Evaluation of a novel 177Lu-labelled therapeutic Affibody molecule with a deimmunized ABD domain and improved biodistribution profile
Yongsheng Liu, Maryam Oroujeni, Yunqi Liao, Anzhelika Vorobyeva, Vitalina Bodenko, Anna Orlova, Mark Konijnenberg, Matilda Carlqvist, E. Wahlberg, Annika Loftenius, Fredrik Y. Frejd, Vladimir Tolmachev
Abstract
Abstract Purpose Fusion of Affibody molecules with an albumin-binding domain (ABD) provides targeting agents, which are suitable for radionuclide therapy. To facilitate clinical translation, the low immunogenic potential of such constructs with targeting properties conserved is required. Methods The HER2-targeting Affibody molecule ZHER2:2891 was fused with a deimmunized ABD variant and DOTA was conjugated to a unique C-terminal cysteine. The novel construct, PEP49989, was labelled with 177 Lu. Affinity, specificity, and in vivo targeting properties of [ 177 Lu]Lu-PEP49989 were characterised. Experimental therapy in mice with human HER2-expressing xenografts was evaluated. Results The maximum molar activity of 52 GBq/µmol [ 177 Lu]Lu-PEP49989 was obtained. [ 177 Lu]Lu-PEP49989 bound specifically to HER2-expressing cells in vitro and in vivo. The HER2 binding affinity of [ 177 Lu]Lu-PEP49989 was similar to the affinity of [ 177 Lu]Lu-ABY-027 containing the parental ABD035 variant. The renal uptake of [ 177 Lu]Lu-PEP49989 was 1.4-fold higher, but hepatic and splenic uptake was 1.7-2-fold lower than the uptake of [ 177 Lu]Lu-ABY-027. The median survival of xenograft-bearing mice treated with 21 MBq [ 177 Lu]Lu-PEP49989 (> 90 days) was significantly longer than the survival of mice treated with vehicle (38 days) or trastuzumab (45 days). Treatment using a combination of [ 177 Lu]Lu-PEP49989 and trastuzumab increased the number of complete tumour remissions. The renal and hepatic toxicity was minimal to mild. Conclusion In preclinical studies, [ 177 Lu]Lu-PEP49989 demonstrated favourable biodistribution and a strong antitumour effect, which was further enhanced by co-treatment with trastuzumab.