Therapeutic activity of an inhaled potent SARS-CoV-2 neutralizing human monoclonal antibody in hamsters

Piepenbrink, Michael S.; Park, Jun-Gyu; Oladunni, Fatai S.; Deshpande, Ashlesha; Basu, Madhubanti; Sarkar, Sanghita; Loos, Andreas; Woo, Jennifer; Lovalenti, Phillip M.; Sloan, Derek D.; Ye, Chengjin; Chiem, Kevin; Bates, Christopher W.; Burch, Reuben E; Erdmann, Nathaniel; Goepfert, Paul; Truong, Vu; Walter, Mark R.; Martínez-Sobrido, Luis; Kobie, James J.

doi:10.1016/j.xcrm.2021.100218

Cited by 60 publications

(69 citation statements)

References 46 publications

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“…SARS-CoV-2 NAbs were produced and purified as previously described (29). SARS-CoV-2 RBD (Wuhan-1) and RBD variants were produced in insect cells as RBD-FC fusion proteins (29,40).…”

Section: Protein Expressionmentioning

confidence: 99%

“…SARS-CoV-2 NAbs were produced and purified as previously described (29). SARS-CoV-2 RBD (Wuhan-1) and RBD variants were produced in insect cells as RBD-FC fusion proteins (29,40). Briefly, RBD-FC fusion proteins (Supplementary Figure 1) were purified from expression media by protein-A affinity chromatography, as previously described (29,40).…”

Section: Protein Expressionmentioning

confidence: 99%

“…SARS-CoV-2 RBD (Wuhan-1) and RBD variants were produced in insect cells as RBD-FC fusion proteins (29,40). Briefly, RBD-FC fusion proteins (Supplementary Figure 1) were purified from expression media by protein-A affinity chromatography, as previously described (29,40). Briefly, 6day transient expressions of RBD-FC WT and variants were performed in drosophila S2 cells.…”

Section: Protein Expressionmentioning

confidence: 99%

“…We previously isolated a series of potent SARS-CoV-2 NAbs from a single convalescent patient and characterized their efficacy in vitro, and for one NAb (1212C2), its efficacy in golden Syrian hamsters, delivered by inhalation (29). The classified NAb/RBD structures (Table 1 and Figure 4) were used to predict the binding epitopes of these NAbs and the resulting assignments were experimentally tested using RBD variant binding and epitope mapping studies.…”

Section: Classification Of Nabs Isolated From a Convalescent Sars-cov-2 Patientmentioning

confidence: 99%

“…This is a large endeavor that ultimately will require protein modeling, combined with synergistic experimental studies and additional 3D structure determinations. As a first step towards this goal, we sought to understand the RBD binding epitopes of a panel of SARS-CoV-2 NAbs, isolated from a single convalescent patient (29). To accomplish this goal, NAb-RBD structures (n=45, Table 1) in the protein databank (pdb) were grouped into five distinct classes based on their RBD binding profiles.…”

Section: Introductionmentioning

confidence: 99%

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Epitope Classification and RBD Binding Properties of Neutralizing Antibodies Against SARS-CoV-2 Variants of Concern

