Cerenkov Luminescence Imaging as a Modality to Evaluate Antibody-Based PET Radiotracers

Abstract

Antibodies, and engineered antibody fragments, labeled with radioisotopes are being developed as radiotracers for the detection and phenotyping of diseases such as cancer. The development of antibody-based radiotracers requires extensive characterization of their in vitro and in vivo properties, including their ability to target tumors in an antigen-selective manner. In this study, we investigated the use of Cerenkov luminescence imaging (CLI) as compared with PET as a modality for evaluating the in vivo behavior of antibody-based radiotracers. Methods: The anti-prostate-specific membrane antigen (PSMA) huJ591 antibody (IgG; 150 kDa) and its minibody (Mb; 80 kDa) format were functionalized with the chelator 1,4,7-triazacyclononane-1-glutaric acid-4,7-diacetic acid (NODAGA) and radiolabeled with the positron-emitting radionuclide 64 Cu (halflife, 12.7 h). Immunoreactive preparations of the radiolabeled antibodies were injected into NCr nu/nu mice harboring PSMA-positive CWR22Rv1 and PSMA-negative PC-3 tumor xenografts. Tumor targeting was evaluated by both PET and CLI. Results: 64 Cu-NODAGA-PSMA-IgG and 64 Cu-NODAGA-PSMA-Mb retained the ability to bind cell surface PSMA, and both radiotracers exhibited selective uptake into PSMA-positive tumors. Under the experimental conditions used, PSMA-selective uptake of 64 Cu-NODAGA-PSMA-IgG and 64 Cu-NODAGA-PSMA-Mb was observed by CLI as early as 3 h after injection, with tumor-to-background ratios peaking at 24 (IgG) and 16 (Mb) h after injection. Targeting data generated by CLI correlated with that generated by PET and necropsy. Conclusion: CLI provided a rapid and simple assessment of the targeting specificity and pharmacokinetics of the antibody-based PET radiotracers that correlated well with the behavior observed by standard PET imaging. Moreover, CLI provided clear discrimination between uptake kinetics of an intact IgG and its small-molecular-weight derivative Mb. These data support the use of CLI for the evaluation of radiotracer performance.

Cerenkov luminescence imaging: physics principles and potential applications in biomedical sciences

“…In [118], Cerenkov-specific contrast agents for pH detection have been developed, while in [119] antibody-based PET radiotracers have been evaluated via CLI.…”

“…Other preclinical CLI applications Potential uses of preclinical CLI which have been evaluated are also intraoperative imaging of radionuclides [ 109 ], surgical resection [ 110 ], endoscopic imaging for intraoperative surgical navigation [ 111 ], study of gene expression [ 57 , 112 – 114 ], dynamic imaging [ 115 ], interscapular brown adipose tissue visualization [ 116 ], quantitive tissue oxygenation assessment [ 117 ], and negative contrast imaging of blood vessel attenuation of Cerenkov light to image vasculature [ 55 ]. In [ 118 ], Cerenkov-specific contrast agents for pH detection have been developed, while in [ 119 ] antibody-based PET radiotracers have been evaluated via CLI.…”

Preclinical optimization of antibody‐based radiopharmaceuticals for cancer imaging and radionuclide therapy—Model, vector, and radionuclide selection

“…While CLI remains largely a semi-quantitative planar imaging modality due to the non-penetrating nature of blue-UV frequency photons, tomographic techniques are currently being developed for small-scale applications including preclinical imaging and endoscopic techniques (Cerenkov Luminescence Tomography 76 ). Several groups have already evaluated CLI in preclinical radioimmuno applications including tumor localization and intraoperative surgical guidance with promising results, 73,77 as expected. CLI procedures implementing agents already approved for other procedures, will likely gain accelerated FDA approval.…”

In situ lymphoma imaging in a spontaneous mouse model using the Cerenkov Luminescence of F-18 and Ga-67 isotopes

“…CLI can be used to examine several radioisotopes that are routinely used in the traditional clinical nuclear medicine toolkit [30][31][32].…”