Targeting Gut-Homing T Cells: The Pharmacological Profile of AMG 181 in Inflammatory Bowel Disease

AMG 181 is a human monoclonal antibody that is being tested in clinical trials for inflammatory bowel disease patients. It is designed to target the α4β7 integrin heterodimer, which is crucial for the homing of T cells to the gut. The antibody prevents the interaction between α4β7 and MAdCAM-1, a key molecule involved in this process.

In experimental studies, AMG 181 demonstrated specific binding to α4β7 integrin and effectively blocked its binding to MAdCAM-1, thereby inhibiting T cell adhesion. The drug's pharmacokinetics and pharmacodynamics were evaluated in cynomolgus monkeys after intravenous or subcutaneous administration. The results showed that the drug's maximum concentration (Cmax) and area under the curve (AUC) increased with dose, with AUC showing a greater than dose-proportional increase. After subcutaneous dosing, the drug exhibited dose-proportional exposure at single doses and after multiple weekly doses.

AMG 181 demonstrated a two- to threefold accumulation after 13 weekly doses and had an 80% bioavailability when administered subcutaneously. The drug had a linear elimination half-life of 12 days and a volume of distribution that approximated the intravascular plasma space. The study also observed correlations between the drug's exposure, immunogenicity, receptor occupancy, and the increase in gut-homing CD4+ central memory T cell count.

The findings suggest that AMG 181 has the desired pharmacological properties and safety profile in cynomolgus monkeys, indicating its potential for further investigation in human trials.