JPWO2021113701A5 - - Google Patents
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- JPWO2021113701A5 JPWO2021113701A5 JP2022533414A JP2022533414A JPWO2021113701A5 JP WO2021113701 A5 JPWO2021113701 A5 JP WO2021113701A5 JP 2022533414 A JP2022533414 A JP 2022533414A JP 2022533414 A JP2022533414 A JP 2022533414A JP WO2021113701 A5 JPWO2021113701 A5 JP WO2021113701A5
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- 125000003275 alpha amino acid group Chemical group 0.000 claims 80
- 239000000427 antigen Substances 0.000 claims 44
- 102000036639 antigens Human genes 0.000 claims 44
- 108091007433 antigens Proteins 0.000 claims 44
- 108010047041 Complementarity Determining Regions Proteins 0.000 claims 25
- 239000008194 pharmaceutical composition Substances 0.000 claims 14
- 102000006942 B-Cell Maturation Antigen Human genes 0.000 claims 11
- 108010008014 B-Cell Maturation Antigen Proteins 0.000 claims 11
- 208000034578 Multiple myelomas Diseases 0.000 claims 9
- 206010035226 Plasma cell myeloma Diseases 0.000 claims 9
- 238000011282 treatment Methods 0.000 claims 7
- 206010028980 Neoplasm Diseases 0.000 claims 6
- 101000801255 Homo sapiens Tumor necrosis factor receptor superfamily member 17 Proteins 0.000 claims 5
- 229940079156 Proteasome inhibitor Drugs 0.000 claims 5
- 201000011510 cancer Diseases 0.000 claims 5
- 102000046935 human TNFRSF17 Human genes 0.000 claims 5
- 238000000034 method Methods 0.000 claims 5
- 239000003207 proteasome inhibitor Substances 0.000 claims 5
- 239000002955 immunomodulating agent Substances 0.000 claims 3
- 229940121354 immunomodulator Drugs 0.000 claims 3
- 230000002584 immunomodulator Effects 0.000 claims 3
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 claims 2
- 238000009175 antibody therapy Methods 0.000 claims 2
- 239000002246 antineoplastic agent Substances 0.000 claims 2
- 229960001467 bortezomib Drugs 0.000 claims 2
- GXJABQQUPOEUTA-RDJZCZTQSA-N bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 claims 2
- 229960002438 carfilzomib Drugs 0.000 claims 2
- BLMPQMFVWMYDKT-NZTKNTHTSA-N carfilzomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)[C@]1(C)OC1)NC(=O)CN1CCOCC1)CC1=CC=CC=C1 BLMPQMFVWMYDKT-NZTKNTHTSA-N 0.000 claims 2
- 108010021331 carfilzomib Proteins 0.000 claims 2
- 229960002204 daratumumab Drugs 0.000 claims 2
- 239000003814 drug Substances 0.000 claims 2
- 229950007752 isatuximab Drugs 0.000 claims 2
- 229960003648 ixazomib Drugs 0.000 claims 2
- MXAYKZJJDUDWDS-LBPRGKRZSA-N ixazomib Chemical compound CC(C)C[C@@H](B(O)O)NC(=O)CNC(=O)C1=CC(Cl)=CC=C1Cl MXAYKZJJDUDWDS-LBPRGKRZSA-N 0.000 claims 2
- 229960004942 lenalidomide Drugs 0.000 claims 2
- GOTYRUGSSMKFNF-UHFFFAOYSA-N lenalidomide Chemical group C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O GOTYRUGSSMKFNF-UHFFFAOYSA-N 0.000 claims 2
- 229960000688 pomalidomide Drugs 0.000 claims 2
- UVSMNLNDYGZFPF-UHFFFAOYSA-N pomalidomide Chemical compound O=C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O UVSMNLNDYGZFPF-UHFFFAOYSA-N 0.000 claims 2
- 229940124597 therapeutic agent Drugs 0.000 claims 2
- 238000011285 therapeutic regimen Methods 0.000 claims 2
- 210000004881 tumor cell Anatomy 0.000 claims 2
- 102100023990 60S ribosomal protein L17 Human genes 0.000 claims 1
- 108010074708 B7-H1 Antigen Proteins 0.000 claims 1
- 102000008203 CTLA-4 Antigen Human genes 0.000 claims 1
