JPWO2019220368A5 - - Google Patents
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- JPWO2019220368A5 JPWO2019220368A5 JP2020564662A JP2020564662A JPWO2019220368A5 JP WO2019220368 A5 JPWO2019220368 A5 JP WO2019220368A5 JP 2020564662 A JP2020564662 A JP 2020564662A JP 2020564662 A JP2020564662 A JP 2020564662A JP WO2019220368 A5 JPWO2019220368 A5 JP WO2019220368A5
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Description
本明細書に引用又は記載されている各特許、特許出願、及び刊行物の開示は、その全文において本明細書に参考として組み込まれる。
以下に、本願の当初の特許請求の範囲に記載の発明を列挙する。
［発明１］
対象において癌を治療する方法であって、治療有効量のＢＣＭＡ×ＣＤ３二重特異性抗体を前記対象に投与して、前記癌を治療することを含み、前記対象が、以前の抗癌治療薬による治療に対して再発又は難治性である、方法。
［発明２］
前記ＢＣＭＡ×ＣＤ３二重特異性抗体が、配列番号２３のＨＣＤＲ１、配列番号２４のＨＣＤＲ２、配列番号２５のＨＣＤＲ３、配列番号２６のＬＣＤＲ１、配列番号２７のＬＣＤＲ２、及び配列番号２８のＬＣＤＲ３を含むＢＣＭＡ結合ドメイン、並びに配列番号３３のＨＣＤＲ１、配列番号３４のＨＣＤＲ２、配列番号３５のＨＣＤＲ３、配列番号３６のＬＣＤＲ１、配列番号３７のＬＣＤＲ２、及び配列番号３８のＬＣＤＲ３を含むＣＤ３結合ドメインを含む、発明２に記載の方法。
［発明３］
前記ＢＣＭＡ結合ドメインが、配列番号２９のＶＨ及び配列番号３０のＶＬを含み、前記ＣＤ３結合ドメインが、配列番号３９のＶＨ及び配列番号４０のＶＬを含む、発明２又は３に記載の方法。
［発明４］
前記ＢＣＭＡ×ＣＤ３二重特異性抗体が、ＩｇＧ４アイソタイプであり、ＨＣ１の４０５位にフェニルアラニン及び４０９位にアルギニン、並びにＨＣ２の４０５位にロイシン及び４０９位にリジンを含み、残基の番号付けが、ＥＵインデックスに従う、発明１～３のいずれか一つに記載の方法。
［発明５］
前記ＢＣＭＡ×ＣＤ３二重特異性抗体が、前記ＨＣ１及び前記ＨＣ２の両方の２２８位にプロリン、２３４位にアラニン、及び２３５位にアラニンを更に含む、発明４に記載の方法。
［発明６］
前記ＢＣＭＡ×ＣＤ３二重特異性抗体が、配列番号３１のＨＣ１、配列番号３２のＬＣ１、配列番号４１のＨＣ２、及び配列番号４２のＬＣ２を含む、発明１～５のいずれか一つに記載の方法。
［発明７］
前記癌が、血液悪性腫瘍である、発明１～６のいずれか一つに記載の方法。
［発明８］
前記血液悪性腫瘍が、多発性骨髄腫である、発明７に記載の方法。
［発明９］
前記多発性骨髄腫が、高リスク多発性骨髄腫である、発明８に記載の方法。
［発明１０］
前記高リスク多発性骨髄腫を有する前記対象が、
ａ）ｔ（４；１４）（ｐ１６；ｑ３２）、
ｂ）ｔ（１４；１６）（ｑ３２；ｑ２３）；
ｃ）ｄｅｌ１７ｐ、
ｄ）１ｑＡｍｐ、
ｅ）ｔ（４；１４）（ｐ１６；ｑ３２）及びｔ（１４；１６）（ｑ３２；ｑ２３）、
ｆ）ｔ（４；１４）（ｐ１６；ｑ３２）及びｄｅｌ１７ｐ、
ｇ）ｔ（１４；１６）（ｑ３２；ｑ２３）及びｄｅｌ１７ｐ、又は
ｈ）ｔ（４；１４）（ｐ１６；ｑ３２）、ｔ（１４；１６）（ｑ３２；ｑ２３）及びｄｅｌ１７ｐ、又はこれらの任意の組み合わせを含む１つ又は２つ以上の染色体異常を有する、発明９に記載の方法。
［発明１１］
前記対象が、抗ＣＤ３８抗体、レナリドミド、ボルテゾミブ、ポマリドミド、カルフィルゾミブ、エロトズマブ、イキサゾミブ、メルファラン、若しくはサリドマイド、又はこれらの任意の組み合わせによる治療に対して難治又は再発性である、発明１～１０のいずれか一つに記載の方法。
［発明１２］
前記対象が、前記抗ＣＤ３８抗体による治療に対して再発性である、発明１１に記載の方法。
［発明１３］
前記抗ＣＤ３８抗体が、配列番号６のＨＣＤＲ１、配列番号７のＨＣＤＲ２、配列番号８のＨＣＤＲ３、配列番号９のＬＣＤＲ１、配列番号１０のＬＣＤＲ２、及び配列番号１１のＬＣＤＲ３を含む、発明１～１２のいずれか一つに記載の方法。
［発明１４］
前記抗ＣＤ３８抗体が、配列番号４のＶＨ及び配列番号５のＶＬを含む、発明１～１３のいずれか一つに記載の方法。
