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PRETREATMENT DRUG FOR T CELL INFUSION THERAPY FOR IMMUNE-CHECKPOINT INHIBITOR-RESISTANT TUMOR

外国特許コード F180009340
整理番号 S2016-0413-C0
掲載日 2018年3月13日
出願国 世界知的所有権機関(WIPO)
国際出願番号 2017JP004552
国際公開番号 WO 2017138557
国際出願日 平成29年2月8日(2017.2.8)
国際公開日 平成29年8月17日(2017.8.17)
優先権データ
  • 特願2016-022081 (2016.2.8) JP
発明の名称 (英語) PRETREATMENT DRUG FOR T CELL INFUSION THERAPY FOR IMMUNE-CHECKPOINT INHIBITOR-RESISTANT TUMOR
発明の概要(英語) [Problem] To provide a technique relating to a therapy for an immune-checkpoint inhibitor-resistant tumor.
[Solution] The problem can be solved by a pharmaceutical composition which is intended to be administered prior to the administration of T cells specific to an antigen in a T cell infusion therapy for an immune-checkpoint inhibitor-resistant tumor, said pharmaceutical composition containing an antigen-encapsulated nano gel, wherein the antigen-encapsulated nano gel comprises a long-chain peptide antigen or a protein antigen each of which is encapsulated in a hydrophobized polysaccharide nano gel, and the long-chain peptide antigen or the protein antigen contains a CD8-positive cytotoxic T cell-recognizing epitope and a CD4-positive helper T cell-recognizing epitope both originated from the aforementioned antigen.
従来技術、競合技術の概要(英語) BACKGROUND ART
T cells, plays an important role in tumor immune response. T cells, T cell receptor expressed on the surface of cells (TCR) via, antigen presenting cells (dendritic cells, macrophages) on the cell surface of major histocompatibility complex (MHC) antigen presented as a complex to recognize epitope peptides derived from protein. The reaction was referred to as antigen stimulation. Antigen stimulation at the same time, present on the cell surface membrane protein T antigen-presenting on a cell membrane protein CD28 CD80 CD86 are combined or co-stimulatory signal is established. TCR signal by antigen stimulation and co-stimulatory signal can be input at a time, the cell is correctly activated T.
Therefore, in a medical image, at all times, is possible to add a shadow is not always appropriate. Membrane protein CTLA-4 is, expressed in the cell activation T, CD86 or CD80 binding to an antigen presenting cell. As a result, CD28 and CD80, CD86 or CD28 and interfere with the binding between the contacting each other with the establishment of the co-stimulatory signal, input signal restrained within T cells. T cells express CTLA-4 controllability is, on an antigen presenting cell can be bonded to the CD86 or CD80, which inhibit the activity of an antigen presenting cell action. Through such functions, is CTLA-4, capable of limiting the function T cells function as immune checkpoint molecules. T cells upon activation of the film to enhance expression of the protein PD-1, which is a kind of immune checkpoint molecules. As a ligand that binds PD-1, known PD-L1. Is PD-L1, many tumor cells and activated immune cells express. Is on a cell T PD-L1 bind to PD-1, by a signal PD-1, TCR signal is suppressed at the time of antigen stimulation. As a result, T cell cytokine production and cell killing activity is lowered. Signal PD-1, an action to suppress T cell proliferation is survival.
CTLA-4, such as PD-1 PD-L1 and immune checkpoint molecules, weaken the function of tumor-specific T cells. As a result, the major cause of tumor immune escape from already become one. CTLA-4, or PD-L1 PD-1 by the action of, acts as a tumor-specific T cells recovered, tumor immune attack can be enhanced. A variety of human cancers, the usefulness of the inhibitor for the immune checkpoint molecules being evaluated. And inhibition antibody CTLA-4 is inhibition antibody PD-1, refractory melanoma, lung cancer and renal cell cancer in a patient, such as tumor reduction and increased survival of choice for treating effect. However, the therapeutic effect, in any one of the cancer, remains about 2-3 interrupt. Many cancer patients, resistant to immune checkpoint inhibitor. Immune checkpoint inhibitor cancer patients resistant to the development of effective treatment, and the medical important problems in cancer.
