Influence of FcRn binding properties on the gastrointestinal absorption and exposure profile of Fc molecules.

The neonatal Fc receptor (FcRn) represents a transport system with the potential to facilitate absorption of biologics across the gastrointestinal barrier. How biologics interact with FcRn to enable their gastrointestinal absorption, and how these interactions might be optimized in a biological therapeutic are not well understood. Thus, we studied the absorption of Fc molecules from the intestine using three IgG-derived Fc variants with different, pH-dependent FcRn binding and release profiles.

Balancing charge in the complementarity-determining regions of humanized mAbs without affecting pI reduces non-specific binding and improves the pharmacokinetics.

Lowering the isoelectric point (pI) through engineering the variable region or framework of an IgG can improve its exposure and half-life via a reduction in clearance mediated through non-specific interactions. As such, net charge is a potentially important property to consider in developing therapeutic IgG molecules having favorable pharmaceutical characteristics. Frequently, it may not be possible to shift the pI of monoclonal antibodies (mAbs) dramatically without the introduction of other liabilities such as increased off-target interactions or reduced on-target binding properties.

Comparison of the kinetics and extent of muscarinic M1-M5 receptor internalization, recycling and downregulation in Chinese hamster ovary cells.

We characterized agonist-induced internalization, recycling and downregulation of each muscarinic receptor subtype (M(1)-M(5)) stably expressed in Chinese hamster ovary (CHO) cells. The radioligands [(3)H]QNB and [(3)H]NMS were used to measure the total and plasma membrane populations of muscarinic receptors, respectively. Following carbachol treatment (1 mM), the rank orders for the rate of carbachol-induced internalization of the muscarinic subtypes were M(2)>M(4)=M(5)>M(3)=M(1), respectively.