- 108010021064 CTLA-4 Antigen Proteins 0.000 claims 1
- 229940045513 CTLA4 antagonist Drugs 0.000 claims 1
- 229940126161 DNA alkylating agent Drugs 0.000 claims 1
- 239000012624 DNA alkylating agent Substances 0.000 claims 1
- 102000009490 IgG Receptors Human genes 0.000 claims 1
- 108010073807 IgG Receptors Proteins 0.000 claims 1
- 229940076838 Immune checkpoint inhibitor Drugs 0.000 claims 1
- 102100024216 Programmed cell death 1 ligand 1 Human genes 0.000 claims 1
- 101710089372 Programmed cell death protein 1 Proteins 0.000 claims 1
- 210000001744 T-lymphocyte Anatomy 0.000 claims 1
- 239000000611 antibody drug conjugate Substances 0.000 claims 1
- 229940049595 antibody-drug conjugate Drugs 0.000 claims 1
- 210000003719 b-lymphocyte Anatomy 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 229940127089 cytotoxic agent Drugs 0.000 claims 1
- 229940121372 histone deacetylase inhibitor Drugs 0.000 claims 1
- 239000003276 histone deacetylase inhibitor Substances 0.000 claims 1
- 230000002519 immonomodulatory effect Effects 0.000 claims 1
- 210000002865 immune cell Anatomy 0.000 claims 1
- 239000012274 immune-checkpoint protein inhibitor Substances 0.000 claims 1
- 229940124622 immune-modulator drug Drugs 0.000 claims 1
- 229940099472 immunoglobulin a Drugs 0.000 claims 1
- 229940027941 immunoglobulin g Drugs 0.000 claims 1
- 210000004180 plasmocyte Anatomy 0.000 claims 1
- 238000001959 radiotherapy Methods 0.000 claims 1
- 238000011476 stem cell transplantation Methods 0.000 claims 1
- 230000003442 weekly effect Effects 0.000 claims 1
Claims (14)
（ａ）前記第１の抗原結合ドメインが、配列番号６８のアミノ酸配列を含むＨＣＤＲ１、配列番号７０のアミノ酸配列を含むＨＣＤＲ２、および配列番号７２のアミノ酸配列を含むＨＣＤＲ３、を含む；および／または
前記第１の抗原結合ドメインが、配列番号８４のアミノ酸配列を含むＬＣＤＲ１、配列番号８６のアミノ酸配列を含むＬＣＤＲ２、および配列番号８８のアミノ酸配列を含むＬＣＤＲ３、を含む；または
（ｂ）前記第１の抗原結合ドメインが、配列番号６６のアミノ酸配列を含むＨＣＶＲ、および配列番号８２のアミノ酸配列を含むＬＣＶＲ、を含む；および／または
（Ｂ）前記第２の抗原結合ドメインが、配列番号９０または配列番号９８のアミノ酸配列を含む重鎖可変領域（ＨＣＶＲ）内に含まれる３つの重鎖相補性決定領域（ＨＣＤＲ１、ＨＣＤＲ２、およびＨＣＤＲ３）、および配列番号８２のアミノ酸配列を含む軽鎖可変領域（ＬＣＶＲ）内に含まれる３つの軽鎖相補性決定領域（ＬＣＤＲ１、ＬＣＤＲ２、およびＬＣＤＲ３）、を含み、場合により、
（ａ）前記第２の抗原結合ドメインが、配列番号９２または配列番号１００のアミノ酸配列を含むＨＣＤＲ１、配列番号９４または配列番号１０２のアミノ酸配列を含むＨＣ
ＤＲ２、および配列番号９６または配列番号１０４のアミノ酸配列を含むＨＣＤＲ３、を含む；および／または
（ｂ）前記第２の抗原結合ドメインが、配列番号８４のアミノ酸配列を含むＬＣＤＲ１、配列番号８６のアミノ酸配列を含むＬＣＤＲ２、および配列番号８８のアミノ酸配列を含むＬＣＤＲ３、を含み、さらに場合により、前記第２の抗原結合ドメインが、
（ｉ）配列番号９２、９４、９６のアミノ酸配列をそれぞれ含む、ＨＣＤＲ１、ＨＣＤＲ２、ＨＣＤＲ３ドメイン、および配列番号８４、８６、８８のアミノ酸配列をそれぞれ含む、ＬＣＤＲ１、ＬＣＤＲ２、ＬＣＤＲ３ドメイン、または配列番号１００、１０２、１０４のアミノ酸配列をそれぞれ含む、ＨＣＤＲ１、ＨＣＤＲ２、ＨＣＤＲ３ドメイン、および配列番号８４、８６、８８のアミノ酸配列をそれぞれ含む、ＬＣＤＲ１、ＬＣＤＲ２、ＬＣＤＲ３ドメイン；または
（ｉｉ）配列番号９０のアミノ酸配列を含むＨＣＶＲ、および配列番号８２のアミノ酸配列を含むＬＣＶＲ、または配列番号９８のアミノ酸配列を含むＨＣＶＲ、および配列番号８２のアミノ酸配列を含むＬＣＶＲ、
を含む、請求項１または２に記載の医薬組成物。 (A) The first antigen-binding domain comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) contained within a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 66, and the sequence three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3) contained within the light chain variable region (LCVR) comprising the amino acid sequence number 82, and optionally,
(a) the first antigen-binding domain comprises HCDR1 comprising the amino acid sequence of SEQ ID NO: 68, HCDR2 comprising the amino acid sequence of SEQ ID NO: 70, and HCDR3 comprising the amino acid sequence of SEQ ID NO: 72; and/or
