PHARMACOKINETICS AND PHARMACODYNAMICS OF AN ANTI-TMPRSS6 MONOCLONAL ANTIBODY IN MICE.

Hepcidin is considered the master regulator of iron homeostasis. Hepcidin controls iron flows by ubiquitination, internalization, and degradation of ferroportin, the sole iron exporter. The expression of hepcidin is downregulated by the transmembrane serine protease 6 (TMPRSS6) through the Bone Morphogenic protein/Suppressor of Mothers against Decapentaplegic (BMP/SMAD) signaling pathway.

DISC-3405 is a novel humanized monoclonal antibody targeting TMPRSS6. The primary mode of action of DISC-3405 is to target and block the biological action of TMPRSS6 with subsequent upregulation of hepcidin leading to decreased iron absorption by enterocytes and decreased iron release from stores.

A murine analog of DISC-3405, r4K12B, was generated to avoid immunogenicity in mouse studies. In this study, r4K12B was intra-peritoneally administered into wild-type mice once at four dose levels (1, 2, 5, 10 mg/kg) and PK/PD parameters were measured at day 1, 2, 3, 5, 7 and 10 post-dosing.

r4K12B showed a greater than proportional PK profile. Serum hepcidin and liver HAMP mRNA levels significantly increased at day 1 post dosing and the duration of effect over time was dose-dependent. The upregulation of hepcidin was accompanied by a decrease in serum iron and transferrin saturation (TSAT), which returned to basal levels in a dose-dependent manner.

These results show that r4K12B can be used in efficacy studies in disease mouse models and further support the therapeutic potential of DISC-3405 as an iron restricting agent.