JPWO2020118216A5 - - Google Patents
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- JPWO2020118216A5 JPWO2020118216A5 JP2021532209A JP2021532209A JPWO2020118216A5 JP WO2020118216 A5 JPWO2020118216 A5 JP WO2020118216A5 JP 2021532209 A JP2021532209 A JP 2021532209A JP 2021532209 A JP2021532209 A JP 2021532209A JP WO2020118216 A5 JPWO2020118216 A5 JP WO2020118216A5
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- 238000000034 method Methods 0.000 claims description 56
- 108010019670 Chimeric Antigen Receptors Proteins 0.000 claims description 50
- 206010028980 Neoplasm Diseases 0.000 claims description 27
- 201000011510 cancer Diseases 0.000 claims description 27
- 102000008394 Immunoglobulin Fragments Human genes 0.000 claims description 26
- 108010021625 Immunoglobulin Fragments Proteins 0.000 claims description 26
- 229920001184 polypeptide Polymers 0.000 claims description 25
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 25
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 25
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 20
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 20
- 201000002528 pancreatic cancer Diseases 0.000 claims description 20
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 20
- 102000004169 proteins and genes Human genes 0.000 claims description 20
- 108090000623 proteins and genes Proteins 0.000 claims description 20
- 210000004027 cell Anatomy 0.000 claims description 19
- 239000000203 mixture Substances 0.000 claims description 19
- 238000002560 therapeutic procedure Methods 0.000 claims description 14
- 230000002401 inhibitory effect Effects 0.000 claims description 12
- 238000011319 anticancer therapy Methods 0.000 claims description 10
- 239000000427 antigen Substances 0.000 claims description 8
- 102000036639 antigens Human genes 0.000 claims description 8
- 108091007433 antigens Proteins 0.000 claims description 8
- 230000004068 intracellular signaling Effects 0.000 claims description 8
- 210000000822 natural killer cell Anatomy 0.000 claims description 7
- 102000039446 nucleic acids Human genes 0.000 claims description 7
- 108020004707 nucleic acids Proteins 0.000 claims description 7
- 150000007523 nucleic acids Chemical class 0.000 claims description 7
- 238000001356 surgical procedure Methods 0.000 claims description 7
- 102000004127 Cytokines Human genes 0.000 claims description 6
- 108090000695 Cytokines Proteins 0.000 claims description 6
- 206010027476 Metastases Diseases 0.000 claims description 6
- 238000011122 anti-angiogenic therapy Methods 0.000 claims description 6
- 230000000259 anti-tumor effect Effects 0.000 claims description 6
- 238000002512 chemotherapy Methods 0.000 claims description 6
- 201000010099 disease Diseases 0.000 claims description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 6
- 238000001415 gene therapy Methods 0.000 claims description 6
- 238000001794 hormone therapy Methods 0.000 claims description 6
- 230000005746 immune checkpoint blockade Effects 0.000 claims description 6
- 238000009169 immunotherapy Methods 0.000 claims description 6
- 230000009401 metastasis Effects 0.000 claims description 6
- 238000001959 radiotherapy Methods 0.000 claims description 6
- 108091007741 Chimeric antigen receptor T cells Proteins 0.000 claims description 5
- 210000001744 T-lymphocyte Anatomy 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 239000012634 fragment Substances 0.000 claims description 4
- 102000004889 Interleukin-6 Human genes 0.000 claims description 3
- 108090001005 Interleukin-6 Proteins 0.000 claims description 3
- 230000000735 allogeneic effect Effects 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 claims description 3
- 229960005277 gemcitabine Drugs 0.000 claims description 3
- 230000011664 signaling Effects 0.000 claims description 3
- 101000914514 Homo sapiens T-cell-specific surface glycoprotein CD28 Proteins 0.000 claims description 2
- 102000001706 Immunoglobulin Fab Fragments Human genes 0.000 claims description 2
- 108010054477 Immunoglobulin Fab Fragments Proteins 0.000 claims description 2
