IgG2m4, an engineered antibody isotype with reduced Fc function.

Area of Science:

• Immunology
• Biotechnology
• Protein Engineering

Background:

• The Fc region of antibodies is crucial for effector functions (ADCC, CDC) and in vivo half-life.
• Modifying Fc-mediated properties is essential for designing effective antibody therapeutics, particularly for
• benign blocker
• antibodies.

Purpose of the Study:

• To develop a novel engineered IgG isotype with diminished Fc functionality.
• To create an antibody variant suitable for applications requiring reduced effector functions while preserving pharmacokinetic properties.

Main Methods:

• Engineering a new IgG isotype, IgG2m4, based on the IgG2 framework.
• Introducing four specific amino acid substitutions (H268Q, V309L, A330S, P331S) derived from the IgG4 isotype.
• Evaluating Fc functionality through in vitro binding assays and in vivo pharmacokinetic studies.

Main Results:

• The engineered IgG2m4 isotype demonstrated reduced binding to complement and Fc gamma receptors in vitro.
• In vivo studies in rhesus models showed that IgG2m4 antibodies maintained a normal serum half-life.
• The modifications successfully attenuated Fc-mediated effector functions.

Conclusions:

• The novel IgG2m4 isotype effectively reduces Fc effector functions while maintaining desirable pharmacokinetic profiles.
• IgG2m4 represents a promising engineered antibody variant for therapeutic applications requiring suppressed ADCC and CDC.
• This engineered isotype offers a valuable tool for antibody-based drug development.