Control of pharmacokinetics of radioimmunoconjugates using chelating agents containing poly(ethylene glycol)

Radioimmunoconjugates (RICs) composed of a monoclonal antibody (mAb) and radioisotope (RI) offer an attractive modality in oncology; however, their low tumor/blood ratio has limited their utility. To establish a novel strategy to improve the tumor/blood ratio without compromising the tumor accumulation of RICs, we developed novel DOTA-based chelating agents containing maleimide and discrete poly(ethylene glycol) (dPEG) scaffolds to synthesize RICs degrading into residualizing radiometabolites with high molecular weight in tumor cells: Mal-DOTA-PEG24 and Mal-DOTA-PEG48 modified by one dPEG scaffold, and Mal-DOTA-(PEG48)₃ modified by three dPEG scaffolds. Trastuzumab-based RICs with Mal-DOTA-PEG24, Mal-DOTA-PEG48, or Mal-DOTA-(PEG48)₃ showed different radioactivity distribution on human epidermal growth factor receptor 2 (HER2)/neu-expressing SK-OV-3 cells; RICs containing a PEGylated chelating agent of higher molecular weight exhibited higher-level retention of radiometabolites in cells after their internalization but increased dissociation from cell surfaces. An RIC containing one dPEG48 scaffold showed the highest tumor accumulation of radioactivity in vivo with a favorable tumor/blood ratio among PEGylated RICs, indicating that the optimized PEGylation of chelating agents markedly contributes to controlling the pharmacokinetics of RICs. These findings suggest the promising property of Mal-DOTA-PEG48 as a radiosynthetic platform to develop RICs with favorable pharmacokinetics.