- 102000017727 Immunoglobulin Variable Region Human genes 0.000 claims description 2
- 108010067060 Immunoglobulin Variable Region Proteins 0.000 claims description 2
- 102100027213 T-cell-specific surface glycoprotein CD28 Human genes 0.000 claims description 2
- 229940127089 cytotoxic agent Drugs 0.000 claims description 2
- 239000002254 cytotoxic agent Substances 0.000 claims description 2
- 239000000032 diagnostic agent Substances 0.000 claims description 2
- 229940039227 diagnostic agent Drugs 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 210000005260 human cell Anatomy 0.000 claims description 2
- 210000004408 hybridoma Anatomy 0.000 claims description 2
- 239000012642 immune effector Substances 0.000 claims description 2
- 229940121354 immunomodulator Drugs 0.000 claims description 2
- 231100000433 cytotoxic Toxicity 0.000 claims 1
- 230000001472 cytotoxic effect Effects 0.000 claims 1
- 210000000496 pancreas Anatomy 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 238000003556 assay Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
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Description
いくつかの局面において、TP-CAFによって発現されかつTS-CAFによって発現されないタンパク質に結合する抗体もしくは抗体断片またはキメラ抗原受容体は、本発明の態様のいずれか1つの抗体もしくは抗体断片またはキメラ抗原受容体である。いくつかの局面において、患者はがんを有する。いくつかの局面において、がんは、FAP+CAFを含むと決定されている。いくつかの局面において、がんは膵臓がんである。いくつかの局面において、本方法は、膵臓がんの転移を阻害する方法である。いくつかの局面において、本方法は、膵臓がんの成長を阻害する方法である。いくつかの局面において、本方法は、少なくとも第2の抗がん療法を施行する段階をさらに含む。いくつかの局面において、第2の抗がん療法は、化学療法、免疫療法、放射線療法、遺伝子療法、外科手術、ホルモン療法、抗血管新生療法、またはサイトカイン療法である。
In some aspects, the antibody or antibody fragment or chimeric antigen receptor that binds a protein expressed by TP-CAF and not expressed by TS-CAF is an antibody or antibody fragment or chimeric antigen receptor of any one of the embodiments of the invention. It is a receptor. In some aspects, the patient has cancer. In some aspects, the cancer is determined to contain FAP + CAF. In some aspects, the cancer is pancreatic cancer. In some aspects, the method is a method of inhibiting pancreatic cancer metastasis. In some aspects, the method is a method of inhibiting the growth of pancreatic cancer. In some aspects, the method further includes administering at least a second anti-cancer therapy. In some aspects, the second anti-cancer therapy is chemotherapy, immunotherapy, radiation therapy, gene therapy, surgery, hormonal therapy, anti-angiogenic therapy, or cytokine therapy.
1つの態様において、IL-6シグナル伝達を抑制する薬剤、ゲムシタビン、および免疫チェックポイント遮断療法を含む組成物の抗腫瘍有効量を投与する段階を含む、疾患を有する対象を処置する方法が、本明細書において提供される。いくつかの局面において、疾患は、がんである。いくつかの局面において、がんは、免疫チェックポイント遮断療法に以前は応答しなかったものである。いくつかの局面において、本方法は、TP-CAFによって発現されかつTS-CAFによって発現されないタンパク質に結合する抗体もしくは抗体断片またはキメラ抗原受容体の有効量を投与する段階をさらに含む。いくつかの局面において、がんは膵臓がんである。いくつかの局面において、本方法は、膵臓がんの転移を阻害する方法である。いくつかの局面において、本方法は、膵臓がんの成長を阻害する方法である。いくつかの局面において、本方法は、いくつかの局面において、本方法は、少なくとも第2の抗がん療法を施行する段階をさらに含む。いくつかの局面において、第2の抗がん療法は、化学療法、免疫療法、放射線療法、遺伝子療法、外科手術、ホルモン療法、抗血管新生療法、またはサイトカイン療法である。
In one embodiment, a method of treating a subject with a disease comprises administering an antitumor effective amount of a composition comprising an agent that suppresses IL-6 signaling, gemcitabine, and immune checkpoint blockade therapy. Provided in the specification. In some aspects, the disease is cancer. In some aspects, the cancer is one that has not previously responded to immune checkpoint blockade therapy. In some aspects, the method further comprises administering an effective amount of an antibody or antibody fragment or chimeric antigen receptor that binds to a protein expressed by TP-CAF and not expressed by TS-CAF. In some aspects, the cancer is pancreatic cancer. In some aspects, the method is a method of inhibiting pancreatic cancer metastasis. In some aspects, the method is a method of inhibiting the growth of pancreatic cancer. In some aspects, the method further comprises administering at least a second anti-cancer therapy. In some aspects, the second anti-cancer therapy is chemotherapy, immunotherapy, radiation therapy, gene therapy, surgery, hormonal therapy, anti-angiogenic therapy, or cytokine therapy.