［発明１５］
前記抗ＣＤ３８抗体が、ＩｇＧ１アイソタイプである、発明１～１４のいずれか一つに記載の方法。
［発明１６］
前記抗ＣＤ３８抗体が、配列番号１２のＨＣ及び配列番号１３のＬＣを含む、発明１～１５のいずれか一つに記載の方法。
［発明１７］
前記抗ＣＤ３８抗体が、
ａ）配列番号１４のＶＨ及び配列番号１５のＶＬ、
ｂ）配列番号１６のＶＨ及び配列番号１７のＶＬ、
ｃ）配列番号１８のＶＨ及び配列番号１９のＶＬ、又は
ｄ）配列番号２０のＶＨ及び配列番号２１のＶＬを含む、発明１～１２のいずれか一つに記載の方法。
［発明１８］
前記抗ＣＤ３８抗体が、ＩｇＧ１アイソタイプである、発明１７に記載の方法。
［発明１９］
前記対象が、ヒトである、発明１～１８のいずれか一つに記載の方法。
［発明２０］
前記対象に１つ又は２つ以上の抗癌治療を施すことを更に含む、発明１～１９のいずれか一つに記載の方法。
［発明２１］
前記１つ又は２つ以上の抗癌治療が、自家幹細胞移植（ＡＳＣＴ）、放射線、手術、化学療法剤、免疫調節剤、及び標的化癌療法からなる群から選択される、発明２０に記載の方法。
［発明２２］
前記１つ又は２つ以上の抗癌治療が、レナリドミド、サリドマイド、ポマリドミド、ボルテゾミブ、カルフィルゾミブ、エロトズマブ、イキサゾミブ、メルファラン、プレドニゾン、若しくはデキサメタゾン、又はこれらの任意の組み合わせからなる群から選択される、発明２１に記載の方法。
［発明２３］
対象において癌を治療する方法であって、治療有効量のＧＰＲＣ５Ｄ×ＣＤ３二重特異性抗体を前記対象に投与して、前記癌を治療することを含み、前記対象が、以前の抗癌治療薬による治療に対して再発又は難治性である、方法。
［発明２４］
前記ＧＰＲＣ５Ｄ×ＣＤ３二重特異性抗体が、配列番号４３のＨＣＤＲ１、配列番号４４のＨＣＤＲ２、配列番号４５のＨＣＤＲ３、配列番号４６のＬＣＤＲ１、配列番号４７のＬＣＤＲ２、及び配列番号４８のＬＣＤＲ３を含むＧＰＲＣ５Ｄ結合ドメイン、並びに配列番号３３のＨＣＤＲ１、配列番号３４のＨＣＤＲ２、配列番号３５のＨＣＤＲ３、配列番号３６のＬＣＤＲ１、配列番号３７のＬＣＤＲ２、及び配列番号３８のＬＣＤＲ３を含むＣＤ３結合ドメインを含む、発明２３に記載の方法。
［発明２５］
前記ＧＰＲＣ５Ｄ結合ドメインが、配列番号４９のＶＨ及び配列番号５０のＶＬを含み、前記ＣＤ３結合ドメインが配列番号３９のＶＨ及び配列番号４０のＶＬを含む、発明２３又は２４に記載の方法。
［発明２６］
前記ＧＰＲＣ５Ｄ×ＣＤ３二重特異性抗体が、ＩｇＧ４アイソタイプであり、ＨＣ１の４０５位にフェニルアラニン及び４０９位にアルギニン、並びにＨＣ２の４０５位にロイシン及び４０９位にリジンを含み、残基の番号付けが、ＥＵインデックスに従う、発明２３～２５のいずれか一つに記載の方法。
［発明２７］
前記ＧＰＲＣ５Ｄ×ＣＤ３二重特異性抗体が、前記ＨＣ１及び前記ＨＣ２の両方の２２８位にプロリン、２３４位にアラニン、及び２３５位にアラニンを更に含む、発明２６に記載の方法。
［発明２８］
前記ＧＰＲＣ５Ｄ×ＣＤ３二重特異性抗体が、配列番号５１のＨＣ１、配列番号５２のＬＣ１、配列番号４１のＨＣ２、及び配列番号４２のＬＣ２を含む、発明２３～２７のいずれか一つに記載の方法。
［発明２９］
前記癌が、血液悪性腫瘍又は固形腫瘍である、発明２３～２８のいずれか一つに記載の方法。
［発明３０］
前記癌が、多発性骨髄腫、リンパ腫、黒色腫、形質細胞白血病、乳癌、子宮内膜癌、卵巣癌、肺癌、胃癌、前立腺癌、腎癌、肝癌、膵癌、結腸癌、食道癌、膀胱癌、又は子宮頸癌である、発明２９に記載の方法。
［発明３１］
前記多発性骨髄腫が、高リスク多発性骨髄腫である、発明３０に記載の方法。
［発明３２］
前記高リスク多発性骨髄腫を有する前記対象が、
ａ）ｔ（４；１４）（ｐ１６；ｑ３２）、
ｂ）ｔ（１４；１６）（ｑ３２；ｑ２３）、
ｃ）ｄｅｌ１７ｐ、
ｄ）１ｑＡｍｐ、
ｅ）ｔ（４；１４）（ｐ１６；ｑ３２）及びｔ（１４；１６）（ｑ３２；ｑ２３）、
ｆ）ｔ（４；１４）（ｐ１６；ｑ３２）及びｄｅｌ１７ｐ、
ｇ）ｔ（１４；１６）（ｑ３２；ｑ２３）及びｄｅｌ１７ｐ、又は
ｈ）ｔ（４；１４）（ｐ１６；ｑ３２）、ｔ（１４；１６）（ｑ３２；ｑ２３）及びｄｅｌ１７ｐ、又はこれらの任意の組み合わせを含む１つ又は２つ以上の染色体異常を有する、発明３１に記載の方法。
［発明３３］
前記対象が、抗ＣＤ３８抗体、レナリドミド、ボルテゾミブ、ポマリドミド、カルフィルゾミブ、エロトズマブ、イキサゾミブ、メルファラン、若しくはサリドマイド、又はこれらの任意の組み合わせによる治療に対して難治又は再発性である、発明２３～３２のいずれか一つに記載の方法。
［発明３４］
