JPWO2019104075A5 - - Google Patents

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JPWO2019104075A5
JPWO2019104075A5 JP2020528052A JP2020528052A JPWO2019104075A5 JP WO2019104075 A5 JPWO2019104075 A5 JP WO2019104075A5 JP 2020528052 A JP2020528052 A JP 2020528052A JP 2020528052 A JP2020528052 A JP 2020528052A JP WO2019104075 A5 JPWO2019104075 A5 JP WO2019104075A5
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癌：「癌」という用語は、異常細胞の制御されない（多くの場合に急速な）成長によって特徴付けられる疾患を指す。癌細胞は、局所的に又は血流及びリンパ系を介して身体の他の部位に広がり得る。様々な癌の例が本明細書に記載され、限定はされないが、乳癌、前立腺癌、卵巣癌、子宮頸癌、皮膚癌、膵臓癌、大腸癌、腎臓癌、肝臓癌、脳腫瘍、副腎癌、自律神経節癌、胆道癌、骨癌、子宮内膜癌、眼癌、卵管癌、生殖管癌、大腸癌、髄膜の癌、食道癌、腹膜癌、下垂体癌、陰茎癌、胎盤癌、胸膜癌、唾液腺癌、小腸癌、胃癌、精巣癌、胸腺癌、甲状腺癌、上部気道癌、尿路癌、膣癌、外陰癌、リンパ腫、白血病、肺癌など、例えば上記のタイプのいずれかの任意のＴＡＡ陽性癌が挙げられる。

Cancer: The term "cancer" refers to diseases characterized by uncontrolled (often rapid) growth of abnormal cells. Cancer cells can spread locally or through the bloodstream and lymphatic system to other parts of the body. Examples of various cancers are described herein, including but not limited to breast cancer, prostate cancer, ovarian cancer, cervical cancer, skin cancer, pancreatic cancer, colon cancer, kidney cancer, liver cancer, brain cancer, adrenal cancer, Autonomic ganglion cancer, biliary tract cancer, bone cancer, endometrial cancer, eye cancer, fallopian tube cancer, genital tract cancer, colon cancer, meningeal cancer, esophageal cancer, peritoneal cancer, pituitary cancer, penile cancer, placental cancer , pleural cancer, salivary gland cancer, small intestine cancer, gastric cancer, testicular cancer, thymic cancer, thyroid cancer, upper respiratory tract cancer, urinary tract cancer, vaginal cancer, vulvar cancer, lymphoma, leukemia, lung cancer, etc., for example any of the above types Any TAA positive cancer is included.

任意のタイプの腫瘍及び任意のタイプのＴＡＡは、本開示のＴＢＭによって標的にされ得ることが予測される。標的され得る癌の例示的なタイプとしては、急性リンパ性白血病、急性骨髄性白血病、胆管癌、Ｂ細胞白血病、Ｂ細胞リンパ腫、胆管癌、骨癌、脳腫瘍、乳癌、トリプルネガティブ乳癌、子宮頸癌、バーキットリンパ腫、慢性リンパ性白血病、慢性骨髄性白血病、大腸癌、子宮内膜癌、食道癌、胆嚢癌、胃癌、消化管癌、神経膠腫、有毛細胞白血病、頭頸部癌、ホジキンリンパ腫、肝臓癌、肺癌、甲状腺髄様癌、黒色腫、多発性骨髄腫、卵巣癌、非ホジキンリンパ腫、膵臓癌、前立腺癌、気道癌、腎臓癌、肉腫、皮膚癌、精巣癌、尿路上皮癌及び他の膀胱癌が挙げられる。しかしながら、当業者は、ＴＡＡが実質的にあらゆるタイプの癌で知られていることを認識するであろう。

It is anticipated that any type of tumor and any type of TAA may be targeted by the TBMs of the present disclosure. Exemplary types of cancers that can be targeted include acute lymphocytic leukemia, acute myeloid leukemia, cholangiocarcinoma, B-cell leukemia, B-cell lymphoma, cholangiocarcinoma, bone cancer , brain cancer, breast cancer, triple-negative breast cancer, cervical cancer. , Burkitt's lymphoma, chronic lymphocytic leukemia, chronic myelogenous leukemia, colon cancer, endometrial cancer, esophageal cancer, gallbladder cancer, gastric cancer, gastrointestinal cancer, glioma, hairy cell leukemia, head and neck cancer, Hodgkin's lymphoma , liver cancer, lung cancer, medullary thyroid cancer, melanoma, multiple myeloma, ovarian cancer, non-Hodgkin's lymphoma, pancreatic cancer, prostate cancer, respiratory tract cancer, renal cancer, sarcoma, skin cancer, testicular cancer, urothelial cancer and other bladder cancers. However, those skilled in the art will recognize that TAAs are known in virtually every type of cancer.

６．１２．治療適応症
本開示のＴＢＭは、ＴＡＡを発現する任意の増殖性疾患（例えば、癌）の治療に使用され得る。特定の実施形態において、癌は、ＨＥＲ２＋癌、急性リンパ性白血病（ＡＬＬ）、急性骨髄性白血病（ＡＭＬ）、副腎皮質癌、肛門癌、虫垂癌、星細胞腫、基底細胞癌、脳腫瘍、胆管癌、膀胱癌、骨癌、乳癌、気管支腫瘍、バーキットリンパ腫、原発不明癌、心臓腫瘍、子宮頸癌、脊索腫、慢性リンパ性白血病（ＣＬＬ）、慢性骨髄性白血病（ＣＭＬ）、慢性骨髄増殖性腫瘍、結腸癌、大腸癌、頭蓋咽頭腫、皮膚Ｔ細胞性リンパ腫、腺管癌、胎児性腫瘍、子宮内膜癌、上衣腫、食道癌、鼻腔神経芽細胞腫、線維性組織球腫、ユーイング肉腫、眼癌、胚細胞腫瘍、胆嚢癌、胃癌、消化管カルチノイド腫瘍、消化管間質性腫瘍、妊娠性絨毛性疾患、神経膠腫、頭頸部癌、有毛細胞白血病、肝細胞癌、組織球増殖症、ホジキンリンパ腫、下咽頭癌、眼内黒色腫、膵島細胞腫瘍、カポジ肉腫、腎臓癌、ランゲルハンス細胞組織球増殖症、喉頭癌、白血病、口唇癌及び口腔癌、肝臓癌、非浸潤性小葉癌、肺癌、リンパ腫、マクログロブリン血症、悪性線維性組織球腫、黒色腫、メルケル細胞癌、中皮腫、原発不明の転移性頸部扁平上皮癌、ＮＵＴ遺伝子が関連する正中線管癌、口腔癌、多発性内分泌腫瘍症候群、多発性骨髄腫、菌状息肉腫、骨髄異形成症候群、骨髄異形成／骨髄増殖性腫瘍、鼻腔癌及び副鼻腔癌、鼻咽腔癌、神経芽細胞腫、非ホジキンリンパ腫、非小細胞肺癌、口腔咽頭癌、骨肉腫、卵巣癌、膵臓癌、乳頭腫症、傍神経節腫、副甲状腺癌、陰茎癌、咽頭癌、褐色細胞腫、下垂体部腫瘍、胸膜肺芽腫、原発性中枢神経系リンパ腫、前立腺癌、直腸癌、腎細胞癌、腎盂癌及び尿管癌、網膜芽細胞腫、ラブドイド腫瘍、唾液腺癌、セザリー症候群、皮膚癌、小細胞肺癌、小腸癌、軟組織肉腫、脊髄腫瘍、胃癌、Ｔ細胞リンパ腫、奇形腫、精巣癌、咽頭癌、胸腺腫及び胸腺癌、甲状腺癌、尿道癌、子宮癌、膣癌、外陰癌並びにウィルムス腫瘍である。

6.12. Therapeutic Indications The TBM of the present disclosure can be used to treat any proliferative disease that expresses TAAs, such as cancer. In certain embodiments, the cancer is HER2+ cancer, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), adrenocortical carcinoma, anal cancer, appendiceal cancer, astrocytoma, basal cell carcinoma, brain tumor, cholangiocarcinoma , bladder cancer, bone cancer, breast cancer, bronchial tumor, Burkitt's lymphoma, carcinoma of unknown primary, cardiac tumor, cervical cancer, chordoma, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myeloproliferative Tumor, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, ductal carcinoma, fetal tumor, endometrial cancer, ependymoma, esophageal cancer, nasal neuroblastoma, fibrous histiocytoma, Ewing sarcoma, eye cancer, germ cell tumor, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor, gestational trophoblastic disease, glioma, head and neck cancer, hairy cell leukemia, hepatocellular carcinoma, tissue Hyperplasia, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, pancreatic islet cell tumor, Kaposi's sarcoma, renal cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, lip and oral cancer, liver cancer, non-invasive Lobular carcinoma, lung cancer, lymphoma, macroglobulinemia, malignant fibrous histiocytoma, melanoma, Merkel cell carcinoma, mesothelioma, metastatic squamous cell carcinoma of the neck of unknown primary, midline duct carcinoma associated with the NUT gene , oral cancer, multiple endocrine tumor syndrome, multiple myeloma, mycosis fungoides, myelodysplastic syndrome, myelodysplastic/myeloproliferative neoplasia, nasal and sinus cancer, nasopharyngeal carcinoma, neuroblastoma , non-Hodgkin's lymphoma, non-small cell lung cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pituitary tumor , pleuropulmonary blastoma, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell carcinoma, renal pelvic and ureteral cancer, retinoblastoma, rhabdoid tumor, salivary gland cancer, Sézary syndrome, skin cancer, small cell lung cancer , small bowel cancer, soft tissue sarcoma, spinal cord tumor, gastric cancer, T-cell lymphoma, teratoma, testicular cancer, pharyngeal cancer, thymoma and thymic cancer, thyroid cancer, urethral cancer, uterine cancer, vaginal cancer, vulvar cancer and Wilms tumor .