or (b) the first antigen-binding domain comprises LCDR1 comprising the amino acid sequence of SEQ ID NO: 84, LCDR2 comprising the amino acid sequence of SEQ ID NO: 86, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 88; (B) said second antigen-binding domain comprises an HCVR comprising the amino acid sequence of SEQ ID NO: 66, and a LCVR comprising the amino acid sequence of SEQ ID NO: 82; and/or (B) said second antigen-binding domain comprises SEQ ID NO: 90 or Three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) contained within the heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 98, and the light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 82. ), and optionally, three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3) contained within
(a) HCDR1 in which the second antigen-binding domain comprises the amino acid sequence of SEQ ID NO: 92 or 100, HC comprising the amino acid sequence of SEQ ID NO: 94 or SEQ ID NO: 102;
DR2, and HCDR3 comprising the amino acid sequence of SEQ ID NO: 96 or SEQ ID NO: 104; and/or (b) the second antigen-binding domain comprises LCDR1 comprising the amino acid sequence of SEQ ID NO: 84, the amino acid sequence of SEQ ID NO: 86; LCDR2 comprising the sequence SEQ ID NO: 88, and LCDR3 comprising the amino acid sequence SEQ ID NO: 88, further optionally said second antigen binding domain comprising:
(i) HCDR1, HCDR2, HCDR3 domains comprising the amino acid sequences of SEQ ID NOs: 92, 94, and 96, respectively, and LCDR1, LCDR2, LCDR3 domains comprising the amino acid sequences of SEQ ID NOs: 84, 86, and 88, respectively, or SEQ ID NO: 100; , HCDR1, HCDR2, HCDR3 domains comprising the amino acid sequences of , 102, 104, respectively; and LCDR1, LCDR2, LCDR3 domains comprising the amino acid sequences of SEQ ID NO: 84, 86, 88, respectively; or (ii) the amino acid sequence of SEQ ID NO: 90. and LCVR comprising the amino acid sequence of SEQ ID NO: 82, or HCVR comprising the amino acid sequence of SEQ ID NO: 98, and LCVR comprising the amino acid sequence of SEQ ID NO: 82,
The pharmaceutical composition according to claim 1 or 2, comprising:
（Ｂ）前記抗体が、配列番号６８、７０、７２のアミノ酸配列をそれぞれ含む、ＨＣＤＲ１、ＨＣＤＲ２、ＨＣＤＲ３ドメイン、および配列番号８４、８６、８８のアミノ酸配列をそれぞれ含む、ＬＣＤＲ１、ＬＣＤＲ２、ＬＣＤＲ３ドメイン、を含む、第１の抗原結合ドメイン、ならびに配列番号１００、１０２、１０４のアミノ酸配列をそれぞれ含む、ＨＣＤＲ１、ＨＣＤＲ２、ＨＣＤＲ３ドメイン、および配列番号８４、８６、８８のアミノ酸配列をそれぞれ含む、ＬＣＤＲ１、ＬＣＤＲ２、ＬＣＤＲ３ドメイン、を含む、第２の抗原結合ドメイン、を含み、場合により、前記抗体が、配列番号６６のアミノ酸配列を含むＨＣＶＲ、および配列番号８２のアミノ酸配列を含むＬＣＶＲ、を含む、第１の抗原結合ドメイン、ならびに配列番号９８のアミノ酸配列を含むＨＣＶＲ、および配列番号８２のアミノ酸配列を含むＬＣＶＲ、を含む、第２の抗原結合ドメイン、を含む；または
（Ｃ）前記抗体が、配列番号２、１８、３４、５０、６６、１２２、および１２４からなる群から選択されるアミノ酸配列を含むＨＣＶＲのＣＤＲ、ならびに配列番号１０、２６、４２、５８、７４、８２、１２３、および１２５からなる群から選択されるアミノ酸配列を含むＬＣＶＲのＣＤＲ、を含む、第１の抗原結合ドメイン、ならびにヒトＣＤ３に特異的に結合する第２の抗原結合ドメイン、を含み、場合により、
（ｉ）前記第１の抗原結合ドメインが、配列番号２／１０、１８／２６、３４／４２、５０／５８、６６／７４、１２２／１２３、１２４／１２５、２／８２、１８／８２、３４／８２、５０／８２、６６／８２、１２２／８２、および１２４／８２からなる群から選択されるＨＣＶＲ／ＬＣＶＲアミノ酸配列の対からのＣＤＲを含み、場合により、前記第１の抗原結合ドメインが、それぞれ、配列番号４－６－８－１２－１４－１６、２０－２２－２４－２８－３０－３２、３６－３８－４０－４４－４６－４８、５２－５４－５６－６０－６２－６４、６８－７０－７２－７６－７８－８０、４－６－８－８４－８６－８８、２０－２２－２４－８４－８６－８８、３６－３８－４０－８４－８６－８８、５２－５４－５６－８４－８６－８８、および６８－７０－７２－８４－８６－８８からなる群から選択されるＨＣＤＲ１－ＨＣＤＲ２－ＨＣＤＲ３－ＬＣＤＲ１－ＬＣＤＲ２－ＬＣＤＲ３ドメインを含み、さらに場合により、前記第１の抗原結合ドメインが、配列番号２／１０、１８／２６、３４／４２、５０／５８、６６／７４、１２２／１２３、１２４／１２５、２／８２、１８／８２、３４／８２、５０／８２、６６／８２、１２２／８２、および１２４／８２からなる群から選択されるＨＣＶＲ／ＬＣＶＲアミノ酸配列の対を含む；および／または