[本発明1001]
IL-6シグナル伝達を抑制する薬剤、ゲムシタビン、および免疫チェックポイント遮断療法を含む組成物の抗腫瘍有効量を投与する段階
を含む、疾患を有する対象を処置する方法。
[本発明1002]
疾患ががんである、本発明1001の方法。
[本発明1003]
がんが、免疫チェックポイント遮断療法に以前は応答しなかったものである、本発明1002の方法。
[本発明1004]
TP-CAFによって発現されかつTS-CAFによって発現されないタンパク質に結合する抗体もしくは抗体断片またはキメラ抗原受容体の有効量を投与する段階；または
N末端からC末端に向かって、抗原結合ドメイン、ヒンジドメイン、膜貫通ドメイン、および細胞内シグナル伝達ドメインを含む、キメラ抗原受容体(CAR)ポリペプチドであって、TP-CAFによって発現されかつTS-CAFによって発現されないタンパク質に結合するCARポリペプチドを発現する、CAR T細胞の抗腫瘍有効量を投与する段階
をさらに含む、本発明1001の方法。
[本発明1005]
がんが膵臓がんである、本発明1002の方法。
[本発明1006]
膵臓がんの転移を阻害する方法としてさらに定義される、本発明1005の方法。
[本発明1007]
膵臓がんの成長を阻害する方法としてさらに定義される、本発明1005の方法。
[本発明1008]
少なくとも第2の抗がん療法を施行する段階をさらに含む、本発明1001の方法。
[本発明1009]
第2の抗がん療法が、化学療法、免疫療法、放射線療法、遺伝子療法、外科手術、ホルモン療法、抗血管新生療法、またはサイトカイン療法である、本発明1008の方法。
[本発明1010]
TP-CAFによって発現されかつTS-CAFによって発現されないタンパク質に結合する抗体もしくは抗体断片またはキメラ抗原受容体を含む、組成物。
[本発明1011]
抗体断片が、組換えscFv (一本鎖断片可変)抗体、Fab断片、F(ab')2断片、またはFv断片である、本発明1010の組成物。
[本発明1012]
抗体が、キメラ抗体または二重特異性抗体である、本発明1010の組成物。
[本発明1013]
キメラ抗体が、ヒト化抗体である、本発明1012の組成物。
[本発明1014]
二重特異性抗体が、
(1) TP-CAFによって発現されかつTS-CAFによって発現されないタンパク質、および
(2) CD3
の両方に結合する、本発明1012の組成物。
[本発明1015]
抗体または抗体断片が、細胞毒性剤に結合されている、本発明1010～1014のいずれかの組成物。
[本発明1016]
抗体または抗体断片が、診断剤に結合されている、本発明1010～1014のいずれかの組成物。
[本発明1017]
本発明1010～1016のいずれかの抗体または抗体断片をコードする、ハイブリドーマまたは操作された細胞。
[本発明1018]
本発明1010～1016のいずれかの1つまたは複数の抗体もしくは抗体断片またはキメラ抗原受容体を含む、薬学的製剤。
[本発明1019]
TP-CAFによって発現されかつTS-CAFによって発現されないタンパク質に結合する抗体もしくは抗体断片またはキメラ抗原受容体の有効量を投与する段階
を含む、その必要がある患者を処置する方法。
[本発明1020]
TP-CAFによって発現されかつTS-CAFによって発現されないタンパク質に結合する抗体もしくは抗体断片またはキメラ抗原受容体が、本発明1010～1016のいずれかの抗体もしくは抗体断片またはキメラ抗原受容体である、本発明1019の方法。
[本発明1021]
患者ががんを有する、本発明1019の方法。
[本発明1022]
がん患者が、FAP+CAFを含むと決定されている、本発明1021の方法。
[本発明1023]
がんが膵臓がんである、本発明1021の方法。
[本発明1024]
膵臓がんの転移を阻害する方法としてさらに定義される、本発明1023の方法。
[本発明1025]
膵臓がんの成長を阻害する方法としてさらに定義される、本発明1023の方法。
[本発明1026]
少なくとも第2の抗がん療法を施行する段階をさらに含む、本発明1019の方法。
[本発明1027]
第2の抗がん療法が、化学療法、免疫療法、放射線療法、遺伝子療法、外科手術、ホルモン療法、抗血管新生療法、またはサイトカイン療法である、本発明1026の方法。
[本発明1028]
N末端からC末端に向かって、抗原結合ドメイン、ヒンジドメイン、膜貫通ドメイン、および細胞内シグナル伝達ドメインを含む、キメラ抗原受容体(CAR)ポリペプチドであって、TP-CAFによって発現されかつTS-CAFによって発現されないタンパク質に結合する、前記CARポリペプチド。
[本発明1029]
抗原結合ドメインが、TP-CAFによって発現されかつTS-CAFによって発現されないタンパク質に結合する第1の抗体に由来するHCDR配列、およびTP-CAFによって発現されかつTS-CAFによって発現されないタンパク質に結合する第2の抗体に由来するLCDR配列を含む、本発明1028のポリペプチド。
[本発明1030]
