The mechanism of hepatic uptake of a radiolabelled monoclonal antibody

Abstract

Clinical and experimental scintigraphic studies have found that radiolabelled antibodies are not only taken up by tumour(s) but also by normal liver. The accumulation of radionuclides in this organ poses a major problem to the use of radiolabelled antibodies as diagnostic and therapeutic tools. In an attempt to understand the mechanism of hepatic uptake and clearance of radiolabelled antibodies, the intrahepatic biodistribution of an 111In-labelled MAb (HMFG1), was determined following i.v. administration to normal male rats. Two hours after administration the liver contained 15% of the injected dose, with most of the remaining radioactivity in the blood. The hepatic burden of the 111In MAb remained constant over the next 72 hr in the face of decreasing blood levels of radioactivity as well as its urinary and faecal excretion. At 2 and 72 hr after injection, 50% and 10% respectively of the hepatic radiolabel was due to blood borne antibody. Following a collagenase-cell isolation procedure, only 23% of the amount remaining in the liver at 2 hr was found to be cell-associated; 66% was lost during the cell isolation and purification procedure. Cellular uptake increased with time so that, by 72 hr after administration, 58% was cell-associated and 29% freely removable. At all timepoints, the parenchymal cells contained more activity than non-parenchymal cells. No evidence of antibody-receptor interactions could be obtained either in vivo or in cultures of hepatic parenchymal and non-parenchymal cells. Our data suggest that the bulk of the hepatic burden of 111In MAb results from extravascular pooling of the antibody.

ING-1, a Monoclonal Antibody Targeting Ep-CAM in Patients with Advanced Adenocarcinomas

“…Hepatic uptake of radiolabeled ING-1 was observed in keeping with previous studies with other monoclonal antibodies that have demonstrated that the liver can take up to 15% of the administered dose of radiolabeled antibody (47). It has been suggested that this is due to extravascular pooling of antibody and not antibody-antigen interactions, which is in keeping with the absence of induced transaminitis or hepatic toxicity in this clinical trial.…”

Near-Infrared Molecular Imaging of Glioblastoma by Miltuximab®-IRDye800CW as a Potential Tool for Fluorescence-Guided Surgery

“…Moreover, there was significantly higher accumulation of Miltuximab ® -IR800 in the tumor when compared to the liver (p = 0.009) or kidneys (p = 0.011). We noted accumulation of systemically delivered monoclonal antibody in the liver for both Miltuximab ® -IR800 and IgG-IR800 isotype control, as expected [46]. In the isotype control IgG-IR800, the uptake of the conjugates was found to be greater in the liver and kidney than in the tumor.…”

A transgenic mouse model for tumour immunotherapy: induction of an anti-idiotype response to human MUC1

“…The monoclonal antibody (mAb) HMFG1 binds to the linear core protein sequence, PDTR, contained within the immunodominant domain of the tandem repeats of MUC1 (Burchell and Taylor-Papadimitriou, 1993). HMFG1 has been used both to localize ovarian cancers by radioimmunoscintigraphy (Boyle et al, 1992) and for radiotherapy (Kosmas et al, 1998).…”