前記対象が、前記抗ＣＤ３８抗体による治療に対して再発又は難治性である、発明３３に記載の方法。
［発明３５］
前記抗ＣＤ３８抗体が、配列番号６のＨＣＤＲ１、配列番号７のＨＣＤＲ２、配列番号８のＨＣＤＲ３、配列番号９のＬＣＤＲ１、配列番号１０のＬＣＤＲ２、及び配列番号１１のＬＣＤＲ３を含む、発明２３～３４のいずれか一つに記載の方法。
［発明３６］
前記抗ＣＤ３８抗体が、配列番号４のＶＨ及び配列番号５のＶＬを含む、発明２３～３５のいずれか一つに記載の方法。
［発明３７］
前記抗ＣＤ３８抗体が、ＩｇＧ１アイソタイプである、発明２３～３６のいずれか一つに記載の方法。
［発明３８］
前記抗ＣＤ３８抗体が、配列番号１２のＨＣ及び配列番号１３のＬＣを含む、発明２３～３７のいずれか一つに記載の方法。
［発明３９］
前記抗ＣＤ３８抗体が、
ａ）配列番号１４のＶＨ及び配列番号１５のＶＬ、
ｂ）配列番号１６のＶＨ及び配列番号１７のＶＬ、
ｃ）配列番号１８のＶＨ及び配列番号１９のＶＬ、又は
ｄ）配列番号２０のＶＨ及び配列番号２１のＶＬを含む、発明２３～３４のいずれか一つに記載の方法。
［発明４０］
前記抗ＣＤ３８抗体が、ＩｇＧ１アイソタイプである、発明３９に記載の方法。
［発明４１］
前記対象が、ヒトである、発明２３～４０のいずれか一つに記載の方法。
［発明４２］
前記対象に１つ又は２つ以上の抗癌治療を施すことを更に含む、発明２３～４１のいずれか一つに記載の方法。
［発明４３］
前記１つ又は２つ以上の抗癌治療が、自家幹細胞移植（ＡＳＣＴ）、放射線、手術、化学療法剤、免疫調節剤、及び標的化癌療法からなる群から選択される、発明４２に記載の方法。
［発明４４］
前記１つ又は２つ以上の抗癌治療が、レナリドミド、サリドマイド、ポマリドミド、ボルテゾミブ、カルフィルゾミブ、エロトズマブ、イキサゾミブ、メルファラン、デキサメタゾン、ビンクリスチン、シクロホスファミド、ヒドロキシダウノルビシン、プレドニゾン、リツキシマブ、イマチニブ、ダサチニブ、ニロチニブ、ボスチニブ、ポナチニブ、バフェチニブ、サラカチニブ、トザセルチブ、若しくはダヌセルチブ、シタラビン、ダウノルビシン、イダルビシン、ミトキサントロン、ヒドロキシウレア、デシタビン、クラドリビン、フルダラビン、トポテカン、エトポシド６－チオグアニン、コルチコステロイド、メトトレキサート、６－メルカプトプリン、アザシチジン、三酸化ヒ素、及び全トランス型レチノイン酸、又はこれらの任意の組み合わせからなる群から選択される、発明４２に記載の方法。
The disclosure of each patent, patent application, and publication cited or described herein is hereby incorporated by reference in its entirety.
Listed below are the inventions originally claimed in this application.
[Invention 1]
A method of treating cancer in a subject, comprising administering to said subject a therapeutically effective amount of a BCMAxCD3 bispecific antibody to treat said cancer, wherein said subject is free of previous anti-cancer therapeutics relapsed or refractory to treatment with
[Invention 2]
A BCMA wherein said BCMAxCD3 bispecific antibody comprises HCDR1 of SEQ ID NO:23, HCDR2 of SEQ ID NO:24, HCDR3 of SEQ ID NO:25, LCDR1 of SEQ ID NO:26, LCDR2 of SEQ ID NO:27, and LCDR3 of SEQ ID NO:28 Invention 2, comprising a binding domain and a CD3 binding domain comprising HCDR1 of SEQ ID NO:33, HCDR2 of SEQ ID NO:34, HCDR3 of SEQ ID NO:35, LCDR1 of SEQ ID NO:36, LCDR2 of SEQ ID NO:37, and LCDR3 of SEQ ID NO:38 The method described in .
