Wallis Jamie, Katti Prateek, Martin Alexander M, Hills Tom, Seymour Leonard W, Shenton Daniel P, Carlisle Robert C
Institute of Biomedical Engineering, University of Oxford, UK.
Department of Oncology, University of Oxford, UK.
Eur J Pharm Sci. 2020 Sep 1;152:105456. doi: 10.1016/j.ejps.2020.105456. Epub 2020 Jul 10.
Vaccines are arguably the most important medical technology developed to date. However, effective treatment of diseases such as breast cancer have so far evaded standard vaccination strategies. One popular target for cancer treatment is the cell surface membrane protein, ErbB-2, also known as Her-2 or neu. It is localised to the cell surface and has raised expression in 15-30% of all breast cancers, as well as in ovarian, colon and lung cancer. Here, a liposomal system comprised of spatially separated ErbB-2 peptide, to activate B cells, and ovalbumin peptide OVA, to provide non-cognate T cell support, was used to generate antibodies against the epitope of the ErbB-2 protein targeted by Pertuzumab, a monoclonal antibody licensed for the treatment of ErbB-2 expressing cancers. After just 7 days a raised (7.3-fold, p<0.01), isotype-switched, humoral immune response specific for the ErbB-2 peptide was achieved in mice with pre-existing immunity to OVA which were exposed to liposomes with external ErbB-2 and internal OVA. The absence of pre-existing OVA immunity in the mice or OVA peptide in the liposomes removed the effect. The effect of this anti-ErbB-2 antibody response was characterised against an ErbB-2 overexpressing tumour cell line both in vitro and in vivo. Notably, antibody responses were demonstrated to induce cell death in vitro, resulting in 96% reduction in viable cells. This study, therefore, demonstrates the feasibility of this approach to generate a rapid, high-titre, isotype-switched, antibody response that specifically targets ErbB-2 overexpression on tumour cells and is capable of inducing cell death in vitro in the absence of complement or immune cells.
疫苗可以说是迄今为止开发的最重要的医学技术。然而，乳腺癌等疾病的有效治疗方法至今仍未被标准疫苗接种策略所攻克。癌症治疗的一个热门靶点是细胞表面膜蛋白ErbB-2，也称为Her-2或neu。它定位于细胞表面，在15%至30%的所有乳腺癌以及卵巢癌、结肠癌和肺癌中表达升高。在此，使用了一种脂质体系统，该系统由空间分离的用于激活B细胞的ErbB-2肽和用于提供非同源T细胞支持的卵清蛋白肽OVA组成，以产生针对帕妥珠单抗（一种被许可用于治疗表达ErbB-2的癌症的单克隆抗体）所靶向的ErbB-2蛋白表位的抗体。仅仅7天后，在对OVA具有预先免疫的小鼠中，当它们暴露于外部带有ErbB-2且内部带有OVA的脂质体时，就实现了针对ErbB-2肽的升高的（7.3倍，p<0.01）、同种型转换的体液免疫反应。小鼠中不存在预先的OVA免疫或脂质体中不存在OVA肽则消除了这种效应。针对体外和体内的一种ErbB-2过表达肿瘤细胞系，对这种抗ErbB-2抗体反应的效果进行了表征。值得注意的是，抗体反应被证明在体外可诱导细胞死亡，导致活细胞减少96%。因此，这项研究证明了这种方法的可行性，即产生一种快速、高滴度、同种型转换的抗体反应，该反应特异性靶向肿瘤细胞上的ErbB-2过表达，并且在没有补体或免疫细胞的情况下能够在体外诱导细胞死亡。
