Nanobody cocktails potently neutralize SARS-CoV-2 D614G N501Y variant and protect mice

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      While most nanobodies show potent neutralization against SARS-CoV-2 using in vitro assays, very few studies have examined the in vivo efficacy of nanobodies for the prevention and treatment for COVID-19 (41, 42). Due to their small size, nanobodies are rapidly cleared through renal elimination, which poses challenges for in vivo studies (43). However, the short half-life of nanobodies can be overcome via fusion to larger proteins such as albumin or to the Fc fragment of IgG (41⇓–43). Furthermore, to the best of our knowledge, no study has examined the potential for nanobody mixtures in the prevention of COVID-19 in vivo, which may be advantageous for controlling more highly infectious variants and reducing the potential for virus escape mutations to develop (7). Due to their unique properties, it will be important to further understand the potential of nanobodies as therapeutics against SARS-CoV-2.

      By screening nanobody phage display libraries generated from two alpacas immunized with coronavirus spike and RBDs, we identified a collection of nanobodies that bound to RBD with low nanomolar (nM) affinities, inhibited RBD-ACE2 complex formation, and neutralized SARS-CoV-2. X-ray crystallography, cryogenic electron microscopy (cryo-EM), and epitope binning experiments identified several combinations of noncompeting nanobodies as potential antibody mixture combinations. Nanobody-Fc fusions effectively blocked ACE2 receptor engagement with naturally occurring RBD variants present in human populations, showed potent neutralization against wild-type (WT) SARS-CoV-2 and an N501Y D614G variant, and, when used prophylactically, protected mice infected with a SARS-CoV-2 N501Y D614G variant.

      Here, immunization of alpacas with recombinant spike and RBD proteins enabled the identification of potent neutralizing nanobodies against SARS-CoV-2 and the N501Y D614G variant. This work describes bivalent nanobody-Fc fusions that bound to noncompeting sites on the RBD and blocked ACE2 receptor engagement against a panel of naturally occurring RBD variants. Furthermore, our nanobody-Fc fusions are high affinity (KD < 0.55 nM) with potent neutralizing activities against SARS-CoV-2 (as low as 0.1 nM).

      Jesus: Hey, Dad? God: Yes, Son? Jesus: Western civilization followed me home. Can I keep it? God: Certainly not! And put it down this minute--you don't know where it's been! Tom Robbins in Another Roadside Attraction

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