Antibody Format and Serum Disposition Govern Ocular Pharmacokinetics of Intravenously Administered Protein Therapeutics

Vittal Shivva,Amrita V Kamath,Susan R Crowell,Hanine Rafidi,Robert F Kelley,C Andrew Boswell

doi:10.3389/fphar.2021.601569

Abstract

Protein therapeutics have witnessed tremendous use and application in recent years in treatment of various diseases. Predicting efficacy and safety during drug discovery and translational development is a key factor for successful clinical development of these therapies. In general, drug related toxicities are predominantly driven by pharmacokinetic (PK) exposure at off-target sites. This work explores the ocular PK of intravenously administered protein therapeutics to understand impact of antibody format on off-site exposure. Species matched non-binding rabbit antibody proteins (rabFab and rabIgG) were intravenously administered to male New Zealand White rabbits at a single 1 mg bolus dose and exposure was measured up to 3 weeks. As anticipated based on absence of FcRn recycling, rabFab has relatively fast systemic PK (CL–943 mL/day and t1/2–1.93 days) compared to rabIgG (CL–18.5 mL/day and t1/2–8.93 days). Similarly, rabFab has lower absolute ocular exposure in ocular compartments (e.g., vitreous and aqueous humor) compared to rabIgG, despite higher relative exposures (measured as percent tissue partition in ocular tissues relative to serum, based on Cmax and AUC). In general, percent tissue partition based on AUC (in aqueous and vitreous humor) relative to serum exposure were 10.4 and 8.62 for rabFab respectively and 1.11 and 0.64 for rabIgG respectively. This work emphasizes size and format based ocular exposure of intravenously administered protein therapeutics. Findings from this work enable prediction of format based ocular exposure for systemically administered antibody based therapeutics and aid in selection of molecule format for clinical candidate to minimize ocular exposure.

Highlights

Monoclonal antibodies and antibody-based therapeutics have emerged as mainstay of drug approvals in recent years (Kaplon et al, 2020; Lu et al, 2020)
There are some anatomical differences between rabbit and human eyes, rabbit is the non-clinical species most commonly used in elucidating ocular pharmacokinetics of drugs, and several reports have showed rabbits to be a reliable preclinical model for assessing ocular PK of drugs and for clinical translation (Del Amo and Urtti, 2015; Ahn et al, 2016)
While the PK of Monoclonal antibodies (mAbs) and Fabs after ITV administration are well established (Crowell et al, 2019; Caruso et al, 2020), no specific reports exists that clearly describe the ocular PK of systemically administered protein therapeutics

Summary

Introduction

Monoclonal antibodies (mAbs) and antibody-based therapeutics have emerged as mainstay of drug approvals in recent years (Kaplon et al, 2020; Lu et al, 2020). Ocular PK of Intravenous Proteins reported to cause ocular toxicity (Renouf et al, 2012; Eaton et al, 2015). Eye is considered an immune privileged site with a variety of static barriers, including layers of cornea, sclera, and retina, bloodaqueous and blood–retinal barriers as well as dynamic barriers such as choroidal, conjunctival blood flow, lymphatic clearance and tear dilution that prevent immune responses and preserve vision under normal homeostatic conditions (Perez et al, 2013). Ocular immune privilege is mainly mediated by regulatory T cells, which are generated by the anterior chamber-associated immune deviation, and ocular resident cells including corneal endothelial cells, retinal pigment epithelial cells, and aqueous humor that encounter cytotoxic effector T cells under normal homeostatic conditions (Mochizuki et al, 2013; Keino et al, 2018)

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