Insight into the avidity-affinity relationship of the bivalent, pH-dependent interaction between IgG and FcRn

Area of Science:

• Biochemistry
• Immunology
• Pharmacology

Background:

• Monoclonal antibodies (mAbs) require favorable pharmacokinetics, like extended serum half-life, for therapeutic efficacy.
• This half-life is modulated by pH-dependent binding to the neonatal Fc receptor (FcRn).
• Previous studies focused on single affinity values, overlooking the dual FcRn binding potential of IgG across endosomal pH gradients.

Purpose of the Study:

• To comprehensively analyze IgG-FcRn interactions, emphasizing both affinity and avidity.
• To investigate the avidity-to-affinity relationship across a physiological pH range.
• To evaluate the utility of switchSENSE technology for FcRn binding kinetics analysis.

Main Methods:

• Utilized switchSENSE technology with immobilized recombinant FcRn on DNA nanolevers.
• Assessed binding kinetics across a pH gradient (pH 5.8–7.4).
• Compared switchSENSE performance with classical Surface Plasmon Resonance (SPR) and other methods.

Main Results:

• Identified an affinity inflection point at pH 7.2 for the engineered IgG1-YTE, indicating enhanced FcRn binding.
• Observed a pH switch for avidity enhancement at pH 6.2 for IgG1-YTE, with avidity abolished at pH 7.4.
• Demonstrated switchSENSE's superior ability to differentiate affinity from avidity compared to SPR.

Conclusions:

• switchSENSE provides reliable kinetic parameters for IgG-FcRn binding modes and their pH-dependent relationship.
• The methodology can decipher the influence of variable Fab arms on FcRn binding, a limitation of SPR.
• This study offers guidance for engineering IgG molecules with optimized FcRn binding properties for improved therapeutic strategies.