γ-Tilmanocept, a New Radiopharmaceutical Tracer for Cancer Sentinel Lymph Nodes, Binds to the Mannose Receptor (CD206)

Abstract

γ-tilmanocept (Technetium-99m–labeled- or 99mTc-tilmanocept) is the first mannose-containing, receptor-directed, radiolabeled tracer for the highly sensitive imaging of sentinel lymph nodes (SLNs) in solid tumor staging. To elucidate the mannose-binding receptor that retains tilmanocept in this microenvironment, human macrophages were used which have high expression of the C-type lectin mannose receptor (MR, CD206). Cy3-labeled tilmanocept exhibited high specificity binding to macrophages that was nearly abolished in competitive inhibition experiments. Furthermore, Cy3-tilmanocept binding was markedly reduced on macrophages deficient in the MR by siRNA treatment, and increased on MR-transfected HEK 293 cells. Finally, confocal microscopy revealed co-localization of Cy3-tilmanocept with the macrophage membrane MR and binding of labeled tilmanocept to MR-positive cells [macrophages and/or dendritic cells (DCs)] in human SLN tissues. Together these data provide strong evidence that CD206 is a major binding receptor for γ-tilmanocept. Identification of CD206 as the γ-tilmanocept-binding receptor enables opportunities for designing receptor-targeted advanced imaging agents and therapeutics for cancer and other diseases.

Targeting of crosstalk between tumor and tumor microenvironment by β‐D mannuronic acid (M2000) in murine breast cancer model

“…Moreover, adherence of tumor cells to extracellular matrix was dramatically abolished by soluble mannose-binding lectin treatment [47]. It has been supported by antitumorigenic effects of mannose-recognizing plant lectins [48], use of mannosylated chitosan for prostate cancer immunotherapy [49], application of mannosylated radiotracers for solid tumor staging [50], and positive correlation between levels of high mannosylation glycoproteins and the tumor burden in both mouse and human during breast cancer progression [51]. It was also demonstrated that the mannosylated proteins stimulate immune system with higher immunogenicity compared to peptides or proteins that are not mannosylated [52,53].…”

Tc‐99m tilmanocept versus Tc‐99m sulfur colloid in breast cancer sentinel lymph node identification: Results from a randomized, blinded clinical trial

“…Previously, we reported the primary end point of this trial found that patients receiving TcSC experienced significantly more pain post‐injection compared to TcTM. While the reason for the difference in pain is not clear, TcTM is a small, 7 nm in diameter molecule with rapid injection site clearance that targets the CD206 receptor in lymph node macrophages . TcSC consists of multi‐sized particles (15–100 nm) that are taken into the lymph nodes via phagocytosis .…”

“…While the reason for the difference in pain is not clear, TcTM is a small, 7 nm in diameter molecule with rapid injection site clearance that targets the CD206 receptor in lymph node macrophages. 6,7 TcSC consists of multi-sized particles (15-100 nm) that are taken into the lymph nodes via phagocytosis. 9,10 With such a significant difference in pain between the two agents, prior to this analysis it was unclear if the different mechanisms of action would also lead to a different number of…”

“…However, since those initial reports numerous radiopharmaceuticals and other agents have entered the world market. Recently, Tc‐99m tilmanocept (TcTM) (Lymphoseek, Navidea Biopharmaceuticals, Inc.), a CD206 receptor targeted lymphatic mapping agent, received United States Food and Drug Administration (FDA) approval for breast cancer and other solid tumors in 2013 …”

Use of 99mTc-Tilmanocept as a Single Agent for Sentinel Lymph Node Identification in Breast Cancer: A Retrospective Pilot Study

“…99m Tc-tilmanocept, a small, receptor-targeted lymphatic mapping agent with demonstrated technical success in numerous tumor types (2)(3)(4)(5), accumulates in SLNs by binding to the CD206 receptor residing on the surface of lymph node macrophages and dendritic cells (6). The agent consists of multiple units of diethylenetriaminepentaacetic acid and mannose, each covalently linked to a dextran backbone (7,8).…”