（ｉｉ）前記第２の抗原結合ドメインが、配列番号９０／８２および９８／８２からなる群から選択されるＨＣＶＲ／ＬＣＶＲアミノ酸配列の対のＣＤＲを含む、請求項１に記載の医薬組成物。 (A) the antibody has HCDR1, HCDR2, HCDR3 domains comprising the amino acid sequences of SEQ ID NOs: 68, 70, and 72, respectively, and LCDR1, LCDR2, LCDR3 domains comprising the amino acid sequences of SEQ ID NOs: 84, 86, and 88, respectively; and an HCDR1, HCDR2, HCDR3 domain comprising an amino acid sequence of SEQ ID NO: 92, 94, 96, respectively, and an LCDR1, LCDR2 comprising an amino acid sequence of SEQ ID NO: 84, 86, 88, respectively. , a second antigen-binding domain comprising an LCDR3 domain, and optionally, the antibody comprises an HCVR comprising the amino acid sequence of SEQ ID NO: 66, and an LCVR comprising the amino acid sequence of SEQ ID NO: 82. and a second antigen-binding domain comprising an HCVR comprising the amino acid sequence of SEQ ID NO: 90 and an LCVR comprising the amino acid sequence of SEQ ID NO: 82; A first antigen-binding domain comprising an HCDR1, HCDR2, HCDR3 domain comprising an amino acid sequence of 68, 70, 72, respectively, and an LCDR1, LCDR2, LCDR3 domain comprising an amino acid sequence of SEQ ID NO: 84, 86, 88, respectively. , and an HCDR1, HCDR2, HCDR3 domain comprising the amino acid sequence of SEQ ID NO: 100, 102, 104, respectively, and an LCDR1, LCDR2, LCDR3 domain comprising the amino acid sequence of SEQ ID NO: 84, 86, 88, respectively. Optionally, the antibody comprises an HCVR comprising the amino acid sequence of SEQ ID NO: 66, and a LCVR comprising the amino acid sequence of SEQ ID NO: 82, and a first antigen-binding domain of SEQ ID NO: 98. or (C) the antibody comprises an HCVR comprising an amino acid sequence of SEQ ID NO: 82, and a LCVR comprising an amino acid sequence of SEQ ID NO: 82; , 122, and 124; and an amino acid sequence selected from the group consisting of SEQ ID NO: 10, 26, 42, 58, 74, 82, 123, and 125. a first antigen-binding domain comprising a CDR of LCVR, and a second antigen-binding domain that specifically binds human CD3;
(i) the first antigen-binding domain is SEQ ID NO: 2/10, 18/26, 34/42, 50/58, 66/74, 122/123, 124/125, 2/82, 18/82, 34/82, 50/82, 66/82, 122/82, and 124/82, optionally said first antigen binding domain are SEQ ID NO: 4-6-8-12-14-16, 20-22-24-28-30-32, 36-38-40-44-46-48, 52-54-56-60-, respectively. 62-64, 68-70-72-76-78-80, 4-6-8-84-86-88, 20-22-24-84-86-88, 36-38-40-84-86- 88, 52-54-56-84-86-88, and 68-70-72-84-86-88; Accordingly, the first antigen-binding domain is SEQ ID NO: 2/10, 18/26, 34/42, 50/58, 66/74, 122/123, 124/125, 2/82, 18/82, 34 /82, 50/82, 66/82, 122/82, and 124/82; and/or (ii) said second antigen-binding domain comprises 90/82 and 98/82. 98/82. 90/82 and 98/82.
（ｉ）前記二重特異性抗体が、配列番号１３０のアミノ酸配列を含む定常領域を含む第１の重鎖を含む；および／または
（ｉｉ）前記二重特異性抗体が、配列番号１３１のアミノ酸配列を含む定常領域を含む第２の重鎖を含む；および／または
（ｂ）前記二重特異性抗体が、配列番号１２６のアミノ酸配列を含む第１の重鎖、配列番号１２７または配列番号１２８のアミノ酸配列を含む第２の重鎖、および配列番号１２９のアミノ酸配列を含む共通の軽鎖を含む、請求項１～４のいずれか一項に記載の医薬組成物。 (a) the bispecific antibody comprises a human IgG heavy chain constant region, optionally;
(i) said bispecific antibody comprises a first heavy chain comprising a constant region comprising the amino acid sequence of SEQ ID NO: 130; and/or (ii) said bispecific antibody comprises an amino acid sequence of SEQ ID NO: 131; and/or (b) said bispecific antibody comprises a first heavy chain comprising an amino acid sequence of SEQ ID NO: 126, SEQ ID NO: 127 or SEQ ID NO: 128. A pharmaceutical composition according to any one of claims 1 to 4, comprising a second heavy chain comprising the amino acid sequence of SEQ ID NO: 129 and a common light chain comprising the amino acid sequence of SEQ ID NO: 129.
