Nectin-4-targeted immunoSPECT/CT imaging and photothermal therapy of triple-negative breast cancer

Background Triple-negative breast cancer (TNBC) is more prone to distant metastasis and visceral recurrence in comparison to other breast cancer subtypes, and is related to dismal prognosis. Nevertheless, TNBC has an undesirable response to targeted therapies. Therefore, to tackle the huge challenges in the diagnosis and treatment of TNBC, Nectin-4 was selected as a theranostic target because it was recently found to be highly expressed in TNBC. We developed anti-Nectin-4 monoclonal antibody (mAb(Nectin-4))-based theranostic pair, Tc-99m-HYNIC-mAb(Nectin-4) and mAb(Nectin-4)-ICG. Tc-99m-HYNIC-mAb(Nectin-4) was applied to conduct immuno-single photon emission computed tomography (SPECT) for TNBC diagnosis and classification, and mAb(Nectin-4)-ICG to mediate photothermal therapy (PTT) for relieving TNBC tumor growth. Methods Nectin-4 expression levels of breast cancer cells (MDA-MB-468: TNBC cells; and MCF-7, non-TNBC cells) were proved by western blot, flow cytometry, and immunofluorescence imagning. Cell uptake assays, SPECT imaging, and biodistribution were performed to evaluate Nectin-4 targeting of Tc-99m-HYNIC-mAb(Nectin-4). A photothermal agent (PTA) mAb(Nectin-4)-ICG was generated and characterized. In vitro photothermal therapy (PTT) mediated by mAb(Nectin-4)-ICG was conducted under an 808 nm laser. Fluorescence (FL) imaging was performed for mAb(Nectin-4)-ICG mapping in vivo. In vivo PTT treatment effects on TNBC tumors and corresponding systematic toxicity were evaluated. Results Nectin-4 is overexpressed in MDA-MB-468 TNBC cells, which could specifically uptake Tc-99m-HYNIC-mAb(Nectin-4) with high targeting in vitro. The corresponding immunoSPECT imaging demonstrated exceptional performance in TNBC diagnosis and molecular classification. mAb(Nectin-4)-ICG exhibited favourable biocompatibility, photothermal effects, and Nectin-4 targeting. FL imaging mapped biodistribution of mAb(Nectin-4)-ICG with excellent tumor-targeting and retention in vivo. Moreover, mAb(Nectin-4)-ICG-mediated PTT provided advanced TNBC tumor destruction efficiency with low systematic toxicity. Conclusion mAb(Nectin-4)-based radioimmunoimaging provides visualization tools for the stratification and diagnosis for TNBC, and the corresponding mAb(Nectin-4)-mediated PTT shows a powerful anti-tumor effect. Our findings demonstrate that this Nectin-4 targeting strategy offers a simple theranostic platform for TNBC.

Automated summary

The study found that Nectin-4 is highly expressed in TNBC, and therefore developed a theranostic pair based on anti-Nectin-4 monoclonal antibodies, Tc-99m-HYNIC-mAb(Nectin-4) and mAb(Nectin-4)-ICG, for TNBC diagnosis and photothermal therapy. The results demonstrated that this strategy provides a simple and effective approach for the diagnosis and treatment of TNBC.