scholarly journals A bispecific monomeric nanobody induces SARS-COV-2 spike trimer dimers

2021 ◽  
Author(s):  
Leo Hanke ◽  
Hrishikesh Das ◽  
Daniel Sheward ◽  
Laura Perez Vidakovics ◽  
Egon Urgard ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Mouse Model ◽  
Transgenic Mouse ◽  
Therapeutic Potential ◽  
Transgenic Mouse Model ◽  
Electron Cryomicroscopy ◽  
Viral Antigens ◽  
Virus Escape ◽  
Therapeutic Molecules ◽  
Novel Strategy

Antibodies binding to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike have therapeutic promise, but emerging variants show the potential for virus escape. Thus, there is a need for therapeutic molecules with distinct and novel neutralization mechanisms. Here we isolated a nanobody that potently neutralizes SARS-CoV-2, including the B.1.351 variant, and cross-neutralizes SARS-CoV. We demonstrate the therapeutic potential of the nanobody in a human ACE2 transgenic mouse model. Using biochemistry and electron cryomicroscopy we show that this nanobody simultaneously interacts with two RBDs from different spike trimers, rapidly inducing the formation of spike trimer-dimers. This naturally elicited bispecific monomeric nanobody establishes a novel strategy for potent immobilization of viral antigens.

scholarly journals A bispecific monomeric nanobody induces spike trimer dimers and neutralizes SARS-CoV-2 in vivo

2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Leo Hanke ◽  
Hrishikesh Das ◽  
Daniel J. Sheward ◽  
Laura Perez Vidakovics ◽  
Egon Urgard ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Mouse Model ◽  
Therapeutic Potential ◽  
Cell Receptor ◽  
Transgenic Mouse Model ◽  
Viral Antigens ◽  
Host Cell Receptor ◽  
Virus Escape ◽  
Therapeutic Molecules

AbstractAntibodies binding to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike have therapeutic promise, but emerging variants show the potential for virus escape. This emphasizes the need for therapeutic molecules with distinct and novel neutralization mechanisms. Here we describe the isolation of a nanobody that interacts simultaneously with two RBDs from different spike trimers of SARS-CoV-2, rapidly inducing the formation of spike trimer–dimers leading to the loss of their ability to attach to the host cell receptor, ACE2. We show that this nanobody potently neutralizes SARS-CoV-2, including the beta and delta variants, and cross-neutralizes SARS-CoV. Furthermore, we demonstrate the therapeutic potential of the nanobody against SARS-CoV-2 and the beta variant in a human ACE2 transgenic mouse model. This naturally elicited bispecific monomeric nanobody establishes an uncommon strategy for potent inactivation of viral antigens and represents a promising antiviral against emerging SARS-CoV-2 variants.

scholarly journals A Novel Anti-inflammatory D-peptide Halts Disease Phenotype Progression in an ALS Mouse Model

2020 ◽  
Author(s):  
Julia Post ◽  
Vanessa Kogel ◽  
Anja Schaffrath ◽  
Philipp Lohmann ◽  
Nadim Joni Shah ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Mouse Model ◽  
Brain Stem ◽  
Transgenic Mouse ◽  
Cell Activation ◽  
Therapeutic Potential ◽  
Transgenic Mouse Model ◽  
Lumbar Spinal Cord ◽  
Disease Phenotype ◽  
Model Of Alzheimer’S Disease

Abstract Background: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterised by selective neuronal death in brain stem and spinal cord. The cause is unknown, but an increasing evidence has firmly certified that neuroinflammation plays a key role in ALS pathogenesis. Neuroinflammation is a pathological hallmark of several neurodegenerative disorders and has been implicated as driver of disease progression. Here, we describe two treatment studies demonstrating the therapeutic potential of a tandem version of the well-known all-d-peptide RD2 (RD2RD2) in a transgenic mouse model of Alzheimer’s disease (APP/PS1) and in a transgenic mouse model of ALS (SOD1*G93A).Methods:APP/PS1 and SOD1*G93A mice were treated intraperitoneally for four weeks mice with RD2RD2 vs placebo. APP/PS1 brain and plasma samples were histologically and biochemically analysed for inflammatory markers, gliosis and amyloid pathology. SOD1*G93A mice were tested longitudinally during treatment in various behavioural and motor coordination tests. Brain and spinal cord samples were investigated immunohistochemically for gliosis and neurodegeneration.Results: Treatment in APP/PS1 mice revealed significant reduction in glial cell activation in the brain and significantly lower levels of inflammatory cytokines in plasma. RD2RD2 treatment in SOD1*G93A mice resulted not only in a reduction of activated astrocytes and microglia in both brain stem and lumbar spinal cord but also in a rescue of neurons in the motor cortex. Moreover, behavioural tests revealed that the disease phenotype of SOD1*G93A mice is halted during treatment.Conclusion: Based on the presented results, we conclude that RD2RD2 is a potential therapeutic candidate against ALS.

scholarly journals A Novel Anti-inflammatory D-peptide Halts Disease Phenotype Progression in an Als Mouse Model

2020 ◽  
Author(s):  
Julia Post ◽  
Vanessa Kogel ◽  
Anja Schaffrath ◽  
Philipp Lohmann ◽  
Nadim Joni Shah ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Mouse Model ◽  
Brain Stem ◽  
Transgenic Mouse ◽  
Cell Activation ◽  
Therapeutic Potential ◽  
Transgenic Mouse Model ◽  
Lumbar Spinal Cord ◽  
Disease Phenotype ◽  
Model Of Alzheimer’S Disease

Abstract Background: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterised by selective neuronal death in brain stem and spinal cord. The cause is unknown, but an increasing evidence has firmly certified that neuroinflammation plays a key role in ALS pathogenesis. Neuroinflammation is a pathological hallmark of several neurodegenerative disorders and has been implicated as driver of disease progression. Here, we describe two treatment studies demonstrating the therapeutic potential of a tandem version of the well-known all-d-peptide RD2 (RD2RD2) in a transgenic mouse model of Alzheimer’s disease (APP/PS1) and in a transgenic mouse model of ALS (SOD1*G93A).Methods:APP/PS1 and SOD1*G93A mice were treated intraperitoneally for four weeks mice with RD2RD2 vs placebo. APP/PS1 brain and plasma samples were histologically and biochemically analysed for inflammatory markers, gliosis and amyloid pathology. SOD1*G93A mice were tested longitudinally during treatment in various behavioural and motor coordination tests. Brain and spinal cord samples were investigated immunohistochemically for gliosis and neurodegeneration.Results: Treatment in APP/PS1 mice revealed significant reduction in glial cell activation in the brain and significantly lower levels of inflammatory cytokines in plasma. RD2RD2 treatment in SOD1*G93A mice resulted not only in a reduction of activated astrocytes and microglia in both brain stem and lumbar spinal cord but also in a rescue of neurons in the motor cortex. Moreover, behavioural tests revealed that the disease phenotype of SOD1*G93A mice is halted during treatment.Conclusion: Based on the presented results, we conclude that RD2RD2 is a potential therapeutic candidate against ALS.

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