JPWO2020056077A5 - - Google Patents
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- JPWO2020056077A5 JPWO2020056077A5 JP2021539336A JP2021539336A JPWO2020056077A5 JP WO2020056077 A5 JPWO2020056077 A5 JP WO2020056077A5 JP 2021539336 A JP2021539336 A JP 2021539336A JP 2021539336 A JP2021539336 A JP 2021539336A JP WO2020056077 A5 JPWO2020056077 A5 JP WO2020056077A5
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- 102000004965 antibodies Human genes 0.000 claims description 65
- 108090001123 antibodies Proteins 0.000 claims description 65
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 50
- 108010045030 monoclonal antibodies Proteins 0.000 claims description 38
- 102000005614 monoclonal antibodies Human genes 0.000 claims description 38
- 239000000427 antigen Substances 0.000 claims description 37
- 102000038129 antigens Human genes 0.000 claims description 37
- 108091007172 antigens Proteins 0.000 claims description 37
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- 150000007523 nucleic acids Chemical class 0.000 claims description 9
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- LQBVNQSMGBZMKD-UHFFFAOYSA-N 4-[4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexen-1-yl]methyl]piperazin-1-yl]-N-[3-nitro-4-(oxan-4-ylmethylamino)phenyl]sulfonyl-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide Chemical compound C=1C=C(Cl)C=CC=1C=1CC(C)(C)CCC=1CN(CC1)CCN1C(C=C1OC=2C=C3C=CNC3=NC=2)=CC=C1C(=O)NS(=O)(=O)C(C=C1[N+]([O-])=O)=CC=C1NCC1CCOCC1 LQBVNQSMGBZMKD-UHFFFAOYSA-N 0.000 claims description 4
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- WIJZXSAJMHAVGX-DHLKQENFSA-N (2S)-N-[(1S)-1-(2-chlorophenyl)-2-[(3,3-difluorocyclobutyl)amino]-2-oxoethyl]-1-(4-cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide Chemical compound FC1=CN=CC(N([C@H](C(=O)NC2CC(F)(F)C2)C=2C(=CC=CC=2)Cl)C(=O)[C@H]2N(C(=O)CC2)C=2N=CC=C(C=2)C#N)=C1 WIJZXSAJMHAVGX-DHLKQENFSA-N 0.000 claims description 2
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Description
本明細書に記載されている任意の方法または組成物は、本明細書に記載されている任意の他の方法または組成物に関して実施されてもよいことが企図されている。本開示の他の目的、特徴および利点は、以下の詳細な説明から明らかとなるであろう。しかしながら、詳細な説明および特定の例は、本発明の特定の態様を示すが、それは説明のためにのみ与えられることが理解されるべきであり、本開示の精神および範囲内で様々な変更および改良がこの詳細な説明から当業者に明らかとなるであろう。
[本発明1001]
（a）SEQ ID NO:100に示されるアミノ酸配列を有する重鎖相補性決定領域（HC-CDR）1、
SEQ ID NO:101に示されるアミノ酸配列を有するHC-CDR2、および
SEQ ID NO:102、224または227に示されるアミノ酸配列を有するHC-CDR3
を含む、重鎖（HC）可変領域（VH）、および
該HC-CDRのうちの1つまたは複数が1つ、2つ、または3つのアミノ酸置換、付加、欠失、またはこれらの組合せを有する、そのバリアント、ならびに
（b）SEQ ID NO:104に示されるアミノ酸配列を有する軽鎖相補性決定領域（LC-CDR）、
アミノ酸配列KASまたはSEQ ID NO:233に示されるアミノ酸配列を有するLC-CDR2、および
SEQ ID NO:105または234に示されるアミノ酸配列を有するLC-CDR3
を含む、軽鎖（LC）可変領域（VL）、および
該LC-CDRのうちの1つまたは複数が1つ、2つ、または3つのアミノ酸置換、付加、欠失、またはこれらの組合せを有する、そのバリアント
を含む、単離されたモノクローナル抗体またはその抗原結合断片。
