biostudies-literatureUnknown12(2)Guleria MTrastuzumab (Herceptin®) is an approved immunotherapeutic agent used for the treatment of metastatic breast cancer over-expressing HER2 antigen receptors. The aim of the present work is to standardize the formulation protocol of [¹⁷⁷Lu]Lu-trastuzumab addressing various reaction parameters, evaluating the efficacy of the radiolabeled product by <i>in vitro</i> investigations, scaling-up the preparation for administration in patients and performing preliminary clinical studies in patients suffering from metastatic breast cancer. Trastuzumab was conjugated with a suitable bi-functional chelating agent namely, <i>p</i>-NCS-benzyl-DOTA. On average 6.15 ± 0.92 <i>p</i>-NCS-benzyl-DOTA molecules were observed to be attached to each trastuzumab moiety. [¹⁷⁷Lu]Lu-trastuzumab could be prepared with >95% radiochemical purity (% RCP) employing the optimized radiolabeling procedure. <i>In vitro</i> studies revealed the affinity of [¹⁷⁷Lu]Lu-trastuzumab towards HER2 +ve cancer cell lines as well as against HER2 protein (<i>K</i> _d = 13.61 nM and 11.36 nM, respectively). The value for percentage immunoreactive fraction (% IRF) for [¹⁷⁷Lu]Lu-trastuzumab was observed to be 76.92 ± 2.80. Bio-distribution studies in Swiss mice revealed non-specific uptake in the blood, liver, lungs and heart followed by gradual clearance of activity predominantly through the hepatobiliary route. Preliminary clinical studies carried out in 8 cancer patients with immunohistochemically proven HER2 positive metastatic breast cancer revealed preferential localization of [¹⁷⁷Lu]Lu-trastuzumab in breast cancer lesions, which was in concordance with [¹⁸F]FDG-PET scans recorded earlier in the same patient indicating the potential of the agent towards radioimmunotheranostic applications.RSC medicinal chemistry263-277https://www.ebi.ac.uk/biostudies/studies/S-EPMC8128050biostudies-literatureFormulation and clinical translation of [¹⁷⁷Lu]Lu-trastuzumab for radioimmunotheranostics of metastatic breast cancer.PMC8128050Rangarajan VSharma RDash AGuleria MDas TSarma HDAmirdhanayagam JfalseFormulation and clinical translation of [¹⁷⁷Lu]Lu-trastuzumab for radioimmunotheranostics of metastatic breast cancer.Trastuzumab (Herceptin®) is an approved immunotherapeutic agent used for the treatment of metastatic breast cancer over-expressing HER2 antigen receptors. The aim of the present work is to standardize the formulation protocol of [¹⁷⁷Lu]Lu-trastuzumab addressing various reaction parameters, evaluating the efficacy of the radiolabeled product by <i>in vitro</i> investigations, scaling-up the preparation for administration in patients and performing preliminary clinical studies in patients suffering from metastatic breast cancer. Trastuzumab was conjugated with a suitable bi-functional chelating agent namely, <i>p</i>-NCS-benzyl-DOTA. On average 6.15 ± 0.92 <i>p</i>-NCS-benzyl-DOTA molecules were observed to be attached to each trastuzumab moiety. [¹⁷⁷Lu]Lu-trastuzumab could be prepared with >95% radiochemical purity (% RCP) employing the optimized radiolabeling procedure. <i>In vitro</i> studies revealed the affinity of [¹⁷⁷Lu]Lu-trastuzumab towards HER2 +ve cancer cell lines as well as against HER2 protein (<i>K</i> _d = 13.61 nM and 11.36 nM, respectively). The value for percentage immunoreactive fraction (% IRF) for [¹⁷⁷Lu]Lu-trastuzumab was observed to be 76.92 ± 2.80. Bio-distribution studies in Swiss mice revealed non-specific uptake in the blood, liver, lungs and heart followed by gradual clearance of activity predominantly through the hepatobiliary route. Preliminary clinical studies carried out in 8 cancer patients with immunohistochemically proven HER2 positive metastatic breast cancer revealed preferential localization of [¹⁷⁷Lu]Lu-trastuzumab in breast cancer lesions, which was in concordance with [¹⁸F]FDG-PET scans recorded earlier in the same patient indicating the potential of the agent towards radioimmunotheranostic applications.2021-01-01T00:00:00Z2021 Mar2024-11-06T18:00:47.808Z2022-02-11T12:47:45.13ZS-EPMC81280503404661510.1039/d0md00319k