Aberrant bispecific antibody pharmacokinetics linked to liver sinusoidal endothelium clearance mechanism in cynomolgus monkeys

Abstract

(2016) Aberrant bispecific antibody pharmacokinetics linked to liver sinusoidal endothelium clearance mechanism in cynomolgus monkeys, mAbs, 8:5, 969-982, DOI: 10.1080/19420862.2016 To link to this article: https://doi.org/10. 1080/19420862.2016 ABSTRACT Bispecific antibodies (BsAbs) can affect multiple disease pathways, thus these types of constructs potentially provide promising approaches to improve efficacy in complex disease indications. The specific and non-specific clearance mechanisms/biology that affect monoclonal antibody (mAb) pharmacokinetics are likely involved in the disposition of BsAbs. Despite these similarities, there are a paucity of studies on the in vivo biology that influences the biodistribution and pharmacokinetics of BsAbs. The present case study evaluated the in vivo disposition of 2 IgG-fusion BsAb formats deemed IgG-ECD (extracellular domain) and IgG-scFv (single-chain Fv) in cynomolgus monkeys. These BsAb molecules displayed inferior in vivo pharmacokinetic properties, including a rapid clearance (> 0.5 mL/hr/kg) and short half-life relative to their mAb counterparts. The current work evaluated factors in vivo that result in the aberrant clearance of these BsAb constructs. Results showed the rapid clearance of the BsAbs that was not attributable to target binding, reduced neonatal Fc receptor (FcRn) interactions or poor molecular/biochemical properties. Evaluation of the cellular distribution of the constructs suggested that the major clearance mechanism was linked to binding/association with liver sinusoidal endothelial cells (LSECs) versus liver macrophages. The role of LSECs in facilitating the clearance of the IgG-ECD and IgG-scFv BsAb constructs described in these studies was consistent with the minimal influence of clodronate-mediated macrophage depletion on the pharmacokinetics of the constructs in cynomolgus monkeys The findings in this report are an important demonstration that the elucidation of clearance mechanisms for some IgG-ECD and IgGscFv BsAb molecules can be unique and complicated, and may require increased attention due to the proliferation of these more complex mAb-like structures.

Mechanisms Influencing the Pharmacokinetics and Disposition of Monoclonal Antibodies and Peptides

“…This section will cover a high-level overview of these mechanisms in the absence of the consideration of their origin; however, a substantial discussion on these processes has been reviewed extensively elsewhere and the reader is directed to other reviews for more information (Bak et al, 2015;Lapto s and Omersel, 2018). Additionally, it has been speculated by our laboratory and others that transformations or modifications can influence the clearance of biologics, particularly through scavenger receptors (Ashraf and Sahu, 2012;Zani et al, 2015;Datta-Mannan et al, 2016;PrabhuDas et al, 2017). The role of scavenger receptors in the disposition of mAbs and peptides is an evolving space that is not presented herein.…”

Hematopoietic cells as site of first-pass catabolism after subcutaneous dosing and contributors to systemic clearance of a monoclonal antibody in mice

“…A role for macrophages is supported by studies in which clodronate treatment reduces clearance of a bispecific antibody in cynomolgus monkeys by 30%. 44 Standard PK evaluations by compartmental and non-compartmental methods assume elimination from the central compartment and do not consider extravascular elimination. The repercussions of this limitation on volume of distribution estimates have already been discussed elsewhere.…”

Targeted Fcγ Receptor (FcγR)-mediated Clearance by a Biparatopic Bispecific Antibody

“…Immune complexes bind different subsets of FcγRs on “professional” phagocytes such as neutrophils, monocytes, and macrophages, including Kupffer cells (KCs) (10), and liver sinusoidal endothelial cells (LSECs), which are responsible for the clearance of small immune complexes (SICs) in the liver (11, 12). The fate of antibody-antigen complexes is governed in part by size (13–16).…”