５６８．癌は、ＨＥＲ２＋癌、急性リンパ性白血病（ＡＬＬ）、急性骨髄性白血病（ＡＭＬ）、副腎皮質癌、肛門癌、虫垂癌、星細胞腫、基底細胞癌、脳腫瘍、胆管癌、膀胱癌、骨癌、乳癌、気管支腫瘍、バーキットリンパ腫、原発不明癌、心臓腫瘍、子宮頸癌、脊索腫、慢性リンパ性白血病（ＣＬＬ）、慢性骨髄性白血病（ＣＭＬ）、慢性骨髄増殖性腫瘍、結腸癌、大腸癌、頭蓋咽頭腫、皮膚Ｔ細胞性リンパ腫、腺管癌、胎児性腫瘍、子宮内膜癌、上衣腫、食道癌、鼻腔神経芽細胞腫、線維性組織球腫、ユーイング肉腫、眼癌、胚細胞腫瘍、胆嚢癌、胃癌、消化管カルチノイド腫瘍、消化管間質性腫瘍、妊娠性絨毛性疾患、神経膠腫、頭頸部癌、有毛細胞白血病、肝細胞癌、組織球増殖症、ホジキンリンパ腫、下咽頭癌、眼内黒色腫、膵島細胞腫瘍、カポジ肉腫、腎臓癌、ランゲルハンス細胞組織球増殖症、喉頭癌、白血病、口唇癌及び口腔癌、肝臓癌、非浸潤性小葉癌、肺癌、リンパ腫、マクログロブリン血症、悪性線維性組織球腫、黒色腫、メルケル細胞癌、中皮腫、原発不明の転移性頸部扁平上皮癌、ＮＵＴ遺伝子が関連する正中線管癌、口腔癌、多発性内分泌腫瘍症候群、多発性骨髄腫、菌状息肉腫、骨髄異形成症候群、骨髄異形成／骨髄増殖性腫瘍、鼻腔癌及び副鼻腔癌、鼻咽腔癌、神経芽細胞腫、非ホジキンリンパ腫、非小細胞肺癌、口腔咽頭癌、骨肉腫、卵巣癌、膵臓癌、乳頭腫症、傍神経節腫、副甲状腺癌、陰茎癌、咽頭癌、褐色細胞腫、下垂体部腫瘍、胸膜肺芽腫、原発性中枢神経系リンパ腫、前立腺癌、直腸癌、腎細胞癌、腎盂癌及び尿管癌、網膜芽細胞腫、ラブドイド腫瘍、唾液腺癌、セザリー症候群、皮膚癌、小細胞肺癌、小腸癌、軟組織肉腫、脊髄腫瘍、胃癌、Ｔ細胞リンパ腫、奇形腫、精巣癌、咽頭癌、胸腺腫及び胸腺癌、甲状腺癌、尿道癌、子宮癌、膣癌、外陰癌並びにウィルムス腫瘍から選択される、実施形態５６７に記載の方法。

568. Cancer includes HER2+ cancer, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), adrenocortical carcinoma, anal cancer, appendix cancer, astrocytoma, basal cell carcinoma, brain tumor, cholangiocarcinoma, bladder cancer, bone cancer , breast cancer, bronchial tumor, Burkitt's lymphoma, carcinoma of unknown primary, cardiac tumor, cervical cancer, chordoma, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myeloproliferative tumor, colon cancer, colon Cancer, craniopharyngioma, cutaneous T-cell lymphoma, ductal carcinoma, fetal tumor, endometrial cancer, ependymoma, esophageal cancer, nasal neuroblastoma, fibrous histiocytoma, Ewing sarcoma, eye cancer, embryo Cellular tumor, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor, gestational trophoblastic disease, glioma, head and neck cancer, hairy cell leukemia, hepatocellular carcinoma, histiocytosis, Hodgkin lymphoma , hypopharyngeal cancer, intraocular melanoma, pancreatic islet cell tumor, Kaposi's sarcoma, renal cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ, lung cancer, lymphoma , macroglobulinemia, malignant fibrous histiocytoma, melanoma, Merkel cell carcinoma, mesothelioma, metastatic squamous cell carcinoma of the neck of unknown primary, midline duct carcinoma associated with the NUT gene, oral cancer, multiple Endocrine tumor syndrome, multiple myeloma, mycosis fungoides, myelodysplastic syndrome, myelodysplastic/myeloproliferative neoplasia, nasal and paranasal sinus cancer, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin's lymphoma, non small cell lung cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pituitary tumor, pleuropulmonary blastoma, Primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell carcinoma, renal pelvic and ureteral cancer, retinoblastoma, rhabdoid tumor, salivary gland cancer, Sézary syndrome, skin cancer, small cell lung cancer, small bowel cancer, soft tissue sarcoma spinal cord tumor, gastric cancer, T-cell lymphoma, teratoma, testicular cancer, pharyngeal cancer, thymoma and thymic carcinoma, thyroid cancer, urethral cancer, uterine cancer, vaginal cancer, vulvar cancer, and Wilms tumor, embodiment 567 The method described in .

１１５４．癌は、ＨＥＲ２＋癌、急性リンパ性白血病（ＡＬＬ）、急性骨髄性白血病（ＡＭＬ）、副腎皮質癌、肛門癌、虫垂癌、星細胞腫、基底細胞癌、脳腫瘍、胆管癌、膀胱癌、骨癌、乳癌、気管支腫瘍、バーキットリンパ腫、原発不明癌、心臓腫瘍、子宮頸癌、脊索腫、慢性リンパ性白血病（ＣＬＬ）、慢性骨髄性白血病（ＣＭＬ）、慢性骨髄増殖性腫瘍、結腸癌、大腸癌、頭蓋咽頭腫、皮膚Ｔ細胞性リンパ腫、腺管癌、胎児性腫瘍、子宮内膜癌、上衣腫、食道癌、鼻腔神経芽細胞腫、線維性組織球腫、ユーイング肉腫、眼癌、胚細胞腫瘍、胆嚢癌、胃癌、消化管カルチノイド腫瘍、消化管間質性腫瘍、妊娠性絨毛性疾患、神経膠腫、頭頸部癌、有毛細胞白血病、肝細胞癌、組織球増殖症、ホジキンリンパ腫、下咽頭癌、眼内黒色腫、膵島細胞腫瘍、カポジ肉腫、腎臓癌、ランゲルハンス細胞組織球増殖症、喉頭癌、白血病、口唇癌及び口腔癌、肝臓癌、非浸潤性小葉癌、肺癌、リンパ腫、マクログロブリン血症、悪性線維性組織球腫、黒色腫、メルケル細胞癌、中皮腫、原発不明の転移性頸部扁平上皮癌、ＮＵＴ遺伝子が関連する正中線管癌、口腔癌、多発性内分泌腫瘍症候群、多発性骨髄腫、菌状息肉腫、骨髄異形成症候群、骨髄異形成／骨髄増殖性腫瘍、鼻腔癌及び副鼻腔癌、鼻咽腔癌、神経芽細胞腫、非ホジキンリンパ腫、非小細胞肺癌、口腔咽頭癌、骨肉腫、卵巣癌、膵臓癌、乳頭腫症、傍神経節腫、副甲状腺癌、陰茎癌、咽頭癌、褐色細胞腫、下垂体部腫瘍、胸膜肺芽腫、原発性中枢神経系リンパ腫、前立腺癌、直腸癌、腎細胞癌、腎盂癌及び尿管癌、網膜芽細胞腫、ラブドイド腫瘍、唾液腺癌、セザリー症候群、皮膚癌、小細胞肺癌、小腸癌、軟組織肉腫、脊髄腫瘍、胃癌、Ｔ細胞リンパ腫、奇形腫、精巣癌、咽頭癌、胸腺腫及び胸腺癌、甲状腺癌、尿道癌、子宮癌、膣癌、外陰癌並びにウィルムス腫瘍から選択される、実施形態１１５３に記載の方法。

1154. Cancer includes HER2+ cancer, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), adrenocortical carcinoma, anal cancer, appendix cancer, astrocytoma, basal cell carcinoma, brain tumor, cholangiocarcinoma, bladder cancer, bone cancer , breast cancer, bronchial tumor, Burkitt's lymphoma, carcinoma of unknown primary, cardiac tumor, cervical cancer, chordoma, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myeloproliferative tumor, colon cancer, colon Cancer, craniopharyngioma, cutaneous T-cell lymphoma, ductal carcinoma, fetal tumor, endometrial cancer, ependymoma, esophageal cancer, nasal neuroblastoma, fibrous histiocytoma, Ewing sarcoma, eye cancer, embryo Cellular tumor, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor, gestational trophoblastic disease, glioma, head and neck cancer, hairy cell leukemia, hepatocellular carcinoma, histiocytosis, Hodgkin lymphoma , hypopharyngeal cancer, intraocular melanoma, pancreatic islet cell tumor, Kaposi's sarcoma, renal cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ, lung cancer, lymphoma , macroglobulinemia, malignant fibrous histiocytoma, melanoma, Merkel cell carcinoma, mesothelioma, metastatic squamous cell carcinoma of the neck of unknown primary, midline duct carcinoma associated with the NUT gene, oral cancer, multiple Endocrine tumor syndrome, multiple myeloma, mycosis fungoides, myelodysplastic syndrome, myelodysplastic/myeloproliferative neoplasia, nasal and paranasal sinus cancer, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin's lymphoma, non small cell lung cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pituitary tumor, pleuropulmonary blastoma, Primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell carcinoma, renal pelvic and ureteral cancer, retinoblastoma, rhabdoid tumor, salivary gland cancer, Sézary syndrome, skin cancer, small cell lung cancer, small bowel cancer, soft tissue sarcoma , spinal cord tumor, gastric cancer, T-cell lymphoma, teratoma, testicular cancer, pharyngeal cancer, thymoma and thymic carcinoma, thyroid cancer, urethral cancer, uterine cancer, vaginal cancer, vulvar cancer, and Wilms tumor, embodiment 1153 The method described in .

