Mapping biological behaviors by application of longer-lived positron emitting radionuclides

Abstract

With the technological development of positron emission tomography (PET) and the advent of novel antibody-directed drug delivery systems, longer-lived positron-emitting radionuclides are moving to the forefront to take important roles in tracking the distribution of biotherapeutics such as antibodies, and for monitoring biological processes and responses. Longer half-life radionuclides possess advantages of convenient on-site preparation procedures for both clinical and non-clinical applications. The suitability of the long half-life radionuclides for imaging intact monoclonal antibodies (mAbs) and their respective fragments, which have inherently long biological half-lives, has attracted increased interest in recent years. In this review, we provide a survey of the recent literature as it applies to the development of nine-selected longer-lived positron emitters with half-lives of 9-140h (e.g., (124)I, (64)Cu, (86)Y and (89)Zr), and describe the biological behaviors of radionuclide-labeled mAbs with respect to distribution and targeting characteristics, potential toxicities, biological applications, and clinical translation potentials.

Keywords: (124)I; (64)Cu; (86)Y; (89)Zr; 1,4,7,10-tetraazacyclododecane-N,N′,N″,N″′-tetraacetic acid; 1,4,7-triazacyclononane-N,N′,N″-1,4,7-triacetic acid; 1-N-(4-aminobenzyl)-3,6,10,13,16,19-hexaazabicyclo[6.6.6]eicosane-1,8-diamine; 1-oxa-4,7,1-tetraazacyclododecane-5-S-(4-isothiocyanatobenzyl)-4,7,10-triacetic acid; 3,6,9,15-tetraazabicyclo[9.3.1]-pentadeca-1(15),11,13-triene-4-S-(4-isothiocyanatobenzyl)-3,6,9-triacetic acid; CHX-A″-DTPA; DOTA; DOTA-DPhe1-Tyr3-octreotide; DOTATOC; DTPA; HPMA; Immuno-PET; Monoclonal antibodies; N-(2-hydroxypropyl)-methacrylamide; N-[R-2-amino-3-(p-isothiocyanato-phenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diamine-N,N,N′,N″,N″-pentaacetic acid; NOTA; Oncology; PIB; PIP; Radioimmunoimaging; SATA; SarAr; bispecific monoclonal antibody; bsMAb; diethylenetriaminepentaacetic acid; p-SCN-Bn-PCTA; p-SCN-Bn-oxo-DO3A; p-iodobenzoate; para-iodophenyl; succinimidyl acetylthioacetate.

Fig. 1

Schematic representation of potential cancer biomarkers for immuno-PET imaging. Cancer biomarkers play important roles in cancer cell proliferation, survival, angiogenesis, invasion and metastasis. The biomarkers can be associated with tumor cells (cytoplasm or surface), in the extracellular matrix (ECM) of tumor tissue, or on tumor vasculature (angiogenesis). Growth factor VEGF can be produced by tumor cells, secreted to ECM, and then bind to its receptors on endothelial cells leading to the initiation of angiogenesis. When PET imaging is employed in monitoring therapeutic efficacy, the biomarkers for cell apoptosis and necrosis, e.g. death receptors or caspase signaling can be targeted in addition to other tumor-specific targets. Note: this is for illustration purposes and does not imply that all biomarkers are present in one tumor tissue. PSMA: prostate-specific membrane antigen; CEA: carcinoembryonic antigen; TGF-β: transforming growth factor beta; TGFR: transforming growth factor receptor; EpCAM: epithelial cell adhesion molecule; EGF: epidermal growth factor; EGFR/HER-2: epidermal growth factor receptor; VEGF: vascular endothelial growth factor; VEGFR: vascular endothelial growth factor receptor; TRAIL: TNF-related apoptosis-inducing ligand.

Fig. 2

Schematic representation of the fate of antibodies (internalized or non-internalized) labeled with residualizing or non-residualizing radionuclides. a. a non-internalized antibody labeled with a non-residualizing radionuclide. Antibodies bind to their antigens in a dynamic association–dissociation equilibrium fashion. b. an internalized antibody labeled with a nonresidualizing radionuclide. After internalization and degradation of the antibody conjugates and receptors, non-residualizing radionuclides (such as ¹²⁴I, ⁷⁶Br) are released from the cell and enter the extracellular space. c. an internalized antibody linked with a residualizing radionuclide. After internalization and degradation of the antibody conjugates and receptors, residualizing radionuclides (such as ⁶⁴Cu, ⁸⁶Y, ⁸⁹Zr) can be trapped in the lysosome. Even if released from lysosome, it can transchelate to intracellular proteins and remain in the cell.

Fig. 3

Representative immuno-PET images from day 1 to day 3 after administration of ⁸⁶YCHX-A”-DTPA-bevacizumab, ⁸⁶Y-CHX-A”-DTPA-panitumumab, ⁸⁶Y-CHX-A”-DTPA-cetuximab in female athymic (NCr) nu/nu mouse bearing VEGF-A positive human ovarian carcinoma SKOV3 xenograft (top) or human colorectal carcinoma LS-174T xenografts (middle, bottom). The tumors are indicated with a white arrow. The scale represents % maximum and minimum threshold intensity. This figure is adapted from Nayak, et al. [71,74,75].

Fig. 4

Factors to be considered when selecting a β⁺ emitter.