抗原結合ドメインが、TP-CAFによって発現されかつTS-CAFによって発現されないタンパク質に結合する抗体に由来するHCDR配列およびLCDR配列を含む、本発明1028のポリペプチド。
[本発明1031]
ヒンジドメインが、CD8aヒンジドメインまたはIgG4ヒンジドメインである、本発明1028のポリペプチド。
[本発明1032]
膜貫通ドメインが、CD8a膜貫通ドメインまたはCD28膜貫通ドメインである、本発明1028のポリペプチド。
[本発明1033]
細胞内シグナル伝達ドメインが、CD3z細胞内シグナル伝達ドメインを含む、本発明1028のポリペプチド。
[本発明1034]
本発明1028～1033のいずれかのCARポリペプチドをコードする、核酸分子。
[本発明1035]
CARポリペプチドをコードする配列が、発現制御配列に機能的に連結されている、本発明1034の核酸分子。
[本発明1036]
本発明1028～1033のいずれかのCARポリペプチドまたは本発明1035の核酸を含む、単離された免疫エフェクター細胞。
[本発明1037]
核酸が、細胞のゲノムに組み込まれている、本発明1036の細胞。
[本発明1038]
T細胞である、本発明1036の細胞。
[本発明1039]
NK細胞である、本発明1036の細胞。
[本発明1040]
ヒト細胞である、本発明1036の細胞。
[本発明1041]
薬学的に許容される担体中に本発明1036の細胞の集団を含む、薬学的組成物。
[本発明1042]
本発明1028～1033のいずれかのキメラ抗原受容体(CAR)ポリペプチドを発現するCAR T細胞の抗腫瘍有効量を投与する段階
を含む、対象を処置する方法。
[本発明1043]
CAR T細胞が同種異系細胞である、本発明1042の方法。
[本発明1044]
CAR T細胞が自家細胞である、本発明1042の方法。
[本発明1045]
CAR T細胞が、対象のHLAに適合している、本発明1042の方法。
[本発明1046]
対象ががんを有する、本発明1042の方法。
[本発明1047]
がんが膵臓がんである、本発明1046の方法。
[本発明1048]
本発明1028～1033のいずれかのキメラ抗原受容体(CAR)ポリペプチドを発現するCAR NK細胞の抗腫瘍有効量を投与する段階
を含む、対象を処置する方法。
[本発明1049]
CAR NK細胞が同種異系細胞である、本発明1048の方法。
[本発明1050]
CAR NK細胞が自家細胞である、本発明1048の方法。
[本発明1051]
CAR NK細胞が、対象のHLAに適合している、本発明1048の方法。
[本発明1052]
対象ががんを有する、本発明1048の方法。
[本発明1053]
がんが膵臓がんである、本発明1052の方法。
[本発明1054]
対象から得られたがん組織を本発明1010～1016のいずれかの抗体または抗体断片と接触させる段階、および
該抗体または該抗体断片の組織への結合を検出する段階
を含む、疾患を有すると患者を診断する方法であって、該抗体または該抗体断片が組織に結合する場合、患者ががんを有すると診断される、前記方法。
本発明の他の目的、特徴、および利点は、以下の詳細な説明から明らかになるであろう。しかしながら、詳細な説明および具体的な実施例は、本発明の好ましい態様を示しているが、この詳細な説明から本発明の趣旨および範囲の中でさまざまな修正および変更が当業者には明らかになるので、例示にすぎないことが理解されるはずである。
[Invention 1001]
A method of treating a subject with a disease, the method comprising administering an anti-tumor effective amount of a composition comprising an agent that inhibits IL-6 signaling, gemcitabine, and immune checkpoint blockade therapy.
[Present invention 1002]
The method of the invention 1001, wherein the disease is cancer.
[Present invention 1003]
1002. The method of the invention 1002, wherein the cancer has not previously responded to immune checkpoint blockade therapy.
[Present invention 1004]
administering an effective amount of an antibody or antibody fragment or chimeric antigen receptor that binds to a protein expressed by TP-CAF and not expressed by TS-CAF; or
