Engineered IgG1-Fc--one fragment to bind them all

Area of Science:

• Biotechnology
• Immunology
• Protein Engineering

Background:

• The crystallizable fragment (Fc) of immunoglobulin G (IgG) is a versatile scaffold for therapeutic design, retaining essential antibody functions.
• Functionalization through structural loop diversification in CH3 domains enables the creation of antigen-binding Fc proteins (Fcabs).

Purpose of the Study:

• To review the engineering of Fcabs from IgG Fc scaffolds for therapeutic development.
• To compare the in vitro and preclinical activity of Fcabs with approved antibodies.
• To discuss methods for engineering biophysical properties and designing heterodimeric Fc-based scaffolds for bispecific antibodies.

Main Methods:

• Design and selection of libraries for Fcabs with nanomolar binding affinity and wild-type-like in vivo half-life.
• Correlation analysis of Fc receptor binding and antibody-dependent cell-mediated cytotoxicity (ADCC).
• Comparative analysis of in vitro and preclinical biological activity.

Main Results:

• Selected Fcabs exhibit potent biological activity comparable to clinically approved antibodies.
• Fcabs demonstrate wild-type-like in vivo half-life and correlated Fc receptor binding and ADCC.
• Engineering methods for biophysical properties and heterodimeric scaffolds are presented.

Conclusions:

• Fcabs represent a promising scaffold for developing novel therapeutics with potential for clinical application.
• The HER2-binding Fcab FS102 entering clinical phase I highlights the scaffold's therapeutic potential.
• Critical analysis of library design efforts provides insights into engineering IgG1-Fc and similar scaffolds.