[本発明1002]
（a）前記HC-CDR1が、SEQ ID NO:100に示されるアミノ酸配列を有し、前記HC-CDR2が、SEQ ID NO:101に示されるアミノ酸配列を有し、かつ前記HC-CDR3が、SEQ ID NO:102、224または227に示されるアミノ酸配列を有し、かつ（b）前記LC-CDR1が、SEQ ID NO:104に示されるアミノ酸配列を有し、前記HC-CDR2が、アミノ酸配列KASまたはSEQ ID NO:233に示されるアミノ酸配列を有し、かつ前記HC-CDR3が、SEQ ID NO:105または234に示されるアミノ酸配列を有する、本発明1001の単離されたモノクローナル抗体またはその抗原結合断片。
[本発明1003]
前記単離されたモノクローナル抗体が、マウス抗体、齧歯動物抗体、ウサギ抗体、キメラ抗体、ヒト化抗体、またはヒト抗体である、本発明1001の単離されたモノクローナル抗体またはその抗原結合断片。
[本発明1004]
前記抗原結合断片が、組換えScFv（単鎖可変断片）抗体、Fab断片、F（ab'）2断片、またはFv断片である、本発明1001の単離されたモノクローナル抗体またはその抗原結合断片。
[本発明1005]
前記単離されたモノクローナル抗体が、ウサギ抗体またはキメラ抗体である、本発明1001の単離されたモノクローナル抗体またはその抗原結合断片。
[本発明1006]
（a）前記VHが、SEQ ID NO:99と少なくとも約90％同一のアミノ酸配列を有し、かつ（b）前記VLが、SEQ ID NO:103と少なくとも90％同一のアミノ酸配列を有する、本発明1005の単離されたモノクローナル抗体またはその抗原結合断片。
[本発明1007]
（a）前記VHが、SEQ ID NO:99に示されるアミノ酸配列を有し、かつ（b）前記VLが、SEQ ID NO:103に示されるアミノ酸配列を有する、本発明1005の単離されたモノクローナル抗体またはその抗原結合断片。
[本発明1008]
前記単離されたモノクローナル抗体がヒト化抗体である、本発明1001の単離されたモノクローナル抗体またはその抗原結合断片。
[本発明1009]
（a）前記VHが、SEQ ID NO:223、225、226、228、229、230または231と少なくとも約90％同一のアミノ酸配列を有し、かつ（b）前記VLが、SEQ ID NO:232、235、236または237と少なくとも90％同一のアミノ酸配列を有する、本発明1008の単離されたモノクローナル抗体またはその抗原結合断片。
[本発明1010]
（a）前記VHが、SEQ ID NO:223、225、226、228、229、230または231に示されるアミノ酸配列を有し、かつ（b）前記VLが、SEQ ID NO:232、235、236または237に示されるアミノ酸配列を有する、本発明1008の単離されたモノクローナル抗体またはその抗原結合断片。
[本発明1011]
同じエピトープについて、本発明1001～1010のいずれかの単離されたモノクローナル抗体またはその抗原結合断片と競合する、単離されたモノクローナル抗体またはその抗原結合断片。
[本発明1012]
本発明1001～1011のいずれかの単離されたモノクローナル抗体またはその抗原結合断片と、薬学的に許容される担体とを含む、薬学的組成物。
[本発明1013]
本発明1001～1011のいずれかの単離されたモノクローナル抗体をコードする、単離された核酸。
[本発明1014]
本発明1013の単離された核酸を含む、ベクター。
[本発明1015]
本発明1014のベクターを含む、宿主細胞。
[本発明1016]
哺乳動物細胞である、本発明1015の宿主細胞。
[本発明1017]
CHO細胞である、本発明1015の宿主細胞。
[本発明1018]
本発明1001～1011のいずれかの単離されたモノクローナル抗体をコードまたは産生する、ハイブリドーマ。
[本発明1019]
抗体を製造する方法であって、該抗体を発現するのに好適な条件下で本発明1015の宿主細胞を培養する工程、および該抗体を回収する工程を含む、方法。
[本発明1020]
本発明1001～1011のいずれかの抗原結合断片を含む、キメラ抗原受容体（CAR）タンパク質。
[本発明1021]
本発明1020のCARタンパク質をコードする、単離された核酸。
[本発明1022]
本発明1021の単離された核酸を含む、ベクター。
[本発明1023]
本発明1021の単離された核酸を含む、操作された細胞。
[本発明1024]
T細胞、NK細胞、またはマクロファージである、本発明1023の操作された細胞。
[本発明1025]
対象においてがんを治療するかまたはその影響を改善する方法であって、治療有効量の本発明1001～1011のいずれかの抗体もしくはその抗原結合断片または本発明1023もしくは1024の操作された細胞を該対象に投与する工程を含む、方法。
[本発明1026]
前記対象における腫瘍負荷を低減または根絶する、本発明1025の方法。
[本発明1027]
腫瘍細胞の数を減少させる、本発明1025の方法。
[本発明1028]
腫瘍サイズを縮小させる、本発明1025の方法。
[本発明1029]
前記対象において腫瘍を根絶する、本発明1025の方法。
[本発明1030]
前記がんが血液悪性腫瘍である、本発明1025の方法。
[本発明1031]
前記血液悪性腫瘍が、骨髄異形成症候群、骨髄増殖性腫瘍、慢性骨髄単球性白血病（CMML）、慢性骨髄性白血病、または急性骨髄性白血病（AML）、急性前骨髄球性白血病（APL）またはM3 AML、急性骨髄単球性白血病またはM4 AML、急性単球性白血病またはM5 AML、急性骨髄芽球性白血病、および真性多血症からなる群より選択される、本発明1030の方法。
[本発明1032]
前記抗体またはその抗原結合断片が、静脈内、動脈内、腫瘍内、または皮下に投与される、本発明1025の方法。
[本発明1033]
