The Contorsbody, an antibody format for agonism: Design, structure, and function

Area of Science:

• Immunology
• Biotechnology
• Structural Biology

Background:

• Antibody engineering is crucial for developing targeted therapies, particularly agonists.
• Achieving agonism often requires specific antibody formats to induce receptor activity.
• Existing antibody formats may not be optimal for inducing receptor dimerization and signal transduction.

Purpose of the Study:

• To design and characterize a novel antibody format, Contorsbody, for inducing receptor agonism.
• To demonstrate the conversion of an antagonist (Trastuzumab) into an agonist using this new format.
• To investigate the structural and functional properties of Contorsbodies for therapeutic applications.

Main Methods:

• Engineering of mono-specific bivalent Y-shape IgGs into single-chain dimers of modified heavy chains.
• Incorporation of antigen-binding motifs into a constrained conformation.
• Utilizing molecular dynamics and electron microscopy for structural analysis.
• Assessing antigen binding and receptor dimerization capabilities.

Main Results:

• The novel Contorsbody format successfully promotes receptor dimerization and induces signal transduction.
• Trastuzumab, an antagonist, was re-formatted into an agonist using the Contorsbody architecture.
• Contorsbodies exhibit increased rigidity and compact structure compared to traditional IgGs.
• Fab fragments in Contorsbodies are positioned for effective 'cis'-dimerization of cell surface receptors.

Conclusions:

• Contorsbodies represent a versatile and effective antibody format for generating agonists.
• This format allows for the conversion of antagonists into agonists with retained binding properties.
• The unique geometry of Contorsbodies enhances their potential for targeted receptor activation and therapeutic development.