Long-acting antibody ligand mimetics for HER4-selective agonism

Area of Science:

• Biotechnology
• Molecular Biology
• Drug Discovery

Background:

• Neuregulin protein 1 (NRG1) is a natural peptide ligand for ErbB family receptors HER3 and HER4.
• Developing stable and specific therapeutic agents targeting these receptors remains a challenge.

Purpose of the Study:

• To engineer an agonistic antibody modality, termed antibody ligand mimetics (ALMs), that mimics NRG1 function.
• To enhance receptor specificity and improve pharmacokinetic properties compared to natural ligands.

Main Methods:

• Incorporated NRG1 into an antibody scaffold to create ALMs.
• Optimized linker and ligand length for native ligand activity in HEK293 cells and iPSC-derived cardiomyocytes.
• Employed a monomeric Fc-ligand fusion platform and selectivity engineering for HER4-dominant agonism.

Main Results:

• Achieved native ligand activity with optimized ALMs in cellular assays.
• Demonstrated HER4-dominant agonism through Fc-ligand fusion and selectivity engineering.
• Showcased potential for improved pharmacokinetics, stability, and developability.

Conclusions:

• Antibody ligand mimetics offer a promising approach for developing targeted therapeutics.
• This strategy can be applied to cardiovascular disease targets and other therapeutic areas.
• ALMs provide differentiated drug molecules with enhanced specificity and extended half-life.