Ultrapotent bispecific antibodies neutralize emerging SARS-CoV-2 variants

Area of Science:

• Immunology
• Virology
• Structural Biology

Background:

• Emerging SARS-CoV-2 variants threaten vaccine and therapeutic antibody efficacy.
• Neutralization requires targeting multiple spike protein sites to overcome viral mutations.

Approach:

• Isolated 216 monoclonal antibodies from COVID-19 patients.
• Designed bispecific antibodies by combining non-overlapping specificities.
• Determined crystal structure of potent antibody CV503 to understand binding and variant evasion.

Key Points:

• Three potent monoclonal antibodies neutralized B.1.1.7 and B.1.351 variants.
• CV503 binds the SARS-CoV-2 RBD ridge, competing with ACE2 and evading key variant residues.
• Five ultrapotent bispecific antibodies inhibited SARS-CoV-2 infection at <1 ng/mL.
• Three bispecific antibodies utilized a novel cross-linking mechanism targeting both NTD and RBD.
• One bispecific antibody demonstrated >100-fold increased potency and in vivo efficacy in a hamster model.

Conclusions:

• Bispecific antibodies offer a promising strategy against SARS-CoV-2 variants.
• These antibodies maintain potency against variants like B.1.351, even with mutations like E484K.
• Bispecific antibodies represent a potential next-generation countermeasure for SARS-CoV-2 variants of concern.