トポイソメラーゼ阻害剤、アントラサイクリントポイソメラーゼ阻害剤、アントラサイクリン、ダウノルビシン、ヌクレオシド代謝阻害剤、シタラビン、低メチル化剤、低用量シタラビン（LDAC）、ダウノルビシンとシタラビンとの組合せ、注射用のダウノルビシンおよびシタラビンリポソーム、ヴィキセオス（登録商標）、アザシチジン、ビダーザ（登録商標）、デシタビン、オールトランスレチノイン酸（ATRA）、ヒ素、三酸化ヒ素、ヒスタミン二塩酸塩、セプレン（登録商標）、インターロイキン-2、アルデスロイキン、プロロイキン（登録商標）、ゲムツズマブオゾガマイシン、マイロターグ（登録商標）、FLT-3阻害剤、ミドスタウリン、ライダプト（登録商標）、クロファラビン、ファルネシルトランスフェラーゼ阻害剤、デシタビン、IDH1阻害剤、イボシデニブ、チブソボ（登録商標）、IDH2阻害剤、エナシデニブ、イディファ（登録商標）、スムーズンド（SMO）阻害剤、グラスデギブ、アルギナーゼ阻害剤、IDO阻害剤、エパカドスタット、BCL-2阻害剤、ベネトクラクス、ベネクレクスタ（登録商標）、白金錯体誘導体、オキサリプラチン、キナーゼ阻害剤、チロシンキナーゼ阻害剤、PI3キナーゼ阻害剤、BTK阻害剤、イブルチニブ、イムブルビカ（登録商標）、アカラブルチニブ、カルクエンス（登録商標）、ザヌブルチニブ、PD-1抗体、PD-L1抗体、CTLA-4抗体、LAG3抗体、ICOS抗体、TIGIT抗体、TIM3抗体、CD40抗体、4-1BB抗体、CD47抗体、SIRP1α抗体または融合タンパク質、E-セレクチンのアンタゴニスト、腫瘍抗原に結合する抗体、T細胞表面マーカーに結合する抗体、骨髄細胞またはNK細胞表面マーカーに結合する抗体、アルキル化剤、ニトロソウレア剤、代謝拮抗物質、抗腫瘍性抗生物質、植物に由来するアルカロイド、ホルモン療法薬、ホルモンアンタゴニスト、アロマターゼ阻害剤、ならびにP糖タンパク質阻害剤からなる群より選択される1つまたは複数の薬物を前記対象に投与する工程をさらに含む、本発明1025の方法。
[本発明1034]
前記単離されたモノクローナル抗体またはその抗原結合断片が、それに連結された抗腫瘍薬物をさらに含む、本発明1025～1033のいずれかの方法。
[本発明1035]
前記抗腫瘍薬物が、光分解性リンカーを介して前記抗体に連結されている、本発明1034の方法。
[本発明1036]
前記抗腫瘍薬物が、酵素切断性リンカーを介して前記抗体に連結されている、本発明1034の方法。
[本発明1037]
前記抗腫瘍薬物が、毒素、放射性同位体、サイトカイン、または酵素である、本発明1034の方法。
[本発明1038]
試料中または対象中のがん細胞またはがん幹細胞を検出する方法であって、
（a）対象または対象由来の試料を、本発明1001～1011のいずれかの抗体またはその抗原結合断片と接触させる工程、および
（b）該対象中または該試料中のがん細胞またはがん幹細胞への該抗体の結合を検出する工程
を含む、方法。
[本発明1039]
前記試料が、体液または生検材料である、本発明1038の方法。
[本発明1040]
前記試料が、血液、骨髄、痰、涙液、唾液、粘液、血清、尿、または糞便である、本発明1038の方法。
[本発明1041]
検出が、免疫組織化学、フローサイトメトリー、FACS、ELISA、RIA、またはウエスタンブロットを含む、本発明1038の方法。
[本発明1042]
工程（a）および（b）の2回目を行い、1回目と比較した検出レベルの変化を決定することをさらに含む、本発明1038の方法。
[本発明1043]
前記単離されたモノクローナル抗体またはその抗原結合断片が標識をさらに含む、本発明1038の方法。
[本発明1044]
前記標識が、ペプチドタグ、酵素、磁性粒子、発色団、蛍光分子、化学発光分子、または色素である、本発明1043の方法。
[本発明1045]
前記単離されたモノクローナル抗体またはその抗原結合断片が、リポソームまたはナノ粒子にコンジュゲートしている、本発明1025～1044のいずれかの方法。
It is contemplated that any method or composition described herein may be performed with respect to any other method or composition described herein. Other objectives, features and advantages of the present disclosure will become apparent from the detailed description below. However, although detailed description and specific examples indicate particular aspects of the invention, it should be understood that they are given for illustration purposes only, and various modifications and variations within the spirit and scope of the present disclosure. Improvements will be apparent to those skilled in the art from this detailed description.
[Invention 1001]
(A) Heavy chain complementarity determining regions (HC-CDR) 1, having the amino acid sequence shown in SEQ ID NO: 100,
HC-CDR2 having the amino acid sequence shown in SEQ ID NO: 101, and
HC-CDR3 having the amino acid sequence shown in SEQ ID NO: 102, 224 or 227
Heavy Chain (HC) Variable Region (VH), and
Variants of which one or more of the HC-CDRs have one, two, or three amino acid substitutions, additions, deletions, or combinations thereof, as well.