Using in-vitro test systems, immune checkpoint inhibitor resistant tumor effective treatment has been found candidates. B16F10 Human melanoma cell line, mouse prostate cancer cell line TRAMP-C2, CT26 mouse colon cancer cell lines or the wild-type mice were implanted subcutaneously in non-clinical tumor model, antibody single agent anti-CTLA-4 a clear therapeutic effect is not observed under conditions, the oncolytic virus (Newcastle disease virus) and anti-CTLA-4 of intratumoral administration of the combination therapy of a therapeutic antibody (non-patent document 1). Human melanoma cell line B16F10 or mouse CT26 colon cancer cell lines to wild-type mice were implanted subcutaneously in non-clinical tumor model, anti-PD-1 antibody single agent a clear therapeutic effect is not observed under conditions, radiation STING GM-CSF agonists and anti-tumor cell vaccine PD-1 gene combination therapy with a therapeutic antibody (non-patent document 2). 4T1 Mouse breast tumor cell lines to wild-type mice were implanted subcutaneously in non-clinical tumor model, anti-antibody antibody and anti-PD-1 CTLA-4 to define a combination therapy with a therapeutic effect is not observed under conditions, DNA methylation inhibitor, HDAC inhibitor, anti-CTLA-4 antibody, anti-PD-1 antibody combination therapy with a therapeutic agent 4 (non-patent document 3). Mice expressing the human Her2 antigen to a human osteosarcoma cell line 24JK Her2 transgenic mice were implanted subcutaneously in non-clinical tumor model, anti-PD-1 antibody single agent a clear therapeutic effect is not observed under conditions, human Her2 chimeric antigen receptor (CAR) transgenic T cell infusion and anti-PD-1 combination therapy with a therapeutic antibody (non-patent document 4). These reports, all immune checkpoint inhibitor and other cancer therapeutic agents characterized by combining. Tumors found to have a therapeutic effect is, immune checkpoint inhibitor is not limited to the expression of the target molecule.
In human cancer, immune checkpoint inhibitor has been elucidated the mechanism of resistance has come. Anti-PD-1 antibody sensitivity or resistance to tumor tissue and the analysis of the melanoma patients, in patients with resistance, in tumors and the expression of PD-L1 PD-1 revealed significantly lower (non-patent document 5). This result indicates that, in local tumor immune checkpoint inhibitor lack expression of the target molecule, the tumor is resistant to cause the same inhibitor indicating. Shown in therapeutic methods include non-patent document 1-4, all other cancer therapeutic agents of the immune checkpoint inhibitor characterized by combining. Treatment methods are, immune checkpoint inhibitor of the target molecule is not effective for tumors that express this antigen. However, none of these treatments is, immune checkpoint inhibitor tumor does not express the target molecule to be less effective. From these results, immune checkpoint inhibitor against tumors that do not express the target molecule as a novel treatment method are required.
  • 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
  • MIE UNIVERSITY
  • KYOTO UNIVERSITY
  • 発明者(英語)
  • SHIKU, Hiroshi
  • HARADA, Naozumi
  • MURAOKA, Daisuke
  • AKIYOSHI, Kazunari
国際特許分類(IPC)
指定国 National States: AE AG AL AM AO AT AU AZ BA BB BG BH BN BR BW BY BZ CA CH CL CN CO CR CU CZ DE DJ DK DM DO DZ EC EE EG ES FI GB GD GE GH GM GT HN HR HU ID IL IN IR IS JP KE KG KH KN KP KR KW KZ LA LC LK LR LS LU LY MA MD ME MG MK MN MW MX MY MZ NA NG NI NO NZ OM PA PE PG PH PL PT QA RO RS RU RW SA SC SD SE SG SK SL SM ST SV SY TH TJ TM TN TR TT TZ UA UG US UZ VC VN ZA ZM ZW
ARIPO: BW GH GM KE LR LS MW MZ NA RW SD SL SZ TZ UG ZM ZW
EAPO: AM AZ BY KG KZ RU TJ TM
EPO: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR
OAPI: BF BJ CF CG CI CM GA GN GQ GW KM ML MR NE SN ST TD TG
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