Clinically Relevant Radioactive Dose Formulation of ¹⁷⁷Lu‐Labeled Cetuximab‐Fab Fragment for Potential Use in Cancer Theranostics

Abstract

The goal of this study is to generate Fab fragment of cetuximab, a chimeric monoclonal antibody targeting epidermal growth factor receptor (EGFR) on the surface of cancer cells, and radiolabel it with 177Lu for potential use in cancer theranostics. Cetuximab‐Fab was produced with high purity through papain digestion of cetuximab, and used for formulation of clinically relevant radioactive dose (∼ 1.3 GBq) of 177Lu‐labeled cetuximab‐Fab after conjugation with a suitable bifunctional chelator, N‐[(R)‐2‐amino‐3‐(para‐isothiocyanato‐phenyl) propyl]‐trans‐(S,S)‐cyclohexane‐1,2‐diamine‐N,N,N′,N′′,N′′‐pentaacetic acid (CHX−A′′‐DTPA). The radiolabeled agent could be prepared with adequate specific activity (50.2 ± 0.6 GBq/μmol), high radiochemical purity (95.3 ± 0.5%) and appreciable in vitro stability under physiological conditions. Biodistribution studies with 177Lu‐CHX−A′′‐DTPA‐cetuximab‐Fab carried out in Swiss mice bearing fibrosarcoma tumors demonstrated significant tumor uptake (10.7 ± 2.2 %ID/g) within 4 h post‐injection (p.i.) with good tumor‐to‐background contrast. While rapid clearance of the radiolabeled agent from non‐target organs/tissues through hepatobiliary and renal routes was observed, tumor uptake remained consistently high up to 7 d p.i. (13.3 ± 3.6 %ID/g). Blocking studies with unlabeled cetuximab confirmed EGFR specificity of the radiotracer in vivo. This study might aid toward future clinical translation of radiolabeled antibody‐fragments in cancer theranostics.

Preparation of 177Lu‐labeled Nimotuzumab for radioimmunotherapy of EGFR‐positive cancers: Comparison of DOTA and CHX‐A″‐DTPA as bifunctional chelators

“…Nevertheless, with the availability of monoclonal antibodies endowed with superior targeting characteristics, synthesis of BFCs forming highly stable coordination complexes with the radiometals of interest and improved targeting strategies, the ambit of radioimmunotherapy is rapidly expanding to the management of other malignancies also. One classical example is the development of radioimmunoconjugates targeting EGFR‐positive epithelial cancers, which is well evident from the reports on radiolabeled anti‐EGFR monoclonal antibodies such as Cetuximab, Panitumumab, and Nimotuzumab . There are few reports on the preparation and evaluation of 177 Lu‐labeled DOTA‐ and DTPA‐conjugated Nimotuzumab while there are no reports on the use of CHX‐A″‐DTPA for radiolabeling Nimotuzumab with 177 Lu.…”