Technetium ⁹⁹ᵐTc tilmanocept

Technetium Tc 99m tilmanocept is a receptor-targeted radiopharmaceutical that is designed to rapidly transit lymphatic vessels; it biotargets, accumulates, and is retained in primary, key predictive, draining lymph nodes (sentinel lymph nodes). The substance, tilmanocept, specifically binds to mannose binding receptor proteins (CD206) that reside on the surface of macrophages and dendritic cells. Macrophages are present in high concentrations in lymph nodes.

Tilmanocept is a macromolecule consisting of multiple units of diethylenetriaminepentaacetic acid (DTPA) and mannose, each synthetically attached to a 10 kDa dextran backbone. The mannose acts as a substrate for the receptor, and the DTPA serves as a chelating agent for labelling with technetium Tc 99m. The mean diameter of tilmanocept is 7 nm and this small molecular size permits enhanced transit into lymphatic channels resulting in rapid and consistent injection site clearance.

Following reconstitution and labelling, technetium Tc 99m tilmanocept is intended to be injected in close proximity to the tumour and used in preoperative gamma detection imaging in conjunction with a stationary gamma camera (scintigraphy), single photon emissioncomputed tomography (SPECT), or SPECT/computerized tomography SPECT/CT, and/or intraoperatively in conjunction with a gamma detection probe to localise sentinel lymph nodes in the lymphatic pathway draining the tumour.

In in vitro studies, technetium Tc 99m tilmanocept exhibited specific and tight binding to human CD206 receptors with a primary binding site affinity of Kd = 2.76 × 10^-11 M. In Phase 1 clinical studies, approximately 0.5 to 1.8% of the dose is accumulated in draining lymph nodes through specific binding after 30 minutes. Technetium Tc 99m tilmanocept binding is independent of tumour type or severity.

Two Phase 1 clinical trials in breast cancer patients and one Phase 1 study in melanoma patients have been completed. The purpose of the studies included the radiopharmacokinetic evaluation of technetium Tc 99m tilmanocept.

Distribution

In one Phase 1 study in breast cancer patients, technetium Tc 99m tilmanocept at all three doses tested (4, 20, and 100 micrograms) exhibited fast injection site clearance (elimination rate constants in the range of 0.222/h to 0.278/h). Uptake of technetium Tc 99m tilmanocept into the primary sentinel node increased dose-dependently (p=0.009): technetium Tc 99m tilmanocept injection at 4, 20, and 100 micrograms produced primary sentinel node levels (LSN) of 0.09 ± 0.20 pmol, 6.53 ± 2.52 pmol, and 10.58 ± 8.43 pmol of technetium Tc 99m tilmanocept, respectively. The percent-of-injected dose reaching the primary sentinel node (IDSN) was 0.05 ± 0.10%, 0.52% ± 0.38%, 0.21% ± 0.17% in the 4, 20, and 100 microgram technetium Tc 99m tilmanocept dose groups, respectively. The plasma ID per gram for two dose levels peaked at 4 hours; the mean values for the 4 and 100 microgram doses were 0.0090/g ± 0.0048%/g and 0.0039%/g ± 0.0046%/g, respectively. The 20 microgram dose peaked at 2.5 hours with a mean ID/g of 0.0023/g ± 0.0005%/g.

In the second Phase 1 study in breast cancer patients in which patients were injected with 20 micrograms technetium Tc 99m tilmanocept, the mean elimination rate constant of technetium Tc 99m tilmanocept was 0.299/h and the drug half-life at the injection site was 2.6 h. The IDSN was 1.68 ± 1.22% in the 3 hour injection-to-surgery group and 1.81% ± 2.19% in the technetium Tc 99m tilmanocept 16 hour injection-to-surgery group.

In the Phase 1 study in melanoma patients, technetium Tc 99m tilmanocept at all three doses tested (20, 100, and 200 micrograms) cleared the injection site with elimination rate constants in the range of 0.227/h to 0.396/h, resulting in drug half-life at the injection site of 1.75 to 3.05 h). Uptake of technetium Tc 99m tilmanocept into the primary sentinel node increased dose-dependently: technetium Tc 99m tilmanocept injection at 20, 100, and 200 micrograms produced LSN values of 5.01 ± 8.02 pmol, 17.5 ± 13.7 pmol, and 58.2 ± 41.2 pmol of technetium Tc 99m tilmanocept, respectively. The IDSN taken up into the primary lymph node was 0.50 for the 20 microgram dose, 0.35% for the 100 microgram dose, 0.58% for the 200 microgram dose of technetium Tc 99m tilmanocept. The plasma ID per gram for two dose levels peaked at 15 minutes; the mean values for the 20 and 200 microgram doses were 0.0104/g ± 0.0135%/g and 0.0065%/g ± 0.0082%/g, respectively. The 100 microgram dose peaked at 1 and 2 hours with a mean ID/g of 0.0018/g ± 0.001%/g at each timepoint.

Elimination

Technetium Tc 99m tilmanocept is eliminated primarily through the kidneys. The metabolism of technetium Tc 99m tilmanocept has not been investigated experimentally. Tilmanocept may be metabolised in the liver to its component molecules, namely dextran (which is renally excreted and/or further metabolised to glucose), mannose (an endogenous sugar) and diethylenetriaminepentaacetic acid (which is renally excreted). As with all general metabolites, especially those in which the liver plays a measurable roll of elimination, some biliary elimination of technetium Tc 99m tilmanocept is also likely to occur.

The ID for liver, kidneys, and bladder as calculated from the whole body scans of breast cancer patients at 1, 2.5, and 12 hours after administration was below 2.6 at all times (all dose levels combined). The ID for liver, kidneys, and bladder as calculated from the whole body scans of melanoma patients at 1 and 12 hours after administration ranged from 1.1 to 3.1% at 1 hour, and all decreased to less than 1% by 12 hours.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, acute and repeated dose toxicity, and genotoxicity.