本出願において引用される全ての刊行物、特許、特許出願及び他の文献は、それぞれの個々の刊行物、特許、特許出願又は他の文献があらゆる目的のために参照により援用されることが個別に示されているのと同程度に、あらゆる目的のためにその全体が参照により本明細書に援用される。本明細書に援用される参照文献の１つ以上と本開示の教示との間に矛盾がある場合、本明細書の教示が意図される。

本発明は以下の態様が含まれる。
［１］
（ａ）ヒトＣＤ２に特異的に結合する抗原結合モジュール１（ＡＢＭ１）と；
（ｂ）ヒトＴ細胞受容体（ＴＣＲ）複合体の構成要素に特異的に結合する抗原結合モジュール２（ＡＢＭ２）と；
（ｃ）ヒト腫瘍関連抗原（ＴＡＡ）に特異的に結合する抗原結合モジュール３（ＡＢＭ３）と
を含む三重特異性結合分子（ＴＢＭ）。
［２］
各抗原結合モジュールは、他の抗原結合モジュールのそれぞれがそのそれぞれの標的に結合されるのと同時にそのそれぞれの標的に結合することが可能である、請求項１に記載のＴＢＭ。
［３］
ＡＢＭ１は、
（ａ）任意選択的に、抗ＣＤ２抗体、抗体フラグメント、ｓｃＦｖ、ｄｓＦｖ、Ｆｖ、Ｆａｂ、ｓｃＦａｂ、（Ｆａｂ’）２、単一ドメイン抗体（ＳＤＡＢ）、ＶＨ若しくはＶＬドメイン又はラクダ科ＶＨＨドメインである免疫グロブリン足場ベースのＡＢＭ；又は
（ｂ）任意選択的に、クニッツドメイン、アドネキシン、アフィボディ、ＤＡＲＰｉｎ、アビマー、アンチカリン、リポカリン、センチリン、バーサボディ、ノッチン、アドネクチン、プロネクチン、アフィチン／ナノフィチン、アフィリン、アトリマー／テトラネクチン、二環式ペプチド、ｃｙｓ－ノット、Ｆｎ３足場、オーボディ、Ｔｎ３、アフィマー、ＢＤ、アドヒロン、デュオカリン、アルファボディ、アルマジロリピートタンパク質、レペボディ又はフィノマーである非免疫グロブリン足場ベースのＡＢＭ
である、請求項１に記載のＴＢＭ。
［４］
ＡＢＭ１は、ｓｃＦｖ又はＦａｂである、請求項３に記載のＴＢＭ。
［５］
ＡＢＭ１は、表９に記載される結合配列のいずれかを含む、請求項３に記載のＴＢＭ。［６］
ＡＢＭ１は、ＣＤ２リガンドの受容体結合ドメインを含む、請求項１に記載のＴＢＭ。［７］
ＡＢＭ１は、ＣＤ５８部分である、請求項１に記載のＴＢＭ。
［８］
ＡＢＭ１は、ＣＤ５８－２のアミノ酸１～９４を含む、請求項７に記載のＴＢＭ。
［９］
ＡＢＭ１は、ＣＤ４８部分である、請求項１に記載のＴＢＭ。
［１０］
ヒトＴＣＲ複合体の前記構成要素は、ＣＤ３である、請求項１に記載のＴＢＭ。
［１１］
ＡＢＭ２は、
（ａ）任意選択的に、抗ＣＤ３抗体、抗体フラグメント、ｓｃＦｖ、ｄｓＦｖ、Ｆｖ、Ｆａｂ、ｓｃＦａｂ、（Ｆａｂ’）２、単一ドメイン抗体（ＳＤＡＢ）、ＶＨ若しくはＶＬドメイン又はラクダ科ＶＨＨドメインである免疫グロブリン足場ベースのＡＢＭ；又は
（ｂ）任意選択的に、クニッツドメイン、アドネキシン、アフィボディ、ＤＡＲＰｉｎ、アビマー、アンチカリン、リポカリン、センチリン、バーサボディ、ノッチン、アドネクチン、プロネクチン、アフィチン／ナノフィチン、アフィリン、アトリマー／テトラネクチン、二環式ペプチド、ｃｙｓ－ノット、Ｆｎ３足場、オーボディ、Ｔｎ３、アフィマー、ＢＤ、アドヒロン、デュオカリン、アルファボディ、アルマジロリピートタンパク質、レペボディ又はフィノマーである非免疫グロブリン足場ベースのＡＢＭ
である、請求項１０に記載のＴＢＭ。
［１２］
ＡＢＭ２は、ｓｃＦｖ又はＦａｂである、請求項１１に記載のＴＢＭ。
［１３］
ＡＢＭ２は、表７Ａ～７Ｄのいずれか１つに記載される結合配列のいずれかを含む、請求項１１に記載のＴＢＭ。
［１４］
ＡＢＭ２は、表７Ａに記載されるＣＤ３－２１のＶＨ及びＶＬ配列を含む、請求項１３に記載のＴＢＭ。
［１５］
ヒトＴＣＲ複合体の前記構成要素は、ＴＣＲのαサブユニットである、請求項１に記載のＴＢＭ。
［１６］
ＡＢＭ２は、抗ＣＤ３抗体、抗体フラグメント、ｓｃＦｖ、Ｆｖ、ｄｓＦｖ、Ｆａｂ、ｓｃＦａｂ、（Ｆａｂ’）２、単一ドメイン抗体（ＳＤＡＢ）、ＶＨ若しくはＶＬドメイン、ラクダ科ＶＨＨドメイン、ＤＡＲＰｉｎ、アビマー、アンチカリン／リポカリン、センチリン、バーサボディ、デュオカリン又はフィノマーである、請求項１５に記載のＴＢＭ。
［１７］
ＴＡＡが受容体である場合、ＡＢＭ３は、前記受容体のリガンドの受容体結合ドメインを含み、及びＴＡＡがリガンドである場合、ＡＢＭ３は、前記リガンドの受容体のリガンド結合ドメインを含む、請求項１に記載のＴＢＭ。
［１８］
ＡＢＭ３は、
（ａ）任意選択的に、抗ＴＡＡ抗体、抗体フラグメント、ｓｃＦｖ、ｄｓＦｖ、Ｆｖ、Ｆａｂ、ｓｃＦａｂ、（Ｆａｂ’）２、単一ドメイン抗体（ＳＤＡＢ）、ＶＨ若しくはＶＬドメイン又はラクダ科ＶＨＨドメインである免疫グロブリン足場ベースのＡＢＭ；又は
（ｂ）任意選択的に、クニッツドメイン、アドネキシン、アフィボディ、ＤＡＲＰｉｎ、アビマー、アンチカリン、リポカリン、センチリン、バーサボディ、ノッチン、アドネクチン、プロネクチン、アフィチン／ナノフィチン、アフィリン、アトリマー／テトラネクチン、二環式ペプチド、ｃｙｓ－ノット、Ｆｎ３足場、オーボディ、Ｔｎ３、アフィマー、ＢＤ、アドヒロン、デュオカリン、アルファボディ、アルマジロリピートタンパク質、レペボディ又はフィノマーである非免疫グロブリン足場ベースのＡＢＭ
である、請求項１に記載のＴＢＭ。
［１９］