[Invention 3]
4. The method of invention 2 or 3, wherein the BCMA binding domain comprises the VH of SEQ ID NO:29 and the VL of SEQ ID NO:30, and the CD3 binding domain comprises the VH of SEQ ID NO:39 and the VL of SEQ ID NO:40.
[Invention 4]
said BCMAxCD3 bispecific antibody is of the IgG4 isotype and contains phenylalanine at position 405 and arginine at position 409 of HC1 and leucine at position 405 and lysine at position 409 of HC2, and the residue numbering is A method according to any one of inventions 1-3 according to the EU index.
[Invention 5]
5. The method of claim 4, wherein said BCMAxCD3 bispecific antibody further comprises proline at position 228, alanine at position 234, and alanine at position 235 of both said HC1 and said HC2.
[Invention 6]
6. The method of any one of Inventions 1-5, wherein the BCMAxCD3 bispecific antibody comprises HC1 of SEQ ID NO:31, LC1 of SEQ ID NO:32, HC2 of SEQ ID NO:41, and LC2 of SEQ ID NO:42. Method.
[Invention 7]
The method according to any one of Inventions 1 to 6, wherein the cancer is hematological malignancy.
[Invention 8]
The method according to invention 7, wherein said hematologic malignancy is multiple myeloma.
[Invention 9]
The method of claim 8, wherein said multiple myeloma is high-risk multiple myeloma.
[Invention 10]
wherein said subject with said high-risk multiple myeloma is
a) t(4;14)(p16;q32),
b) t(14;16)(q32;q23);
c) del17p,
d) 1qAmp,
e) t(4;14)(p16;q32) and t(14;16)(q32;q23),
f) t(4;14)(p16;q32) and del17p,
g) t(14;16)(q32;q23) and del17p, or
h) having one or more chromosomal abnormalities comprising t(4;14)(p16;q32), t(14;16)(q32;q23) and del17p, or any combination thereof, Invention 9 The method described in .
[Invention 11]
Any of Inventions 1-10, wherein said subject is refractory or relapsed to treatment with an anti-CD38 antibody, lenalidomide, bortezomib, pomalidomide, carfilzomib, elotuzumab, ixazomib, melphalan, or thalidomide, or any combination thereof. or the method described in one.
[Invention 12]
The method of invention 11, wherein said subject is relapsed to treatment with said anti-CD38 antibody.
[Invention 13]
The method of Inventions 1-12, wherein the anti-CD38 antibody comprises HCDR1 of SEQ ID NO:6, HCDR2 of SEQ ID NO:7, HCDR3 of SEQ ID NO:8, LCDR1 of SEQ ID NO:9, LCDR2 of SEQ ID NO:10, and LCDR3 of SEQ ID NO:11. A method according to any one of the preceding claims.
[Invention 14]
14. The method of any one of inventions 1-13, wherein said anti-CD38 antibody comprises the VH of SEQ ID NO:4 and the VL of SEQ ID NO:5.
[Invention 15]
The method of any one of inventions 1-14, wherein said anti-CD38 antibody is of the IgG1 isotype.
[Invention 16]
16. The method of any one of inventions 1-15, wherein said anti-CD38 antibody comprises HC of SEQ ID NO: 12 and LC of SEQ ID NO: 13.
[Invention 17]
The anti-CD38 antibody is
a) VH of SEQ ID NO: 14 and VL of SEQ ID NO: 15,
b) VH of SEQ ID NO: 16 and VL of SEQ ID NO: 17,
c) VH of SEQ ID NO: 18 and VL of SEQ ID NO: 19, or
d) A method according to any one of inventions 1-12, comprising the VH of SEQ ID NO:20 and the VL of SEQ ID NO:21.
[Invention 18]
The method of invention 17, wherein said anti-CD38 antibody is of the IgG1 isotype.
[Invention 19]
The method of any one of Inventions 1-18, wherein the subject is a human.
[Invention 20]
20. The method of any one of inventions 1-19, further comprising administering one or more anti-cancer therapies to said subject.
[Invention 21]
21. The method of claim 20, wherein said one or more anti-cancer therapies are selected from the group consisting of autologous stem cell transplantation (ASCT), radiation, surgery, chemotherapeutic agents, immunomodulatory agents, and targeted cancer therapies. Method.
[Invention 22]
The invention wherein said one or more anti-cancer therapies are selected from the group consisting of lenalidomide, thalidomide, pomalidomide, bortezomib, carfilzomib, elotuzumab, ixazomib, melphalan, prednisone, or dexamethasone, or any combination thereof. 21. The method according to 21.
[Invention 23]
A method of treating cancer in a subject comprising administering to said subject a therapeutically effective amount of a GPRC5DxCD3 bispecific antibody to treat said cancer, wherein said subject is free of previous anti-cancer therapeutics relapsed or refractory to treatment with
[Invention 24]
GPRC5D wherein said GPRC5DxCD3 bispecific antibody comprises HCDR1 of SEQ ID NO:43, HCDR2 of SEQ ID NO:44, HCDR3 of SEQ ID NO:45, LCDR1 of SEQ ID NO:46, LCDR2 of SEQ ID NO:47, and LCDR3 of SEQ ID NO:48 Invention 23, comprising a binding domain and a CD3 binding domain comprising HCDR1 of SEQ ID NO:33, HCDR2 of SEQ ID NO:34, HCDR3 of SEQ ID NO:35, LCDR1 of SEQ ID NO:36, LCDR2 of SEQ ID NO:37, and LCDR3 of SEQ ID NO:38 The method described in .