（ａ）前記第１の重鎖が、配列番号６６のアミノ酸配列を含む第１の重鎖可変領域を含み、前記第２の重鎖は、配列番号９０のアミノ酸配列を含む第２の重鎖可変領域を含み、前記共通の軽鎖は、配列番号８２のアミノ酸配列を含む軽鎖可変領域を含む；または
（ｂ）前記第１の重鎖が、配列番号６６のアミノ酸配列を含む第１の重鎖可変領域を含み、前記第２の重鎖は、配列番号９８のアミノ酸配列を含む第２の重鎖可変領域を含み、前記共通の軽鎖は、配列番号８２のアミノ酸配列を含む軽鎖可変領域を含む、医薬組成物。 A pharmaceutical composition comprising a bispecific antibody for use in a method of treating multiple myeloma in a subject in need of treatment, the bispecific antibody comprising human B cells. a first heavy chain and a common light chain pair comprising a first antigen binding domain that specifically binds mature antigen (BCMA) and a second antigen binding domain that specifically binds human CD3 a second heavy chain and a common light chain pair, wherein the first antigen-binding domain comprises the amino acid sequences of SEQ ID NOs: 68, 70, 72, 84, 86, and 88, respectively. a chain complementarity determining region (CDR) and three light chain CDRs, said second antigen binding domain comprising the amino acid sequences of SEQ ID NOs: 92, 94, 96, 84, 86, and 88, respectively. said bispecific antibody comprising a heavy chain CDR and three light chain CDRs, said bispecific antibody being administered to said subject at a dose of 1 mg per week, optionally;
(a) the first heavy chain comprises a first heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 66, and the second heavy chain comprises a second heavy chain comprising the amino acid sequence of SEQ ID NO: 90; or (b) said first heavy chain comprises a first heavy chain comprising an amino acid sequence of SEQ ID NO: 66; a heavy chain variable region, said second heavy chain comprising a second heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 98, and said common light chain comprising a light chain comprising an amino acid sequence of SEQ ID NO: 82. A pharmaceutical composition comprising a variable region.
（ｂ）前記第１の重鎖が、配列番号１２６のアミノ酸配列を含み、前記第２の重鎖は、配列番号１２８のアミノ酸配列を含み、前記共通の軽鎖は、配列番号１２９のアミノ酸配列を含む、
請求項７に記載の医薬組成物。 (a) the first heavy chain comprises the amino acid sequence of SEQ ID NO: 126, the second heavy chain comprises the amino acid sequence of SEQ ID NO: 127, and the common light chain comprises the amino acid sequence of SEQ ID NO: 129; or (b) said first heavy chain comprises the amino acid sequence of SEQ ID NO: 126, said second heavy chain comprises the amino acid sequence of SEQ ID NO: 128, and said common light chain comprises the amino acid sequence of SEQ ID NO: 128; Contains a 129 amino acid sequence,
The pharmaceutical composition according to claim 7.
（ｂ）前記二重特異性抗体が、分割された一次用量を含む投与レジメンで投与される；および／または
（ｃ）前記二重特異性抗体の用量が、１週間に３ｍｇ～９００ｍｇの用量で前記対象に投与される、
請求項１～８のいずれか一項に記載の医薬組成物。 (a) the method comprises administering to the subject a second therapeutic agent or therapeutic regimen, optionally the second therapeutic agent or therapeutic regimen being a chemotherapeutic agent, a DNA alkylating agent, an immunomodulatory agent; , proteasome inhibitors, histone deacetylase inhibitors, radiotherapy, stem cell transplantation, different bispecific antibodies that interact with different tumor cell surface antigens and T cell or immune cell antigens, antibody-drug conjugates, anti-tumor agents. comprising a conjugated bispecific antibody, PD-1, PD-L1, or CTLA-4 checkpoint inhibitor, or a combination thereof;
(b) said bispecific antibody is administered in a dosing regimen comprising divided primary doses; and/or (c) said bispecific antibody is administered in a dose of 3 mg to 900 mg per week. administered to said subject;
Pharmaceutical composition according to any one of claims 1 to 8.
（ｂ）前記ＢＣＭＡ＋がんが多発性骨髄腫であり、前記対象が以前にプロテアソーム阻害剤または免疫調節薬で治療されていて、場合により、
（ｉ）前記プロテアソーム阻害剤が、ボルテゾミブ、カルフィルゾミブ、またはイキサゾミブである；または
（ｉｉ）前記免疫調節薬が、レナリドミドまたはポマリドミドである、
請求項１～９のいずれか一項に記載の医薬組成物。 (a) said BCMA+ cancer is multiple myeloma and said subject has been previously treated with anti-CD38 antibody therapy, and optionally said anti-CD38 antibody is daratumumab or isatuximab; or (b) said the BCMA+ cancer is multiple myeloma, and the subject has been previously treated with a proteasome inhibitor or immunomodulator, optionally;
(i) the proteasome inhibitor is bortezomib, carfilzomib, or ixazomib; or (ii) the immunomodulator is lenalidomide or pomalidomide.
Pharmaceutical composition according to any one of claims 1 to 9.
