Rapid imaging of tumor cell death in vivo using C2Am

Abstract:

Abstract Cell death is an important target for imaging the early response of tumors to treatment. We describe here the validation of C2Am, a phosphatidylserine-binding agent based on the C2A domain of synaptotagmin-I, for detecting tumor cell death in vivo. Methods: The capability of (99m)Technetium-, (111)Indium-labelled or near- infrared fluorophore-labelled derivatives of C2Am for imaging tumor cell death was evaluated in implanted and genetically engineered [Fig.1] mouse models of lymphoma and in a human colorectal xenograft, using single photon CT (SPECT) and planar near-infrared fluorescence imaging, respectively [1,2]. Results: (99m)Tc-C2Am and (111)In-C2Am showed favorable biodistribution profiles, with predominantly renal clearance and low nonspecific retention in the spleen and liver at 24 h after probe administration. (99m)Tc-C2Am and (111In)-C2Am generated tumor-to-muscle ratios in drug-treated tumors of 4.3× and 2.2×, respectively, at 2 h and 7.3× and 4.1×, respectively, at 24 h after administration. A fluorophore-labelled C2Am derivative also showed predominantly renal clearance and high specificity and sensitivity for detecting low levels of tumor cell death (<5%). There was a significant correlation (R=0.9) between fluorescently labelled C2Am binding and histologic markers of cell death (cleaved caspase-3); no such correlation was observed with a site-directed mutant of C2Am that does not bind phosphatidylserine (iC2Am). Conclusions: Given the favorable biodistribution profile of radiolabelled C2Am derivatives, and their ability to produce rapid and cell death-specific image contrast, these agents have potential for clinical translation, particularly as PET tracers. We have initiated GMP manufacture and toxicology studies required for a Phase 1 trial. References: [1] Neves AA, Xie B, Fawcett S, Alam IS, Witney TH, de Backer MM, Summers J, Hughes W, McGuire S, Soloviev D, Miller J, Howat WJ, Hu DE, Rodrigues TB, Lewis DY, Brindle KM. Rapid Imaging of Tumor Cell Death In Vivo Using the C2A Domain of Synaptotagmin-I. (2017) J Nucl Med. 58:881-887. [2] Xie B, Tomaszewski MR, Neves AA, Ros S, Hu DE, McGuire S, Mullins SR, Tice D, Sainson RCA, Bohndiek SE, Wilkinson RW, Brindle KM. Optoacoustic Detection of Early Therapy-Induced Tumor Cell Death Using a Targeted Imaging Agent. (2017) Clin Cancer Res. 23:6893-6903. Citation Format: Andre A. Neves, Kevin M. Brindle. Rapid imaging of tumor cell death in vivo using C2Am [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4116.

Authors:

AA Neves, KM Brindle

Journal:

Cancer Research

Citation info:

78(13_Supplement):4116-4116

Publication date:

1st Jul 2018

Full text

DOI