(B) Light chain complementarity determining regions (LC-CDRs) having the amino acid sequence shown in SEQ ID NO: 104,
LC-CDR2 having the amino acid sequence shown in the amino acid sequence KAS or SEQ ID NO: 233, and
LC-CDR3 having the amino acid sequence shown in SEQ ID NO: 105 or 234
Including light chain (LC) variable region (VL), and
A variant in which one or more of the LC-CDRs have one, two, or three amino acid substitutions, additions, deletions, or combinations thereof.
An isolated monoclonal antibody or antigen-binding fragment thereof, including.
[Invention 1002]
(A) The HC-CDR1 has the amino acid sequence shown in SEQ ID NO: 100, the HC-CDR2 has the amino acid sequence shown in SEQ ID NO: 101, and the HC-CDR3 has the amino acid sequence shown in SEQ ID NO: 101. It has the amino acid sequence shown in SEQ ID NO: 102, 224 or 227, and (b) the LC-CDR1 has the amino acid sequence shown in SEQ ID NO: 104, and the HC-CDR2 has the amino acid sequence. The isolated monoclonal antibody of the present invention 1001 having the amino acid sequence shown in KAS or SEQ ID NO: 233 and the HC-CDR3 having the amino acid sequence shown in SEQ ID NO: 105 or 234 or the like thereof. Antibodies binding fragment.
[Invention 1003]
The isolated monoclonal antibody of the present invention 1001 or an antigen-binding fragment thereof, wherein the isolated monoclonal antibody is a mouse antibody, a rodent antibody, a rabbit antibody, a chimeric antibody, a humanized antibody, or a human antibody.
[Invention 1004]
The isolated monoclonal antibody of the present invention 1001 or an antigen-binding fragment thereof, wherein the antigen-binding fragment is a recombinant ScFv (single chain variable fragment) antibody, Fab fragment, F (ab') 2 fragment, or Fv fragment.
[Invention 1005]
The isolated monoclonal antibody of the present invention 1001 or an antigen-binding fragment thereof, wherein the isolated monoclonal antibody is a rabbit antibody or a chimeric antibody.
[Invention 1006]
(A) The VH has an amino acid sequence that is at least about 90% identical to SEQ ID NO: 99, and (b) the VL has an amino acid sequence that is at least 90% identical to SEQ ID NO: 103. An isolated monoclonal antibody of invention 1005 or an antigen-binding fragment thereof.
[Invention 1007]
The isolated VH of the present invention 1005 has (a) the VH having the amino acid sequence shown in SEQ ID NO: 99 and (b) the VL having the amino acid sequence shown in SEQ ID NO: 103. Monoclonal antibody or antigen-binding fragment thereof.
[Invention 1008]
The isolated monoclonal antibody of the present invention 1001 or an antigen-binding fragment thereof, wherein the isolated monoclonal antibody is a humanized antibody.
[Invention 1009]
(A) The VH has an amino acid sequence that is at least about 90% identical to SEQ ID NO: 223, 225, 226, 228, 229, 230 or 231 and (b) the VL has SEQ ID NO: 232. , 235, 236 or 237, an isolated monoclonal antibody or antigen-binding fragment thereof of the present invention 1008 having an amino acid sequence that is at least 90% identical.
[Invention 1010]
(A) The VH has the amino acid sequence shown in SEQ ID NO: 223, 225, 226, 228, 229, 230 or 231 and (b) the VL has SEQ ID NO: 232, 235, 236. Alternatively, an isolated monoclonal antibody or antigen-binding fragment thereof of the present invention 1008 having the amino acid sequence shown in 237.
[Invention 1011]
An isolated monoclonal antibody or antigen-binding fragment thereof that competes with the isolated monoclonal antibody or antigen-binding fragment thereof according to any one of 1001 to 1010 of the present invention for the same epitope.
[Invention 1012]
A pharmaceutical composition comprising an isolated monoclonal antibody or antigen-binding fragment thereof according to any one of 1001 to 1011 of the present invention and a pharmaceutically acceptable carrier.
[Invention 1013]
An isolated nucleic acid encoding an isolated monoclonal antibody of any of 1001-1011 of the present invention.
[Invention 1014]
A vector comprising the isolated nucleic acid of the present invention 1013.
[Invention 1015]
A host cell comprising the vector of the present invention 1014.
[Invention 1016]
The host cell of the present invention 1015, which is a mammalian cell.
[Invention 1017]
The host cell of the present invention 1015, which is a CHO cell.
[Invention 1018]
A hybridoma that encodes or produces an isolated monoclonal antibody of any of 1001-1011 of the present invention.
[Invention 1019]
A method for producing an antibody, which comprises a step of culturing the host cell of the present invention 1015 under conditions suitable for expressing the antibody, and a step of recovering the antibody.
[Invention 1020]
A chimeric antigen receptor (CAR) protein comprising any of the antigen binding fragments of the present invention 1001-1011.