[Invention 25]
25. The method of invention 23 or 24, wherein said GPRC5D binding domain comprises VH of SEQ ID NO:49 and VL of SEQ ID NO:50, and said CD3 binding domain comprises VH of SEQ ID NO:39 and VL of SEQ ID NO:40.
[Invention 26]
said GPRC5DxCD3 bispecific antibody is of the IgG4 isotype and contains phenylalanine at position 405 and arginine at position 409 of HC1 and leucine at position 405 and lysine at position 409 of HC2, wherein the residue numbering is 26. The method of any one of inventions 23-25 according to the EU index.
[Invention 27]
The method of invention 26, wherein said GPRC5DxCD3 bispecific antibody further comprises proline at position 228, alanine at position 234, and alanine at position 235 of both said HC1 and said HC2.
[Invention 28]
28. The method of any one of inventions 23-27, wherein the GPRC5DxCD3 bispecific antibody comprises HC1 of SEQ ID NO:51, LC1 of SEQ ID NO:52, HC2 of SEQ ID NO:41, and LC2 of SEQ ID NO:42. Method.
[Invention 29]
The method of any one of inventions 23-28, wherein said cancer is a hematologic malignancy or a solid tumor.
[Invention 30]
The cancer is multiple myeloma, lymphoma, melanoma, plasma cell leukemia, breast cancer, endometrial cancer, ovarian cancer, lung cancer, gastric cancer, prostate cancer, renal cancer, liver cancer, pancreatic cancer, colon cancer, esophageal cancer, bladder cancer , or cervical cancer.
[Invention 31]
31. The method of invention 30, wherein said multiple myeloma is high-risk multiple myeloma.
[Invention 32]
wherein said subject with said high-risk multiple myeloma is
a) t(4;14)(p16;q32),
b) t(14;16)(q32;q23),
c) del17p,
d) 1qAmp,
e) t(4;14)(p16;q32) and t(14;16)(q32;q23),
f) t(4;14)(p16;q32) and del17p,
g) t(14;16)(q32;q23) and del17p, or
h) having one or more chromosomal abnormalities comprising t(4;14)(p16;q32), t(14;16)(q32;q23) and del17p, or any combination thereof, Invention 31 The method described in .
[Invention 33]
Any of inventions 23-32, wherein said subject is refractory or relapsed to treatment with an anti-CD38 antibody, lenalidomide, bortezomib, pomalidomide, carfilzomib, elotuzumab, ixazomib, melphalan, or thalidomide, or any combination thereof or the method described in one.
[Invention 34]
34. The method of invention 33, wherein said subject is relapsed or refractory to treatment with said anti-CD38 antibody.
[Invention 35]
The method of Inventions 23-34, wherein the anti-CD38 antibody comprises HCDR1 of SEQ ID NO:6, HCDR2 of SEQ ID NO:7, HCDR3 of SEQ ID NO:8, LCDR1 of SEQ ID NO:9, LCDR2 of SEQ ID NO:10, and LCDR3 of SEQ ID NO:11. A method according to any one of the preceding claims.
[Invention 36]
36. The method of any one of inventions 23-35, wherein said anti-CD38 antibody comprises the VH of SEQ ID NO:4 and the VL of SEQ ID NO:5.
[Invention 37]
The method of any one of Inventions 23-36, wherein said anti-CD38 antibody is of the IgG1 isotype.
[Invention 38]
38. The method of any one of inventions 23-37, wherein said anti-CD38 antibody comprises HC of SEQ ID NO: 12 and LC of SEQ ID NO: 13.
[Invention 39]
The anti-CD38 antibody is
a) VH of SEQ ID NO: 14 and VL of SEQ ID NO: 15,
b) VH of SEQ ID NO: 16 and VL of SEQ ID NO: 17,
c) VH of SEQ ID NO: 18 and VL of SEQ ID NO: 19, or
d) A method according to any one of inventions 23-34, comprising the VH of SEQ ID NO:20 and the VL of SEQ ID NO:21.
[Invention 40]
The method of invention 39, wherein said anti-CD38 antibody is of the IgG1 isotype.
[Invention 41]
The method of any one of Inventions 23-40, wherein the subject is a human.
[Invention 42]
42. The method of any one of inventions 23-41, further comprising administering one or more anti-cancer therapies to said subject.
[Invention 43]
43. The method of claim 42, wherein said one or more anti-cancer therapies are selected from the group consisting of autologous stem cell transplantation (ASCT), radiation, surgery, chemotherapeutic agents, immunomodulatory agents, and targeted cancer therapies. Method.
[Invention 44]
the one or more anti-cancer treatments are lenalidomide, thalidomide, pomalidomide, bortezomib, carfilzomib, elotuzumab, ixazomib, melphalan, dexamethasone, vincristine, cyclophosphamide, hydroxydaunorubicin, prednisone, rituximab, imatinib, dasatinib, Nilotinib, bosutinib, ponatinib, bafetinib, salacatinib, tozasertib, or danusertib, cytarabine, daunorubicin, idarubicin, mitoxantrone, hydroxyurea, decitabine, cladribine, fludarabine, topotecan, etoposide 6-thioguanine, corticosteroids, methotrexate, 6-mercapto 43. The method of invention 42, wherein the method is selected from the group consisting of purines, azacytidine, arsenic trioxide, and all-trans retinoic acid, or any combination thereof.
