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

Foreign code F180009340
File No. S2016-0413-C0
Posted date Mar 13, 2018
Country WIPO
International application number 2017JP004552
International publication number WO 2017138557
Date of international filing Feb 8, 2017
Date of international publication Aug 17, 2017
Priority data
  • P2016-022081 (Feb 8, 2016) JP
Title PRETREATMENT DRUG FOR T CELL INFUSION THERAPY FOR IMMUNE-CHECKPOINT INHIBITOR-RESISTANT TUMOR
Abstract [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.
Outline of related art and contending technology 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.
Scope of claims (In Japanese)[請求項1]
免疫チェックポイント阻害剤抵抗性腫瘍に対するT細胞輸注療法において、抗原に特異的なT細胞の投与する前に投与される医薬組成物であって、前記抗原に由来するCD8陽性細胞傷害性T細胞認識エピトープ及び/又はCD4陽性ヘルパーT細胞認識エピトープを含む長鎖ペプチド抗原又は蛋白質抗原を疎水化多糖ナノゲルに搭載した抗原搭載ナノゲルを含有する医薬組成物。
[請求項2]
免疫チェックポイント阻害剤抵抗性腫瘍に対するT細胞輸注療法において、前記抗原搭載ナノゲルを投与した後に投与するための前記抗原に特異的なT細胞を含む医薬組成物であって、前記抗原搭載ナノゲルが前記抗原に由来するCD8陽性細胞傷害性T細胞認識エピトープ及び/又はCD4陽性ヘルパーT細胞認識エピトープを含む長鎖ペプチド抗原又は蛋白質抗原を疎水化多糖ナノゲルに搭載した医薬組成物。
[請求項3]
更に、免疫増強剤が抗原搭載ナノゲルと共に投与される、又は免疫増強剤が抗原搭載ナノゲルに含まれている請求項1又は請求項2に記載の組成物。
[請求項4]
前記抗原に特異的なT細胞が、前記抗原を認識するT細胞受容体又はキメラ抗原受容体を発現するT細胞である、請求項1~請求項3のいずれか1項記載の組成物。
[請求項5]
前記長鎖ペプチド抗原が23~120個のアミノ酸から成る請求項1~請求項4のいずれか1項記載の組成物。
[請求項6]
長鎖ペプチド抗原に含まれるT細胞認識エピトープの間に、2~10個のチロシン、2~10個のスレオニン、2~10個のヒスチジン、2~10個のグルタミン及び2~10個のアスパラギンから成る群から選択される配列を含む請求項1~請求項5のいずれか1項記載の組成物。
[請求項7]
前記疎水化多糖がプルラン及びコレステリル基を含む請求項1~請求項6のいずれか1項記載の組成物。
[請求項8]
前記免疫増強剤が、TLR(Toll様受容体)アゴニスト(CpGオリゴDNA又はPoly-IC RNA)、STINGアゴニスト又はRLR(RIG-I様受容体)アゴニストからなる群から選択される少なくとも一つである請求項3~請求項7のいずれか1項記載の組成物。
[請求項9]
前記抗原が腫瘍特異的抗原蛋白質又は腫瘍間質特異的抗原蛋白質である請求項1~請求項8のいずれか1項記載の組成物。
[請求項10]
前記抗原搭載ナノゲルの投与経路が、皮下、皮内、筋肉内、腫瘍内及び静脈内からなる群から選択される少なくとも一つの経路によって投与される請求項1~請求項9のいずれか1項記載の組成物。
[請求項11]
前記抗原搭載ナノゲルが、前記抗原に特異的なT細胞を含む医薬組成物の投与の少なくとも1日前に投与される請求項1~請求項10のいずれか1項記載の組成物。
[請求項12]
静脈内投与されたときに腫瘍局所のマクロファージに選択的に物質を送達するデリバリーシステムであって、プルラン及びコレステリル基を含む疎水化多糖から成る粒子径80nm以下のナノゲル。
[請求項13]
免疫チェックポイント阻害剤に抵抗性を持つ腫瘍に有効な治療薬を特定するための非ヒト哺乳類腫瘍モデルであって、前記腫瘍がマウス繊維肉腫CMS5aであり、非ヒト哺乳類がマウスである非ヒト哺乳類腫瘍モデル。
  • Applicant
  • ※All designated countries except for US in the data before July 2012
  • MIE UNIVERSITY
  • KYOTO UNIVERSITY
  • Inventor
  • SHIKU, Hiroshi
  • HARADA, Naozumi
  • MURAOKA, Daisuke
  • AKIYOSHI, Kazunari
IPC(International Patent Classification)
Specified countries 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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