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THIOPURINE-HYPERSENSITIVE CHIMERIC-ANTIGEN-RECEPTOR GENE-MODIFIED LYMPHOCYTE UPDATE

外国特許コード F180009459
整理番号 (S2017-0066-N0)
掲載日 2018年7月31日
出願国 世界知的所有権機関(WIPO)
国際出願番号 2017JP038217
国際公開番号 WO 2018079497
国際出願日 平成29年10月23日(2017.10.23)
国際公開日 平成30年5月3日(2018.5.3)
優先権データ
  • 特願2016-209066 (2016.10.25) JP
発明の名称 (英語) THIOPURINE-HYPERSENSITIVE CHIMERIC-ANTIGEN-RECEPTOR GENE-MODIFIED LYMPHOCYTE UPDATE
発明の概要(英語) The present invention addresses the problem of providing a novel suicide gene system which allows for control of a chimeric-antigen-receptor gene-modified lymphocyte after being administered using a highly safe method, in order to further advance clinical applications of CAR therapies. According to the present invention, a genetically modified lymphocyte which expresses a chimeric antigen receptor is prepared by introducing, into a target cell, a target antigen-specific chimeric antigen receptor gene, and a first nucleic acid construct which intracellularly produces an siRNA which targets the NUDT15 gene and/or a second nucleic acid construct which intracellularly produces an siRNA which targets the TPMT gene.
従来技術、競合技術の概要(英語) BACKGROUND ART
(CAR) chimeric antigen receptor gene or gene T cell receptor (TCR) genetically engineered (T cells, NK cells etc.) lymphocyte cell therapy (chemotherapy CAR) is used, an effective treatment for cancer refractory as expected. CD19 Particular CAR-T cell therapy targeting a dramatic tumor cell B may produce a therapeutic effect. CAR-T duration of the treatment effect in the body and is closely related to the duration of the cells. Genetically modified lymphocytes in the administration, blood cytokines and a high on/off-target effects becomes a problem. Further, the genetic modification made from the same donor lymphocytes in the administration, graft versus host disease (GVHD) with the risk.
CAR/TCR lymphocytes suicide gene and gene can be introduced into, or can be reduced to avoid the risk of the above can be considered. As a suicide gene, herpes simplex virus thymidine kinase (HSV-TK), CD20,inducible Caspase9 (iCasp9) of the 1 type has been developed (Non-Patent Document 1, 2). All these suicide gene system, and a suicide gene corresponding to a combination of a suicide activation action. Typically, cell death-inducing an irreversible suicide system because the path is used, once the operating system expected to suicide treatment effect is also finished at that time. However, blood cytokines and GVHD high reversible side effects such as a suicide gene to the case where the system is powered up, an appropriate amount (small) activation by administration of a suicide of the aberrant activation only genetically engineered lymphocytes are removed, side effects after resolution of CAR/TCR is again modified by the duration of the lymphocyte function is desirable from the standpoint of the cost of medical services and therapeutic effects.
HSV-TK suicide gene is, operated by ganciclovir. Therefore, the patient is undergoing treatment of viral infection with ganciclovir cannot be used at the time. Ganciclovir dose in humans, safety and usage is established for, by adjusting the dosage, the genetic modification can modulate the function of the lymphocytes is a possibility that the suicide. However, HSV-TK gene product protein from the virus immunogenic because high, transgenic lymphocytes were eliminated by the patient's immune system is, in the body cannot be long-term survival. CD20 Suicide gene is, actuated by the rituximab. As a side effect of the on-target by administration of rituximab in a decrease of the cell B. Rituximab dose in the human, and the established usage, drug comparatively high level of safety. CD20 Gene is not introduced and immunogenicity. However, the effect of CD20 suicide gene, complement-dependent cytotoxicity and for antibody-dependent cellular cytotoxicity activity, T cell surface expression of CD20 in the degree of the patient's immune status (presence or absence of effector cells) depends largely on. iCasp 9 Is, CID(chemical inducer of dimerization; AP1903) a low molecular compound by the dimerization, endogenous Caspase 3 to activate the T cells by inducing apoptosis. Immunogenicity is Caspase 9, the cell killing effect is in a fast and powerful, does not depend on the patient's immune status. However, since the CID is not medicine, a suitable dose, which are not clear and safety of usage, the adjustment of the dose-dependent suicide function is currently difficult.
  • 出願人(英語)
  • ※2012年7月以前掲載分については米国以外のすべての指定国
  • SHINSHU UNIVERSITY
  • NAGOYA UNIVERSITY
  • 発明者(英語)
  • NAKAZAWA Yozo
  • MATSUDA Kazuyuki
  • MORITA Daisuke
  • MURAMATSU Hideki
  • OKUNO Yusuke
  • TAKAHASHI Yoshiyuki
国際特許分類(IPC)
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