A chimeric antigen receptor (CAR) polypeptide comprising, from the N-terminus to the C-terminus, an antigen-binding domain, a hinge domain, a transmembrane domain, and an intracellular signaling domain, the polypeptide being expressed by a TP-CAF and a TS - The method of the invention 1001 further comprising administering an anti-tumor effective amount of CAR T cells expressing a CAR polypeptide that binds to a protein not expressed by CAF.
[Present invention 1005]
The method of the invention 1002, wherein the cancer is pancreatic cancer.
[Present invention 1006]
The method of the invention 1005, further defined as a method of inhibiting metastasis of pancreatic cancer.
[Present invention 1007]
The method of the invention 1005, further defined as a method of inhibiting the growth of pancreatic cancer.
[Present invention 1008]
1001. The method of the invention 1001 further comprising administering at least a second anti-cancer therapy.
[Present invention 1009]
The method of the invention 1008, wherein the second anti-cancer therapy is chemotherapy, immunotherapy, radiation therapy, gene therapy, surgery, hormonal therapy, anti-angiogenic therapy, or cytokine therapy.
[Present invention 1010]
A composition comprising an antibody or antibody fragment or a chimeric antigen receptor that binds a protein expressed by TP-CAF and not expressed by TS-CAF.
[Present invention 1011]
The composition of the invention 1010, wherein the antibody fragment is a recombinant scFv (single chain fragment variable) antibody, Fab fragment, F(ab') 2 fragment, or Fv fragment.
[Invention 1012]
The composition of the invention 1010, wherein the antibody is a chimeric antibody or a bispecific antibody.
[Present invention 1013]
The composition of the invention 1012, wherein the chimeric antibody is a humanized antibody.
[Present invention 1014]
Bispecific antibodies are
(1) Proteins expressed by TP-CAF and not expressed by TS-CAF, and
(2) CD3
A composition of the invention 1012, which binds to both.
[Present invention 1015]
The composition of any of the inventions 1010-1014, wherein the antibody or antibody fragment is conjugated to a cytotoxic agent.
[Invention 1016]
The composition of any of the inventions 1010-1014, wherein the antibody or antibody fragment is conjugated to a diagnostic agent.
