Intranasal administration of SARS-CoV-2 neutralizing human antibody prevents infection in mice

AbstractPrevention of SARS-CoV-2 infection at the point of nasal entry is a novel strategy that has the potential to help contain the ongoing pandemic. Using our proprietary technologies, we have engineered a human antibody that recognizes SARS-CoV-2 S1 spike protein with an enhanced affinity for mucin to improve the antibody’s retention in respiratory mucosa. The modified antibody, when administered into mouse nostrils, was shown to block infection in mice that were exposed to high titer SARS-CoV-2 pseudovirus 10 hours after the initial antibody treatment. Our data show that the protection against SARS-CoV-2 infection is effective in both nasal and lung areas 7 days after viral exposure. The modified antibody is stable in a nasal spray formulation and maintains its SARS-CoV-2 neutralizing activity. Nasal spray of the modified antibody can be developed as an affordable and effective prophylactic product to protect people from infection by exposure to SARS-CoV-2 virus in the air.One-sentence summaryA Fc-modified human antibody prevents SARS-CoV-2 viral infection via nasal administration

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Ivermectin repurposing for COVID-19 therapy: Safety and pharmacokinetic assessment of a novel nasal spray formulation in a pig model

10.1101/2020.10.23.352831 ◽

2020 ◽

Cited By ~ 1

Author(s):

J. Errecalde ◽

A. Lifschitz ◽

G. Vecchioli ◽

L. Ceballos ◽

F. Errecalde ◽

...

Keyword(s):

Nasal Spray ◽

Oral Route ◽

Nasal Administration ◽

Application Site ◽

Concentration Profiles ◽

Spray Application ◽

Post Dose ◽

Drug Concentrations ◽

Spray Formulation

AbstractHigh ivermectin (IVM) concentrations suppress in vitro SARS-CoV-2 replication. Nasal IVM spray (N-IVM-spray) administration may contribute to attaining high drug concentrations in nasopharyngeal (NP) tissue, a primary site of virus entrance/replication. The safety and pharmacokinetic performance of a new N-IVM spray formulation in a piglet model were assessed. Crossbred piglets (10–12 kg) were treated with either one or two (12 h apart) doses of N-IVM-spray (2 mg, 1 puff/nostril) or orally (0.2 mg/kg). The overall safety of N-IVM-spray was assessed (clinical, haematological, serum biochemical determinations), and histopathology evaluation of the application site tissues performed. The IVM concentration profiles measured in plasma and respiratory tract tissues (nasopharynx and lungs) after the nasal spray treatment (one and two applications) were compared with those achieved after the oral administration. Animals tolerated well the novel N–IVM-spray formulation. No local/systemic adverse events were observed. After nasal administration, the highest IVM concentrations were measured in NP and lung tissues. Significant increases in IVM concentration profiles in both NP-tissue and lungs were observed after the 2-dose nasal administrations. The nasal/oral IVM concentration ratios in NP and lung tissues (at 6 h post-dose) markedely increased by repeating the spray application. The fast attainment of high and persistent IVM concentrations in NP tissue is the main advantage of the nasal over the oral route. These original results are encouraging to support the undertaking of further clinical trials to evaluate the safety/efficacy of the nasal IVM spray application in the treatment and/or prevention of COVID-19.

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Safety and Pharmacokinetic Assessments of a Novel Ivermectin Nasal Spray Formulation in a Pig Model

Journal of Pharmaceutical Sciences ◽

10.1016/j.xphs.2021.01.017 ◽

2021 ◽

Author(s):

Jorge Errecalde ◽

Adrian Lifschitz ◽

Graciela Vecchioli ◽

Laura Ceballos ◽

Francisco Errecalde ◽

...

Keyword(s):

Nasal Spray ◽

Pig Model ◽

Spray Formulation

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Structural analysis of COVID-19 spike protein in recognizing the ACE2 receptor of different mammalian species and its susceptibility to viral infection

3 Biotech ◽

10.1007/s13205-020-02599-2 ◽

2021 ◽

Vol 11 (2) ◽

Author(s):

Tirthankar Koley ◽

Shivani Madaan ◽

Sanghati Roy Chowdhury ◽

Manoj Kumar ◽

Punit Kaur ◽

...

