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

Abstract

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 (mAbNectin-4)-based theranostic pair, 99mTc-HYNIC-mAbNectin-4 and mAbNectin-4-ICG. 99mTc-HYNIC-mAbNectin-4 was applied to conduct immuno-single photon emission computed tomography (SPECT) for TNBC diagnosis and classification, and mAbNectin-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 99mTc-HYNIC-mAbNectin-4. A photothermal agent (PTA) mAbNectin-4-ICG was generated and characterized. In vitro photothermal therapy (PTT) mediated by mAbNectin-4-ICG was conducted under an 808 nm laser. Fluorescence (FL) imaging was performed for mAbNectin-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 99mTc-HYNIC-mAbNectin-4 with high targeting in vitro. The corresponding immunoSPECT imaging demonstrated exceptional performance in TNBC diagnosis and molecular classification. mAbNectin-4-ICG exhibited favourable biocompatibility, photothermal effects, and Nectin-4 targeting. FL imaging mapped biodistribution of mAbNectin-4-ICG with excellent tumor-targeting and retention in vivo. Moreover, mAbNectin-4-ICG-mediated PTT provided advanced TNBC tumor destruction efficiency with low systematic toxicity. Conclusion mAbNectin-4-based radioimmunoimaging provides visualization tools for the stratification and diagnosis for TNBC, and the corresponding mAbNectin-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.

[225Ac]Ac/[89Zr]Zr-labeled N4MU01 radioimmunoconjugates as theranostics against nectin-4 positive triple negative breast cancer

“…This study describes the preclinical evaluation of a fully human anti-nectin-4 antibody as a PET imaging probe for the early detection of TNBCs and its development as a radioimmunotherapeutic agent. While a few groups have evaluated anti-nectin-4 immunoPET/SPECT imaging, photothermal probes and ADCs, no reports of alpha particle ( 225 Ac) radioimmunotherapy (RIT) of nectin-4 exist in the literature [28, 29]…”

“…N4MU01 probe was evaluated (microPET and biodistribution studies) using nectin-4 positive TNBC xenografts with high and medium receptor densities. Shao et al[29] studied the tumor uptake of [ 99m Tc]Tc-HYNIC-mAbNectin-4 in nectin-4 positive MDA-MB-468 xenograft.89 Zr]Zr-DFO-AGS-22M6 in spite of its apparent lower KD of 0.01 nM[8]. In addition, [ 89 Zr]Zr-DFO-N4MU01displayed fast distribution half-life t1/2α of 3.37 h and a relatively moderate clearance t1/2β of 63 h compared with other very slow-clearing IgGs such as trastuzumab which is advantageous for imaging.…”

18F-5-FPN: A Specific Probe for Monitoring Photothermal Therapy Response in Malignant Melanoma

“…Treatment groups were anesthetized with 2% pentobarbital sodium solution (80 mg/kg, i.p.) and positioned left lateral decubitus to expose the tumors under an 808 nm laser for 10 min (power = 1 W, distance from the light source to the highest point of the tumor = 1.5 cm). , During the entire procedure, an infrared thermal imaging camera (EasIR-4; Gaode Infrared Limited Company, Wuhan, China) was used to monitor the temperature changes in the tumor area continuously. The maximum temperatures were recorded at 20 s intervals in the first 3 min, followed by 1 min intervals to 10 min, and we continued recording for 3 min after the laser was switched off.…”

Nectins and Nectin-like Molecules in Colorectal Cancer: Role in Diagnostics, Prognostic Values, and Emerging Treatment Options: A Literature Review

“…Molecule itself can be a putative target for the development of new therapeutics. Nectin-4 can be utilized for new target-specific probes to improve tumor visualization and metastases detection in single-photon emission computerized tomography (SPECT) [ 130 ].…”