前記ＴＡＡは、ＴＳＨＲ、ＣＤ１７１、ＣＳ－１、ＣＬＬ－１、ＧＤ３、Ｔｎ Ａｇ、ＦＬＴ３、ＣＤ３８、ＣＤ４４ｖ６、Ｂ７Ｈ３、ＫＩＴ、ＩＬ－１３Ｒａ２、ＩＬ－１１Ｒａ、ＰＳＣＡ、ＰＲＳＳ２１、ＶＥＧＦＲ２、ルイスＹ、ＣＤ２４、ＰＤＧＦＲ－β、ＳＳＥＡ－４、ＭＵＣ１、ＥＧＦＲ、ＥＧＦＲｖＩＩＩ、ＮＣＡＭ、ＣＡＩＸ、ＬＭＰ２、ＥｐｈＡ２、フコシルＧＭ１、ｓＬｅ、ＧＭ３、ＴＧＳ５、ＨＭＷＭＡＡ、ｏ－アセチル－ＧＤ２、ＧＤ２、葉酸受容体α、葉酸受容体β、ＴＥＭ１／ＣＤ２４８、ＴＥＭ７Ｒ、ＣＬＤＮ６、ＧＰＲＣ５Ｄ、ＣＸＯＲＦ６１、ＣＤ９７、ＣＤ１７９ａ、ＡＬＫ、ポリシアル酸、ＰＬＡＣ１、ＧｌｏｂｏＨ、ＮＹ－ＢＲ－１、ＵＰＫ２、ＨＡＶＣＲ１、ＡＤＲＢ３、ＰＡＮＸ３、ＧＰＲ２０、ＬＹ６Ｋ、ＯＲ５１Ｅ２、ＴＡＡＲＰ、ＷＴ１、ＥＴＶ６－ＡＭＬ、精子タンパク質１７、ＸＡＧＥ１、Ｔｉｅ ２、ＭＡＤ－ＣＴ－１、ＭＡＤ－ＣＴ－２、Ｆｏｓ関連抗原１、ｐ５３突然変異体、ｈＴＥＲＴ、肉腫転座切断点、ＭＬ－ＩＡＰ、ＥＲＧ（ＴＭＰＲＳＳ２ ＥＴＳ融合遺伝子）、ＮＡ１７、ＰＡＸ３、アンドロゲン受容体、サイクリンＢ１、ＭＹＣＮ、ＲｈｏＣ、ＣＹＰ１Ｂ１、ＢＯＲＩＳ、ＳＡＲＴ３、ＰＡＸ５、ＯＹ－ＴＥＳ１、ＬＣＫ、ＡＫＡＰ－４、ＳＳＸ２、ＣＤ７９ａ、ＣＤ７９ｂ、ＣＤ７２、ＬＡＩＲ１、ＦＣＡＲ、ＬＩＬＲＡ２、ＣＤ３００ＬＦ、ＣＬＥＣ１２Ａ、ＢＳＴ２、ＥＭＲ２、ＬＹ７５、ＧＰＣ３、ＦＣＲＬ５、ＩＧＬＬ１、ＣＤ１９、ＣＤ２０、ＣＤ３０、ＥＲＢＢ２、ＲＯＲ１、ＦＬＴ３、ＴＡＡＧ７２、ＣＤ２２、ＣＤ３３、ＧＤ２、ＢＣＭＡ、ｇｐ１００Ｔｎ、ＦＡＰ、チロシナーゼ、ＥＰＣＡＭ、ＣＥＡ、Ｉｇｆ－Ｉ受容体、カドヘリン１７、ＣＤ３２ｂ、ＧＰＮＭＢ、ＧＰＲ６４、ＨＥＲ３、ＬＲＰ６、ＬＹＰＤ８、ＮＫＧ２Ｄ、ＳＬＣ３４Ａ２、ＳＬＣ３９Ａ６、ＳＬＩＴＲＫ６、ＴＡＣＳＴＤ２又はＥｐｈＢ２である、請求項１８に記載のＴＢＭ。
［２０］
前記ＴＡＡは、ＢＣＭＡである、請求項１８に記載のＴＢＭ。
［２１］
ＡＢＭ３は、表１２Ａ、１２Ｂ、１２Ｃ、１２Ｄ、１２Ｅ又は１２Ｆのいずれか１つに記載される結合配列のいずれかを含む、請求項２０に記載のＴＢＭ。
［２２］
前記ＴＡＡは、ＣＤ１９である、請求項１８に記載のＴＢＭ。
［２３］
ＡＢＭ３は、表１３に記載される結合配列のいずれかを含む、請求項２２に記載のＴＢＭ。
［２４］
前記ＴＡＡは、Ｈｅｒ２である、請求項１８に記載のＴＢＭ。
［２５］
前記ＴＡＡは、メソテリンである、請求項１８に記載のＴＢＭ。
［２６］
ＡＢＭ３は、ｓｃＦｖ又はＦａｂである、請求項１８に記載のＴＢＭ。
［２７］
３価ＴＢＭである、請求項１に記載のＴＢＭ。
［２８］
前記３価ＴＢＭは、図１Ｂ～１Ｕ及び１Ｖ～１Ｚに示される形態のいずれか１つを有する、請求項２７に記載のＴＢＭ。
［２９］
図１Ｉに示される形態を有する、請求項２８に記載のＴＢＭ。
［３０］
前記ＡＢＭは、Ｔ６として示される形態を有する、請求項２９に記載のＴＢＭ。
［３１］
４価ＴＢＭである、請求項１に記載のＴＢＭ。
［３２］
５価ＴＢＭである、請求項１に記載のＴＢＭ。
［３３］
６価ＴＢＭである、請求項１に記載のＴＢＭ。
［３４］
請求項１～３３のいずれか一項に記載のＴＢＭ及び細胞傷害性薬剤又は細胞増殖抑制性薬剤を含むコンジュゲート。
［３５］
請求項１～３３のいずれか一項に記載のＴＢＭ及び賦形剤を含む医薬組成物。
［３６］
癌に罹患した対象を治療する方法であって、癌に罹患している対象に、有効量の、請求項１～３３のいずれか一項に記載のＴＢＭを投与することを含む方法。
［３７］
前記癌は、ＨＥＲ２＋癌、急性リンパ性白血病（ＡＬＬ）、急性骨髄性白血病（ＡＭＬ）、副腎皮質癌、肛門癌、虫垂癌、星細胞腫、基底細胞癌、脳腫瘍、胆管癌、膀胱癌、骨癌、乳癌、気管支腫瘍、バーキットリンパ腫、原発不明癌、心臓腫瘍、子宮頸癌、脊索腫、慢性リンパ性白血病（ＣＬＬ）、慢性骨髄性白血病（ＣＭＬ）、慢性骨髄増殖性腫瘍、結腸癌、大腸癌、頭蓋咽頭腫、皮膚Ｔ細胞性リンパ腫、腺管癌、胎児性腫瘍、子宮内膜癌、上衣腫、食道癌、鼻腔神経芽細胞腫、線維性組織球腫、ユーイング肉腫、眼癌、胚細胞腫瘍、胆嚢癌、胃癌、消化管カルチノイド腫瘍、消化管間質性腫瘍、妊娠性絨毛性疾患、神経膠腫、頭頸部癌、有毛細胞白血病、肝細胞癌、組織球増殖症、ホジキンリンパ腫、下咽頭癌、眼内黒色腫、膵島細胞腫瘍、カポジ肉腫、腎臓癌、ランゲルハンス細胞組織球増殖症、喉頭癌、白血病、口唇癌及び口腔癌、肝臓癌、非浸潤性小葉癌、肺癌、リンパ腫、マクログロブリン血症、悪性線維性組織球腫、黒色腫、メルケル細胞癌、中皮腫、原発不明の転移性頸部扁平上皮癌、ＮＵＴ遺伝子が関連する正中線管癌、口腔癌、多発性内分泌腫瘍症候群、多発性骨髄腫、菌状息肉腫、骨髄異形成症候群、骨髄異形成／骨髄増殖性腫瘍、鼻腔癌及び副鼻腔癌、鼻咽腔癌、神経芽細胞腫、非ホジキンリンパ腫、非小細胞肺癌、口腔咽頭癌、骨肉腫、卵巣癌、膵臓癌、乳頭腫症、傍神経節腫、副甲状腺癌、陰茎癌、咽頭癌、褐色細胞腫、下垂体部腫瘍、胸膜肺芽腫、原発性中枢神経系リンパ腫、前立腺癌、直腸癌、腎細胞癌、腎盂癌及び尿管癌、網膜芽細胞腫、ラブドイド腫瘍、唾液腺癌、セザリー症候群、皮膚癌、小細胞肺癌、小腸癌、軟組織肉腫、脊髄腫瘍、胃癌、Ｔ細胞リンパ腫、奇形腫、精巣癌、咽頭癌、胸腺腫及び胸腺癌、甲状腺癌、尿道癌、子宮癌、膣癌、外陰癌並びにウィルムス腫瘍から選択される、請求項３６に記載の方法。
［３８］
請求項１～３３のいずれか一項に記載のＴＢＭをコードする１つ又は複数の核酸。
［３９］
請求項１～３３のいずれか一項に記載のＴＢＭを発現するように操作された細胞。
［４０］
１つ以上のプロモーターの制御下において、請求項１～３３のいずれか一項に記載のＴＢＭをコードする１つ以上の核酸配列を含む１つ以上の発現ベクターでトランスフェクトされた細胞。
［４１］
ＴＢＭを産生する方法であって、
（ａ）前記ＴＢＭが発現される条件において、請求項４０に記載の細胞を培養することと；
（ｂ）細胞培養物から前記ＴＢＭを回収することと
を含む方法。

All publications, patents, patent applications and other documents cited in this application are individually acknowledged that each individual publication, patent, patent application or other document is incorporated by reference for all purposes. is hereby incorporated by reference in its entirety for all purposes. In the event of any conflict between one or more of the references incorporated herein and the teachings of this disclosure, the teachings of this disclosure are intended.

