Sentinel lymph node (SLN) mapping is common, however question remains as to what the ideal imaging agent is and how such an agent might provide reliable and stable localization of SLNs. (99m)Tc-labeled nanocolloid human serum albumin (Nanocoll) is the most commonly used radio-labeled colloid in Europe and remains the standard of care (SOC). It is used in conjunction with vital blue dyes (VBDs) which relies on simple lymphatic drainage for localization. Although the exact mechanism of Nanocoll SLN localization is unknown, there is general agreement that Nanocoll exhibits the optimal size distribution and radiolabeling properties of the commercially available radiolabel colloids. [(99m)Tc]Tilmanocept is a novel radiopharmaceutical designed to address these deficiencies. Our aim was to compare [(99m)Tc]Tilmanocept to Nanocoll for SLN mapping in breast cancer. Data from the Phase III clinical trials of [(99m)Tc]Tilmanocept's concordance with VBD was compared to a meta-analysis of a review of the literature to identify a (99m)Tc albumin colloid SOC. The primary endpoints were SLN localization rate and degree of localization. Six studies were used for a meta-analysis to identify the colloid-based SOC. Five studies (6,134 patients) were used to calculate the SOC localization rate of 95.91 % (CI 0.9428-0.9754) and three studies (1,380 patients) were used for the SOC SLN degree of localization of 1.6683 (CI 1.5136-1.8230). The lower bound of the confidence interval was used for comparison to Tilmanocept. Tilmanocept data included 148 patients, and pooled analysis revealed a 99.99 % (CI 0.9977-1.0000) localization rate and degree of localization of 2.16 (CI 1.964-2.3600). Tilmanocept was superior to the Nanocoll SOC for both endpoints (P < 0.0001).
Summary In considering the challenges of approaches to clinical imaging, we are faced with choices that sometimes are impacted by rather dogmatic notions about what is a better or worse technology to achieve the most useful diagnostic image for the patient. For example, is PET or SPECT most useful in imaging any particular disease dissemination? The dictatorial approach would be to choose PET, all other matters being equal. But is such a totalitarian attitude toward imaging selection still valid? In the face of new receptor targeted SPECT agents one must consider the remarkable specificity and sensitivity of these agents. 99mTc-Tilmanocept is one of the newest of these agents, now approved for guiding sentinel node biopsy (SLNB) in several solid tumors. Tilmanocept has a Kd of 3×10−11 M, and it specificity for the CD206 receptor is unlike any other agent to date. This coupled with a number of facts, that specific disease-associated macrophages express this receptor (100 to 150 thousand receptors), the receptor has multiple binding sites for tilmanocept (>2 sites per receptor) and that these receptors are recycled every 15 minutes to bind more tilmanocept (acting as intracellular “drug compilers” of tilmanocept into non-degraded vesicles), give serious pause as to how we select our approaches to diagnostic imaging. Clinically, the size of SLNs varies greatly, some, anatomically, below the machine resolution of SPECT. Yet, with tilmanocept targeting, the SLNs are highly visible with macrophages stably accruing adequate 99mTc-tilmanocept counting statistics, as high target-to-background ratios can compensate for spatial resolution blurring. Importantly, it may be targeted imaging agents per se, again such as tilmanocept, which may significantly shrink any perceived chasm between the imaging technologies and anchor the diagnostic considerations in the targeting and specificity of the agent rather than any lingering dogma about the hardware as the basis for imaging approaches. Beyond the elements of imaging applications of these agents is their evolution to therapeutic agents as well, and even in the neo-logical realm of theranostics. Characteristics of agents such as tilmanocept that exploit the natural history of diseases with remarkably high specificity are the expectations for the future of patient- and disease-centered diagnosis and therapy.
