Inhalable Nanobody (PiN-21) prevents and treats SARS-CoV-2 infections in Syrian hamsters at ultra-low doses

Abstract

Globally, there is an urgency to develop effective, low-cost therapeutic interventions for coronavirus disease 2019 (COVID-19). We previously generated the stable and ultrapotent homotrimeric Pittsburgh inhalable Nanobody 21 (PiN-21). Using Syrian hamsters that model moderate to severe COVID-19 disease, we demonstrate the high efficacy of PiN-21 to prevent and treat SARS-CoV-2 infection. Intranasal delivery of PiN-21 at 0.6 mg/kg protects infected animals from weight loss and substantially reduces viral burdens in both lower and upper airways compared to control. Aerosol delivery of PiN-21 facilitates deposition throughout the respiratory tract and dose minimization to 0.2 mg/kg. Inhalation treatment quickly reverses animals’ weight loss after infection, decreases lung viral titers by 6 logs leading to drastically mitigated lung pathology, and prevents viral pneumonia. Combined with the marked stability and low production cost, this innovative therapy may provide a convenient and cost-effective option to mitigate the ongoing pandemic.

The development of Nanosota-1 as anti-SARS-CoV-2 nanobody drug candidates

“…Nanobody therapeutics derived from camelid antibodies has advantages relative to conventional antibodies. Although several studies have reported nanobody drug candidates that specifically target SARS-CoV-2 ( Huo et al, 2020 ; Hanke et al, 2020 ; Xiang et al, 2020 ; Schoof et al, 2020 ; Wrapp et al, 2020a ; Pymm et al, 2021 ; Nambulli et al, 2021 ), as of this writing, only two studies have evaluated their nanobody drug candidates in an animal model for anti-SARS-CoV-2 therapeutic efficacy ( Pymm et al, 2021 ; Nambulli et al, 2021 ). None of these studies have evaluated their nanobody drug candidates for in vitro thermostability, in vivo stability, or tissue biodistribution.…”

“…The series may also be developed to become part of cocktail therapies that target multiple sites on SARS-CoV-2. Third, despite its rapid clearance from the blood, Nanosota-1C could be used as an inhaler to treat infections in the respiratory tracts ( Van Heeke et al, 2017 ; Nambulli et al, 2021 ) or as an oral drug to treat infections in the intestines ( Vega et al, 2013 ). The worldwide distribution of COVID-19 in the world calls for the large-scale manufacturing of anti-SARS-CoV-2 therapeutics.…”

Potent neutralizing nanobodies resist convergent circulating variants of SARS-CoV-2 by targeting diverse and conserved epitopes

“…Recently, the high preclinical efficacy of an ultrapotent Nb construct (PiN-21) has been demonstrated in a sensitive COVID-19 animal model. At a very low dose (0.2 mg/kg), the PiN-21 inhalation treatment quickly protects animals' weight loss after SARS-CoV-2 infection, decreases lung viral titers by a million fold which leads to drastically mitigated lung pathology, while preventing viral pneumonia 14 . Potent neutralizing Nbs, therefore, represent a convenient and cost-effective therapeutic option to help mitigate the evolving pandemic.…”

A potent SARS-CoV-2 neutralising nanobody shows therapeutic efficacy in the Syrian golden hamster model of COVID-19

“…Recently, mice challenged intranasally with SARS-CoV-2, and then treated prophylactically IP with a nanobody Fc fusion has also been shown to reduce viral load in the lungs 17 . More recently, Nebulli et al 18 , showed that nasal administration of a nanobody 6 h after viral challenge also reduced viral load and weight change in the Syrian hamster model. Our data are consistent with these results but our treatment with the C5 trimer 24 h after viral challenge when the clinical manifestations of disease rst become apparent is a more demanding test of nanobody e cacy and arguably a more realistic model of therapeutic treatment.…”

“…Secondly, while conventional antibodies that comprise two disulphide-linked polypeptides, heavy and light chain, typically require mammalian cells for production, nanobodies can be manufactured using readily available microbial systems. The potency of nanobodies against SARS-CoV-2 7 infection has been demonstrated in cell-based assays [8][9][10][11][12][13][14][15][16] and most recently in animal studies 17,18 . Several strategies for engineering VHH into a multivalent species are known.…”