Pertuzumab biosimilar (Hisun Pharma)

Monoclonal antibodies targeting HER2, a receptor overexpressed in certain cancer cells, have greatly improved the treatment of HER2-positive cancers. In addition, anti-HER2 antibodies play a critical role in diagnostic applications, enabling accurate detection of HER2 expression levels. Advancing antibody-based therapies and diagnostic tools require a thorough understanding of binding interactions, but it remains challenging due to complex antibody protein structure and its flexibility, particularly within their complementarity-determining regions. In this study we utilized LightDock, a molecular docking tool simulating protein-protein interactions which can incorporate flexibility that allows the in silico analysis of flexible proteins like antibody. Using LightDock we investigated interaction sites between the recently developed by our group anti-HER2 antibodies and their specific antigen HER2 protein. Despite the high variability in the obtained results, a statistics-based approach identified two recurring HER2 regions as potential binding sites and functionally relevant areas in receptor biology. This variability in predicted docking interfaces reflects the inherent complexity of antibody-antigen interactions. This structure based docking approach provides a cost-effective method to analyze antibody-protein interactions and offers preliminary insight into possible epitopes targeted by the novel anti-HER2 antibodies. However, our data indicates that at this time point further validation using experimental techniques will be beneficial to refine and increase the accuracy of the results obtained in silico. This report highlights the value of the computational docking in antibody-protein interaction studies, demonstrating significant potential with present and upcoming advancements in computer-based approaches.

Patients with HER2+ breast cancer (BC) frequently develop leptomeningeal metastases (LM). While HER2-targeted therapies have demonstrated efficacy in the neoadjuvant, adjuvant, and metastatic settings, including for parenchymal brain metastases, their efficacy for patients with LM has not been studied in a randomized controlled trial. However, several single-armed prospective studies, case series and case reports have studied oral, intravenous, or intrathecally administered HER2-targeted therapy regimens for patients with HER2+ BC LM.

We conducted a systematic review and meta-analysis of individual patient data to evaluate the efficacy of HER2-targeted therapies in HER2+ BC LM in accordance with PRISMA guidelines. Targeted therapies evaluated were trastuzumab (intrathecal or intravenous), pertuzumab, lapatinib, neratinib, tucatinib, trastuzumab-emtansine and trastuzumab-deruxtecan. The primary endpoint was overall survival (OS), with CNS-specific progression-free survival (PFS) as a secondary endpoint.

7780 abstracts were screened, identifying 45 publications with 208 patients, corresponding to 275 lines of HER2-targeted therapy for BC LM which met inclusion criteria. In univariable and multivariable analyses, we observed no significant difference in OS and CNS-specific PFS between intrathecal trastuzumab compared to oral or intravenous administration of HER2-targeted therapy. Anti-HER2 monoclonal antibody-based regimens did not demonstrate superiority over HER2 tyrosine kinase inhibitors. In a cohort of 15 patients, treatment with trastuzumab-deruxtecan was associated with prolonged OS compared to other HER2-targeted therapies and compared to trastuzumab-emtansine.

The results of this meta-analysis, comprising the limited data available, suggest that intrathecal administration of HER2-targeted therapy for patients with HER2+ BC LM confers no additional benefit over oral and/or IV treatment regimens. Although the number of patients receiving trastuzumab deruxtecan in this cohort is small, this novel agent offers promise for this patient population and requires further investigation in prospective studies.