（ｂ）前記ＢＣＭＡ＋がんが、再発または難治性の多発性骨髄腫である；および／または
（ｃ）前記対象が、以前の治療に対して少なくとも三重難治性であり、場合により、前記対象が、以前の治療に対して四重難治性または五重難治性ある、
請求項１～１０のいずれか一項に記載の医薬組成物。 (a) the subject has been diagnosed with a multiple myeloma immunosubtype selected from immunoglobulin G, immunoglobulin A, lambda light chain, or kappa light chain, or the subject has extramedullary plasma cell have a tumor;
(b) said BCMA+ cancer is relapsed or refractory multiple myeloma; and/or (c) said subject is at least triple refractory to previous treatments; , quadruple refractory or quintuple refractory to previous treatment,
Pharmaceutical composition according to any one of claims 1 to 10.
前記二重特異性抗体が、
（ａ）ヒトＢ細胞成熟抗原（ＢＣＭＡ）に特異的に結合する第１の抗原結合ドメインを含む第１の重鎖および共通の軽鎖の対と、ヒトＣＤ３に特異的に結合する第２の抗原結合ドメインを含む第２の重鎖および共通の軽鎖の対とを含み、前記第１の抗原結合ドメインが、それぞれ配列番号６８、７０、７２、８４、８６、および８８のアミノ酸配列を含む、３つの重鎖相補性決定領域（ＣＤＲ）と３つの軽鎖ＣＤＲとを含み、前記第２の抗原結合ドメインが、それぞれ配列番号９２、９４、９６、８４、８６、および８８のアミノ酸配列を含む、３つの重鎖ＣＤＲと３つの軽鎖ＣＤＲとを含むか、または、
（ｂ）ヒトＢ細胞成熟抗原（ＢＣＭＡ）に特異的に結合する第１の抗原結合ドメインを含む第１の重鎖および共通の軽鎖の対と、ヒトＣＤ３に特異的に結合する第２の抗原結合ドメインを含む第２の重鎖および共通の軽鎖の対とを含み、前記第１の抗原結合ドメインが、それぞれ配列番号６８、７０、７２、８４、８６、および８８のアミノ酸配列を含む
、３つの重鎖相補性決定領域（ＣＤＲ）と３つの軽鎖ＣＤＲとを含み、前記第２の抗原結合ドメインが、それぞれ配列番号１００、１０２、１０４、８４、８６、および８８のアミノ酸配列を含む、３つの重鎖ＣＤＲと３つの軽鎖ＣＤＲとを含み、場合により、
（ｉ）前記二重特異性抗体が、ヒトＢ細胞成熟抗原（ＢＣＭＡ）に特異的に結合する第１の抗原結合ドメインを含む、第１の重鎖および共通の軽鎖の対と、ヒトＣＤ３に特異的に結合する第２の抗原結合ドメインを含む第２の重鎖および共通の軽鎖の対と、を含み、前記第１の抗原結合ドメインが、それぞれ配列番号６８、７０、７２、８４、８６、および８８のアミノ酸配列を含む、３つの重鎖相補性決定領域（ＣＤＲ）と３つの軽鎖ＣＤＲとを含み、前記第２の抗原結合ドメインが、それぞれ配列番号９２、９４、９６、８４、８６、および８８のアミノ酸配列を含む、３つの重鎖ＣＤＲと３つの軽鎖ＣＤＲとを含み、場合により、前記第１の重鎖が、配列番号６６のアミノ酸配列を含む第１の重鎖可変領域を含み、前記第２の重鎖は、配列番号９０のアミノ酸配列を含む第２の重鎖可変領域を含み、前記共通の軽鎖は、配列番号８２のアミノ酸配列を含む軽鎖可変領域を含み、さらに場合により、前記第１の重鎖が、配列番号１２６のアミノ酸配列を含み、前記第２の重鎖は、配列番号１２７のアミノ酸配列を含み、前記共通の軽鎖は、配列番号１２９のアミノ酸配列を含む；または
（ｉｉ）前記二重特異性抗体が、ヒトＢ細胞成熟抗原（ＢＣＭＡ）に特異的に結合する第１の抗原結合ドメインを含む、第１の重鎖および共通の軽鎖の対と、ヒトＣＤ３に特異的に結合する第２の抗原結合ドメインを含む第２の重鎖および共通の軽鎖の対と、を含み、前記第１の抗原結合ドメインが、それぞれ配列番号６８、７０、７２、８４、８６、および８８のアミノ酸配列を含む、３つの重鎖相補性決定領域（ＣＤＲ）と３つの軽鎖ＣＤＲとを含み、前記第２の抗原結合ドメインが、それぞれ配列番号１００、１０２、１０４、８４、８６、および８８のアミノ酸配列を含む、３つの重鎖ＣＤＲと３つの軽鎖ＣＤＲとを含み、場合により、前記第１の重鎖が、配列番号６６のアミノ酸配列を含む第１の重鎖可変領域を含み、前記第２の重鎖は、配列番号９８のアミノ酸配列を含む第２の重鎖可変領域を含み、前記共通の軽鎖は、配列番号８２のアミノ酸配列を含む軽鎖可変領域を含み、さらに場合により、前記第１の重鎖が、配列番号１２６のアミノ酸配列を含み、前記第２の重鎖は、配列番号１２８のアミノ酸配列を含み、前記共通の軽鎖は、配列番号１２９のアミノ酸配列を含む、医薬組成物。 A pharmaceutical composition comprising a bispecific antibody for use in a method of treating multiple myeloma in a subject in need of treatment, the bispecific antibody comprising: administered to said subject in a dosing regimen consisting of a first dose during the first week of said dosing regimen, a second dose during the second week of said dosing regimen, and a third dose during the third week of said dosing regimen; the tertiary dose is equal to or greater than the secondary dose; the secondary dose is greater than the primary dose;
The bispecific antibody is
(a) a first heavy chain and a common light chain pair comprising a first antigen binding domain that specifically binds human B cell maturation antigen (BCMA) and a second pair that specifically binds human CD3; a second heavy chain comprising an antigen-binding domain and a common pair of light chains, said first antigen-binding domain comprising the amino acid sequence of SEQ ID NOs: 68, 70, 72, 84, 86, and 88, respectively. , three heavy chain complementarity determining regions (CDRs) and three light chain CDRs, wherein the second antigen-binding domain has the amino acid sequences of SEQ ID NOs: 92, 94, 96, 84, 86, and 88, respectively. comprising three heavy chain CDRs and three light chain CDRs, or
(b) a first heavy chain and a common light chain pair comprising a first antigen binding domain that specifically binds human B cell maturation antigen (BCMA) and a second pair that specifically binds human CD3; a second heavy chain comprising an antigen-binding domain and a common pair of light chains, said first antigen-binding domain comprising the amino acid sequence of SEQ ID NOs: 68, 70, 72, 84, 86, and 88, respectively. , three heavy chain complementarity determining regions (CDRs) and three light chain CDRs, wherein the second antigen binding domain has the amino acid sequences of SEQ ID NOs: 100, 102, 104, 84, 86, and 88, respectively. 3 heavy chain CDRs and 3 light chain CDRs, optionally,
