JP2022151836A - 免疫調節及び抗腫瘍関連ナノボディ及びその核酸コード配列、並びにその使用 - Google Patents
免疫調節及び抗腫瘍関連ナノボディ及びその核酸コード配列、並びにその使用 Download PDFInfo
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Abstract
Description
T細胞(即ち、末梢血単核細胞)の増殖及び活性化アッセイ(T cell(i.e. peripheral blood mononuclear cell、PBMC) proliferation and activation assay)により、T細胞塊の増殖及び活性化と、PBMCにおけるCD3陽性T細胞の増殖とを向上させることができることを証明し、
免疫組織化学的(immunocytochemistry、ICC)染色により、腫瘍細胞に結合して腫瘍細胞を死滅させることができることを証明し、
酵素結合免疫吸着測定法(enzyme linked immunosorbent assay、ELISA)により、腫瘍細胞におけるサイトカイン(cytokine)の分泌を促進させることができることを証明し、
動物実験により、がん細胞の増殖を抑制し、がん及び免疫関連疾患を治療する効果を達成することができることを証明する。
本明細書に記載の数値は、概算値である。全ての実験データは、その数値の±20%、好ましいは±10%、より好ましくは±5%を示す。
本実施例において、免疫調節及び抗腫瘍関連ナノボディ(immunomodulation and antitumor-related nanobody)(即ち、PD-L1、HLA-G及びCD3εナノボディをベースとした三重特異性T細胞エンゲージャー(PD-L1×HLA-G×CD3ε nanobody-based triple specific T-cell engager、PD-L1×HLA-G×CD3ε nanobody-based TriTE)、以下、Nb-TriTEと称する)の製造プロセスは、以下の通りである。
本実施例において、Nb-TriTEの表面プラズモン共鳴結合分析(surface plasmon resonance binding assay、SPR bindingassay)の操作手順は、以下の通りである。BIAcore T200(Biacore-GE Healthcare、Piscataway、NJ)により、CM5又はNTAチップをSPR分析する。
本実施例において、Nb-TriTEのT細胞(即ち、末梢血単核細胞)増殖分析(T cell(i.e.、peripheral blood mononuclear cell、PBMC)proliferation assay)の操作手順は、以下の通りである。1×105のPBMC細胞を12ウェルプレートに接種した後、それぞれ臨床用CD3εモノクローナル抗体OKT3(5μg、Invitrogen、Cat:MA1-10175)及びProleukin(IL-2:200U)、又は10μg/mlのNb-TriTEを添加する。
本実施例において、腫瘍細胞、T細胞、及びNb-TriTE(即ち、VHHナノボディ)の免疫細胞化学的分析(immunocytochemistry)の操作手順は、以下の通りである。腫瘍細胞(4×104又は1×105)を6ウェルプレートのスライドガラスに接種し、一晩培養する。
本実施例において、Nb-TriTE及びPBMCによるA549-ヒト肺腺がん細胞株、MDA-MB-231-ヒト乳がん細胞株、U87-神経膠芽腫(glioblastoma)細胞株、SKOV3-ヒト卵巣がん細胞株、及びFaDu-ヒト口腔がん細胞株(ATCC(AmericanTypeCultureCollection、ATCC)から購入)に対する細胞溶解の向上を評価する。操作手順は、以下の通りである。1×105の腫瘍細胞を12ウェルプレートに接種し、一晩静置する。翌日、腫瘍細胞を含有するウェルに5×105の一次PBMCを添加し、さらにNb-TriTEを添加する。48時間後、生/死細胞に介する細胞毒性分析(LIVE/DEAD cell-mediated cytotoxicity assay)により、フローサイトメトリーで、一次PBMCの腫瘍細胞に対する特異的溶解を確定する。