The present invention includes the following aspects.
[1]
(a) an antigen binding module 1 (ABM1) that specifically binds to human CD2;
(b) antigen binding module 2 (ABM2) that specifically binds to a component of the human T cell receptor (TCR) complex;
(c) a trispecific binding molecule (TBM) comprising antigen binding module 3 (ABM3) that specifically binds to a human tumor-associated antigen (TAA).
[2]
2. The TBM of claim 1, wherein each antigen binding module is capable of binding its respective target at the same time as each of the other antigen binding modules is bound to its respective target.
[3]
ABM1 is
(a) optionally an anti-CD2 antibody, antibody fragment, scFv, dsFv, Fv, Fab, scFab, (Fab')2, single domain antibody (SDAB), VH or VL domain or camelid VHH domain immunoglobulin scaffold-based ABMs; Non-immunoglobulin scaffold-based ABMs that are atrimers/tetranectins, bicyclic peptides, cys-knots, Fn3 scaffolds, obodies, Tn3s, affimers, BDs, adherons, duocalins, alphabodies, armadillo repeat proteins, repebodies or finomers
The TBM of claim 1, wherein:
[4]
4. The TBM of claim 3, wherein ABM1 is scFv or Fab.
[5]
4. The TBM of claim 3, wherein ABM1 comprises any of the binding sequences listed in Table 9. [6]
2. The TBM of claim 1, wherein ABM1 comprises the receptor binding domain of CD2 ligand. [7]
2. The TBM of claim 1, wherein ABM1 is the CD58 moiety.
[8]
The TBM of claim 7, wherein ABM1 comprises amino acids 1-94 of CD58-2.
[9]
2. The TBM of claim 1, wherein ABM1 is the CD48 moiety.
[10]
2. The TBM of claim 1, wherein said component of the human TCR complex is CD3.
[11]
ABM2 is
(a) optionally an anti-CD3 antibody, antibody fragment, scFv, dsFv, Fv, Fab, scFab, (Fab')2, single domain antibody (SDAB), VH or VL domain or camelid VHH domain immunoglobulin scaffold-based ABMs; Non-immunoglobulin scaffold-based ABMs that are atrimers/tetranectins, bicyclic peptides, cys-knots, Fn3 scaffolds, obodies, Tn3s, affimers, BDs, adherons, duocalins, alphabodies, armadillo repeat proteins, repebodies or finomers
11. The TBM of claim 10, wherein:
[12]
12. The TBM of claim 11, wherein ABM2 is scFv or Fab.
[13]
12. The TBM of claim 11, wherein ABM2 comprises any of the binding sequences listed in any one of Tables 7A-7D.
[14]
14. The TBM of claim 13, wherein ABM2 comprises the CD3-21 VH and VL sequences listed in Table 7A.
[15]
2. The TBM of claim 1, wherein said component of the human TCR complex is the alpha subunit of the TCR.
[16]
ABM2 is anti-CD3 antibody, antibody fragment, scFv, Fv, dsFv, Fab, scFab, (Fab')2, single domain antibody (SDAB), VH or VL domain, camelid VHH domain, DARPin, avimer, anticalin 16. The TBM of claim 15, which is /lipocalin, centinin, versabodies, duocalins or fynomers.
[17]
Claim 1, wherein when the TAA is a receptor, ABM3 comprises a receptor binding domain of a ligand of said receptor, and when TAA is a ligand, ABM3 comprises a ligand binding domain of a receptor of said ligand. TBM as described in .
[18]
ABM3 is
(a) optionally an anti-TAA antibody, antibody fragment, scFv, dsFv, Fv, Fab, scFab, (Fab')2, single domain antibody (SDAB), VH or VL domain or camelid VHH domain immunoglobulin scaffold-based ABMs; Non-immunoglobulin scaffold-based ABMs that are atrimers/tetranectins, bicyclic peptides, cys-knots, Fn3 scaffolds, obodies, Tn3s, affimers, BDs, adherons, duocalins, alphabodies, armadillo repeat proteins, repebodies or finomers
The TBM of claim 1, wherein:
[19]
The TAAs are TSHR, CD171, CS-1, CLL-1, GD3, Tn Ag, FLT3, CD38, CD44v6, B7H3, KIT, IL-13Ra2, IL-11Ra, PSCA, PRSS21, VEGFR2, Lewis Y, CD24, PDGFR-β, SSEA-4, MUC1, EGFR, EGFRvIII, NCAM, CAIX, LMP2, EphA2, Fucosyl GM1, sLe, GM3, TGS5, HMWMAA, o-acetyl-GD2, GD2, folate receptor α, folate receptor β , TEM1/CD248, TEM7R, CLDN6, GPRC5D, CXORF61, CD97, CD179a, ALK, polysialic acid, PLAC1, GloboH, NY-BR-1, UPK2, HAVCR1, ADRB3, PANX3, GPR20, LY6K, OR51E2, TAARP, WT1, ETV6-AML, sperm protein 17, XAGE1, Tie 2, MAD-CT-1, MAD-CT-2, Fos-associated antigen 1, p53 mutant, hTERT, sarcoma translocation breakpoint, ML-IAP, ERG (TMPRSS2 ETS fusion gene), NA17, PAX3, androgen receptor, cyclin B1, MYCN, RhoC, CYP1B1, BORIS, SART3, PAX5, OY-TES1, LCK, AKAP-4, SSX2, CD79a, CD79b, CD72, LAIR1, FCAR, LILRA2, CD300LF, CLEC12A, BST2, EMR2, LY75, GPC3, FCRL5, IGLL1, CD19, CD20, CD30, ERBB2, ROR1, FLT3, TAAG72, CD22, CD33, GD2, BCMA, gp100Tn, FAP, tyrosinase, EPCAM, CEA, 19. The TBM of claim 18, which is an Igf-I receptor, cadherin 17, CD32b, GPNMB, GPR64, HER3, LRP6, LYPD8, NKG2D, SLC34A2, SLC39A6, SLITRK6, TACSTD2 or EphB2.
[20]
19. The TBM of claim 18, wherein said TAA is BCMA.
[21]
21. The TBM of claim 20, wherein ABM3 comprises any of the binding sequences listed in any one of Tables 12A, 12B, 12C, 12D, 12E or 12F.
[22]
19. The TBM of claim 18, wherein said TAA is CD19.
[23]
23. The TBM of claim 22, wherein ABM3 comprises any of the binding sequences listed in Table 13.
[24]
19. The TBM of claim 18, wherein said TAA is Her2.
[25]
19. The TBM of claim 18, wherein said TAA is mesothelin.
[26]
19. The TBM of claim 18, wherein ABM3 is scFv or Fab.
[27]
2. The TBM of claim 1, which is a trivalent TBM.
[28]
28. The TBM of claim 27, wherein said trivalent TBM has any one of the forms shown in FIGS. 1B-1U and 1V-1Z.
[29]
29. The TBM of claim 28, having the configuration shown in Figure 1I.
[30]
30. The TBM of claim 29, wherein the ABM has a morphology designated as T6.
[31]
2. The TBM of claim 1, which is a tetravalent TBM.
[32]
2. The TBM of claim 1, which is a pentavalent TBM.
[33]
2. The TBM of claim 1, which is a hexavalent TBM.
[34]
A conjugate comprising the TBM of any one of claims 1-33 and a cytotoxic or cytostatic agent.
[35]
A pharmaceutical composition comprising the TBM of any one of claims 1-33 and an excipient.
[36]
34. A method of treating a subject afflicted with cancer comprising administering to the subject afflicted with cancer an effective amount of the TBM of any one of claims 1-33.
[37]
Said cancer is HER2+ cancer, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), adrenocortical carcinoma, anal cancer, appendix cancer, astrocytoma, basal cell carcinoma, brain tumor, cholangiocarcinoma, bladder cancer, bone cancer , breast cancer, bronchial tumor, Burkitt's lymphoma, cancer of unknown primary, cardiac tumor, cervical cancer, chordoma, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myeloproliferative tumor, colon cancer, Colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, ductal carcinoma, fetal tumor, endometrial cancer, ependymoma, esophageal cancer, nasal neuroblastoma, fibrous histiocytoma, Ewing sarcoma, eye cancer, Germ cell tumor, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor, gestational trophoblastic disease, glioma, head and neck cancer, hairy cell leukemia, hepatocellular carcinoma, histiocytosis, Hodgkin Lymphoma, hypopharyngeal carcinoma, intraocular melanoma, pancreatic islet cell tumor, Kaposi's sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ, lung cancer, Lymphoma, macroglobulinemia, malignant fibrous histiocytoma, melanoma, Merkel cell carcinoma, mesothelioma, metastatic squamous cell carcinoma of the neck of unknown primary, midline duct carcinoma associated with the NUT gene, oral cancer, multiple endocrine neoplasm syndrome, multiple myeloma, mycosis fungoides, myelodysplastic syndrome, myelodysplastic/myeloproliferative neoplasia, nasal and paranasal sinus cancer, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin's lymphoma, Non-small cell lung cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pituitary tumor, pleuropulmonary blastoma , primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell carcinoma, renal pelvic and ureteral cancer, retinoblastoma, rhabdoid tumor, salivary gland cancer, Sézary syndrome, skin cancer, small cell lung cancer, small bowel cancer, soft tissue sarcoma, spinal cord tumor, gastric cancer, T-cell lymphoma, teratoma, testicular cancer, pharyngeal cancer, thymoma and thymic carcinoma, thyroid cancer, urethral cancer, uterine cancer, vaginal cancer, vulvar cancer and Wilms tumor. 36. The method according to 36.
[38]
One or more nucleic acids encoding a TBM according to any one of claims 1-33.
[39]
A cell engineered to express the TBM of any one of claims 1-33.
[40]
A cell transfected with one or more expression vectors comprising one or more nucleic acid sequences encoding the TBM of any one of claims 1-33 under the control of one or more promoters.
[41]
A method of producing TBM, comprising:
(a) culturing the cells of claim 40 in conditions in which said TBM is expressed;
(b) recovering said TBM from cell culture.