Claims (14)
ｉｉ）前記ＢＣＭＡ結合ドメインが、配列番号２９のＶＨ及び配列番号３０のＶＬを含み、前記ＣＤ３結合ドメインが、配列番号３９のＶＨ及び配列番号４０のＶＬを含む、請求項１に記載の組成物。 ii) the BCMA binding domain comprises the VH of SEQ ID NO:29 and the VL of SEQ ID NO:30, and the CD3 binding domain comprises the VH of SEQ ID NO:39 and the VL of SEQ ID NO:40; .
場合により、前記ＢＣＭＡ×ＣＤ３二重特異性抗体が、前記ＨＣ１及び前記ＨＣ２の両方の２２８位にプロリン、２３４位にアラニン、及び２３５位にアラニンを更に含む、 optionally, said BCMAxCD3 bispecific antibody further comprises a proline at position 228, an alanine at position 234, and an alanine at position 235 of both said HC1 and said HC2;
ｉｉ）前記ＢＣＭＡ×ＣＤ３二重特異性抗体が、配列番号３１のＨＣ１、配列番号３２のＬＣ１、配列番号４１のＨＣ２、及び配列番号４２のＬＣ２を含む、 ii) said BCMAxCD3 bispecific antibody comprises HC1 of SEQ ID NO:31, LC1 of SEQ ID NO:32, HC2 of SEQ ID NO:41, and LC2 of SEQ ID NO:42;
ｉｉｉ）前記癌が、血液悪性腫瘍であり、 iii) said cancer is a hematologic malignancy;
場合により、前記血液悪性腫瘍が、高リスク多発性骨髄腫を含む多発性骨髄腫であり、 optionally, said hematologic malignancy is multiple myeloma, including high-risk multiple myeloma;
例えば、前記高リスク多発性骨髄腫を有する前記対象が、 For example, if said subject with said high-risk multiple myeloma is
ａ）ｔ（４；１４）（ｐ１６；ｑ３２）、 a) t(4;14)(p16;q32),
ｂ）ｔ（１４；１６）（ｑ３２；ｑ２３）； b) t(14;16)(q32;q23);
ｃ）ｄｅｌ１７ｐ、 c) del17p,
ｄ）１ｑＡｍｐ、 d) 1qAmp,
ｅ）ｔ（４；１４）（ｐ１６；ｑ３２）及びｔ（１４；１６）（ｑ３２；ｑ２３）、 e) t(4;14)(p16;q32) and t(14;16)(q32;q23),
ｆ）ｔ（４；１４）（ｐ１６；ｑ３２）及びｄｅｌ１７ｐ、 f) t(4;14)(p16;q32) and del17p,
ｇ）ｔ（１４；１６）（ｑ３２；ｑ２３）及びｄｅｌ１７ｐ、又は g) t(14;16)(q32;q23) and del17p, or
ｈ）ｔ（４；１４）（ｐ１６；ｑ３２）、ｔ（１４；１６）（ｑ３２；ｑ２３）及びｄｅｌ１７ｐ、又はこれらの任意の組み合わせを含む１つ又は２つ以上の染色体異常を有する、及び／又は h) has one or more chromosomal abnormalities including t(4;14)(p16;q32), t(14;16)(q32;q23) and del17p, or any combination thereof, and/ or
ｉｖ）前記対象が、抗ＣＤ３８抗体、レナリドミド、ボルテゾミブ、ポマリドミド、カルフィルゾミブ、エロトズマブ、イキサゾミブ、メルファラン、若しくはサリドマイド、又はこれらの任意の組み合わせによる治療に対して難治又は再発性であり、 iv) said subject is refractory or relapsed to treatment with an anti-CD38 antibody, lenalidomide, bortezomib, pomalidomide, carfilzomib, elotuzumab, ixazomib, melphalan, or thalidomide, or any combination thereof;
場合により、前記対象が、前記抗ＣＤ３８抗体による治療に対して再発性である、請求項１又は２に記載の組成物。 3. The composition of claim 1 or 2, wherein optionally said subject is relapsed to treatment with said anti-CD38 antibody.
ｉｉ）前記抗ＣＤ３８抗体が、配列番号４のＶＨ及び配列番号５のＶＬを含む、 ii) said anti-CD38 antibody comprises the VH of SEQ ID NO:4 and the VL of SEQ ID NO:5;
ｉｉｉ）前記抗ＣＤ３８抗体が、ＩｇＧ１アイソタイプである、及び／又は iii) said anti-CD38 antibody is of the IgG1 isotype, and/or
ｉｖ）前記抗ＣＤ３８抗体が、配列番号１２のＨＣ及び配列番号１３のＬＣを含む、 iv) said anti-CD38 antibody comprises HC of SEQ ID NO: 12 and LC of SEQ ID NO: 13;
請求項１～３のいずれか一項に記載の組成物。A composition according to any one of claims 1-3.