Keyword(s):

Structural Analysis ◽

Viral Infection ◽

Mammalian Species ◽

Spike Protein

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Convergent Antibody Responses to SARS-CoV-2 Infection in Convalescent Individuals

10.1101/2020.05.13.092619 ◽

2020 ◽

Cited By ~ 43

Author(s):

Davide F. Robbiani ◽

Christian Gaebler ◽

Frauke Muecksch ◽

Julio C. C. Lorenzi ◽

Zijun Wang ◽

...

Keyword(s):

Virus Entry ◽

Protein S ◽

Memory B Cells ◽

Antibody Responses ◽

Spike Protein ◽

Human Antibody ◽

Receptor Binding Domain ◽

Single Digit ◽

Specific Antibodies ◽

Specific Memory

AbstractDuring the COVID-19 pandemic, SARS-CoV-2 infected millions of people and claimed hundreds of thousands of lives. Virus entry into cells depends on the receptor binding domain (RBD) of the SARS-CoV-2 spike protein (S). Although there is no vaccine, it is likely that antibodies will be essential for protection. However, little is known about the human antibody response to SARS-CoV-21–5. Here we report on 149 COVID-19 convalescent individuals. Plasmas collected an average of 39 days after the onset of symptoms had variable half-maximal neutralizing titers ranging from undetectable in 33% to below 1:1000 in 79%, while only 1% showed titers >1:5000. Antibody cloning revealed expanded clones of RBD-specific memory B cells expressing closely related antibodies in different individuals. Despite low plasma titers, antibodies to three distinct epitopes on RBD neutralized at half-maximal inhibitory concentrations (IC50s) as low as single digit ng/mL. Thus, most convalescent plasmas obtained from individuals who recover from COVID-19 do not contain high levels of neutralizing activity. Nevertheless, rare but recurring RBD-specific antibodies with potent antiviral activity were found in all individuals tested, suggesting that a vaccine designed to elicit such antibodies could be broadly effective.

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Studies in humanized mice and convalescent humans yield a SARS-CoV-2 antibody cocktail

Science ◽

10.1126/science.abd0827 ◽

2020 ◽

Vol 369 (6506) ◽

pp. 1010-1014 ◽

Cited By ~ 115

Author(s):

Johanna Hansen ◽

Alina Baum ◽

Kristen E. Pascal ◽

Vincenzo Russo ◽

Stephanie Giordano ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Selective Pressure ◽

Three Dimensional ◽

Spike Protein ◽

Humanized Mice ◽

Dimensional Structure ◽

Antibody Treatment ◽

Virus Escape ◽

Escape Mutants ◽

Antibody Cocktail

Neutralizing antibodies have become an important tool in treating infectious diseases. Recently, two separate approaches yielded successful antibody treatments for Ebola—one from genetically humanized mice and the other from a human survivor. Here, we describe parallel efforts using both humanized mice and convalescent patients to generate antibodies against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein, which yielded a large collection of fully human antibodies that were characterized for binding, neutralization, and three-dimensional structure. On the basis of these criteria, we selected pairs of highly potent individual antibodies that simultaneously bind the receptor binding domain of the spike protein, thereby providing ideal partners for a therapeutic antibody cocktail that aims to decrease the potential for virus escape mutants that might arise in response to selective pressure from a single-antibody treatment.

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Nasal Administration and Plasma Pharmacokinetics of Parathyroid Hormone Peptide PTH 1-34 for the Treatment of Osteoporosis

Pharmaceutics ◽

10.3390/pharmaceutics11060265 ◽

2019 ◽

Vol 11 (6) ◽

pp. 265 ◽

Cited By ~ 2

Author(s):

Richard G. Pearson ◽

Tahir Masud ◽

Elaine Blackshaw ◽

Andrew Naylor ◽

Michael Hinchcliffe ◽

...

