MedComm | A potent neutralizing nanobody against SARS-CoV-2 with inhaled delivery potential


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The world-wide spread of coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 is the third major coronavirus outbreak in the past 20 years. SARS-CoV-2 is closely related to SARS-CoV, several SARS-like bat CoVs, and pangolin coronaviruses. However, SARSCoV-2 demonstrates a higher human-to-human transmissibility than SARS-CoV. Patients with confirmed SARS-CoV-2 infection had mild to severe respiratory illness with symptoms of fever, cough, headache, dyspnea, and pneumonia. To date, treating this infection is still a big challenge.

Heavy-chain-only antibodies (HCAbs) isolated from camels provide an alternative paradigm in development of therapeutic antibodies. HCAbs consist of only two heavy chains without light chains, thereby only containing a single variable domain (VHH) referred to as a single-domain antibody or nanobody (Nb) in the absence of the effector domain. In addition to having affinities and specificities for antigens similar to those of traditional antibodies, Nbs show smaller size and higher stability than most antibodies. Given these biophysical advantages, Nbs can be easily nebulized and delivered directly to lungs via an inhaler, which makes Nbs a particularly promising format for developing neutralizing antibodies targeting respiratory pathogens including SARS-CoV-2.

Here, the authors reported nanobody (Nb) phage display libraries derived from four camels immunized with the SARS-CoV-2 spike receptor-binding domain (RBD), from which 381 Nbs were identified to recognize SARS-CoV-2-RBD. Furthermore, seven Nbs were shown to block interaction of human angiotensin-converting enzyme 2 (ACE2) with SARS-CoV-2-RBD variants and two Nbs blocked the interaction of human ACE2 with bat-SL-CoV-WIV1-RBD and SARS-CoV-1-RBD. Among these candidates, Nb11-59 exhibited the highest activity against authentic SARS-CoV-2 with 50% neutralizing dose (ND50) of 0.55 µg/ml (Fig. 1). Nb11-59 can be produced on large scale in Pichia pastoris, with 20 g/L titer and 99.36% purity. It also showed good stability profile, and nebulization did not impact its stability. Overall, Nb11-59 might be a promising prophylactic and therapeutic molecule against COVID-19, especially through inhalation delivery.

Fig. 1 Evaluation of neutralizing potential of seven Nbs using plaque reduction neutralization test

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