本実施例において、市販のELISAキット(ThermoFisherScientific)を使用してヒトサイトカインであるパーフォリン(perforin)、グランザイムB(granzymeB)、腫瘍壊死因子α(tumor necrosis factor alpha、TNF-α)、及びインターフェロンγ(interferon gamma、IFN-γ)を測定する。操作手順は、以下の通りである。
本実施例の操作手順は、以下の通りである。6至8周齢のNOD/SCIDγ(NSG)マウスは、The Jackson Laboratoryから購入する。マウスは、肺腫瘍異種移植(xenograft)モデルに用いられる。肺腫瘍に対して、Luc+ A549細胞をMatrigel含有PBSに再懸濁し、そして、細胞(5×105/20μL)をマウスの右背側に皮下注射する。
T細胞(即ち、末梢血単核細胞)の増殖及び活性化アッセイ(T cell(i.e. peripheral blood mononuclear cell、PBMC) proliferation and activation assay)により、T細胞塊の増殖及び活性化と、PBMCにおけるCD3陽性T細胞の増殖とを向上させることができることを証明し、
免疫組織化学的(immunocytochemistry、ICC)染色により、腫瘍細胞に結合して腫瘍細胞を死滅させることができることを証明し、
酵素結合免疫吸着測定法(enzyme linked immunosorbent assay、ELISA)により、腫瘍細胞におけるサイトカイン(cytokine)の分泌を促進させることができることを証明し、
動物実験により、がん細胞の増殖を抑制し、がん及び免疫関連疾患を治療する効果を達成することができることを証明する。
Claims (11)
- ヒト白血球抗原-G(human leukocyte antigen-G、HLA-G)、プログラム細胞死リガンド1(programmed cell death ligand 1、PD-L1)、及びCD3ε(CD3 epsilon)に特異的に結合し、かつ、配列番号1と、配列番号2と、配列番号3とのアミノ酸配列の組み合わせを含むことを特徴とする、
免疫調節及び抗腫瘍関連ナノボディ。 - 前記アミノ酸配列は、前記免疫調節及び抗腫瘍関連ナノボディの重鎖可変ドメイン(heavy chain variable domain、VHH)のアミノ酸配列であることを特徴とする、請求項1に記載の免疫調節及び抗腫瘍関連ナノボディ。
- フラグメント結晶化可能領域(fragment crystallizable region、Fcregion)をさらに含むことを特徴とする、請求項2に記載の免疫調節及び抗腫瘍関連ナノボディ。
- 第2抗体に共役することによって三重特異性T細胞エンゲージャー(triple specific T-cell engager、TriTE)を形成することを特徴とする、請求項3に記載の免疫調節及び抗腫瘍関連ナノボディ。
- CD3ε陽性細胞を活性化及び/又は凝集させることを特徴とする、請求項4に記載の免疫調節及び抗腫瘍関連ナノボディ。
- 腫瘍細胞を死滅させる効果を有することを特徴とする、請求項5に記載の免疫調節及び抗腫瘍関連ナノボディ。
- 前記腫瘍細胞は、肺腺がん細胞、乳がん細胞、神経膠芽腫細胞、卵巣がん細胞、口腔がん細胞、及びそれらの組み合わせからなる群から選ばれることを特徴とする、請求項6に記載の免疫調節及び抗腫瘍関連ナノボディ。
- 請求項1~7のいずれか1項に記載の免疫調節及び抗腫瘍関連ナノボディのアミノ酸配列をコードし、かつ、配列番号4と、配列番号5と、配列番号6とのヌクレオチド配列の組み合わせを含むことを特徴とする、単離された核酸。
- 請求項1~7のいずれか1項に記載の免疫調節及び抗腫瘍関連ナノボディと、医薬上許容可能な担体とを含むことを特徴とする、医薬成分物。
- がん及び免疫関連疾患を治療する医薬品を製造するための請求項1~7のいずれか1項に記載の免疫調節及び抗腫瘍関連ナノボディの使用。
- 前記がんは、肺腺がん、乳がん、神経膠芽腫、卵巣がん、口腔がん、及びそれらの組み合わせからなる群から選ばれることを特徴とする、請求項10に記載の免疫調節及び抗腫瘍関連ナノボディの使用。
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