Target-independent variable region mediated effects on antibody clearance can be FcRn independent.

Abstract:

:The importance of the neonatal Fc receptor (FcRn) in extending the serum half-life of monoclonal antibodies (mAbs) is well demonstrated, and has led to the development of multiple engineering approaches designed to alter Fc interactions with FcRn. Recent reports have additionally highlighted the effect of nonspecific interactions on antibody pharmacokinetics (PK), suggesting an FcRn-independent mechanism for mAb clearance. In this report we examine a case study of 2 anti-interleukin-12/23 antibodies, ustekinumab and briakinumab, which share the same target and Fc, but differ in variable region sequences. Ustekinumab displayed near baseline signal in a wide range of early stage developability assays for undesirable protein/protein interactions, while briakinumab showed significant propensity for self- and cross-interactions. This phenotypic difference correlates with faster clearance rates for briakinumab in both human FcRn transgenic and FcRn knockout mice. These findings support a dominant contribution for FcRn-independent clearance for antibodies with high nonspecificity, and highlight a key role for early stage developability screening to eliminate clones with such high nonspecific disposition PK.

journal_name

MAbs

journal_title

mAbs

authors

Kelly RL,Yu Y,Sun T,Caffry I,Lynaugh H,Brown M,Jain T,Xu Y,Wittrup KD

doi

10.1080/19420862.2016.1208330

subject

Has Abstract

pub_date

2016-10-01 00:00:00

pages

1269-1275

issue

7

eissn

1942-0862

issn

1942-0870

journal_volume

8

pub_type

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