Claims (33)

（ａ）ヒトＣＤ２に特異的に結合する抗原結合モジュール１（ＡＢＭ１）と；
（ｂ）ヒトＴ細胞受容体（ＴＣＲ）複合体の構成要素に特異的に結合する抗原結合モジュール２（ＡＢＭ２）と；
（ｃ）ヒト腫瘍関連抗原（ＴＡＡ）に特異的に結合する抗原結合モジュール３（ＡＢＭ３）と
を含む三重特異性結合分子（ＴＢＭ）であって、
ＡＢＭ１、ＡＢＭ２及びＡＢＭ３が、Ｆｃドメイン、ペプチドリンカー又はその組み合わせを介して互いに連結される、ＴＢＭ。 (a) an antigen binding module 1 (ABM1) that specifically binds to human CD2;
(b) antigen binding module 2 (ABM2) that specifically binds to a component of the human T cell receptor (TCR) complex;
(c) a trispecific binding molecule (TBM) comprising an antigen binding module 3 (ABM3) that specifically binds to a human tumor-associated antigen (TAA) ,
TBM, wherein ABM1, ABM2 and ABM3 are linked together via an Fc domain, a peptide linker or a combination thereof . 各抗原結合モジュールは、他の抗原結合モジュールのそれぞれがそのそれぞれの標的に結合されるのと同時にそのそれぞれの標的に結合することが可能である、請求項１に記載のＴＢＭ。 2. The TBM of claim 1, wherein each antigen binding module is capable of binding its respective target at the same time as each of the other antigen binding modules is bound to its respective target. ＡＢＭ１は、ABM1 is
（ａ）免疫グロブリン足場ベースのＡＢＭ；又は (a) an immunoglobulin scaffold-based ABM; or
（ｂ）非免疫グロブリン足場ベースのＡＢＭ(b) non-immunoglobulin scaffold-based ABM
である、請求項１又は２に記載のＴＢＭ。3. The TBM of claim 1 or 2, wherein ＡＢＭ１は、
（ａ）抗ＣＤ２抗体、抗体フラグメント、ｓｃＦｖ、ｄｓＦｖ、Ｆｖ、Ｆａｂ、ｓｃＦａｂ、（Ｆａｂ’）２、単一ドメイン抗体（ＳＤＡＢ）、ＶＨ若しくはＶＬドメイン又はラクダ科ＶＨＨドメインである免疫グロブリン足場ベースのＡＢＭ；又は
（ｂ）クニッツドメイン、アドネキシン、アフィボディ、ＤＡＲＰｉｎ、アビマー、アンチカリン、リポカリン、センチリン、バーサボディ、ノッチン、アドネクチン、プロネクチン、アフィチン／ナノフィチン、アフィリン、アトリマー／テトラネクチン、二環式ペプチド、ｃｙｓ－ノット、Ｆｎ３足場、オーボディ、Ｔｎ３、アフィマー、ＢＤ、アドヒロン、デュオカリン、アルファボディ、アルマジロリピートタンパク質、レペボディ又はフィノマーである非免疫グロブリン足場ベースのＡＢＭ
である、請求項１又は２に記載のＴＢＭ。 ABM1 is
(a ) anti-CD2 antibodies, antibody fragments, scFv, dsFv, Fv, Fab, scFab, (Fab')2, single domain antibodies (SDAB), immunoglobulin scaffold-based VH or VL domains or camelid VHH domains or (b ) Kunitz domains, Adnexins, Affibodies, DARPins, Avimers, Anticalins, Lipocalins, Sentilins, Versabodies, Knottins, Adnectins, Pronectins, Affitins/Nanophytins, Affilins, Atrimers/Tetranectins, Bicyclic peptides, Non-immunoglobulin scaffold-based ABMs that are cys-knots, Fn3 scaffolds, obodies, Tn3, affimers, BDs, adherons, duocalins, alphabodies, armadillo repeat proteins, repebodies or finomers
3. The TBM of claim 1 or 2 , wherein ＡＢＭ１は、ｓｃＦｖ又はＦａｂである、請求項３又は４に記載のＴＢＭ。 5. The TBM of claim 3 or 4 , wherein ABM1 is scFv or Fab. ＡＢＭ１は、（ａ）配列番号２４７～２５２のアミノ酸配列をそれぞれ含むＣＤＲ－Ｈ１、ＣＤＲ－Ｈ２、ＣＤＲ－Ｈ３、ＣＤＲ－Ｌ１、ＣＤＲ－Ｌ２及びＣＤＲ－Ｌ３；（ｂ）配列番号２５３～２５４のアミノ酸配列をそれぞれ含むＶＨ及びＶＬ；（ｃ）配列番号２５５～２５６のアミノ酸配列をそれぞれ含むＶＨ及びＶＬ；又は（ｄ）配列番号２５７～２５８のアミノ酸配列をそれぞれ含むＶＨ及びＶＬを含む、請求項３～５のいずれか一項に記載のＴＢＭ。 ABM1 comprises (a) CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3 comprising the amino acid sequences of SEQ ID NOs:247-252, respectively; (b) SEQ ID NOs:253-254 (c) VH and VL respectively comprising the amino acid sequences of SEQ ID NOs:255-256; or (d) VH and VL respectively comprising the amino acid sequences of SEQ ID NOs:257-258. 3. The TBM according to any one of items 3-5 . ＡＢＭ１は、ＣＤ２リガンドの受容体結合ドメインを含む、請求項１又は２に記載のＴＢＭ。 3. The TBM of claim 1 or 2 , wherein ABM1 comprises the receptor binding domain of CD2 ligand. ＡＢＭ１は、ＣＤ５８部分である、請求項１又は２に記載のＴＢＭ。 3. The TBM of claim 1 or 2 , wherein ABM1 is the CD58 moiety. ＡＢＭ１は、配列番号２５８のアミノ酸３０～１２３を含む、請求項８に記載のＴＢＭ。 9. The TBM of claim 8, wherein ABM1 comprises amino acids 30-123 of SEQ ID NO:258 . ヒトＴＣＲ複合体の前記構成要素は、ＣＤ３である、請求項１～９のいずれか一項に記載のＴＢＭ。 The TBM of any one of claims 1-9, wherein said component of the human TCR complex is CD3. ＡＢＭ２は、
（ａ）免疫グロブリン足場ベースのＡＢＭ；又は
（ｂ）非免疫グロブリン足場ベースのＡＢＭ
である、請求項１０に記載のＴＢＭ。 ABM2 is
( a) an immunoglobulin scaffold-based ABM; or
(b) non-immunoglobulin scaffold-based ABM
11. The TBM of claim 10, wherein: ＡＢＭ２は、
（ａ）抗ＣＤ３抗体、抗体フラグメント、ｓｃＦｖ、ｄｓＦｖ、Ｆｖ、Ｆａｂ、ｓｃＦａｂ、（Ｆａｂ’）２、単一ドメイン抗体（ＳＤＡＢ）、ＶＨ若しくはＶＬドメイン又はラクダ科ＶＨＨドメインである免疫グロブリン足場ベースのＡＢＭ；又は
（ｂ）クニッツドメイン、アドネキシン、アフィボディ、ＤＡＲＰｉｎ、アビマー、アンチカリン、リポカリン、センチリン、バーサボディ、ノッチン、アドネクチン、プロネクチン、アフィチン／ナノフィチン、アフィリン、アトリマー／テトラネクチン、二環式ペプチド、ｃｙｓ－ノット、Ｆｎ３足場、オーボディ、Ｔｎ３、アフィマー、ＢＤ、アドヒロン、デュオカリン、アルファボディ、アルマジロリピートタンパク質、レペボディ又はフィノマーである非免疫グロブリン足場ベースのＡＢＭ
である、請求項１０に記載のＴＢＭ。 ABM2 is
(a ) anti-CD3 antibodies, antibody fragments, scFv, dsFv, Fv, Fab, scFab, (Fab')2, single domain antibodies (SDAB), immunoglobulin scaffold-based VH or VL domains or camelid VHH domains or (b ) Kunitz domains, Adnexins, Affibodies, DARPins, Avimers, Anticalins, Lipocalins, Sentilins, Versabodies, Knottins, Adnectins, Pronectins, Affitins/Nanophytins, Affilins, Atrimers/Tetranectins, Bicyclic peptides, Non-immunoglobulin scaffold-based ABMs that are cys-knots, Fn3 scaffolds, obodies, Tn3, affimers, BDs, adherons, duocalins, alphabodies, armadillo repeat proteins, repebodies or finomers
