified CH3 domain comprises the amino acid modified L351Y, F405A and Y407V, and the second polypeptide sequence of the modified CH3 domain is the amino acid modified T366L, K392M and T394W. (B) The first polypeptide sequence of the modified CH3 domain comprises the amino acid modified L351Y, F405A and Y407V, and the second polypeptide sequence of the modified CH3 domain is said amino acid modified T366L. , K392L and T394W; or (c) the first polypeptide sequence of the modified CH3 domain comprises the amino acid modified T350V, L351Y, F405A and Y407V and said second polypeptide sequence of the modified CH3 domain. Includes the amino acid modifications T350V, T366L, K392M and T394W;
Or (d) the first polypeptide sequence of the modified CH3 domain comprises the amino acid modified T350V, L351Y, F405A and Y407V, and the second polypeptide sequence of the modified CH3 domain is said amino acid modified T350V. Includes T366L, K392L and T394W;
Or (e) the first polypeptide sequence of the modified CH3 domain comprises the amino acid modified T350V, L351Y, S400E, F405A and Y407V, and the second polypeptide sequence of the modified CH3 domain is said amino acid modification. Includes T350V, T366L, N390R, K392M and T394W.
23. The antibody-drug conjugate according to claim 23 .
抗ＨＥＲ２バイパラトピック抗体は、ＳＥＱ ＩＤ ＮＯ：３６に示される配列を含む第１の重鎖（Ｈ１）、ＳＥＱ ＩＤ ＮＯ：６３に示される配列を含む第２の重鎖（Ｈ２）、およびＳＥＱ ＩＤ ＮＯ：２４に示される配列を含む軽鎖（Ｌ１）を含み、
オーリスタチン類似体およびリンカーは、構造：
Ａ－Ｓ－は、前記抗ＨＥＲ２バイパラトピック抗体への付着点であり、
前記低い平均ＤＡＲは、１．８～２．５の平均ＤＡＲである、
前記抗体－薬物コンジュゲート。 An antibody-drug conjugate comprising an anti-HER2 biparatopic antibody conjugated to an auristatin analog via a linker (L) with a low average drug-antibody ratio (DAR).
The anti-HER2 biparatopic antibody is a first heavy chain (H1) containing the sequence shown in SEQ ID NO: 36, a second heavy chain (H2) containing the sequence shown in SEQ ID NO: 63, and a SEQ. ID NO: Containing a light chain (L1) comprising the sequence shown in 24,
Auristatin analogs and linkers are structured:
AS-is an adhesion point to the anti-HER2 biparatopic antibody.
The low average DR is an average DA of 1.8-2.5.
The antibody-drug conjugate .
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| PCT/CA2019/050303 WO2019173911A1 (en) | 2018-03-13 | 2019-03-12 | Anti-her2 biparatopic antibody-drug conjugates and methods of use |
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