[Invention 1021]
An isolated nucleic acid encoding the CAR protein of the invention 1020.
[Invention 1022]
A vector comprising the isolated nucleic acid of the invention 1021.
[Invention 1023]
Manipulated cells containing the isolated nucleic acid of the invention 1021.
[Invention 1024]
Manipulated cells of the invention 1023, which are T cells, NK cells, or macrophages.
[Invention 1025]
A method of treating or ameliorating the effects of cancer in a subject, wherein a therapeutically effective amount of an antibody of the invention 1001-1011 or an antigen-binding fragment thereof or engineered cells of the invention 1023 or 1024 are used. A method comprising the step of administering to the subject.
[Invention 1026]
The method of the present invention 1025 for reducing or eradicating tumor loading in the subject.
[Invention 1027]
The method of the present invention 1025, which reduces the number of tumor cells.
[Invention 1028]
The method of the present invention 1025 for reducing tumor size.
[Invention 1029]
The method of the present invention 1025 for eradicating a tumor in the subject.
[Invention 1030]
The method of the present invention 1025, wherein the cancer is a hematological malignancies.
[Invention 1031]
The hematological malignant tumor is myeloplastic syndrome, myeloproliferative tumor, chronic myelomonocytic leukemia (CMML), chronic myelogenous leukemia, or acute myelogenous leukemia (AML), acute premyelocytic leukemia (APL) or The method of the present invention 1030, selected from the group consisting of M3 AML, acute myelomonocytic leukemia or M4 AML, acute monospherical leukemia or M5 AML, acute myeloblastic leukemia, and true hypertension.
[Invention 1032]
The method of the present invention 1025, wherein the antibody or antigen-binding fragment thereof is administered intravenously, intraarterially, intratumorally, or subcutaneously.
[Invention 1033]
Topoisomerase inhibitor, anthracyclintpoisomerase inhibitor, anthracycline, daunorbisin, nucleoside metabolism inhibitor, citarabin, low methylating agent, low-dose citarabin (LDAC), combination of daunorbisin and citarabin, daunorbisin and citarabin liposomes for injection, Vixeos (Registered Trademarks), Azacitidine, Vidaza®, Decitabin, All Transretinoic Acid (ATRA), Arsenic, Arsenic Trioxide, Histamine Dihydrochloride, Seplene®, Interleukin-2, Aldesroykin, Proroykin (Registered Trademarks), Gemtuzumab ozogamicin, Myrotarg®, FLT-3 Inhibitor, Midstaurin, Rydapt®, Clofarabine, Farnesyltransferase Inhibitor, Decitabin, IDH1 Inhibitor, Ivosidenib, Tibusovo (Registered Trademark) Registered Trademarks), IDH2 Inhibitors, Enacidenib, Idifa®, Smoothund (SMO) Inhibitors, Grassdegib, Arginase Inhibitors, IDO Inhibitors, Epacadostat, BCL-2 Inhibitors, VENCLEXTA, VENCLEXTA®, Platinum complex derivative, oxaliplatin, kinase inhibitor, tyrosine kinase inhibitor, PI3 kinase inhibitor, BTK inhibitor, ibrutinib, imbruvica®, acalaburtinib, calcens®, zanubrutinib, PD-1 antibody, PD- L1 antibody, CTLA-4 antibody, LAG3 antibody, ICOS antibody, TIGIT antibody, TIM3 antibody, CD40 antibody, 4-1BB antibody, CD47 antibody, SIRP1α antibody or fusion protein, E-selectin antagonist, antibody that binds to tumor antigen, Antibodies that bind to T cell surface markers, antibodies that bind to bone marrow or NK cell surface markers, alkylating agents, nitrosoureas, metabolic antagonists, antitumor antibiotics, plant-derived alkaloids, hormone therapeutics, hormones The method of the invention 1025, further comprising administering to said subject one or more drugs selected from the group consisting of antagonists, aromatase inhibitors, and P glycoprotein inhibitors.
[Invention 1034]
The method of any of 1025-1033 of the present invention, wherein the isolated monoclonal antibody or antigen-binding fragment thereof further comprises an antitumor drug linked thereto.
[Invention 1035]
The method of the present invention 1034, wherein the antitumor drug is linked to the antibody via a photodegradable linker.
[Invention 1036]
The method of the present invention 1034, wherein the antitumor drug is linked to the antibody via an enzyme-cleaving linker.
[Invention 1037]
The method of the present invention 1034, wherein the antitumor drug is a toxin, radioisotope, cytokine, or enzyme.
[Invention 1038]
A method for detecting cancer cells or cancer stem cells in a sample or subject.
(A) A step of contacting a subject or a sample derived from the subject with an antibody of the present invention 1001 to 1011 or an antigen-binding fragment thereof, and
(B) A step of detecting the binding of the antibody to cancer cells or cancer stem cells in the subject or sample.
Including, how.
[Invention 1039]
The method of the present invention 1038, wherein the sample is a body fluid or biopsy material.
