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

// Helene Carpenet 1, 2 , Armelle Cuvillier 3 , Aurelie Perraud 2 , Ophelie Martin 4 , Gael Champier 3 , Marie-Odile Jauberteau 2 , Jacques Monteil 1, 2, 4 and Isabelle Quelven 1, 2, 4 1 Nuclear Medicine Department, Dupuytren University Hospital, 87042 Limoges, France 2 EA 3842 – Cellular Homeostasis and Diseases, Faculty of Medicine, University of Limoges, 87025 Limoges, France 3 B Cell Design SAS, 87000 Limoges, France 4 UMR CNRS 7276 – CRIBL, University of Limoges, 87025 Limoges, France Correspondence to: Isabelle Quelven, email: isabelle.quelven@unilim.fr Armelle Cuvillier, email: armelle.cuvillier@b-cell-design.com Keywords: anti-CEA IgA, radiolabelling, mucosal biodistribution, metastases, colorectal cancer imaging Received: December 21, 2016      Accepted: July 03, 2017      Published: July 27, 2017 ABSTRACT By radiolabelling monomeric (m) and polymeric (p) IgA with technetium 99m ( 99m Tc), 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 99m Tc-tricarbonyl after derivatisation by 2-iminothiolane. 99m Tc-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, 99m Tc-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 99m Tc-IgA uptake. Pre-clinical experiments highlighted significant differences between 99m Tc-IgA and 99m Tc-IgG biodistributions. Furthermore, tumoural model studies suggested potential targeting potency of pIgA in mucosal tissues.