Stellabody: A novel hexamer-promoting mutation for improved IgG potency.

Area of Science:

• Immunology
• Biotechnology
• Protein Engineering

Background:

• Immunoglobulin G (IgG) hexamerisation is a natural process influencing antibody function.
• Existing mutations enhancing IgG hexamerisation primarily target surface residues.
• Enhanced hexamerisation can significantly improve antibody-dependent cellular cytotoxicity (ADCC) and antigen binding.

Purpose of the Study:

• To explore novel strategies for engineering IgG hexamerisation.
• To investigate the impact of modifying the buried H429 residue in the CH3 domain.
• To introduce Stellabody technology for controlled IgG hexamerisation.

Main Methods:

• Engineering of the H429 residue within the CH3 domain of IgG.
• Development of Stellabody technology with distinct amino acid substitutions (H429F, H429Y).
• Assessment of hexamerisation outcomes, including on-target and pH-sensitive mechanisms.

Main Results:

• H429F mutation leads to monomeric IgG that hexamerises upon target binding ('on-target' hexamerisation).
• H429Y mutation results in pH-sensitive hexamers forming in solution before antigen binding.
• Stellabody technology demonstrates broad applicability across various antibody formats and therapeutic targets.

Conclusions:

• Engineering the H429 residue offers a unique approach to control IgG hexamerisation.
• Stellabody technology provides distinct mechanisms for enhanced antibody potency and function.
• This technology has wide-ranging applications in developing next-generation antibody-based immunotherapeutics.