Potent bivalent nanobody constructs that protect against the SARS-CoV-2 XBB variant

Area of Science:

• Immunology
• Virology
• Biotechnology

Background:

• Approved SARS-CoV-2 antibody therapeutics exhibit reduced efficacy against emerging Omicron variants.
• Development of novel treatments targeting current SARS-CoV-2 variants is critical.

Purpose of the Study:

• To develop novel XBB-specific antibody-like therapeutics targeting SARS-CoV-2 Omicron variants.
• To evaluate the efficacy of these therapeutics in vitro and in vivo.

Main Methods:

• Screening a yeast surface-displayed single-domain antibody library against the XBB spike protein receptor binding domain.
• Selection of lead nanobodies (XNb 4.13, XNb 4.14, XNb 4.15) based on binding affinity.
• Fusion of nanobodies to a mouse Fc domain and in vitro/in vivo efficacy testing.

Main Results:

• Three lead nanobody-Fc constructs (XNb 4.13-Fc, XNb 4.14-Fc, XNb 4.15-Fc) showed sub-nanomolar binding affinity to the XBB spike protein.
• XNb 4.13-Fc and XNb 4.14-Fc demonstrated in vitro neutralization of XBB.
• Therapeutic administration protected mice from XBB challenge, reducing viral lung titers.

Conclusions:

• Novel antibody-like nanobody-Fc constructs effectively target SARS-CoV-2 XBB variants.
• These therapeutics show potential for protecting against current and emerging COVID-19 strains.