Human IgG lacking effector functions demonstrate lower FcRn-binding and reduced transplacental transport

Area of Science:

• Immunology
• Biotechnology
• Pharmacology

Background:

• Human IgG1 antibodies engineered for reduced Fcγ receptor and C1q binding (G1Δnab) eliminate effector functions.
• Preserving long half-life and placental transfer via neonatal Fc receptor (FcRn) binding is crucial for therapeutic IgG applications.

Purpose of the Study:

• To investigate the impact of G1Δnab mutations on human IgG1 binding to FcRn.
• To assess the transcellular transport of G1Δnab antibodies across FcRn-expressing cell lines and an ex vivo placenta model.

Main Methods:

• Characterization of pH-dependent binding kinetics between G1Δnab antibodies and human FcRn.
• Assessment of G1Δnab antibody transport across human cell line monolayers expressing FcRn.
• Evaluation of G1Δnab antibody transport in an ex vivo human placenta model.

Main Results:

• G1Δnab mutants exhibited reduced affinity for human FcRn (2.0-fold and 1.6-fold).
• Transport of G1Δnab mutants across FcRn-expressing cell lines was approximately 75% of wild-type, with no difference in human umbilical vein endothelial cells.
• G1Δnab mutation decreased transport in an ex vivo placenta model.

Conclusions:

• G1Δnab mutations, located away from the FcRn-binding site, exert long-distance effects on FcRn binding affinity and transcellular transport.
• These findings are significant for designing therapeutic human IgG antibodies with precisely tailored effector functions and pharmacokinetic properties.