Open AccessFormulation and clinical translation of [177Lu]Lu-trastuzumab for radioimmunotheranostics of metastatic breast cancer
Author(s) -
Mohini Guleria,
Rohit Sharma,
Jeyachitra Amirdhanayagam,
Haladhar Dev Sarma,
Venkatesh Rangarajan,
Ashutosh Dash,
Tapas Das
Publication year - 2021
Publication title -
rsc medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.754
H-Index - 55
ISSN - 2632-8682
DOI - 10.1039/d0md00319k
Subject(s) - trastuzumab , medicine , metastatic breast cancer , oncology , breast cancer , 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 [ 177 Lu]Lu-trastuzumab addressing various reaction parameters, evaluating the efficacy of the radiolabeled product by in vitro 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, p -NCS-benzyl-DOTA. On average 6.15 ± 0.92 p -NCS-benzyl-DOTA molecules were observed to be attached to each trastuzumab moiety. [ 177 Lu]Lu-trastuzumab could be prepared with >95% radiochemical purity (% RCP) employing the optimized radiolabeling procedure. In vitro studies revealed the affinity of [ 177 Lu]Lu-trastuzumab towards HER2 +ve cancer cell lines as well as against HER2 protein ( K d = 13.61 nM and 11.36 nM, respectively). The value for percentage immunoreactive fraction (% IRF) for [ 177 Lu]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 [ 177 Lu]Lu-trastuzumab in breast cancer lesions, which was in concordance with [ 18 F]FDG-PET scans recorded earlier in the same patient indicating the potential of the agent towards radioimmunotheranostic applications.