Radiolabelled polymeric IgA: from biodistribution to a new molecular imaging tool in colorectal cancer lung metastases.

Ophélie Martin,Isabelle Quelven,Aurélie Perraud,Helene Carpenet,Gaël Champier,Jacques Monteil,Marie-Odile Jauberteau,Armelle Cuvillier

doi:10.18632/oncotarget.19616

Abstract

By radiolabelling monomeric (m) and polymeric (p) IgA with technetium 99m (99mTc), this study assessed IgA biodistribution and tumour-targeting potency. IgA directed against carcinoembryonic antigen (CEA), a colorectal cancer marker, was selected to involve IgA mucosal tropism.Ig was radiolabelled with 99mTc-tricarbonyl after derivatisation by 2-iminothiolane. 99mTc-IgA was evaluated by in vitro analysis. The biodistributions of radiolabelled anti-CEA mIgA, pIgA and IgG were compared in normal mice. Anti-CEA pIgA tumour uptake was studied in mice bearing the WiDr caecal orthotopic graft.IgA radiolabelling was obtained with a high yield, was stable in PBS and murine plasma, and did not alter IgA binding functionality (Kd ≈ 25 nM). Biodistribution studies in normal mice confirmed that radiolabelled pIgA – and to a lesser extent, mIgA – showed strong and fast mucosal tropism and a shorter serum half-life than IgG. In caecal tumour model mice, evaluation of the anti-CEA-pIgA biodistribution showed a high uptake in lung metastases, confirmed by histological analysis. However, no radioactivity uptake increase in the tumoural caecum was discerned from normal intestinal tissue, probably due to high IgA caecal natural tropism. In microSPECT/CT imaging, 99mTc-IgA confirmed its diagnostic potency of tumour in mucosal tissue, even if detection threshold by in vivo imaging was higher than post mortem studies. Contribution of the FcαRI receptor, studied with transgenic mouse model (Tsg SCID-CD89), did not appear to be determinant in 99mTc-IgA uptake.Pre-clinical experiments highlighted significant differences between 99mTc-IgA and 99mTc-IgG biodistributions. Furthermore, tumoural model studies suggested potential targeting potency of pIgA in mucosal tissues.

Highlights

Colorectal cancer (CRC) is the most commonly diagnosed cancer worldwide
To optimise IgA radiolabelling with the tricarbonyl core, increasing quantities of antibody were tested by derivatisation with 2-IT (Figure 1)
This work reported anti-carcinoembryonic antigen (CEA) IgA radiolabelling with 99mTc to evaluate IgA biodistribution compared with IgG, and to estimate IgA tumour-targeting potency

Summary

Introduction

Colorectal cancer (CRC) is the most commonly diagnosed cancer worldwide. For the past few years, almost 1.4 million new cases have been diagnosed every year (representing 9.7% of all cancers), with 450,000 new cases being reported in Europe (where CRC is the secondmost common cancer, representing 13% of all cancers). Despite the above, according to a review by Bradley no definitive consensus on the optimal imaging staging strategy has yet been established for CRC [1]. More specific and sensitive non-invasive methods are needed. One such method is immunoscintigraphy, a useful technique that has continued to expand since the 1980s commensurate with monoclonal expansion. Concerning staging of CRC, the main interest in immunoscintigraphy lies in its sensitivity for detecting distant metastasis

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