The CombYSelect platform enables reliable IgG heterodimerization by precisely engineering targeted mutations, primarily tyrosine and serine substitutions, within the IgG1 CH3 domain. This highly selective in silico approach narrows the combinatorial space to a manageable number of variations, allowing for comprehensive computational screening to identify optimal binding free energy (ΔΔG) and structural compatibility. The outcome is the robust formation of bispecific IgG-like molecules that retain natural stability and Fc functionality.

Crystal structure analyses have confirmed that dynamic π-stacking and polar interactions at engineered sites are crucial for preferential heavy chain pairing, which reduces unwanted homodimer formation and maximizes expression yield. This technological advancement simplifies bispecific antibody development, enabling efficient dual antigen targeting with minimal impact on manufacturability or pharmacokinetics. Extended applications include functional Fc fusion proteins and cytokine traps.

Representative Advantages: 

• Fewer mutations allow rapid, cost-effective antibody optimization

• High expression yield and stability across designs

• Simplified production and scalability for drug candidates

• Broad compatibility with multiple IgG isotypes and diverse antigen combinations

• Flexibility for modular, multi-targeted therapeutics and next-generation biologics

This combination of efficiency, flexibility, and robustness makes CombYSelect an ideal solution for advanced bispecific and multispecific antibody drug development.