Engineering HIV antibodies with enhanced breadth and potency of neutralization through multistate affinity maturation

Area of Science:

• Immunology
• Virology
• Biochemistry

Background:

• Broadly neutralizing antibodies (bnAbs) are crucial for therapeutic and prophylactic HIV interventions.
• Existing bnAbs may lack sufficient breadth and potency against diverse HIV envelope glycoprotein (Env) variants.
• Overcoming HIV's antigenic heterogeneity is key to developing effective antibody-based treatments.

Purpose of the Study:

• To engineer enhanced broadly neutralizing antibodies (bnAbs) against HIV with improved breadth and potency.
• To identify mutation patterns conferring improved binding across diverse HIV Env variants.
• To develop a generalizable strategy for creating therapeutic antibodies against diverse pathogens.

Main Methods:

• Utilized a multistate antibody engineering approach.
• Integrated deep mutational scanning with combinatorial library screening across HIV Env variants.
• Performed iterative optimization of a CD4-binding site bnAb.

Main Results:

• Identified mutation patterns that enhance binding across antigenically distinct HIV Env targets.
• Developed a lead bnAb candidate with improved breadth and up to 100-fold higher potency.
• Demonstrated maintained biophysical and pharmacokinetic profiles suitable for clinical development.
• Structural analyses revealed stabilizing interactions at the bnAb/Env interface.

Conclusions:

• Systematic in vitro engineering can generate bnAbs with enhanced breadth and potency.
• The developed strategy offers a generalizable approach for therapeutic antibody development against diverse pathogens like HIV.
• Engineered bnAbs show promise for overcoming HIV's viral diversity and advancing clinical applications.