[Invention 1017]
A hybridoma or engineered cell encoding an antibody or antibody fragment of any of the invention 1010-1016.
[Invention 1018]
A pharmaceutical formulation comprising one or more antibodies or antibody fragments or chimeric antigen receptors of any of the invention 1010-1016.
[Invention 1019]
A method of treating a patient in need thereof comprising administering an effective amount of an antibody or antibody fragment or chimeric antigen receptor that binds to a protein expressed by TP-CAF and not expressed by TS-CAF.
[Invention 1020]
The present invention, wherein the antibody or antibody fragment or chimeric antigen receptor that binds to a protein expressed by TP-CAF and not expressed by TS-CAF is the antibody or antibody fragment or chimeric antigen receptor of any of the present inventions 1010 to 1016. Invention 1019 methods.
[Invention 1021]
The method of the invention 1019, wherein the patient has cancer.
[Invention 1022]
1021. The method of the invention 1021, wherein the cancer patient is determined to contain FAP + CAF.
[Invention 1023]
The method of the invention 1021, wherein the cancer is pancreatic cancer.
[Invention 1024]
1023. A method of the invention, further defined as a method of inhibiting metastasis of pancreatic cancer.
[Invention 1025]
1023. A method of the invention, further defined as a method of inhibiting the growth of pancreatic cancer.
[Invention 1026]
The method of the invention 1019 further comprising administering at least a second anti-cancer therapy.
[Invention 1027]
1026. The method of the invention 1026, wherein the second anti-cancer therapy is chemotherapy, immunotherapy, radiation therapy, gene therapy, surgery, hormonal therapy, anti-angiogenic therapy, or cytokine therapy.
[Invention 1028]
A chimeric antigen receptor (CAR) polypeptide comprising, from the N-terminus to the C-terminus, an antigen-binding domain, a hinge domain, a transmembrane domain, and an intracellular signaling domain, the polypeptide being expressed by a TP-CAF and a TS - said CAR polypeptide, which binds to a protein not expressed by CAF.
[Invention 1029]
an HCDR sequence derived from the first antibody that binds to a protein expressed by TP-CAF and not expressed by TS-CAF, and an antigen-binding domain binds to a protein expressed by TP-CAF and not expressed by TS-CAF; A polypeptide of the invention 1028 comprising an LCDR sequence derived from a second antibody.
[Invention 1030]
A polypeptide of the invention 1028, wherein the antigen binding domain comprises HCDR and LCDR sequences derived from an antibody that binds to a protein expressed by TP-CAF and not expressed by TS-CAF.
[Present invention 1031]
The polypeptide of the invention 1028, wherein the hinge domain is a CD8a hinge domain or an IgG4 hinge domain.
[Invention 1032]
The polypeptide of the invention 1028, wherein the transmembrane domain is a CD8a transmembrane domain or a CD28 transmembrane domain.
[Present invention 1033]
The polypeptide of the invention 1028, wherein the intracellular signaling domain comprises a CD3z intracellular signaling domain.
[Present invention 1034]
A nucleic acid molecule encoding a CAR polypeptide of any of the invention 1028-1033.
[Invention 1035]
The nucleic acid molecule of the invention 1034, wherein the CAR polypeptide-encoding sequence is operably linked to an expression control sequence.
[Invention 1036]
An isolated immune effector cell comprising a CAR polypeptide of any of the invention 1028-1033 or a nucleic acid of the invention 1035.
[Present invention 1037]
1036. The cell of the invention 1036, wherein the nucleic acid is integrated into the cell's genome.
[Invention 1038]
The cell of the present invention 1036 which is a T cell.
[Invention 1039]
Cells of the present invention 1036 which are NK cells.
[Invention 1040]
The cell of the present invention 1036 which is a human cell.
[Present invention 1041]
A pharmaceutical composition comprising a population of cells of the invention 1036 in a pharmaceutically acceptable carrier.
[Invention 1042]
A method of treating a subject comprising administering an antitumor effective amount of a CAR T cell expressing a chimeric antigen receptor (CAR) polypeptide of any of the invention 1028-1033.
