A bispecific immunotoxin (IHPP) with a long half-life targeting HER2 and PDGFRβ exhibited improved efficacy against HER2-positive tumors in a mouse xenograft model
A bispecific immunotoxin (IHPP) with a long half-life targeting HER2 and PDGFRβ exhibited improved efficacy against HER2-positive tumors in a mouse xenograft model
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具有长半衰期的双特异性免疫毒素 (IHPP) 靶向 HER2 和 PDGFRβ，在小鼠异种移植模型中表现出针对 HER2 阳性肿瘤的更高功效
DOI：
10.1016/j.ijpharm.2020.120037
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发表时间：
2021-01-05
影响因子：
5.8
通讯作者：
Lin, Juntang
中科院分区：
文献类型：
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作者：
Guo, Rui;Yang, Yun;Lin, Juntang
多种信号通路通常参与肿瘤的发展。与单特异性抗体相比，双特异性抗体可以同时识别两种不同的抗原，因此更适合治疗病因复杂的肿瘤疾病。免疫毒素具有良好的抗肿瘤活性，然而，单一靶向限制了其有效性。在此，我们设计了基于假单胞菌外毒素A（PE）的双特异性免疫毒素IgBD-HER 2-PDGFR β-PE 38，其可以区分肿瘤中的HER 2和PDGFR β靶点。同时，IgG亲和性可以延长免疫毒素体内注射后的血清滞留。本工作首次在体外检测了免疫毒素的选择性结合和抗肿瘤作用。与对照组相比，IgBD-HER 2-PDGFR β-PE 38在NCI-N87皮下异种移植模型中表现出针对HER 2阳性肿瘤的改善的功效。然后，对源自携带NCI-N87肿瘤的小鼠的不同治疗组的肿瘤组织进行转录组测序。基于人类基因筛选出7个显著差异表达的基因，并基于Reactome Pathway Database富集差异表达的小鼠基因。最后用实时荧光定量PCR和ELISA方法对测序结果进行验证。因此，新的构建体双特异性免疫毒素代表了一种潜在的有吸引力的治疗方式，并且所提出的策略使它们有希望用于开发抗HER 2癌症治疗剂。
Multiple signaling pathways are usually involved in the development of tumors. Compared with monospecific antibodies, bispecific antibodies can recognize two different antigens at the same time, so they are more suitable for treating tumor diseases with complex etiology. Immunotoxins have good antitumor activity, however, single targeting limits their effectiveness. Herein, we designed a Pseudomonas exotoxin A (PE)-based bispecific immunotoxin IgBD-HER2-PDGFR beta-PE38 which could distinguish HER2 and PDGFR beta target in tumor. Meanwhile, IgG-affinity could extend the serum retention of immunotoxins after in vivo injection. In this work, we first detected the selective binding of the immunotoxins and antitumor effect in vitro. Compared with control group, IgBD-HER2-PDGFR beta-PE38 exhibited improved efficacy against HER2-positive tumors in an NCI-N87 subcutaneous xenograft model. Then, transcriptome sequencing was performed on tumor tissue originating from different treatment groups of mice bearing NCI-N87 tumors. Seven significantly differentially expressed genes were screened based on human genes, and the differential mouse genes were enriched based on the Reactome Pathway Database. At last, the RNA sequencing results were verified by real-time PCR and ELISA. Therefore, the new construct bispecific immunotoxin represents a potentially attractive therapeutic modality, and the proposed strategy make them promising for use in the development of anti-HER2 cancer therapeutics.