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The SARfaris: GPCR, Kinase, ADME

Friday, 30 August 2013

New Drug Approvals 2013 - Pt. XII - Technetium Tc 99m Tilmanocept (LymphoSeekTM)

ATC code: V09IA09

On March 13th 2013, the FDA approved Technetium Tc 99m Tilmanocept (LymphoSeekTM), a radioactive diagnostic agent indicated for lymphatic mapping with a hand-held gamma counter to assist in the localisation of lymph nodes draining a primary tumour site in patients with breast cancer or melanoma

Melanoma is a malignant skin tumour, which, although rather uncommon, causes 75% of skin cancer related deaths.  Breast cancer accounts for almost 23% of all cancers in women and in 2008 caused 13.7% of cancer related deaths in women. Lymph nodes drain lymphatic fluid coming from tissues, if the tissues contain a tumour, the node will retain cancer cells coming from it. By removing and analysing the lymph node, precious informations can be obtained regarding the spread of the tumour.

Technetium Tc 99m Tilmanocept (ChEMBL: CHEMBL2108726) acts by accumulating in lymphatic tissue and selectively binding to mannose binding receptor (CD206, ChEMBL: CHEMBL2176854, Uniprot:P22897) found on macrophage and dendritic cells membrane. In vitro studies show that Technetium Tc 99m Tilmanocept binds to the human mannose binding receptor with an affinity of Kd = 2.76 x 10-11 M. Clinical studies show that it accumulates in lymph nodes within 10 min and up to 30 hours after the injection.

The PDBe entry (PDBe: 1egg) for a crystal structure of the macrophage mannose receptor is shown below.

Tilmanocept is a macromolecule composed of multiple units of diethylenetriaminepentaacetic acid (DTPA) and mannose, each covalently bonded to a 10 kDa backbone of dextran. The DTPA acts as a chelating agent for labelling with Technetium 99m (Tc 99m), while mannose, a naturally occurring sugar, acts as a target ligand. The active component is radioactive Tc 99m, a synthetic element widely used in nuclear medicine that decays with a half-life of 6 hours emitting Gamma-2 photons. The molecular formula of Technetium Tc 99m Tilmanocept is [C6H10O5]n.(C19H28N4O9S99mTc)b.(C13H24N2O5S2)c.(C5H11NS)a. It contains 3-8 conjugated DTPA molecules (b); 12-20 conjugated mannose molecules (c) with 0-17 amine side chains (a) remaining free. The calculated average molecular weight of Tilmanocept ranges from 15,281 to 23,454 g/mol.

The recommended dose of Technetium Tc 99m Tilmanocept is 18.5 MBq (0.5 mCi) as a radioactivity dose and 50 mcg as a mass dose, administered via injection at least 15 minutes prior the lymph node mapping. Technetium Tc 99m Tilmanocept has a half-life at the injection site of 1.75 to 3.05 hours.

LymphoSeek is produced by Navidea Biopharmaceuticals, Inc.
Full prescribing information can be found here.

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