et al. 2021

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Severe acute respiratory syndrome coronavirus-2 (SAR-CoV-2) causes coronavirus disease 2019 (COVID19) that is responsible for short and long-term disease, as well as death, in susceptible hosts. The receptor binding domain (RBD) of the SARS-CoV-2 Spike (S) protein binds to cell surface angiotensin converting enzyme type-II (ACE2) to initiate viral attachment and ultimately viral pathogenesis. The SARS-CoV-2 S RBD is a major target of neutralizing antibodies (NAbs) that block RBD - ACE2 interactions. In this report, NAb-RBD binding epitopes in the protein databank were classified as C1, C1D, C2, C3, or C4, using a RBD binding profile (BP), based on NAb-specific RBD buried surface area and used to predict the binding epitopes of a series of uncharacterized NAbs. Naturally occurring SARS-CoV-2 RBD sequence variation was also quantified to predict NAb binding sensitivities to the RBD-variants. NAb and ACE2 binding studies confirmed the NAb classifications and determined whether the RBD variants enhanced ACE2 binding to promote viral infectivity, and/or disrupted NAb binding to evade the host immune response. Of 9 single RBD mutants evaluated, K417T, E484K, and N501Y disrupted binding of 65% of the NAbs evaluated, consistent with the assignment of the SARS-CoV-2 P.1 Japan/Brazil strain as a variant of concern (VoC). RBD variants E484K and N501Y exhibited ACE2 binding equivalent to a Wuhan-1 reference SARS-CoV-2 RBD. While slightly less disruptive to NAb binding, L452R enhanced ACE2 binding affinity. Thus, the L452R mutant, associated with the SARS-CoV-2 California VoC (B.1.427/B.1.429-California), has evolved to enhance ACE2 binding, while simultaneously disrupting C1 and C2 NAb classes. The analysis also identified a non-overlapping antibody pair (1213H7 and 1215D1) that bound to all SARS-CoV-2 RBD variants evaluated, representing an excellent therapeutic option for treatment of SARS-CoV-2 WT and VoC strains.

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“…SARS-CoV-2 NAbs were produced and purified as previously described (29). SARS-CoV-2 RBD (Wuhan-1) and RBD variants were produced in insect cells as RBD-FC fusion proteins (29,40).…”

Section: Protein Expressionmentioning

confidence: 99%

Section: Protein Expressionmentioning

confidence: 99%

Section: Protein Expressionmentioning

confidence: 99%

Section: Classification Of Nabs Isolated From a Convalescent Sars-cov-2 Patientmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Epitope Classification and RBD Binding Properties of Neutralizing Antibodies Against SARS-CoV-2 Variants of Concern

et al. 2021

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Pulmonary Delivery of Antibody for the Treatment of Respiratory Diseases

Sécher,

Heuzé-Vourc’h

2023

AAPS Introductions in the Pharmaceutical Sciences

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Inhalation monoclonal antibody therapy: a new way to treat and manage respiratory infections

Parray

Shukla

Perween

et al. 2021

Appl Microbiol Biotechnol

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The route of administration of a therapeutic agent has a substantial impact on its success. Therapeutic antibodies are usually administered systemically, either directly by intravenous route, or indirectly by intramuscular or subcutaneous injection. However, treatment of diseases contained within a specific tissue necessitates a better alternate route of administration for targeting localised infections. Inhalation is a promising non-invasive strategy for antibody delivery to treat respiratory maladies because it provides higher concentrations of antibody in the respiratory airways overcoming the constraints of entry through systemic circulation and uncertainity in the amount reaching the target tissue. The nasal drug delivery route is one of the extensively researched modes of administration, and nasal sprays for molecular drugs are deemed successful and are presently commercially marketed. This review highlights the current state and future prospects of inhaled therapies, with an emphasis on the use of monoclonal antibodies for the treatment of respiratory infections, as well as an overview of their importance, practical challenges, and clinical trial outcomes. Key points • Immunologic strategies for preventing mucosal transmission of respiratory pathogens. • Mucosal-mediated immunoprophylaxis could play a major role in COVID-19 prevention. • Applications of monoclonal antibodies in passive immunisation.

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Therapeutic activity of an inhaled potent SARS-CoV-2 neutralizing human monoclonal antibody in hamsters

Cited by 60 publications

References 46 publications

Epitope Classification and RBD Binding Properties of Neutralizing Antibodies Against SARS-CoV-2 Variants of Concern

Epitope Classification and RBD Binding Properties of Neutralizing Antibodies Against SARS-CoV-2 Variants of Concern

Pulmonary Delivery of Antibody for the Treatment of Respiratory Diseases

Inhalation monoclonal antibody therapy: a new way to treat and manage respiratory infections

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