Pharmacokinetic characteristics of therapeutic antibodies

Abstract

Summary Because of their high molecular weight and their highly hydrophilic character, therapeutic antibodies behave differently in terms of absorption, distribution and elimination compared to conventional drugs. Also, their pharmacokinetic profile varies significantly among individuals. After subcutaneous administration, antibodies are absorbed via the lymphatic system and become systemically bioavailable with some delay. The physicochemical properties of the molecules hinder their distribution from the bloodstream into the tissue. Elimination occurs by proteolysis in various organs (skin, muscle, liver), but mainly within the reticuloendothelial system. Also relevant is the elimination through target antigens (especially in the case of cell‐bound target antigens) as well as a recycling process through binding to the neonatal Fc receptor that provides protection from lysosomal degradation. Depending on the immunogenicity of the therapeutic antibody and the individual immune response, neutralizing antibodies can develop. Pharmacokinetic conditions can be optimized by coadministration of, for example, methotrexate. Moreover, risk factors for the loss of immunological tolerance, such as on‐demand therapy or elective switching of therapeutic antibodies, should be avoided.

Quantification of IgG monoclonal antibody clearance in tissues

“…Our determined tissue clearances are broadly consistent with published reports stating that the liver, muscle and skin are the major contributors to the systemic clearance of antibodies. 2,18,19 Nevertheless, compared with published results, the presented analysis has pronounced differences in the order and extent by which each tissue contributes to the total systemic clearance. For example, this is apparent when we directly compare our derived values with the tissue clearance values often used in large molecule PBPK models 26,27 that are derived by distributing the total clearance according to the fractional organ weight, 28 hence assuming equal catabolic activity per gram tissue for all organs.…”

“…Most descriptions of antibody disposition separate clearance into "endogenous" or "non-specific" clearance and "target-mediated" clearance. 1,2 Non-specific degradation of antibodies occurs by pinocytosis following cellular endosomal uptake and subsequent lysosomal proteolytic degradation into amino acids or smaller peptides. 3 Cellular uptake of antibodies is thought to occur mostly in endothelial and haematopoietic cells.…”

Handlungsempfehlung zur Therapieumstellung von Immunsuppressiva auf Dupilumab bei Patienten mit atopischer Dermatitis

“…Neben der zielantigenvermittelten Elimination (sog. "antigen sink") und einer geringen Proteolyserate in der Leber erfolgt die Elimination v. a. über das retikuloendotheliale System in der Interaktion mit Makrophagen und Monozyten sowie durch unspezifische Pino-/Endozytose von Endothelzellen, die auch in Abhängigkeit von der Expression des nFcR (Brambell-Rezeptor) einen Recycling-Prozess steuern [42]. Eine Bildung von endogenen Antikörpern gegen Dupilumab (sog.…”

Efficacy of antibody-based therapies against Middle East respiratory syndrome coronavirus (MERS-CoV) in common marmosets

“…These two different administration routes were chosen to achieve high systemic bioavailability; I.V. administration immediately results in high circulating neutralizing antibody titers whereas S.C. administration results in a slower systemic distribution of antibodies, therefore allowing a longer bioavailability (Wohlrab, 2015). Animals treated with hyperimmune plasma reached a neutralizing titer between 40 and 160 at 2 dpi and maintained these levels throughout the experiment.…”