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.

Cross‐Interaction Chromatography‐Based QSAR Model for Early‐Stage Screening to Facilitate Enhanced Developability of Monoclonal Antibody Therapeutics

“…Furthermore, increased nonspecific interaction could alter the pharmacokinetics of the mAbs. Negative correlation between IgG–FcRn interaction and half‐life has been observed in previous studies for mAbs with identical Fc region and different variable regions leading to differing pharmacokinetic outcomes …”

Evaluation of an Fcrn Affinity Chromatographic Method for Igg1-Type Antibodies and Evaluation of Igg Variants

“…Therefore, experience with the method itself and the interpretation of results are still limited. Kelly et al recently published a study, where Fabmediated nonspecific effects might contribute to clearance and also might influence the results observed during FcRn affinity chromatography by nonspecific binding to the column matrix [36]. This is currently addressed in an ongoing study and preliminary results indicate no unspecific Fab-charge-mediated matrix interaction.…”

Biophysical properties of the clinical-stage antibody landscape

“…However, for most of the measures we find this not to be the case, with a small but significant population of molecules exhibiting unusually unfavorable values for one or more measures. An example would be the PSR measurement, high values of which have been shown previously to correlate well with pharmacokinetics (PK) in mice (19,20). In the earlier work (see, for example, figure 2A of ref.…”

“…Perhaps the flaws indicated by these attributes were overcome through creative and/or exhaustive efforts in cell-line development, cell-culture optimization, and formulation to result in a vialed drug that meets minimum standards for advancement. However, of course the impact of such fixes ends at the moment of parenteral administration, at which point negative impact on drug pharmacokinetics might result in negative clinical trial outcomes [see, for a possible example, the case of briakinumab vs. ustekinumab (20,23)]. Intravenous administration, which still dominates the approved set, is less demanding of high concentrations and thus may be more tolerant of suboptimal aggregation behavior.…”