DELIVERY OF MONOCLONAL ANTIBODIES THROUGH THE LYMPHATICS: CHARACTERIZATION BY COMPARTMENTAL MODELING.

To investigate the effectiveness of subcutaneous administration for targeting antibody to lymph nodes, the authors have used data on the kinetics of anti-H-2K**K antibody in K**K -positive and K**K -negative mice to construct a compartmental model of antibody biodistribution. Modeling analysis revealed that antibody injected subcutaneously into negative mice leaves the injection site via convection of material in newly formed lymph, rapidly enters the nodes of the lymphatic chain and finally enters the bloodstream, presumably by the thoracic duct. A small fraction of lymph is shunted around the popliteal nodes (25%) and around the lumbar nodes (15%). The kinetics of antibody injected subcutaneously into positive mice are defined largely by the binding of antibody to nearby cells. As a result of such binding, antibody is retained in the foot and the popliteal and lumbar nodes. The modeling analysis predicts dose-dependent kinetics: increasing dose results in increased uptake in the nodes. Doses that saturate the nodes can be expected to appear in the blood, thus increasing systemic toxicity and reducing signal-to-noise ratio.