Drug discovery: Llama-derived antibodies neutralize SARS-CoV-2

Two nanobodies — small, stable antibody variants derived from llamas — that can neutralize SARS-CoV-2 in cell culture by blocking its interaction with the human ACE2 receptor are reported in a Nature Structural & Molecular Biology paper.

Passive immunization, which involves giving a patient virus-neutralizing agents — either serum from people previously infected with SARS-CoV-2 or purified antibodies — could represent a useful therapy for COVID-19. Antibodies against SARS-CoV-1 can neutralize the virus by blocking the binding of the virus’ spike protein to ACE2, but many do not cross-react with SARS-CoV-2. Human antibodies, like those of most mammals, have two chains (heavy and light), but camelids, such as llamas, also possess an additional single heavy chain antibody variant, known as a nanobody. Nanobodies are small, stable and easily produced and thus often serve as alternatives to conventional antibodies for diagnostics and imaging. They are currently being developed against SARS-CoV-2 as research tools and potential therapeutics.

James Naismith, Raymond Owens and colleagues report the identification and characterization of two closely related nanobodies (H11-H4 and H11-D4) that can block the attachment of the SARS-CoV-2 spike to ACE2 in cell culture. The nanobodies target a region of the protein immediately adjacent to and slightly overlapping with the ACE2 binding region. Both nanobodies were shown to neutralize live SARS-CoV-2, with H11-H4 showing particularly high potency and additive neutralisation with a human antibody.

The authors suggest that the nanobodies may find application alone or in combination with other antibodies used for passive immunization of patients with severe COVID-19. As camelid-derived antibodies are highly conserved with their human counterparts, they are likely to generate only low immune responses against them in humans; nevertheless, well developed humanization strategies are available.