[Invention 1043]
1042. The method of the invention 1042, wherein the CAR T cells are allogeneic cells.
[Present invention 1044]
1042. The method of the invention 1042, wherein the CAR T cells are autologous cells.
[Invention 1045]
1042. The method of the invention 1042, wherein the CAR T cells are HLA matched to the subject.
[Invention 1046]
1042. The method of the invention 1042, wherein the subject has cancer.
[Invention 1047]
1046. The method of the invention 1046, wherein the cancer is pancreatic cancer.
[Invention 1048]
A method of treating a subject comprising administering an anti-tumor effective amount of CAR NK cells expressing a chimeric antigen receptor (CAR) polypeptide of any of the invention 1028-1033.
[Invention 1049]
1048. The method of the invention, wherein the CAR NK cells are allogeneic cells.
[Invention 1050]
The method of the invention 1048, wherein the CAR NK cells are autologous cells.
[Present invention 1051]
1048. The method of the invention, wherein the CAR NK cells are HLA matched to the subject.
[Invention 1052]
1048. The method of the invention, wherein the subject has cancer.
[Present invention 1053]
1052. The method of the invention 1052, wherein the cancer is pancreatic cancer.
[Present invention 1054]
contacting a cancerous tissue obtained from a subject with the antibody or antibody fragment of any of the present inventions 1010 to 1016; and detecting binding of the antibody or antibody fragment to the tissue. A method of diagnosing a patient, wherein the patient is diagnosed as having cancer if the antibody or antibody fragment binds to tissue.
Other objects, features, and advantages of the invention will become apparent from the detailed description below. However, while the detailed description and specific examples indicate preferred embodiments of the invention, it will be apparent to those skilled in the art from this detailed description that various modifications and changes within the spirit and scope of the invention will be apparent to those skilled in the art. Therefore, it should be understood that this is merely an example.
B. キットおよび診断薬
態様のさまざまな局面において、治療剤ならびに/または他の治療剤および送達剤を含有するキットが想定される。本発明の態様は、態様の治療法を調整および/または施行するためのキットを企図する。キットは、本発明の態様の薬学的組成物のいずれかを含有する1つまたは複数の密封したバイアルを含んでもよい。キットは、例えば、少なくとも1つの抗TP-CAF抗体、ならびに態様の成分を調製、処方、および/もしくは投与するための、または本発明の方法の1つもしくは複数の段階を実施するための試薬を含んでもよい。いくつかの態様において、キットは、キットの成分と反応しない容器である適当な容器、例えば、エッペンドルフチューブ、アッセイプレート、注射器、ボトル、またはチューブも含んでもよい。容器は、プラスチックまたはガラスのような、滅菌可能な材料から作製されてもよい。
B. Kits and Diagnostics In various aspects of the embodiments, kits containing therapeutic agents and/or other therapeutic and delivery agents are envisioned. Embodiments of the invention contemplate kits for preparing and/or administering the therapeutic methods of the embodiments. Kits may include one or more sealed vials containing any of the pharmaceutical compositions of embodiments of the invention. Kits include, for example, at least one anti-TP-CAF antibody and reagents for preparing, formulating, and/or administering the components of the embodiments or for carrying out one or more steps of the methods of the invention. May include. In some embodiments, the kit may also include a suitable container that does not react with the components of the kit, such as an Eppendorf tube, assay plate, syringe, bottle, or tube. The container may be made from sterilizable materials, such as plastic or glass.
本発明の態様のいずれかの化合物または療法の患者への適用は、薬剤の、もしあれば毒性を考慮して、こうした化合物の適用のための一般的なプロトコルにしたがうであろう。それゆえ、いくつかの態様では、併用療法が原因である毒性をモニタリングする段階がある。
Application of a compound or therapy of any of the embodiments of the invention to a patient will follow general protocols for the application of such compounds, taking into account the toxicity, if any, of the drug. Therefore, in some embodiments there is a step of monitoring toxicity due to combination therapy.
