Subcutaneous bioavailability of therapeutic antibodies as a function 
of FcRn binding affinity in mice

Combined glyco- and protein-Fc engineering simultaneously enhance cytotoxicity and half-life of a therapeutic antibody

“…57 Likewise, the N434Y variant has increased binding to murine FcRn at both pH6.0 and 7.4 resulting in comparable half-life to the IgG-WT in mice. 58 Nevertheless, we show in this study that several variants including this mutation N434Y result in half-life extension in hFcRn mice, emphasizing the limitations of using wild-type mice as preclinical models for the analysis of engineered mAbs.…”

Mechanisms of Subcutaneous Absorption of Rituximab in Rats

“…For example, the s.c. bioavailability of 7E3 IgG1 was 3-fold higher in wild-type compared with FcRn-deficient mice (Wang et al, 2008). Increased affinity of mAbs to FcRn at pH 6.0 was associated with greater s.c. bioavailability, whereas an increased affinity at pH 7.4 led to a decrease in s.c. absorption in mice (Deng et al, 2010(Deng et al, , 2012. In contrast, no definitive effect of altering FcRn affinity on s.c. bioavailability was found for a series of IgG4 variants in cynomolgus monkeys (Datta-Mannan et al, 2012).…”

Lessons for the clinic from rituximab pharmacokinetics and pharmacodynamics

“…Recirculation of mAbs and transcytosis through FcRn are important mechanisms of mAb stabilization in vivo and distribution across tissues, respectively. [28][29][30] Thus, Fc modifications aimed at improving bioavailability and/or stability of therapeutic mAbs in vivo are being actively sought by several groups, even though a considerable amount of work is still required to define the best strategies and translate the laboratory findings into the clinic. Indeed, improved binding at acid pH does not necessarily translate into longer half-life and better bioavailability.…”

“…Indeed, improved binding at acid pH does not necessarily translate into longer half-life and better bioavailability. 29,30 Finally, RTX can bind to C1q and activate the classical complement cascade. C1q is a protein complex composed of 18 peptides that form 6 identical globular heads on a single stem structure (often compared with a bunch of tulips).…”

“…and s.c. administration of antibodies, FcRn plays an important role by reducing mAb catabolism and mediating mAb transport across endothelial cells, thus promoting the distribution of the antibodies across tissues. 30,59 The volume of distribution of RTX at steady-state is approximately 9.6 L. Since the plasma volume is only 3-3.5 L, this suggests that the mAb distributes into the extracellular spaces of tissues, except the CNS. 65,66 Indeed, the blood-brain barrier physically impedes entry of macromolecules into the CNS, severely limiting distribution of RTX after i.v.…”