Intricacies in the Preparation of Patient Doses of [177Lu]Lu-Rituximab and [177Lu]Lu-Trastuzumab Using Low Specific Activity [177Lu]LuCl3: Methodological Aspects

The development of humanized monoclonal antibodies (MAbs) with Lutetium-177 ([¹⁷⁷Lu]Lu³⁺) has brought a paradigm shift in the arena of targeted therapy of various cancers. [¹⁷⁷Lu]Lu-DOTA-Rituximab and [¹⁷⁷Lu]Lu-DOTA-Trastuzumab have gained prominence due to their improved therapeutic efficacy in the treatment of lymphoma and breast cancer. The clinical dose formulation of these radiolabeled MAbs, using low specific activity [¹⁷⁷Lu]LuCl₃, requires extensive optimization of the radiolabeling protocol. The present study merits the development of a single protocol which has been optimized for conjugation of Rituximab and Trastuzumab with p-NCS-benzyl-DOTA and further radiolabeling these immunoconjugates (ICs) with low specific activity [¹⁷⁷Lu]LuCl₃. Herein, we report a consistent and reproducible protocol for clinical dose formulations of [¹⁷⁷Lu]Lu-DOTA-Rituximab and [¹⁷⁷Lu]Lu-DOTA-Trastuzumab (~9.25 GBq each, equivalent to ~2 patient doses) with radiochemical yield (RCY) between 84 and 86% and radiochemical purities (RCP) >99%. The in vitro stabilities of both these radioimmunoconjugates (RICs) were retained up to 120 h post-radiolabeling, upon storage with L-ascorbic acid as stabilizer (concentration: ~ 220–240 μg/37MBq) at −20 °C. The ready-to-use formulation of clinical doses[¹⁷⁷Lu]Lu-DOTA-Rituximab and [¹⁷⁷Lu]Lu-DOTA-Trastuzumab has been successfully achieved by employing a single optimized protocol. While [¹⁷⁷Lu]Lu-DOTA-Rituximab has exhibited a high degree of localization in retroperitoneal nodal mass of refractory lymphoma patient, high uptake of [¹⁷⁷Lu]Lu-DOTA-Trastuzumab has been observed in metastatic breast carcinoma patient with multiple skeletal metastases.