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

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.

Automated summary

Multiple signaling pathways are involved in tumor development, making bispecific antibodies more suitable for treating complex tumor diseases. A novel PE-based bispecific immunotoxin designed in this study showed improved efficacy against HER2-positive tumors. Transcriptome sequencing and real-time PCR were used to verify the results, indicating the potential of these bispecific immunotoxins for anti-HER2 cancer therapeutics.