[Invention 1040]
The method of the present invention 1038, wherein the sample is blood, bone marrow, sputum, tears, saliva, mucus, serum, urine, or feces.
[Invention 1041]
The method of the invention 1038, wherein detection comprises immunohistochemistry, flow cytometry, FACS, ELISA, RIA, or Western blot.
[Invention 1042]
The method of the present invention 1038, further comprising performing a second of steps (a) and (b) to determine a change in detection level compared to the first.
[Invention 1043]
The method of the present invention 1038, wherein the isolated monoclonal antibody or antigen binding fragment thereof further comprises a label.
[Invention 1044]
The method of 1043 of the invention, wherein the label is a peptide tag, enzyme, magnetic particles, chromophore, fluorescent molecule, chemically luminescent molecule, or dye.
[Invention 1045]
The method of any of the inventions 1025-1044, wherein the isolated monoclonal antibody or antigen-binding fragment thereof is conjugated to a liposome or nanoparticles.
Claims (26)
SEQ ID NO:101に示されるアミノ酸配列を有するHC-CDR2、および
SEQ ID NO:102、224または227に示されるアミノ酸配列を有するHC-CDR3
を含む、重鎖（HC）可変領域（VH）、および
該HC-CDRのうちの1つまたは複数が1つ、2つ、または3つのアミノ酸置換、付加、欠失、またはこれらの組合せを有する、そのバリアント、ならびに
（b）SEQ ID NO:104に示されるアミノ酸配列を有する軽鎖相補性決定領域（LC-CDR）、
アミノ酸配列KASまたはSEQ ID NO:233に示されるアミノ酸配列を有するLC-CDR2、および
SEQ ID NO:105または234に示されるアミノ酸配列を有するLC-CDR3
を含む、軽鎖（LC）可変領域（VL）、および
該LC-CDRのうちの1つまたは複数が1つ、2つ、または3つのアミノ酸置換、付加、欠失、またはこれらの組合せを有する、そのバリアント
を含む、単離されたモノクローナル抗体またはその抗原結合断片。 (A) Heavy chain complementarity determining regions (HC-CDR) 1, having the amino acid sequence shown in SEQ ID NO: 100,
HC-CDR2 having the amino acid sequence shown in SEQ ID NO: 101, and
HC-CDR3 having the amino acid sequence shown in SEQ ID NO: 102, 224 or 227
Heavy chain (HC) variable regions (VHs), including, and one or more of the HC-CDRs having one, two, or three amino acid substitutions, additions, deletions, or combinations thereof. , The variants thereof, and (b) the light chain complementarity determining regions (LC-CDR) having the amino acid sequence shown in SEQ ID NO: 104.
LC-CDR2 having the amino acid sequence shown in the amino acid sequence KAS or SEQ ID NO: 233, and
LC-CDR3 having the amino acid sequence shown in SEQ ID NO: 105 or 234
The light chain (LC) variable region (VL), including, and one or more of the LC-CDRs having one, two, or three amino acid substitutions, additions, deletions, or combinations thereof. , An isolated monoclonal antibody or antigen-binding fragment thereof, including a variant thereof.
（ii）前記抗原結合断片が、組換えScFv（単鎖可変断片）抗体、Fab断片、F（ab'）2断片、もしくはFv断片である、
請求項1記載の単離されたモノクローナル抗体またはその抗原結合断片。 (I) The isolated monoclonal antibody is a mouse antibody, a rodent antibody, a rabbit antibody, a chimeric antibody, a humanized antibody, or a human antibody, or
(Ii) The antigen-binding fragment is a recombinant ScFv (single chain variable fragment) antibody, a Fab fragment, an F (ab') 2 fragment, or an Fv fragment.
The isolated monoclonal antibody according to claim 1 or an antigen-binding fragment thereof.
（i）（a）前記VHが、SEQ ID NO:99と少なくとも約90％同一のアミノ酸配列を有し、かつ（b）前記VLが、SEQ ID NO:103と少なくとも90％同一のアミノ酸配列を有する、または
（ii）（a）前記VHが、SEQ ID NO:99に示されるアミノ酸配列を有し、かつ（b）前記VLが、SEQ ID NO:103に示されるアミノ酸配列を有する、
請求項1記載の単離されたモノクローナル抗体またはその抗原結合断片。 The isolated monoclonal antibody is a rabbit antibody or a chimeric antibody, and
(I) (a) The VH has an amino acid sequence that is at least about 90% identical to SEQ ID NO: 99, and (b) the VL has an amino acid sequence that is at least 90% identical to SEQ ID NO: 103. Have or
(Ii) (a) the VH has the amino acid sequence set forth in SEQ ID NO: 99, and (b) the VL has the amino acid sequence set forth in SEQ ID NO: 103.
The isolated monoclonal antibody according to claim 1 or an antigen-binding fragment thereof.
