CAR-T（CAR-T）细胞疗法在非肿瘤性疾病中的应用
Chimeric antigen receptor T (CAR-T) cell therapy in non-oncological diseases.
CAR-T（CAR-T）细胞在血液系统恶性肿瘤中的应用推动了这种免疫治疗形式的显著进展。
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
靶向 CD66e/CEACAM5 的高特异性全人抗体与 CAR-T 细胞在体内外对表达 CD66e 的肿瘤细胞具有细胞毒性
英文原题：A highly-specific fully-human antibody and CAR-T cells targeting CD66e/CEACAM5 are cytotoxic for CD66e-expressing cancer cells in vitro and in vivo.
查看英文原题
A highly-specific fully-human antibody and CAR-T cells targeting CD66e/CEACAM5 are cytotoxic for CD66e-expressing cancer cells in vitro and in vivo.
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中文摘要
神经内分泌前列腺癌（NEPC）约占致死性转移性去势抵抗性前列腺癌（CRPC）的20%。NEPC在所有前列腺癌中具有最具侵袭性的生物学行为，并与患者不良预后相关。由于NEPC与其他类型前列腺癌相比表现出不同的细胞表面表达谱，因此尚无有效的NEPC治疗方法。近年来，癌胚抗原相关细胞黏附分子5（CEACAM5）（也称为CEA或CD66e）被认为可能是NEPC的特异性表面蛋白标志物。
因此，我们鉴定了一种新的全人源抗CEACAM5单克隆抗体1G9，它以高亲和力和特异性结合CEACAM5最靠近膜的A3和B3结构域。它对其他CEACAM家族成员、CEACAM5的膜远端结构域或5800种人膜蛋白均无脱靶结合。IgG1 1G9在体外和体内对CEACAM5阳性前列腺癌细胞表现出CEACAM5特异性ADCC活性。基于scFv 1G9的CAR-T 细胞在前列腺癌小鼠模型中诱导了特异性且强效的抗肿瘤活性。
我们的结果表明，基于1G9的IgG1和CAR-T 细胞是治疗CEACAM5阳性NEPC及其他癌症的有前景的候选疗法。
展开英文摘要原文
Neuro-endocrine prostate cancer (NEPC) accounts for about 20% of lethal metastatic castration-resistant prostate cancer (CRPC). NEPC has the most aggressive biologic behavior of all prostate cancers and is associated with poor patient outcome.
Effective treatment for NEPC is not available because NEPC exhibit distinct cell-surface expression profiles compared to other types of prostate cancer. Recently, the carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) (known as CEA or CD66e) was suggested to be a specific surface protein marker for NEPC.
Therefore, we identified a new, fully-human anti-CEACAM5 monoclonal antibody, 1G9, which bound to the most proximal membrane domains, A3 and B3, of CEACAM5 with high affinity and specificity. It shows no off-target binding to other CEACAM family members, membrane distal domains of CEACAM5, or 5800 human membrane proteins.
IgG1 1G9 exhibited CEACAM5-specific ADCC activity toward CEACAM5-positive prostate cancer cells in vitro and in vivo. Chimeric antigen receptor T cells (CAR-T) based on scFv 1G9 induced specific and strong antitumor activity in a mouse model of prostate cancer.
Our results suggest that IgG1 and CAR-T cells based on 1G9 are promising candidate therapeutics for CEACAM5-positive NEPC and other cancers.
论文信息
- 作者
- Baek DS、Kim YJ、Vergara S、Conard A、Adams C、Calero G、Ishima R、Mellors JW
- 第一作者单位
- Center for Antibody Therapeutics, Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Electronic address: dub5@pitt.edu.United States
- 通讯作者单位
- Center for Antibody Therapeutics, Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Abound Bio, Pittsburgh, PA, USA. Electronic address: mit666666@pitt.edu.United States
- 文献类型
- 非美国政府资助研究
- 期刊
- Cancer letters2022 Jan 28
- 原文标识
- PubMed 34740610 · DOI 10.1016/j.canlet.2021.10.041