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Effects of an Unlabeled Loading Dose on Tumor-Specific Uptake of a Fluorescently Labeled Antibody for Optical Surgical Navigation.

ABSTRACT: PURPOSE:Intraoperative optical imaging to guide surgeons during oncologic resections offers a unique and promising solution to the ambiguity of cancer margins to tactile and visual assessment that results in devastatingly high rates of positive margins. Sequestering of labeled antibodies by normal tissues with high expression of the antibody target, or "antigen sinks", diminishes the efficacy of these probes to provide contrast between the tumor and background tissues by decreasing the amount of circulating probe available for uptake by the tumor and by increasing the fluorescence of non-tumor tissues. We hypothesized that administering a dose of unlabeled antibody prior to infusion of the near-infrared (NIR) fluorescently labeled antibody would improve tumor-specific uptake and contrast of the fluorescently labeled probe by occupying extra-tumoral binding sites, thereby increasing the amount of labeled probe available for uptake by the tumor. PROCEDURES:In this study, we explore this concept by testing two different "pre-load" doses of unlabeled cetuximab (the standard 10-mg test dose, and a larger, experimental 100-mg test dose) in six patients receiving cetuximab conjugated to the fluorescent dye IRDye800CW (cetuximab-IRDye800CW) in a clinical trial, and compared the amount of fluorescent antibody in tumor and background tissues, as well as the tumor-specific contrast of each. RESULTS:The patients receiving the larger preload (100 mg) of unlabeled cetuximab demonstrated significantly higher concentrations (9.5 vs. 0.1 ?g) and a longer half-life (30.3 vs. 20.6 days) of the labeled cetuximab in plasma, as well as significantly greater tumor fluorescence (32.3 vs. 9.3 relative fluorescence units) and tumor to background ratios (TBRs) (5.5 vs. 1.7). CONCLUSIONS:Administering a preload of unlabeled antibody prior to infusion of the fluorescently labeled drug may be a simple and effective way to improve the performance of antibody-based probes to guide surgical resection of solid malignancies.

SUBMITTER: Moore LS

PROVIDER: S-EPMC5679006 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Effects of an Unlabeled Loading Dose on Tumor-Specific Uptake of a Fluorescently Labeled Antibody for Optical Surgical Navigation.

Moore Lindsay S LS Rosenthal Eben L EL de Boer Esther E Prince Andrew C AC Patel Neel N Richman Joshua M JM Morlandt Anthony B AB Carroll William R WR Zinn Kurt R KR Warram Jason M JM

Molecular imaging and biology 20170801 4

<h4>Purpose</h4>Intraoperative optical imaging to guide surgeons during oncologic resections offers a unique and promising solution to the ambiguity of cancer margins to tactile and visual assessment that results in devastatingly high rates of positive margins. Sequestering of labeled antibodies by normal tissues with high expression of the antibody target, or "antigen sinks", diminishes the efficacy of these probes to provide contrast between the tumor and background tissues by decreasing the a ...[more]

PMID: 27830425

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Project description:We developed a stand-alone, real-time optical detection device capable of reading fluorescence intensities from cell samples with high sensitivity and precision, for use as a portable fluorescent sensor for sensing fluorescently labeled enterohemorrhagic Escherichia coli (EHEC) Shiga toxins (Stxs). In general, the signal intensity from the fluorescently labeled Stxs was weak due to the small number of molecules bound to each cell. To address this technical challenge, we used a highly sensitive light detector (photomultiplier tube: PMT) to measure fluorescence, and designed a portable optical housing to align optical parts precisely; the housing itself was fabricated on a 3D printer. In addition, an electric circuit that amplified PMT output was designed and integrated into the system. The system shows the toxin concentration in the sample on a liquid crystal display (LCD), and a microcontroller circuit is used to read PMT output, process data, and display results. In contrast to other portable fluorescent detectors, the system works alone, without any peripheral computer or additional apparatus; its total size is about 17 × 13 × 9 cm3, and it weighs about 770 g. The detection limit was 0.01 ppm of Alexa Fluor 488 in PBS, which is ten thousand times lower than those of other smartphone-based systems and sufficiently sensitive for use with a portable optical detector. We used the portable real-time optical sensing system to detect Alexa Fluor 488-tagged Stx2B-subunits bound to monocytic THP-1 cells expressing the toxin receptor globotriaosylceramide (Gb3). The device did not detect a signal from Gb3-negative PD36 cells, indicating that it was capable of specifically detecting Stxs bound to cells expressing the toxin receptor. Following the development of a rapid and autonomous method for fluorescently tagging cells in food samples, the optical detection system described here could be used for direct detection of Shiga toxins in food in the field.

Dataset Information

Effects of an Unlabeled Loading Dose on Tumor-Specific Uptake of a Fluorescently Labeled Antibody for Optical Surgical Navigation.

Publications

Effects of an Unlabeled Loading Dose on Tumor-Specific Uptake of a Fluorescently Labeled Antibody for Optical Surgical Navigation.

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