(i) the bispecific antibody comprises a first heavy chain and a common light chain pair comprising a first antigen binding domain that specifically binds human B cell maturation antigen (BCMA); a second heavy chain and a common light chain pair comprising a second antigen-binding domain that specifically binds to SEQ ID NO: 68, 70, 72, 84, respectively. , 86, and 88, and the second antigen-binding domain comprises SEQ ID NOs: 92, 94, 96, 84, 86, and 88; optionally, said first heavy chain comprising the amino acid sequence of SEQ ID NO: 66. wherein the second heavy chain comprises a second heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 90, and the common light chain comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 82. further optionally, said first heavy chain comprises an amino acid sequence of SEQ ID NO: 126, said second heavy chain comprises an amino acid sequence of SEQ ID NO: 127, and said common light chain comprises an amino acid sequence of SEQ ID NO: 127; or (ii) said bispecific antibody comprises a first antigen binding domain that specifically binds human B cell maturation antigen (BCMA); a second heavy chain and a common light chain pair comprising a second antigen-binding domain that specifically binds to human CD3, said first antigen-binding domain each comprising: The second antigen-binding domain comprises three heavy chain complementarity determining regions (CDRs) and three light chain CDRs, comprising the amino acid sequences of SEQ ID NOs: 68, 70, 72, 84, 86, and 88; comprises three heavy chain CDRs and three light chain CDRs, each comprising an amino acid sequence of SEQ ID NO: 100, 102, 104, 84, 86, and 88, and optionally said first heavy chain having an amino acid sequence of SEQ ID NO: 66. said second heavy chain comprises a second heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 98, and said common light chain comprises a second heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 98; 82, and further optionally, said first heavy chain comprises an amino acid sequence of SEQ ID NO: 126, and said second heavy chain comprises an amino acid sequence of SEQ ID NO: 128. , wherein said common light chain comprises the amino acid sequence of SEQ ID NO: 129.
（ｂ）前記二次用量が、３ｍｇ～４００ｍｇである；
（ｃ）前記三次用量が、３ｍｇ～８００ｍｇである；
（ｄ）前記一次用量が、５ｍｇである；
（ｅ）前記二次用量が、２５ｍｇである；
（ｆ）前記三次用量が、５０ｍｇ～８００ｍｇである；
（ｇ）前記投与レジメンの１週間に１回の投与期間中、少なくとも１２週間、１週間に１回の三次用量の投与を含み、場合により、前記投与レジメンの前記１週間に１回の投与期間に続く前記投与レジメンの隔週の投与期間中に、２週間に１回の三次用量の投与をさらに含む；および／または
（ｈ）前記対象が、以前に、抗ＣＤ３８抗体療法、プロテアソーム阻害剤、または免疫調節薬で治療されていて、場合により、
（Ｉ）前記抗ＣＤ３８抗体が、ダラツムマブまたはイサツキシマブである；
（ＩＩ）前記プロテアソーム阻害剤が、ボルテゾミブ、カルフィルゾミブ、またはイキサゾミブである；または
（ＩＩＩ）前記免疫調節薬が、レナリドミドまたはポマリドミドである；および／または
（ｉ）前記多発性骨髄腫が、再発または難治性の多発性骨髄腫である、
請求項１２に記載の医薬組成物。 (a) said primary dose is 1-5 mg;
(b) said secondary dose is between 3 mg and 400 mg;
(c) said tertiary dose is between 3 mg and 800 mg;
(d) said primary dose is 5 mg;
(e) said secondary dose is 25 mg;
(f) said tertiary dose is between 50 mg and 800 mg;
(g) including administration of a tertiary dose once per week for at least 12 weeks during the once weekly dosing period of said dosing regimen; and/or (h) said subject has previously received anti-CD38 antibody therapy, a proteasome inhibitor, or treated with immunomodulatory drugs and, in some cases,
(I) the anti-CD38 antibody is daratumumab or isatuximab;
(II) the proteasome inhibitor is bortezomib, carfilzomib, or ixazomib; or (III) the immunomodulator is lenalidomide or pomalidomide; and/or (i) the multiple myeloma is relapsed or refractory. multiple myeloma,
Pharmaceutical composition according to claim 12.