Keyword(s):

Nasal Spray ◽

Subcutaneous Injection ◽

Relative Bioavailability ◽

Nasal Delivery ◽

Absolute Bioavailability ◽

Preclinical Model ◽

Permeation Enhancer ◽

Treatment Of Osteoporosis ◽

Plasma Pharmacokinetics ◽

Spray Formulation

Nasal delivery of large peptides such as parathyroid 1-34 (PTH 1-34) can benefit from a permeation enhancer to promote absorption across the nasal mucosa into the bloodstream. Previously, we have published an encouraging bioavailability (78%), relative to subcutaneous injection in a small animal preclinical model, for a liquid nasal spray formulation containing the permeation enhancer polyethylene glycol (15)-hydroxystearate (Solutol® HS15). We report here the plasma pharmacokinetics of PTH 1-34 in healthy human volunteers receiving the liquid nasal spray formulation containing Solutol® HS15. For comparison, data for a commercially manufactured teriparatide formulation delivered via subcutaneous injection pen are also presented. Tc-99m-DTPA gamma scintigraphy monitored the deposition of the nasal spray in the nasal cavity and clearance via the inferior meatus and nasopharynx. The 50% clearance time was 17.8 min (minimum 10.9, maximum 74.3 min). For PTH 1-34, mean plasma Cmax of 5 pg/mL and 253 pg/mL were obtained for the nasal spray and subcutaneous injection respectively; relative bioavailability of the nasal spray was ≤1%. Subsequently, we investigated the pharmacokinetics of the liquid nasal spray formulation as well as a dry powder nasal formulation also containing Solutol® HS15 in a crossover study in an established ovine model. In this preclinical model, the relative bioavailability of liquid and powder nasal formulations was 1.4% and 1.0% respectively. The absolute bioavailability of subcutaneously administered PTH 1-34 (mean 77%, range 55–108%) in sheep was in agreement with published human data for teriparatide (up to 95%). These findings have important implications in the search for alternative routes of administration of peptides for the treatment of osteoporosis, and in terms of improving translation from animal models to humans.

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Pharmacokinetic and Pharmacodynamic Properties of a Micro-Dose Nasal Spray Formulation of Desmopressin (AV002) in Healthy Water-Loaded Subjects

Pharmaceutical Research ◽

10.1007/s11095-019-2628-1 ◽

2019 ◽

Vol 36 (6) ◽

Author(s):

Karl-Erik Andersson ◽

James Longstreth ◽

Benjamin M. Brucker ◽

Lysanne Campeau ◽

Linda Cheng ◽

...

Keyword(s):

Nasal Spray ◽

Spray Formulation

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Thallium-201 Imaging in Intact Olfactory Sensory Neurons with Reduced Pre-Synaptic Inhibition In Vivo

Molecular Neurobiology ◽

10.1007/s12035-020-02078-y ◽

2020 ◽

Vol 57 (12) ◽

pp. 4989-4999

Author(s):

Hideaki Shiga ◽

Hiroshi Wakabayashi ◽

Kohshin Washiyama ◽

Tomohiro Noguchi ◽

Tomo Hiromasa ◽

...

Keyword(s):

Olfactory Bulb ◽

Sensory Neurons ◽

Action Potentials ◽

Migration Rate ◽

Intranasal Administration ◽

Thallium 201 ◽

Nasal Administration ◽

Olfactory Sensory Neurons ◽

Synaptic Inhibition

Abstract In this study, we determined whether the 201Tl (thallium-201)-based olfactory imaging is affected if olfactory sensory neurons received reduced pre-synaptic inhibition signals from dopaminergic interneurons in the olfactory bulb in vivo. The thallium-201 migration rate to the olfactory bulb and the number of action potentials of olfactory sensory neurons were assessed 3 h following left side nasal administration of rotenone, a mitochondrial respiratory chain complex I inhibitor that decreases the number of dopaminergic interneurons without damaging the olfactory sensory neurons in the olfactory bulb, in mice (6–7 animals per group). The migration rate of thallium-201 to the olfactory bulb was significantly increased following intranasal administration of thallium-201 and rotenone (10 μg rotenone, p = 0.0012; 20 μg rotenone, p = 0.0012), compared with that in control mice. The number of action potentials was significantly reduced in the olfactory sensory neurons in the rotenone treated side of 20 μg rotenone-treated mice, compared with that in control mice (p = 0.0029). The migration rate of thallium-201 to the olfactory bulb assessed with SPECT-CT was significantly increased in rats 24 h after the left intranasal administration of thallium-201 and 100 μg rotenone, compared with that in control rats (p = 0.008, 5 rats per group). Our results suggest that thallium-201 migration to the olfactory bulb is increased in intact olfactory sensory neurons with reduced pre-synaptic inhibition from dopaminergic interneurons in olfactory bulb glomeruli.

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