ａ）配列番号１４のＶＨ及び配列番号１５のＶＬ、 a) VH of SEQ ID NO: 14 and VL of SEQ ID NO: 15,
ｂ）配列番号１６のＶＨ及び配列番号１７のＶＬ、 b) VH of SEQ ID NO: 16 and VL of SEQ ID NO: 17,
ｃ）配列番号１８のＶＨ及び配列番号１９のＶＬ、又は c) VH of SEQ ID NO: 18 and VL of SEQ ID NO: 19, or
ｄ）配列番号２０のＶＨ及び配列番号２１のＶＬを含み、 d) comprising the VH of SEQ ID NO:20 and the VL of SEQ ID NO:21;
場合により、前記ａ）、ｂ）、ｃ）又はｄ）の抗ＣＤ３８抗体が、ＩｇＧ１アイソタイプである、 Optionally, said anti-CD38 antibody of a), b), c) or d) is of the IgG1 isotype.
請求項１～３のいずれか一項に記載の組成物。A composition according to any one of claims 1-3.
ｉ）前記１つ又は２つ以上の抗癌治療が、自家幹細胞移植（ＡＳＣＴ）、放射線、手術、化学療法剤、免疫調節剤、及び標的化癌療法からなる群から選択される、及び／又は i) said one or more anti-cancer therapies are selected from the group consisting of autologous stem cell transplantation (ASCT), radiation, surgery, chemotherapeutic agents, immunomodulatory agents, and targeted cancer therapies; and/or
ｉｉ）前記１つ又は２つ以上の抗癌治療が、レナリドミド、サリドマイド、ポマリドミド、ボルテゾミブ、カルフィルゾミブ、エロトズマブ、イキサゾミブ、メルファラン、プレドニゾン、若しくはデキサメタゾン、又はこれらの任意の組み合わせからなる群から選択される、 ii) said one or more anti-cancer therapies are selected from the group consisting of lenalidomide, thalidomide, pomalidomide, bortezomib, carfilzomib, elotuzumab, ixazomib, melphalan, prednisone, or dexamethasone, or any combination thereof ,
請求項１～６のいずれか一項に記載の組成物。A composition according to any one of claims 1-6.
ｉｉ）前記ＧＰＲＣ５Ｄ結合ドメインが、配列番号４９のＶＨ及び配列番号５０のＶＬを含み、前記ＣＤ３結合ドメインが配列番号３９のＶＨ及び配列番号４０のＶＬを含む、 ii) said GPRC5D binding domain comprises VH of SEQ ID NO:49 and VL of SEQ ID NO:50, and said CD3 binding domain comprises VH of SEQ ID NO:39 and VL of SEQ ID NO:40;
請求項８に記載の組成物。A composition according to claim 8 .
場合により、前記ＧＰＲＣ５Ｄ×ＣＤ３二重特異性抗体が、前記ＨＣ１及び前記ＨＣ２の両方の２２８位にプロリン、２３４位にアラニン、及び２３５位にアラニンを更に含む、 optionally, said GPRC5DxCD3 bispecific antibody further comprises a proline at position 228, an alanine at position 234, and an alanine at position 235 of both said HC1 and said HC2;
ｉｉ）前記ＧＰＲＣ５Ｄ×ＣＤ３二重特異性抗体が、配列番号５１のＨＣ１、配列番号５２のＬＣ１、配列番号４１のＨＣ２、及び配列番号４２のＬＣ２を含む、 ii) said GPRC5DxCD3 bispecific antibody comprises HC1 of SEQ ID NO:51, LC1 of SEQ ID NO:52, HC2 of SEQ ID NO:41, and LC2 of SEQ ID NO:42;
ｉｉｉ）前記癌が、血液悪性腫瘍又は固形腫瘍であり、 iii) said cancer is a hematologic malignancy or solid tumor;
場合により、前記癌が、高リスク多発性骨髄腫を含む多発性骨髄腫、リンパ腫、黒色腫、形質細胞白血病、乳癌、子宮内膜癌、卵巣癌、肺癌、胃癌、前立腺癌、腎癌、肝癌、膵癌、結腸癌、食道癌、膀胱癌、又は子宮頸癌であり、 Optionally, said cancer is multiple myeloma, including high-risk multiple myeloma, lymphoma, melanoma, plasma cell leukemia, breast cancer, endometrial cancer, ovarian cancer, lung cancer, stomach cancer, prostate cancer, renal cancer, liver cancer , pancreatic cancer, colon cancer, esophageal cancer, bladder cancer, or cervical cancer;
例えば、前記高リスク多発性骨髄腫を有する前記対象が、 For example, if said subject with said high-risk multiple myeloma is
ａ）ｔ（４；１４）（ｐ１６；ｑ３２）、 a) t(4;14)(p16;q32),
ｂ）ｔ（１４；１６）（ｑ３２；ｑ２３）、 b) t(14;16)(q32;q23),
ｃ）ｄｅｌ１７ｐ、 c) del17p,
ｄ）１ｑＡｍｐ、 d) 1qAmp,
ｅ）ｔ（４；１４）（ｐ１６；ｑ３２）及びｔ（１４；１６）（ｑ３２；ｑ２３）、 e) t(4;14)(p16;q32) and t(14;16)(q32;q23),
ｆ）ｔ（４；１４）（ｐ１６；ｑ３２）及びｄｅｌ１７ｐ、 f) t(4;14)(p16;q32) and del17p,
ｇ）ｔ（１４；１６）（ｑ３２；ｑ２３）及びｄｅｌ１７ｐ、又は g) t(14;16)(q32;q23) and del17p, or
ｈ）ｔ（４；１４）（ｐ１６；ｑ３２）、ｔ（１４；１６）（ｑ３２；ｑ２３）及びｄｅｌ１７ｐ、又はこれらの任意の組み合わせを含む１つ又は２つ以上の染色体異常を有する、及び／又は h) has one or more chromosomal abnormalities including t(4;14)(p16;q32), t(14;16)(q32;q23) and del17p, or any combination thereof, and/ or
ｉｖ）前記対象が、抗ＣＤ３８抗体、レナリドミド、ボルテゾミブ、ポマリドミド、カルフィルゾミブ、エロトズマブ、イキサゾミブ、メルファラン、若しくはサリドマイド、又はこれらの任意の組み合わせによる治療に対して難治又は再発性であり、 iv) said subject is refractory or relapsed to treatment with an anti-CD38 antibody, lenalidomide, bortezomib, pomalidomide, carfilzomib, elotuzumab, ixazomib, melphalan, or thalidomide, or any combination thereof;
場合により、前記対象が、前記抗ＣＤ３８抗体による治療に対して再発又は難治性である、 optionally, said subject is relapsed or refractory to treatment with said anti-CD38 antibody;
請求項８又は９に記載の組成物。A composition according to claim 8 or 9.
