Quantification of IgG monoclonal antibody clearance in tissues

Abstract

Monoclonal antibodies are an important therapeutic entity, and knowledge of antibody pharmacokinetics has steadily increased over the years. Despite this effort, little is known about the extent of IgG antibody degradation in different tissues of the body. While studies have been published identifying sites of degradation with the use of residualizing and non-residualizing radiolabels, quantitative tissue clearances have not yet been derived. Here, we show that in physiologically-based pharmacokinetic (PBPK) models we can combine mouse data of Indium-111 and Iodine-125 labeled antibodies with prior physiologic knowledge to determine tissue-specific intrinsic clearances. Unspecific total tissue clearance (mL/day) in the mouse was estimated to be: liver = 4.75; brain = 0.02; gut = 0.40; heart = 0.07; kidney = 0.97; lung = 0.20; muscle = 3.02; skin = 3.89; spleen = 0.45; rest of body = 2.16. The highest catabolic activity (per g tissue) was in spleen for an FcRn wild-type antibody, but shifts to the liver for an antibody with reduced FcRn affinity. In the model developed, this shift can be explained by the liver having a greater FcRn-mediated protection capacity than the spleen. The quantification of tissue intrinsic clearances and FcRn salvage capacity increases our understanding of quantitative processes that drive the therapeutic responses of antibodies. This knowledge is critical, for instance to estimate the non-specific cellular uptake and degradation of antibodies used for targeted delivery of payloads.

Interstitial IgG antibody pharmacokinetics assessed by combined in vivo‐ and physiologically‐based pharmacokinetic modelling approaches

“…c Fixed values based on (Eigenmann et al . ), note: bone and adipose assumed. d Relative values derived from Shah & Betts () and scaled to a 25‐g mouse.…”

“…Tissue‐intrinsic clearances were integrated based on previously published contribution of tissue clearances to the total plasma clearance (Eigenmann et al . ). A schematic representation of the model is provided in Fig.…”

Capacity limits of asialoglycoprotein receptor-mediated liver targeting

“…It is of note, however, that the liver has been found to be a major elimination organ for monoclonal antibodies. 30 Therefore, a radiolabeled non-targeting antibody Figure 3. Schematic illustration of the target-mediated drug disposition model.…”

Radiolabeled IgG antibodies: Impact of various labels on neonatal Fc receptor binding

“…Two polypeptides, a 31‐kDa transmembrane anchored chain (FcRn α‐chain) and a 10‐kDa β 2 ‐microglobulin chain (β 2 m), participate in binding to the C H 2‐C H 3 interdomain region of the IgG constant part. The receptor binds IgGs in a strictly pH‐dependent manner with high affinity at pH 6 in the acidified endosome and low affinity at physiological pH of 7.4 in plasma . The IgG:FcRn complexes are recycled back to the surface of the cell, whereas unbound proteins undergo lysosomal degradation.…”

“…The receptor binds IgGs in a strictly pH-dependent manner with high affinity at pH 6 in the acidified endosome and low affinity at physiological pH of 7.4 in plasma. 4 The IgG:FcRn complexes are recycled back to the surface of the cell, whereas unbound proteins undergo lysosomal degradation. Studies with wild-type (wt) and FcRn-knockout (FcRn-KO) mice have been used to show the impact of FcRn receptor binding on IgG clearance (CL).…”