Lymphoseek (tilmanocept) is a macromolecule consisting of multiple units of diethylenetriaminepentaacetic acid (DTPA) and mannose, each covalently attached to a 10 kDa dextran backbone. The mannose acts as a ligand for the receptor, and the DTPA serves as a chelating agent for labeling with technetium Tc 99m.

12.2 Pharmacodynamics In in vitro studies, Lymphoseek exhibited binding to human mannose binding receptor with a primary binding site affinity of Kd = 2.76 x 10-11 M.

In clinical studies, Lymphoseek has been detectable in lymph nodes within 10 minutes and up to 30 hours after injection. It is recommended that intraoperative lymphatic mapping be conducted between 15 minutes and 15 hours following injection.

12.3 Pharmacokinetics In dose-ranging clinical studies, injection site clearance rates were similar across all Lymphoseek doses (4 to 200 mcg) with a mean elimination rate constant in the range of 0.222 to 0.396/hr, resulting in a drug half-life at the injection site of 1.75 to 3.05 hours.
The amount of the accumulated radioactive dose in the liver, kidney, and bladder reached a maximum 1 hour post administration of Lymphoseek and was approximately 1% to 2% of the injected dose in each tissue.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Studies to assess the carcinogenicity potential of tilmanocept have not been conducted. Tilmanocept was not mutagenic in vitro in the Ames bacterial mutation assay and in the in vitro mouse lymphoma test, and was negative in the in vivo micronucleus test in mice.

Studies on reproductive fertility have not been conducted.

14 CLINICAL STUDIES
Lymphoseek safety and efficacy were assessed in two open-label, multicenter, single arm, within-subject active comparator trials of patients with melanoma or breast cancer. Prior to the nodal mapping procedure, the patients had no nodal or metastatic disease by standard tumor staging criteria. Diagnostic efficacy was determined by the number of histology-confirmed lymph nodes detected by Lymphoseek. Lymphoseek (50 mcg; 0.5 mCi) was injected into patients at least 15 minutes prior to the scheduled surgery, and blue dye was injected shortly prior to initiation of the surgery. Intraoperative lymphatic mapping was performed using a hand-held gamma detection probe followed by excision of lymph nodes identified by Lymphoseek, blue dye, or the surgeons visual and palpation examination. The resected lymph nodes were eva luated for histopathology.

In Study One, of 179 patients who received Lymphoseek, 94 (53%) had known or suspected breast cancer and 85 (48%) had known or suspected melanoma. The median age was 59 years (range 20 to 90 years) and most (72%) were women.

In Study Two, of 153 patients who received Lymphoseek, 77 (50%) had known or suspected breast cancer and 76 (50%) had known or suspected melanoma. The median age was 61 years (range 26 to 88 years) and most (68%) were women.
Approximately 94% of patients from the two studies underwent preoperative lymphoscintigraphy to help identify nodal basins and to facilitate