Pharmacokinetic Developability and Disposition Profiles of Bispecific Antibodies: A Case Study with Two Molecules.

Amita Datta-Mannan,Stephanie Key,Yiqing Feng,Paul Cain,Robin Brown

doi:10.3390/antib11010002

Abstract

Bispecific antibodies (BsAb) that engage multiple pathways are a promising therapeutic strategy to improve and prolong the efficacy of biologics in complex diseases. In the early stages of discovery, BsAbs often exhibit a broad range of pharmacokinetic (PK) behavior. Optimization of the neonatal Fc receptor (FcRn) interactions and removal of undesirable physiochemical properties have been used to improve the ‘pharmacokinetic developability’ for various monoclonal antibody (mAb) therapeutics, yet there is a sparsity of such information for BsAbs. The present work evaluated the influence of FcRn interactions and inherent physiochemical properties on the PK of two related single chain variable fragment (scFv)-based BsAbs. Despite their close relation, the two BsAbs exhibit disparate PK in cynomolgus monkeys with BsAb-1 having an aberrant clearance of ~2 mL/h/kg and BsAb-2 displaying a an ~10-fold slower clearance (~0.2 mL/h/kg). Evaluation of the physiochemical characteristics of the molecules, including charge, non-specific binding, thermal stability, and hydrophobic properties, as well as FcRn interactions showed some differences. In-depth drug disposition results revealed that a substantial disparity in the complete release from FcRn at a neutral pH is a primary factor contributing to the rapid clearance of the BsAb-1 while other biophysical characteristics were largely comparable between molecules.

Highlights

With three approvals and another ~100 in clinical development, bispecific antibodies (BsAbs) represent an important class of therapeutic modalities [1,2]
In previous reports we demonstrated that the association with liver sinusoidal endothelial cells (LSECs) led to the accumulation of BsAbs in liver and was responsible for the unusually rapid clearance of several BsAbs including some IgG‐
In previous reports we demonstrated that the association with liver sinusoidal endothelial cells (LSECs) led to the accumulation of BsAbs in liver and was responsible for the unusually rapid clearance of several BsAbs including some IgGscFv constructs [14]

Summary

Introduction

With three approvals and another ~100 in clinical development, bispecific antibodies (BsAbs) represent an important class of therapeutic modalities [1,2]. The intent of BsAb therapy is for a single molecule to interfere with multiple disease pathways by recognizing two different epitopes or antigens These interactions can expand and prolong the efficacy of these modalities in complex disease indications. The IgG-like BsAb molecules consist of subunits on individual antibodies attached to an agonistic/antagonistic mAb that impart the ability to bind dual soluble or membrane bound ligands or a combination of both. These formats include DVD-Ig, cross-mAbs, IgG-extracellular domain (ECD), and IgG-scFv constructs [6,7]

Methods

Results

Conclusion