11. The TBM of claim 10 , wherein: ＡＢＭ２は、ｓｃＦｖ又はＦａｂである、請求項１１又は１２に記載のＴＢＭ。 13. The TBM of claim 11 or 12 , wherein ABM2 is scFv or Fab. ＡＢＭ２は、（ａ）表７Ａに記載されるＣＤ３－１～ＣＤ３－２８のいずれかのＶＨ及びＶＬ対；（ｂ）表７Ａに記載されるＣＤ３－２１～ＣＤ３－２８のいずれかのｓｃＦｖ；（ｃ）表７Ｂに記載されるＣＤ３－１～ＣＤ３－１２８のいずれかのＣＤＲ－Ｈ１、ＣＤＲ－Ｈ２、ＣＤＲ－Ｈ３、ＣＤＲ－Ｌ１、ＣＤＲ－Ｌ２及びＣＤＲ－Ｌ３；（ｄ）表７Ｃに記載されるＣＤ３－１～ＣＤ３－２１のいずれかのＣＤＲ－Ｈ１、ＣＤＲ－Ｈ２、ＣＤＲ－Ｈ３、ＣＤＲ－Ｌ１、ＣＤＲ－Ｌ２及びＣＤＲ－Ｌ３；又は（ｅ）表７Ｄに記載されるＣＤ３－１～ＣＤ３－２０のいずれかのＣＤＲ－Ｈ１、ＣＤＲ－Ｈ２、ＣＤＲ－Ｈ３、ＣＤＲ－Ｌ１、ＣＤＲ－Ｌ２及びＣＤＲ－Ｌ３を含む、請求項１１～１３のいずれか一項に記載のＴＢＭ。 ABM2 is (a) a VH and VL pair of any of CD3-1 to CD3-28 listed in Table 7A; (b) a scFv of any of CD3-21 to CD3-28 listed in Table 7A; (c) CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3 of any of CD3-1 through CD3-128 listed in Table 7B; CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3 of any of CD3-1 to CD3-21 listed; or (e) CD3- listed in Table 7D 14. The TBM of any one of claims 11-13 , comprising the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3 of any of CDR-H1 to CD3-20 . ＡＢＭ２は、表７Ａに記載されるＣＤ３－２１のＶＨ及びＶＬ配列を含む、請求項１４に記載のＴＢＭ。 15. The TBM of claim 14 , wherein ABM2 comprises the CD3-21 VH and VL sequences listed in Table 7A. ヒトＴＣＲ複合体の前記構成要素は、ＴＣＲのαサブユニットである、請求項１～９のいずれか一項のいずれかに記載のＴＢＭ。 The TBM of any one of claims 1-9, wherein said component of the human TCR complex is the α subunit of the TCR. ＴＡＡが受容体である場合、ＡＢＭ３は、前記受容体のリガンドの受容体結合ドメインを含み、及びＴＡＡがリガンドである場合、ＡＢＭ３は、前記リガンドの受容体のリガンド結合ドメインを含む、請求項１～１６のいずれか一項に記載のＴＢＭ。 Claim 1, wherein when the TAA is a receptor, ABM3 comprises a receptor binding domain of a ligand of said receptor, and when TAA is a ligand, ABM3 comprises a ligand binding domain of a receptor of said ligand. 17. The TBM of any one of claims 1-16. ＡＢＭ３は、
（ａ）免疫グロブリン足場ベースのＡＢＭ；又は
（ｂ）非免疫グロブリン足場ベースのＡＢＭ
である、請求項１～１６のいずれか一項に記載のＴＢＭ。 ABM3 is
(a) an immunoglobulin scaffold-based ABM; or
(b) non-immunoglobulin scaffold-based ABM
The TBM according to any one of claims 1 to 16, wherein the TBM is ＡＢＭ３は、
（ａ）抗ＴＡＡ抗体、抗体フラグメント、ｓｃＦｖ、ｄｓＦｖ、Ｆｖ、Ｆａｂ、ｓｃＦａｂ、（Ｆａｂ’）２、単一ドメイン抗体（ＳＤＡＢ）、ＶＨ若しくはＶＬドメイン又はラクダ科ＶＨＨドメインである免疫グロブリン足場ベースのＡＢＭ；又は
（ｂ）クニッツドメイン、アドネキシン、アフィボディ、ＤＡＲＰｉｎ、アビマー、アンチカリン、リポカリン、センチリン、バーサボディ、ノッチン、アドネクチン、プロネクチン、アフィチン／ナノフィチン、アフィリン、アトリマー／テトラネクチン、二環式ペプチド、ｃｙｓ－ノット、Ｆｎ３足場、オーボディ、Ｔｎ３、アフィマー、ＢＤ、アドヒロン、デュオカリン、アルファボディ、アルマジロリピートタンパク質、レペボディ又はフィノマーである非免疫グロブリン足場ベースのＡＢＭ
である、請求項１～１６のいずれか一項に記載のＴＢＭ。 ABM3 is
(a ) anti-TAA antibodies, antibody fragments, scFv, dsFv, Fv, Fab, scFab, (Fab')2, single domain antibodies (SDAB), immunoglobulin scaffold-based VH or VL domains or camelid VHH domains or (b ) Kunitz domains, Adnexins, Affibodies, DARPins, Avimers, Anticalins, Lipocalins, Sentilins, Versabodies, Knottins, Adnectins, Pronectins, Affitins/Nanophytins, Affilins, Atrimers/Tetranectins, Bicyclic peptides, Non-immunoglobulin scaffold-based ABMs that are cys-knots, Fn3 scaffolds, obodies, Tn3, affimers, BDs, adherons, duocalins, alphabodies, armadillo repeat proteins, repebodies or finomers
The TBM according to any one of claims 1 to 16 , which is 前記ＴＡＡは、ＴＳＨＲ、ＣＤ１７１、ＣＳ－１、ＣＬＬ－１、ＧＤ３、Ｔｎ Ａｇ、ＦＬＴ３、ＣＤ３８、ＣＤ４４ｖ６、Ｂ７Ｈ３、ＫＩＴ、ＩＬ－１３Ｒａ２、ＩＬ－１１Ｒａ、ＰＳＣＡ、ＰＲＳＳ２１、ＶＥＧＦＲ２、ルイスＹ、ＣＤ２４、ＰＤＧＦＲ－β、ＳＳＥＡ－４、ＭＵＣ１、ＥＧＦＲ、ＥＧＦＲｖＩＩＩ、ＮＣＡＭ、ＣＡＩＸ、ＬＭＰ２、ＥｐｈＡ２、フコシルＧＭ１、ｓＬｅ、ＧＭ３、ＴＧＳ５、ＨＭＷＭＡＡ、ｏ－アセチル－ＧＤ２、ＧＤ２、葉酸受容体α、葉酸受容体β、ＴＥＭ１／ＣＤ２４８、ＴＥＭ７Ｒ、ＣＬＤＮ６、ＧＰＲＣ５Ｄ、ＣＸＯＲＦ６１、ＣＤ９７、ＣＤ１７９ａ、ＡＬＫ、ポリシアル酸、ＰＬＡＣ１、ＧｌｏｂｏＨ、ＮＹ－ＢＲ－１、ＵＰＫ２、ＨＡＶＣＲ１、ＡＤＲＢ３、ＰＡＮＸ３、ＧＰＲ２０、ＬＹ６Ｋ、ＯＲ５１Ｅ２、ＴＡＡＲＰ、ＷＴ１、ＥＴＶ６－ＡＭＬ、精子タンパク質１７、ＸＡＧＥ１、Ｔｉｅ ２、ＭＡＤ－ＣＴ－１、ＭＡＤ－ＣＴ－２、Ｆｏｓ関連抗原１、ｐ５３突然変異体、ｈＴＥＲＴ、肉腫転座切断点、ＭＬ－ＩＡＰ、ＥＲＧ（ＴＭＰＲＳＳ２ ＥＴＳ融合遺伝子）、ＮＡ１７、ＰＡＸ３、アンドロゲン受容体、サイクリンＢ１、ＭＹＣＮ、ＲｈｏＣ、ＣＹＰ１Ｂ１、ＢＯＲＩＳ、ＳＡＲＴ３、ＰＡＸ５、ＯＹ－ＴＥＳ１、ＬＣＫ、ＡＫＡＰ－４、ＳＳＸ２、ＣＤ７９ａ、ＣＤ７９ｂ、ＣＤ７２、ＬＡＩＲ１、ＦＣＡＲ、ＬＩＬＲＡ２、ＣＤ３００ＬＦ、ＣＬＥＣ１２Ａ、ＢＳＴ２、ＥＭＲ２、ＬＹ７５、ＧＰＣ３、ＦＣＲＬ５、ＩＧＬＬ１、ＣＤ１９、ＣＤ２０、ＣＤ３０、ＥＲＢＢ２、ＲＯＲ１、ＦＬＴ３、ＴＡＡＧ７２、ＣＤ２２、ＣＤ３３、ＧＤ２、ＢＣＭＡ、ｇｐ１００Ｔｎ、ＦＡＰ、チロシナーゼ、ＥＰＣＡＭ、ＣＥＡ、Ｉｇｆ－Ｉ受容体、カドヘリン１７、ＣＤ３２ｂ、ＧＰＮＭＢ、ＧＰＲ６４、ＨＥＲ３、ＬＲＰ６、ＬＹＰＤ８、ＮＫＧ２Ｄ、ＳＬＣ３４Ａ２、ＳＬＣ３９Ａ６、ＳＬＩＴＲＫ６、ＴＡＣＳＴＤ２又はＥｐｈＢ２である、請求項１８又は１９に記載のＴＢＭ。 The TAAs are TSHR, CD171, CS-1, CLL-1, GD3, Tn Ag, FLT3, CD38, CD44v6, B7H3, KIT, IL-13Ra2, IL-11Ra, PSCA, PRSS21, VEGFR2, Lewis Y, CD24, PDGFR-β, SSEA-4, MUC1, EGFR, EGFRvIII, NCAM, CAIX, LMP2, EphA2, Fucosyl GM1, sLe, GM3, TGS5, HMWMAA, o-acetyl-GD2, GD2, folate receptor α, folate receptor β , TEM1/CD248, TEM7R, CLDN6, GPRC5D, CXORF61, CD97, CD179a, ALK, polysialic acid, PLAC1, GloboH, NY-BR-1, UPK2, HAVCR1, ADRB3, PANX3, GPR20, LY6K, OR51E2, TAARP, WT1, ETV6-AML, sperm protein 17, XAGE1, Tie 2, MAD-CT-1, MAD-CT-2, Fos-associated antigen 1, p53 mutant, hTERT, sarcoma translocation breakpoint, ML-IAP, ERG (TMPRSS2 ETS fusion gene), NA17, PAX3, androgen receptor, cyclin B1, MYCN, RhoC, CYP1B1, BORIS, SART3, PAX5, OY-TES1, LCK, AKAP-4, SSX2, CD79a, CD79b, CD72, LAIR1, FCAR, LILRA2, CD300LF, CLEC12A, BST2, EMR2, LY75, GPC3, FCRL5, IGLL1, CD19, CD20, CD30, ERBB2, ROR1, FLT3, TAAG72, CD22, CD33, GD2, BCMA, gp100Tn, FAP, tyrosinase, EPCAM, CEA, 20. The TBM of claim 18 or 19 , which is Igf-I receptor, Cadherin 17, CD32b, GPNMB, GPR64, HER3, LRP6, LYPD8, NKG2D, SLC34A2, SLC39A6, SLITRK6, TACSTD2 or EphB2. ＡＢＭ３は、ｓｃＦｖ又はＦａｂである、請求項１８～２０のいずれか一項に記載のＴＢＭ。 The TBM of any one of claims 18-20, wherein ABM3 is scFv or Fab. Ｆｃドメインを含む、請求項１～２１のいずれか一項に記載のＴＢＭ。The TBM of any one of claims 1-21, comprising an Fc domain. ３価ＴＢＭである、請求項１～２２のいずれか一項に記載のＴＢＭ。 