High-affinity omalizumab variants with optimized disruptive potency prevent anaphylaxis in vivo

Area of Science:

• Immunology
• Allergy Research
• Biotechnology

Background:

• Omalizumab, a monoclonal antibody targeting IgE, is used for allergic conditions but requires frequent high doses due to moderate affinity.
• Existing next-generation anti-IgE antibodies have shown safety or efficacy limitations.
• There is a need for improved anti-IgE therapies with enhanced binding affinity and potency.

Purpose of the Study:

• To engineer omalizumab variants with increased IgE binding affinity and epitope specificity.
• To develop antibodies with enhanced potency to actively dissociate IgE from FcεRI.
• To improve the efficacy and therapeutic potential of anti-IgE treatments.

Main Methods:

• Utilized yeast display selection on mutated omalizumab libraries.
• Identified anti-IgE clone C03 and engineered flexible variants C03-H1L2 and C03-H2L2.
• Assessed IgE binding affinity, FcεRI binding inhibition, and IgE displacement potency.

Main Results:

• C03 antibodies exhibited ~10-fold higher IgE binding affinity than omalizumab.
• Engineered variants demonstrated superior inhibition of IgE binding to FcεRI.
• C03 variants effectively displaced FcεRI-bound IgE without inducing cell activation and prevented anaphylaxis in mice after a single dose.

Conclusions:

• Higher affinity and disruptive potency are crucial for next-generation anti-IgE therapies.
• Engineered C03 variants represent a promising advancement in anti-IgE treatment.
• These findings support the optimization of current therapeutic strategies for allergic diseases.