（i）（a）前記VHが、SEQ ID NO:223、225、226、228、229、230もしくは231と少なくとも約90％同一のアミノ酸配列を有し、かつ（b）前記VLが、SEQ ID NO:232、235、236もしくは237と少なくとも90％同一のアミノ酸配列を有する、または
（ii）（a）前記VHが、SEQ ID NO:223、225、226、228、229、230または231に示されるアミノ酸配列を有し、かつ（b）前記VLが、SEQ ID NO:232、235、236または237に示されるアミノ酸配列を有する、
請求項1記載の単離されたモノクローナル抗体またはその抗原結合断片。 The isolated monoclonal antibody is a humanized antibody and
(I) (a) the VH has an amino acid sequence that is at least about 90% identical to SEQ ID NO: 223, 225, 226, 228, 229, 230 or 231 and (b) the VL is SEQ ID ID. Has at least 90% identical amino acid sequence to NO: 232, 235, 236 or 237, or
(Ii) (a) the VH has the amino acid sequence set forth in SEQ ID NO: 223, 225, 226, 228, 229, 230 or 231 and (b) the VL has SEQ ID NO: 232, Having the amino acid sequence shown in 235, 236 or 237,
The isolated monoclonal antibody according to claim 1 or an antigen-binding fragment thereof.
（i）前記対象における腫瘍負荷が低減もしくは根絶する、
（ii）腫瘍細胞の数が減少する、
（iii）腫瘍サイズが縮小する、および／または
（iv）前記対象において腫瘍が根絶する、
請求項17記載の医薬。 By administration of the above-mentioned medicine
(I) Tumor load in the subject is reduced or eradicated,
(Ii) The number of tumor cells decreases,
(Iii) Tumor size shrinks and / or
(Iv) Tumor eradication in the subject,
The medicine according to claim 17 .
（ii）トポイソメラーゼ阻害剤、アントラサイクリントポイソメラーゼ阻害剤、アントラサイクリン、ダウノルビシン、ヌクレオシド代謝阻害剤、シタラビン、低メチル化剤、低用量シタラビン（LDAC）、ダウノルビシンとシタラビンとの組合せ、注射用のダウノルビシンおよびシタラビンリポソーム、ヴィキセオス（登録商標）、アザシチジン、ビダーザ（登録商標）、デシタビン、オールトランスレチノイン酸（ATRA）、ヒ素、三酸化ヒ素、ヒスタミン二塩酸塩、セプレン（登録商標）、インターロイキン-2、アルデスロイキン、プロロイキン（登録商標）、ゲムツズマブオゾガマイシン、マイロターグ（登録商標）、FLT-3阻害剤、ミドスタウリン、ライダプト（登録商標）、クロファラビン、ファルネシルトランスフェラーゼ阻害剤、デシタビン、IDH1阻害剤、イボシデニブ、チブソボ（登録商標）、IDH2阻害剤、エナシデニブ、イディファ（登録商標）、スムーズンド（SMO）阻害剤、グラスデギブ、アルギナーゼ阻害剤、IDO阻害剤、エパカドスタット、BCL-2阻害剤、ベネトクラクス、ベネクレクスタ（登録商標）、白金錯体誘導体、オキサリプラチン、キナーゼ阻害剤、チロシンキナーゼ阻害剤、PI3キナーゼ阻害剤、BTK阻害剤、イブルチニブ、イムブルビカ（登録商標）、アカラブルチニブ、カルクエンス（登録商標）、ザヌブルチニブ、PD-1抗体、PD-L1抗体、CTLA-4抗体、LAG3抗体、ICOS抗体、TIGIT抗体、TIM3抗体、CD40抗体、4-1BB抗体、CD47抗体、SIRP1α抗体もしくは融合タンパク質、E-セレクチンのアンタゴニスト、腫瘍抗原に結合する抗体、T細胞表面マーカーに結合する抗体、骨髄細胞もしくはNK細胞表面マーカーに結合する抗体、アルキル化剤、ニトロソウレア剤、代謝拮抗物質、抗腫瘍性抗生物質、植物に由来するアルカロイド、ホルモン療法薬、ホルモンアンタゴニスト、アロマターゼ阻害剤、ならびにP糖タンパク質阻害剤からなる群より選択される1つもしくは複数の薬物と組み合わせて使用される、
請求項17記載の医薬。 (I) Administered intravenously, intraarterally, intratumorally, or subcutaneously, or
(Ii) Topoisomerase inhibitor, anthracyclintpoisomerase inhibitor, anthracycline, downorbisin, nucleoside metabolism inhibitor, citarabin, low methylating agent, low-dose citarabin (LDAC), combination of dounorbisin and citarabin, daunorbisin and citarabin for injection. Liplips, Vixeos®, Azacitidine, Vidaza®, Decitabin, All Transretinoic Acid (ATRA), Arsenic, Arsenic Trioxide, Histamine Dihydrochloride, Seplen®, Interleukin-2, Ardesroykin , Proroykin®, Gemtuzumab ozogamicin, Myrotarg®, FLT-3 inhibitor, Midstauline, Rydapt®, Clofarabin, Farnesyl transferase inhibitor, Decitabin, IDH1 inhibitor, Ivosidenib , Tibusovo®, IDH2 Inhibitor, Enacidenib, Idifa®, Smoothund (SMO) Inhibitor, Grassdegib, Arginase Inhibitor, IDO Inhibitor, Epacadostat, BCL-2 Inhibitor, VENCLEXTA, VENCLEXTA (Registered) Trademarks), Platinum Complex Derivatives, Oxaliplatin, Kinase Inhibitors, Tyrosine Kinase Inhibitors, PI3 Kinase Inhibitors, BTK Inhibitors, Ibrutinib, Imbruvica®, Acarabrutinib, Calquens®, Zanubrutinib, PD-1 Antibodies , PD-L1 antibody, CTLA-4 antibody, LAG3 antibody, ICOS antibody, TIGIT antibody, TIM3 antibody, CD40 antibody, 4-1BB antibody, CD47 antibody, SIRP1α antibody or fusion protein, E-selectin antagonist, tumor antigen binding Antibodies, antibodies that bind to T cell surface markers, antibodies that bind to bone marrow or NK cell surface markers, alkylating agents, nitrosoureas, metabolic antagonists, antitumor antibiotics, plant-derived alkaloids, hormone therapy Used in combination with one or more drugs selected from the group consisting of drugs, hormone antagonists, aromatase inhibitors, and P glycoprotein inhibitors.