TBM according to any one of claims 1 to 22 , which is a trivalent TBM. 前記３価ＴＢＭは、図１Ｂ～１Ｕ及び１Ｖ～１Ｚに示される形態のいずれか１つを有する、請求項２３に記載のＴＢＭ。 24. The TBM of claim 23 , wherein the trivalent TBM has any one of the forms shown in FIGS. 1B-1U and 1V-1Z. ４価ＴＢＭ、５価ＴＢＭまたは６価ＴＢＭである、請求項１～２２のいずれか一項に記載のＴＢＭ。 TBM according to any one of claims 1 to 22 , which is a tetravalent TBM, a pentavalent TBM or a hexavalent TBM. 請求項１～２５のいずれか一項に記載のＴＢＭ及び細胞傷害性薬剤又は細胞増殖抑制性薬剤を含むコンジュゲート。 A conjugate comprising the TBM of any one of claims 1-25 and a cytotoxic or cytostatic agent. 請求項１～２５のいずれか一項に記載のＴＢＭ及び賦形剤を含む医薬組成物。 A pharmaceutical composition comprising TBM according to any one of claims 1-25 and an excipient. 癌に罹患した対象を治療するための医薬組成物であって、有効量の、請求項１～２５のいずれか一項に記載のＴＢＭを含む、医薬組成物。 A pharmaceutical composition for treating a subject with cancer, comprising an effective amount of the TBM of any one of claims 1-25. 前記癌は、ＨＥＲ２＋癌、急性リンパ性白血病（ＡＬＬ）、急性骨髄性白血病（ＡＭＬ）、副腎皮質癌、肛門癌、虫垂癌、星細胞腫、基底細胞癌、脳腫瘍、胆管癌、膀胱癌、骨癌、乳癌、気管支腫瘍、バーキットリンパ腫、原発不明癌、心臓腫瘍、子宮頸癌、脊索腫、慢性リンパ性白血病（ＣＬＬ）、慢性骨髄性白血病（ＣＭＬ）、慢性骨髄増殖性腫瘍、結腸癌、大腸癌、頭蓋咽頭腫、皮膚Ｔ細胞性リンパ腫、腺管癌、胎児性腫瘍、子宮内膜癌、上衣腫、食道癌、鼻腔神経芽細胞腫、線維性組織球腫、ユーイング肉腫、眼癌、胚細胞腫瘍、胆嚢癌、胃癌、消化管カルチノイド腫瘍、消化管間質性腫瘍、妊娠性絨毛性疾患、神経膠腫、頭頸部癌、有毛細胞白血病、肝細胞癌、組織球増殖症、ホジキンリンパ腫、下咽頭癌、眼内黒色腫、膵島細胞腫瘍、カポジ肉腫、腎臓癌、ランゲルハンス細胞組織球増殖症、喉頭癌、白血病、口唇癌及び口腔癌、肝臓癌、非浸潤性小葉癌、肺癌、リンパ腫、マクログロブリン血症、悪性線維性組織球腫、黒色腫、メルケル細胞癌、中皮腫、原発不明の転移性頸部扁平上皮癌、ＮＵＴ遺伝子が関連する正中線管癌、口腔癌、多発性内分泌腫瘍症候群、多発性骨髄腫、菌状息肉腫、骨髄異形成症候群、骨髄異形成／骨髄増殖性腫瘍、鼻腔癌及び副鼻腔癌、鼻咽腔癌、神経芽細胞腫、非ホジキンリンパ腫、非小細胞肺癌、口腔咽頭癌、骨肉腫、卵巣癌、膵臓癌、乳頭腫症、傍神経節腫、副甲状腺癌、陰茎癌、咽頭癌、褐色細胞腫、下垂体部腫瘍、胸膜肺芽腫、原発性中枢神経系リンパ腫、前立腺癌、直腸癌、腎細胞癌、腎盂癌及び尿管癌、網膜芽細胞腫、ラブドイド腫瘍、唾液腺癌、セザリー症候群、皮膚癌、小細胞肺癌、小腸癌、軟組織肉腫、脊髄腫瘍、胃癌、Ｔ細胞リンパ腫、奇形腫、精巣癌、咽頭癌、胸腺腫及び胸腺癌、甲状腺癌、尿道癌、子宮癌、膣癌、外陰癌並びにウィルムス腫瘍からなる群から選択される、請求項２８に記載の医薬組成物。 Said cancer is HER2+ cancer, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), adrenocortical carcinoma, anal cancer, appendix cancer, astrocytoma, basal cell carcinoma, brain tumor, cholangiocarcinoma, bladder cancer, bone cancer , breast cancer, bronchial tumor, Burkitt's lymphoma, cancer of unknown primary, cardiac tumor, cervical cancer, chordoma, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myeloproliferative tumor, colon cancer, Colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, ductal carcinoma, fetal tumor, endometrial cancer, ependymoma, esophageal cancer, nasal neuroblastoma, fibrous histiocytoma, Ewing sarcoma, eye cancer, Germ cell tumor, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor, gestational trophoblastic disease, glioma, head and neck cancer, hairy cell leukemia, hepatocellular carcinoma, histiocytosis, Hodgkin Lymphoma, hypopharyngeal carcinoma, intraocular melanoma, pancreatic islet cell tumor, Kaposi's sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, lip and oral cancer, liver cancer, lobular carcinoma in situ, lung cancer, Lymphoma, macroglobulinemia, malignant fibrous histiocytoma, melanoma, Merkel cell carcinoma, mesothelioma, metastatic squamous cell carcinoma of the neck of unknown primary, midline duct carcinoma associated with the NUT gene, oral cancer, multiple endocrine neoplasm syndrome, multiple myeloma, mycosis fungoides, myelodysplastic syndrome, myelodysplastic/myeloproliferative neoplasia, nasal and paranasal sinus cancer, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin's lymphoma, Non-small cell lung cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pituitary tumor, pleuropulmonary blastoma , primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell carcinoma, renal pelvic and ureteral cancer, retinoblastoma, rhabdoid tumor, salivary gland cancer, Sézary syndrome, skin cancer, small cell lung cancer, small bowel cancer, soft tissue selected from the group consisting of sarcoma, spinal cord tumor, gastric cancer, T-cell lymphoma, teratoma, testicular cancer, pharyngeal cancer, thymoma and thymic carcinoma, thyroid cancer, urethral cancer, uterine cancer, vaginal cancer, vulvar cancer and Wilms tumor 29. The pharmaceutical composition of claim 28 . 請求項１～２５のいずれか一項に記載のＴＢＭをコードする１つ又は複数の核酸。 One or more nucleic acids encoding a TBM according to any one of claims 1-25 . 請求項１～２５のいずれか一項に記載のＴＢＭを発現するように操作された細胞。 A cell engineered to express the TBM of any one of claims 1-25. １つ以上のプロモーターの制御下において、請求項１～２５のいずれか一項に記載のＴＢＭをコードする１つ以上の核酸配列を含む１つ以上の発現ベクターでトランスフェクトされた細胞。 A cell transfected with one or more expression vectors comprising one or more nucleic acid sequences encoding the TBM of any one of claims 1-25 under the control of one or more promoters. ＴＢＭを産生する方法であって、
（ａ）前記ＴＢＭが発現される条件において、請求項３１又は３２に記載の細胞を培養することと；
（ｂ）細胞培養物から前記ＴＢＭを回収することと
を含む方法。

A method of producing TBM, comprising:
(a) culturing the cells of claim 31 or 32 in conditions in which said TBM is expressed;
(b) recovering said TBM from cell culture.
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