Claims (18)
N末端からC末端に向かって、抗原結合ドメイン、ヒンジドメイン、膜貫通ドメイン、および細胞内シグナル伝達ドメインを含む、キメラ抗原受容体(CAR)ポリペプチドであって、TP-CAFによって発現されかつTS-CAFによって発現されないタンパク質に結合するCARポリペプチドを発現する、CAR T細胞の抗腫瘍有効量を投与する段階
を含む、請求項1または2記載の使用のための組成物。 said method administering an effective amount of an antibody or antibody fragment or chimeric antigen receptor that binds to a protein expressed by TP-CAF and not expressed by TS-CAF; or
A chimeric antigen receptor (CAR) polypeptide comprising, from N-terminus to C-terminus, an antigen-binding domain, a hinge domain, a transmembrane domain, and an intracellular signaling domain, said chimeric antigen receptor (CAR) polypeptide expressed by TP-CAF and TS - administering an anti-tumor effective amount of CAR T cells expressing a CAR polypeptide that binds to a protein not expressed by CAF
3. A composition for use according to claim 1 or 2 , comprising
(1) TP-CAFによって発現されかつTS-CAFによって発現されないタンパク質、および
(2) CD3
の両方に結合する二重特異性抗体である、または
該抗体または抗体断片が、細胞毒性剤もしくは診断剤に結合されている、
請求項5記載の組成物。 said antibody fragment is a recombinant scFv (single chain fragment variable) antibody, Fab fragment, F(ab') 2 fragment or Fv fragment , or said antibody is a chimeric antibody , preferably a humanized antibody, or bispecific antibodies, preferably
(1) proteins expressed by TP-CAF and not by TS-CAF, and
(2) CD3
is a bispecific antibody that binds to both, or
said antibody or antibody fragment is conjugated to a cytotoxic or diagnostic agent ;
6. The composition of claim 5 .
前記抗原結合ドメインが、TP-CAFによって発現されかつTS-CAFによって発現されないタンパク質に結合する抗体に由来するHCDR配列およびLCDR配列を含む、または
前記ヒンジドメインが、CD8aヒンジドメインもしくはIgG4ヒンジドメインである、または
前記膜貫通ドメインが、CD8a膜貫通ドメインもしくはCD28膜貫通ドメインである、または
前記細胞内シグナル伝達ドメインが、CD3z細胞内シグナル伝達ドメインを含む、
請求項11記載のポリペプチド。 wherein said antigen binding domain binds a HCDR sequence from a first antibody that binds a protein expressed by TP-CAF and not expressed by TS-CAF and a protein expressed by TP-CAF and not expressed by TS-CAF comprising an LCDR sequence from a second antibody that
said antigen binding domain comprises HCDR and LCDR sequences from an antibody that binds to a protein expressed by TP-CAF and not expressed by TS-CAF, or
said hinge domain is a CD8a hinge domain or an IgG4 hinge domain, or
said transmembrane domain is a CD8a transmembrane domain or a CD28 transmembrane domain, or
wherein said intracellular signaling domain comprises a CD3z intracellular signaling domain;
12. The polypeptide of claim 11 .
該抗体または該抗体断片の組織への結合を検出する段階
を含む、疾患を有すると患者を示す方法であって、該抗体または該抗体断片が組織に結合する場合、患者ががんを有すると示される、前記方法。 contacting cancer tissue obtained from the subject with the antibody or antibody fragment of claim 5 or 6 ; and detecting binding of the antibody or antibody fragment to the tissue. A method of indicating , wherein a patient is indicated to have cancer if said antibody or said antibody fragment binds to tissue.
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| PCT/US2019/065008 WO2020118216A1 (en) | 2018-12-08 | 2019-12-06 | Identification and targeting of tumor promoting carcinoma associated fibroblasts for diagnosis and treatment of cancer and other diseases |
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| JP5904552B2 (en) * | 2010-05-28 | 2016-04-13 | 国立研究開発法人国立がん研究センター | Pancreatic cancer treatment |
| WO2016145030A1 (en) * | 2015-03-11 | 2016-09-15 | Providence Health & Services-Oregon | Compositions and methods for enhancing the efficacy of cancer therapy |
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