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 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.

The Syk inhibitor fostamatinib disodium (R788) inhibits tumor growth in the Eμ- TCL1 transgenic mouse model of CLL by blocking antigen-dependent B-cell receptor signaling

Blood ◽  
2010 ◽  
Vol 116 (23) ◽  
pp. 4894-4905 ◽  
Author(s):  
Mirza Suljagic ◽  
Pablo G. Longo ◽  
Sara Bennardo ◽  
Emerald Perlas ◽  
Giuseppe Leone ◽  
...  
Keyword(s):  
Mouse Model ◽  
B Cell ◽  
Transgenic Mouse ◽  
Cell Receptor ◽  
Transgenic Mouse Model ◽  
B Cell Receptor ◽  
Promising Therapeutic Approach ◽  
Bcr Signaling ◽  
Syk Inhibitor

Abstract Inhibition of antigen-dependent B-cell receptor (BCR) signaling is considered a promising therapeutic approach in chronic lymphocytic leukemia (CLL), but experimental in vivo evidence to support this view is still lacking. We have now investigated whether inhibition of BCR signaling with the selective Syk inhibitor fostamatinib disodium (R788) will affect the growth of the leukemias that develop in the Eμ-TCL1 transgenic mouse model of CLL. Similarly to human CLL, these leukemias express stereotyped BCRs that react with autoantigens exposed on the surface of senescent or apoptotic cells, suggesting that they are antigen driven. We show that R788 effectively inhibits BCR signaling in vivo, resulting in reduced proliferation and survival of the malignant B cells and significantly prolonged survival of the treated animals. The growth-inhibitory effect of R788 occurs despite the relatively modest cytotoxic effect in vitro and is independent of basal Syk activity, suggesting that R788 functions primarily by inhibiting antigen-dependent BCR signals. Importantly, the effect of R788 was found to be selective for the malignant clones, as no disturbance in the production of normal B lymphocytes was observed. Collectively, these data provide further rationale for clinical trials with R788 in CLL and establish the BCR-signaling pathway as an important therapeutic target in this disease.

scholarly journals Assessing the therapeutic potential of APPs⍺ in a tau transgenic mouse model of Alzheimers disease

2020 ◽  
Author(s):  
Charlotte Bold ◽  
Danny Baltissen ◽  
Susann Ludewig ◽  
Roman Spilger ◽  
Karl Rohr ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Mouse Model ◽  
Therapeutic Potential ◽  
Large Body ◽  
Transgenic Mouse Model ◽  
Spine Density ◽  
General Applicability ◽  
Plaque Deposition

A large body of evidence indicates a neuroprotective and neurotrophic function for APPs⍺ not only in vitro, but also when expressed by AAV vectors in vivo such as in APP/PS1 transgenic AD model mice with Aβ-induced pathology. Previously, we could show that APPs⍺ rescued deficits of APP/PS1 in synaptic plasticity and spine density and also reduced plaque deposition. Thus, it is crucial to test a more general applicability of APPs⍺ as a treatment for AD and to assess whether APPs⍺ is also beneficial in mice with tau-induced pathology.

scholarly journals Distinct uptake, amplification, and release of SARS-CoV-2 by M1 and M2 alveolar macrophages

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Jiadi Lv ◽  
Zhenfeng Wang ◽  
Yajin Qu ◽  
Hua Zhu ◽  
Qiangqiang Zhu ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Mouse Model ◽  
Alveolar Macrophages ◽  
Transgenic Mouse Model ◽  
Lysosomal Ph ◽  
Viral Spread ◽  
Lysosomal System ◽  
Endosomal Ph ◽  
Alternatively Activated ◽  
Classically Activated

AbstractSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) invades the alveoli, where abundant alveolar macrophages (AMs) reside. How AMs respond to SARS-CoV-2 invasion remains elusive. Here, we show that classically activated M1 AMs facilitate viral spread; however, alternatively activated M2 AMs limit the spread. M1 AMs utilize cellular softness to efficiently take up SARS-CoV-2. Subsequently, the invaded viruses take over the endo-lysosomal system to escape. M1 AMs have a lower endosomal pH, favoring membrane fusion and allowing the entry of viral RNA from the endosomes into the cytoplasm, where the virus achieves replication and is packaged to be released. In contrast, M2 AMs have a higher endosomal pH but a lower lysosomal pH, thus delivering the virus to lysosomes for degradation. In hACE2 transgenic mouse model, M1 AMs are found to facilitate SARS-CoV-2 infection of the lungs. These findings provide insights into the complex roles of AMs during SARS-CoV-2 infection, along with potential therapeutic targets.

scholarly journals Murine monoclonal antibodies against RBD of SARS-CoV-2 neutralize authentic wild type SARS-CoV-2 as well as B.1.1.7 and B.1.351 viruses and protect in vivo in a mouse model in a neutralization dependent manner

2021 ◽  
Author(s):  
Fatima Amanat ◽  
Shirin Strohmeier ◽  
Wen-Hsin Lee ◽  
Sandhya Bangaru ◽  
Andrew B Ward ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Severe Acute Respiratory Syndrome ◽  
Mouse Model ◽  
Neutralizing Antibodies ◽  
Dependent Manner ◽  
Receptor Binding Domain ◽  
Wild Type ◽  
Murine Monoclonal Antibodies

After first emerging in December 2019 in China, severe acute respiratory syndrome 2 (SARS-CoV-2) has since caused a pandemic leading to millions of infections and deaths worldwide. Vaccines have been developed and authorized but supply of these vaccines is currently limited. With new variants of the virus now emerging and spreading globally, it is essential to develop therapeutics that are broadly protective and bind conserved epitopes in the receptor binding domain (RBD) or the whole spike of SARS-CoV-2. In this study, we have generated mouse monoclonal antibodies (mAbs) against different epitopes on the RBD and assessed binding and neutralization against authentic SARS-CoV-2. We have demonstrated that antibodies with neutralizing activity, but not non-neutralizing antibodies, lower viral titers in the lungs when administered in a prophylactic setting in vivo in a mouse challenge model. In addition, most of the mAbs cross-neutralize the B.1.351 as well as the B.1.1.7 variants in vitro.

Sign in / Sign up

Export Citation Format

Share Document