Institute of Biology and Biomedicine, Lobachevsky State University of Nizhny Novgorod, 23 Gagarin ave., Nizhny Novgorod 603950, Russia.
Laboratory of Molecular Immunology, Institute of Bioorganic Chemistry of the Russian Academy of Sciences, 16/10 Miklukho-Maklay St., Moscow 117997, Russia.
Int J Mol Sci. 2019 May 15;20(10):2399. doi: 10.3390/ijms20102399.
High immunogenicity and systemic toxicity are the main obstacles limiting the clinical use of the therapeutic agents based on exotoxin A. In this work, we studied the immunogenicity, general toxicity and antitumor effect of the targeted toxin DARPin-LoPE composed of HER2-specific DARPin and a low immunogenic exotoxin A fragment lacking immunodominant human B lymphocyte epitopes. The targeted toxin has been shown to effectively inhibit the growth of HER2-positive human ovarian carcinoma xenografts, while exhibiting low non-specific toxicity and side effects, such as vascular leak syndrome and liver tissue degradation, as well as low immunogenicity, as was shown by specific antibody titer. This represents prospects for its use as an agent for targeted therapy of HER2-positive tumors.
高免疫原性和全身毒性是限制基于外毒素 A 的治疗剂临床应用的主要障碍。在这项工作中，我们研究了由 HER2 特异性 DARPin 和缺乏免疫显性人 B 淋巴细胞表位的低免疫原性外毒素 A 片段组成的靶向毒素 DARPin-LoPE 的免疫原性、一般毒性和抗肿瘤作用。该靶向毒素已被证明能有效抑制 HER2 阳性人卵巢癌异种移植物的生长，同时表现出低非特异性毒性和副作用，如血管渗漏综合征和肝组织降解，以及低免疫原性，如特异性抗体滴度所示。这为其作为一种用于治疗 HER2 阳性肿瘤的靶向治疗剂的应用提供了前景。