BackgroundIn rheumatoid arthritis (RA), infiltrating macrophages play a critical role in the immunopathogenesis of the disease by generating pro-inflammatory cytokines and chemokines and by contributing directly to joint damage. Current imaging modalities do not directly assess activated macrophage-mediated disease processes in RA. Use of non-invasive imaging to detect macrophage infiltration of synovial joints may allow for more sensitive identification of synovitis and earlier recognition of RA, identify joints at risk for progressive inflammation and destruction, provide a better means of quantifying joint inflammation and disease activity, and measure or even predict response to macrophage-directed therapy. Tc 99 m tilmanocept is a synthetic radiopharmaceutical imaging agent that binds with high affinity to the mannose receptor (CD206) located on the cell surface of synovial macrophages. We investigated whether subcutaneous (SC) administration of tilmanocept labelled with Tc 99 m could specially image macrophage mediated inflammation in RA but not in healthy control (HC) subjects.ObjectivesTo investigate whether subcutaneous (SC) administration of tilmanocept labelled with Tc 99 m could specially image macrophage mediated inflammation in RA but not in healthy control (HC) subjects.MethodsSubjects received a SC injection of either 50 µg or 200 µg tilmanocept radiolabeled with 2mCi Tc99m in 0.4 mL. 18 subjects were enrolled as follows – Cohort 1: HC: 50 µg/2mCi; n=5; Cohort 2: HC: 200 µg/2mCi; n=4; Cohort 3: RA 50 µg/2mCi; n=4; Cohort 4: RA 200 µg/2mCi; n=5. Subjects were imaged with whole body planar scans at 2–3 hours and 4–6 hours post injection as well as separate 5 min planar images of both hands. If there were areas of increased localization, SPECT images were obtained.ResultsTc 99 m tilmanocept localised most effectively at the 200 µg mass dose 2–3 hours post- administration in RA subjects (cohort 4). Localization was observed in 60% of the subjects in joints of the bilateral wrists, hands, and knees. No localization was observed in HCs receiving the same mass dose (cohort 2).Abstract AB0248 – Figure 1Contrast of wrist and elbow of SC RA subjectConclusionsOur findings represent a potential advance in the imaging of RA using a novel immunodiagnostic imaging strategy to specifically visualise macrophage-mediated elements of the RA disease process. This study demonstrates the potential for Tc 99 m tilmanocept to be used as an imaging tool for macrophage-mediated synovial inflammation in RA patients. This strategy can be used to identify patients at risk for activated macrophage-mediated joint damage, to quantify synovitis and disease activity, to provide further insight into immune-mediated mechanisms ofRA, and to enable future targeted delivery of immunomodulatory therapeutics.AcknowledgementsNavidea BiopharmaceuticalsRussell Engleman Rheumatology Research Centre, University of California San FranciscoDisclosure of InterestJ. Graf Grant/research support from: Navidea Biopharmacueuticals, B. Abbruzzese: None...
Sentinel lymph node (SLN) mapping and identification is a primary component of surgical therapies for breast cancers, melanomas, pediatric soft tissue sarcomas, and certain other cancers. The current standard of care for identifying SLNs to inject into a tumor (or near a tumor) a blue dye (often called “vital blue dye”), of which several are available, in conjunction with a radiolabeled (99mTc) tracer, available as either a technetium sulfur colloid or as a technetium labeled albumin formulation. The exact formulations used vary, especially between those used in the United States and Europe. All such compounds are effectively agents of passive transport in the lymphatic ducts and are “inert” with regard to any biomarker recognition specificity. Allegedly, such agents move passively from the tumor/tumor basin into lymph nodes with a presumptive tumor-node anatomic nexus and the nodes are elucidated as blue and/or radioactive, the former based on excision line-of-sight, the latter based on intraoperative evaluation with a gamma-detecting probe. But because such components do not bear any specificity, that is, bind or accumulate lymph nodes bearing targets, they either remain static at the injection site and/or quickly drain away, reducing their real-time clinical effectiveness. A novel 99mTc-labeled, prospectively designed, low Mr molecule (99mTc DTPA Mannosyl Dextran; Tilmanocept) targeted as a ligand for the mannose binding receptor (MBR) of lymphatic reticuloendothelial cells and intended for real-time intraoperative gamma mapping of tumor-lymphatic nexuses has been synthesized and clinically tested in Phase 3 clinical studies in breast cancer and melanoma. The results of the development process and clinical testing indicate: 1) The prospective molecular designs resulted in safety and clinical performance characteristics that provided times from agent injection to patient evaluation that were significantly reduced compared to currently applied 99mTc-labeled agents; and 2) The specificity, sensitivity, and performance with regard to anatomic localization, false negative rates, and receptor retention exceed those of other colorimetric and 99mTc-labeled agents. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5231. doi:10.1158/1538-7445.AM2011-5231
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.