Engineering SARS-CoV-2 specific cocktail antibodies into a bispecific format improves neutralizing potency and...

Area of Science:

• Immunology
• Virology
• Biotechnology

Background:

• Neutralizing antibody therapies for COVID-19 often require expensive cocktails to prevent antibody resistance.
• Bispecific antibodies (bsAbs) are engineered to target multiple epitopes simultaneously, potentially overcoming limitations of traditional antibody cocktails.

Purpose of the Study:

• To engineer and compare two distinct bispecific antibody designs against SARS-CoV-2.
• To evaluate the efficacy, potency, and breadth of neutralization of these bsAbs against various SARS-CoV-2 variants.

Main Methods:

• Engineering of two bsAbs with different designs: IgG-(scFv)2 (14-H-06) and CrossMAb (14-crs-06).
• Comparison of bsAbs with parental antibodies and their cocktail.
• Assessment of antigen-binding and virus-neutralizing activities using various SARS-CoV-2 variants.
• Structural analysis via X-ray crystallography and cryo-electron microscopy (cryo-EM).
• Infection studies in mouse models.

Main Results:

• The IgG-(scFv)2 bsAb (14-H-06) showed enhanced antigen-binding and virus-neutralizing activity against multiple SARS-CoV-2 variants compared to the cocktail.
• 14-H-06 exhibited broader neutralizing activity and higher therapeutic efficacy in mouse models than the cocktail.
• Structural and computational analyses revealed distinct binding models and higher inter-spike crosslinking potential for 14-H-06.

Conclusions:

• Rationally engineered bispecific antibodies, particularly the IgG-(scFv)2 design, represent a promising and cost-effective strategy for COVID-19 therapy.
• bsAbs can improve therapeutic potency and breadth of neutralization against SARS-CoV-2 variants, offering an alternative to complex antibody cocktails.