Abstract
Many chronic inflammatory diseases are treated by administration of “biological” therapies in terms of fully human and humanized monoclonal antibodies or Fc fusion proteins. These tools have widespread efficacy and are favored because they generally exhibit high specificity for target with a low toxicity. However, the design of clinically applicable humanized antibodies is complicated by the need to circumvent normal antibody clearance mechanisms to maintain therapeutic dosing, whilst avoiding development of off target antibody dependent cellular toxicity. Classically, professional phagocytic immune cells are responsible for scavenging and clearance of antibody via interactions with the Fc portion. Immune cells such as macrophages, monocytes, and neutrophils express Fc receptor subsets, such as the FcγR that can then clear immune complexes. Another, the neonatal Fc receptor (FcRn) is key to clearance of IgG in vivo and serum half-life of antibody is explicitly linked to function of this receptor. The liver is a site of significant expression of FcRn and indeed several hepatic cell populations including Kupffer cells and liver sinusoidal endothelial cells (LSEC), play key roles in antibody clearance. This combined with the fact that the liver is a highly perfused organ with a relatively permissive microcirculation means that hepatic binding of antibody has a significant effect on pharmacokinetics of clearance. Liver disease can alter systemic distribution or pharmacokinetics of antibody-based therapies and impact on clinical effectiveness, however, few studies document the changes in key membrane receptors involved in antibody clearance across the spectrum of liver disease. Similarly, the individual contribution of LSEC scavenger receptors to antibody clearance in a healthy or chronically diseased organ is not well characterized. This is an important omission since pharmacokinetic studies of antibody distribution are often based on studies in healthy individuals and thus may not reflect the picture in an aging or chronically diseased population. Therefore, in this review we consider the expression and function of key antibody-binding receptors on LSEC, and the features of therapeutic antibodies which may accentuate clearance by the liver. We then discuss the implications of this for the design and utility of monoclonal antibody-based therapies.
Highlights
The Growing Importance of Therapeutic AntibodiesMonoclonal antibody-based therapies for a variety of conditions have been available since the late 1980s
Once bound to FcγR a monoclonal antibody is internalized into an endosome. They encounter membrane bound FcRn (Roopenian and Akilesh, 2007) which is responsible for the protection of IgG catabolism, recycling the antibody to the surface leading to an increased half-life
In other studies, humanized antibody designed to target tumor cells by binding to a TNFR stimulatory receptor (CD137) on immune cells to promote anti-tumor immunity responses (Qi et al, 2019) such as Urlumab (Segal et al, 2017) was associated with liver toxicity, inflammation and liver related adverse events
Summary
Monoclonal antibody-based therapies for a variety of conditions have been available since the late 1980s. When designing a new antibody-based therapy there is a need to minimize interactions with non-target molecules and tissues other than the therapeutic target. These issues can be resolved by careful engineering of antibody to reduce immunogenicity, maximize efficacy, and minimize clearance. Antibodies destined for use in chronic conditions need to have the longest possible half-life and minimal clearance rates to support a favorable administration strategy and ensure dosing frequency is not prohibitive. We consider strategies that could be utilized to minimize hepatic clearance, and the impact of age or chronic disease on endothelial: antibody interactions. We begin with a review of therapeutic antibody generation and structure before considering implications for hepatic targeting and explanations for reported adverse events in clinical use
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