Integrative structural insights into the IgG-FcRn interactions revealed by engineered FcRn-immobilized affinity...

Area of Science:

• Biochemistry
• Immunology
• Structural Biology

Background:

• Therapeutic antibody serum half-life is primarily determined by interactions with the neonatal Fc receptor (FcRn).
• The precise molecular mechanisms governing IgG-FcRn binding, particularly the influence of non-Fc domains and surface charges, remain incompletely elucidated.
• Current experimental methods like surface plasmon resonance present challenges for accurate FcRn affinity evaluation.

Purpose of the Study:

• To investigate the molecular basis of IgG-FcRn interactions beyond the Fc domain.
• To establish a link between antibody physicochemical properties and FcRn binding affinity.
• To elucidate the role of antibody light chain surface charges in FcRn affinity.

Main Methods:

• Development of an engineered FcRn-immobilized column for affinity chromatography.
• Analysis of diverse antibody types to correlate physicochemical characteristics with FcRn affinity.
• Utilizing charge-engineered mutants to assess the impact of specific amino acid residues on FcRn binding.

Main Results:

• Established a method for evaluating FcRn affinity using affinity chromatography.
• Identified key physicochemical characteristics influencing antibody-FcRn interactions.
• Demonstrated that surface charges on the antibody light chain lateral surface significantly affect FcRn affinity.

Conclusions:

• The study provides novel insights into the molecular determinants of IgG-FcRn interactions.
• Antibody light chain charge distribution is a critical factor influencing FcRn binding and, consequently, in vivo pharmacokinetics.
• A structural model of the IgG-FcRn complex was proposed to explain the charge-dependent binding mechanism.