The medicine according to claim 17 .
（i）それに連結された抗腫瘍薬物をさらに含む、または
（ii）リポソームもしくはナノ粒子にコンジュゲートしている、
請求項17～20のいずれか一項記載の医薬。 The isolated monoclonal antibody or antigen-binding fragment thereof
(I) Further containing or associated with an antitumor drug associated with it
(Ii) conjugated to liposomes or nanoparticles,
The medicine according to any one of claims 17 to 20 .
（i）光分解性リンカーもしくは酵素切断性リンカーを介して前記抗体に連結されている、かつ／または
（ii）毒素、放射性同位体、サイトカイン、もしくは酵素である、
請求項21記載の医薬。 The isolated monoclonal antibody or antigen-binding fragment thereof further comprises an antitumor drug linked thereto, and the antitumor drug comprises.
(I) Linked to the antibody via a photodegradable or enzyme-cleaving linker and / or
(Ii) Toxins, radioisotopes, cytokines, or enzymes,
The medicine according to claim 21 .
（a）対象由来の試料を、請求項1～6のいずれか一項記載の抗体またはその抗原結合断片と接触させる工程、および
（b）該試料中のがん細胞またはがん幹細胞への該抗体の結合を検出する工程
を含む、方法。 A method for detecting cancer cells or cancer stem cells in a sample.
(A ) A step of contacting a sample derived from a subject with the antibody according to any one of claims 1 to 6 or an antigen-binding fragment thereof, and (b ) to cancer cells or cancer stem cells in the sample . A method comprising the step of detecting the binding of the antibody.
（i）体液もしくは生検材料である、または
（ii）血液、骨髄、痰、涙液、唾液、粘液、血清、尿、もしくは糞便である、
請求項23記載の方法。 The sample is
(I) Body fluid or biopsy material, or
(Ii) Blood, bone marrow, sputum, tears, saliva, mucus, serum, urine, or feces,
23. The method of claim 23 .
（ii）方法が、工程（a）および（b）の2回目を行い、1回目と比較した検出レベルの変化を決定することをさらに含む、
請求項23記載の方法。 (I) Detection includes immunohistochemistry, flow cytometry, FACS, ELISA, RIA, or Western blot, or
(Ii) The method further comprises performing the second steps (a) and (b) to determine the change in detection level compared to the first.
23. The method of claim 23 .
（i）標識をさらに含む、
（ii）ペプチドタグ、酵素、磁性粒子、発色団、蛍光分子、化学発光分子、もしくは色素である標識をさらに含む、または
（iii）リポソームもしくはナノ粒子にコンジュゲートしている、
請求項23記載の方法。 The isolated monoclonal antibody or antigen-binding fragment thereof
(I) Including additional signs,
(Ii) Further comprising or labeling a peptide tag, enzyme, magnetic particle, chromophore, fluorescent molecule, chemically luminescent molecule, or dye.
(Iii) conjugated to liposomes or nanoparticles,
23. The method of claim 23 .
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
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| US201862730715P | 2018-09-13 | 2018-09-13 | |
| US62/730,715 | 2018-09-13 | ||
| PCT/US2019/050727 WO2020056077A1 (en) | 2018-09-13 | 2019-09-12 | Novel lilrb4 antibodies and uses thereof |
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| JP2022500084A JP2022500084A (en) | 2022-01-04 |
| JPWO2020056077A5 true JPWO2020056077A5 (en) | 2022-07-19 |
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| JP2021539336A Pending JP2022500084A (en) | 2018-09-13 | 2019-09-12 | New LILRB4 antibody and its use |
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| US (1) | US20210371518A1 (en) |
| EP (1) | EP3849608B1 (en) |
| JP (1) | JP2022500084A (en) |
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| WO2022081900A1 (en) * | 2020-10-15 | 2022-04-21 | Bioincept, Llc | Systems, compositions and methods of determining viability of embryos using the same |
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