Improving target cell specificity using a novel monovalent bispecific IgG design.

Area of Science:

• Immunology and Biotechnology
• Antibody Engineering

Background:

• Monovalent bispecific antibodies offer unique therapeutic mechanisms but face engineering and manufacturing challenges due to heavy and light chain pairing complexities.
• Existing methods struggle with efficient production of homogeneous bispecific antibody populations.

Purpose of the Study:

• To introduce and validate a novel platform, DuetMab, for the efficient production of monovalent bispecific immunoglobulin G (IgG) molecules.
• To demonstrate the capability of DuetMab to enable concurrent antigen binding by monovalent bispecific IgGs.

Main Methods:

• The DuetMab platform integrates knobs-into-holes (KIH) technology for heavy chain heterodimerization.
• Engineered disulfide bonds in the CH1-CL interface enhance cognate heavy and light chain pairing efficiency.
• Antibody pairs targeting EGFR/HER2 (cetuximab/trastuzumab) and CD40/CD70 were utilized to validate the platform.

Main Results:

• DuetMab antibodies were produced in a highly purified and active form.
• Demonstrated for the first time that monovalent bispecific IgGs can simultaneously bind two distinct antigens on the same cell.
• This concurrent binding compensates for monovalency-associated avidity loss and improves target cell selectivity.

Conclusions:

• The DuetMab platform provides an efficient method for producing homogeneous monovalent bispecific IgGs.
• DuetMab-generated antibodies exhibit enhanced target cell selectivity through concurrent antigen binding, overcoming limitations of monovalency.