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| PCT/US2020/063395 WO2021113701A1 (en) | 2019-12-06 | 2020-12-04 | Methods of treating multiple myeloma with bispecific anti-bcma x anti-cd3 antibodies |
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| IL85035A0 (en) | 1987-01-08 | 1988-06-30 | Int Genetic Eng | Polynucleotide molecule,a chimeric antibody with specificity for human b cell surface antigen,a process for the preparation and methods utilizing the same |
| DK0590058T3 (en) | 1991-06-14 | 2004-03-29 | Genentech Inc | Humanized heregulin antibody |
| MY159787A (en) | 2006-06-02 | 2017-01-31 | Regeneron Pharma | High affinity antibodies to human il-6 receptor |
| CN103833855A (en) | 2009-06-26 | 2014-06-04 | 瑞泽恩制药公司 | Readily isolated bispecific antibodies with native immunoglobulin format |
| US10143186B2 (en) | 2010-02-08 | 2018-12-04 | Regeneron Pharmaceuticals, Inc. | Common light chain mouse |
| JOP20200236A1 (en) * | 2012-09-21 | 2017-06-16 | Regeneron Pharma | Anti-cd3 antibodies, bispecific antigen-binding molecules that bind cd3 and cd20, and uses thereof |
| TWI682941B (en) | 2013-02-01 | 2020-01-21 | 美商再生元醫藥公司 | Antibodies comprising chimeric constant domains |
| AR095374A1 (en) * | 2013-03-15 | 2015-10-14 | Amgen Res (Munich) Gmbh | UNION MOLECULES FOR BCMA AND CD3 |
| EP2982692A1 (en) * | 2014-08-04 | 2016-02-10 | EngMab AG | Bispecific antibodies against CD3epsilon and BCMA |
| EP3283106B1 (en) * | 2015-04-13 | 2021-12-22 | Pfizer Inc. | Therapeutic antibodies and their uses |
| IL298041A (en) * | 2015-08-17 | 2023-01-01 | Janssen Pharmaceutica Nv | Anti-bcma antibodies, bispecific antigen binding molecules that bind bcma and cd3, and uses thereof |
| CA2999385A1 (en) | 2015-09-23 | 2017-03-30 | Regeneron Pharmaceuticals, Inc. | Optimized anti-cd3 bispecific antibodies and uses thereof |
| CA3009161A1 (en) * | 2015-12-22 | 2017-06-29 | Regeneron Pharmaceuticals, Inc. | Combination of anti-pd-1 antibodies and bispecific anti-cd20/anti-cd3 antibodies to treat cancer |
| MA43955B1 (en) * | 2016-02-03 | 2022-02-28 | Amgen Inc | Bite-format bispecific anti-bcma and anti-cd3 antibodies |
| CA3037732A1 (en) * | 2016-09-23 | 2018-03-29 | Regeneron Pharmaceuticals, Inc. | Anti-steap2 antibodies, antibody-drug conjugates, and bispecific antigen-binding molecules that bind steap2 and cd3, and uses thereof |
| MD3515487T2 (en) * | 2016-09-23 | 2023-11-30 | Regeneron Pharma | Bi specific anti-MUC16-cd3 antibodies and anti-MUC16 drug conjugates |
| CN110167964B (en) * | 2016-11-02 | 2023-12-01 | 百时美施贵宝公司 | Combination of bispecific antibodies and immunopharmaceuticals against BCMA and CD3 for the treatment of multiple myeloma |
| BR112021000919A2 (en) * | 2018-07-19 | 2021-04-27 | Regeneron Pharmaceuticals, Inc. | chimeric antigen receptors with bcma specificity and uses thereof |
| MX2021000488A (en) * | 2018-07-19 | 2021-04-12 | Regeneron Pharma | BISPECIFIC ANTI-BCMA x ANTI-CD3 ANTIBODIES AND USES THEREOF. |
| CA3132587A1 (en) * | 2019-03-21 | 2020-09-24 | Regeneron Pharmaceuticals, Inc. | Combination of il-4/il-13 pathway inhibitors and plasma cell ablation for treating allergy |
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