ｉｉ）前記抗ＣＤ３８抗体が、配列番号４のＶＨ及び配列番号５のＶＬを含む、 ii) said anti-CD38 antibody comprises the VH of SEQ ID NO:4 and the VL of SEQ ID NO:5;
ｉｉｉ）前記抗ＣＤ３８抗体が、ＩｇＧ１アイソタイプである、及び／又は iii) said anti-CD38 antibody is of the IgG1 isotype, and/or
ｉｖ）前記抗ＣＤ３８抗体が、配列番号１２のＨＣ及び配列番号１３のＬＣを含む、 iv) said anti-CD38 antibody comprises HC of SEQ ID NO: 12 and LC of SEQ ID NO: 13;
請求項８～１０のいずれか一項に記載の組成物。A composition according to any one of claims 8-10.
ａ）配列番号１４のＶＨ及び配列番号１５のＶＬ、 a) VH of SEQ ID NO: 14 and VL of SEQ ID NO: 15,
ｂ）配列番号１６のＶＨ及び配列番号１７のＶＬ、 b) VH of SEQ ID NO: 16 and VL of SEQ ID NO: 17,
ｃ）配列番号１８のＶＨ及び配列番号１９のＶＬ、又は c) VH of SEQ ID NO: 18 and VL of SEQ ID NO: 19, or
ｄ）配列番号２０のＶＨ及び配列番号２１のＶＬを含み、 d) comprising the VH of SEQ ID NO:20 and the VL of SEQ ID NO:21;
場合により、前記ａ）、ｂ）、ｃ）又はｄ）の抗ＣＤ３８抗体が、ＩｇＧ１アイソタイプである、 Optionally, said anti-CD38 antibody of a), b), c) or d) is of the IgG1 isotype.
請求項８～１０のいずれか一項に記載の組成物。A composition according to any one of claims 8-10.
ｉ）前記１つ又は２つ以上の抗癌治療が、自家幹細胞移植（ＡＳＣＴ）、放射線、手術、化学療法剤、免疫調節剤、及び標的化癌療法からなる群から選択される、及び／又は i) said one or more anti-cancer therapies are selected from the group consisting of autologous stem cell transplantation (ASCT), radiation, surgery, chemotherapeutic agents, immunomodulatory agents, and targeted cancer therapies; and/or
ｉｉ）前記１つ又は２つ以上の抗癌治療が、レナリドミド、サリドマイド、ポマリドミド、ボルテゾミブ、カルフィルゾミブ、エロトズマブ、イキサゾミブ、メルファラン、デキサメタゾン、ビンクリスチン、シクロホスファミド、ヒドロキシダウノルビシン、プレドニゾン、リツキシマブ、イマチニブ、ダサチニブ、ニロチニブ、ボスチニブ、ポナチニブ、バフェチニブ、サラカチニブ、トザセルチブ、若しくはダヌセルチブ、シタラビン、ダウノルビシン、イダルビシン、ミトキサントロン、ヒドロキシウレア、デシタビン、クラドリビン、フルダラビン、トポテカン、エトポシド６－チオグアニン、コルチコステロイド、メトトレキサート、６－メルカプトプリン、アザシチジン、三酸化ヒ素、及び全トランス型レチノイン酸、又はこれらの任意の組み合わせからなる群から選択される、 ii) said one or more anti-cancer therapies are lenalidomide, thalidomide, pomalidomide, bortezomib, carfilzomib, elotuzumab, ixazomib, melphalan, dexamethasone, vincristine, cyclophosphamide, hydroxydaunorubicin, prednisone, rituximab, imatinib; dasatinib, nilotinib, bosutinib, ponatinib, bafetinib, salacatinib, tozasertib, or danusertib, cytarabine, daunorubicin, idarubicin, mitoxantrone, hydroxyurea, decitabine, cladribine, fludarabine, topotecan, etoposide 6-thioguanine, corticosteroids, methotrexate, 6 - selected from the group consisting of mercaptopurine, azacytidine, arsenic trioxide, and all-trans retinoic acid, or any combination thereof;
請求項８～１３のいずれか一項に記載の組成物。A composition according to any one of claims 8-13.
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