scholarly journals SARS-CoV-2 spike therapeutic antibodies in the age of variants

2021 ◽  
Vol 218 (5) ◽  
Author(s):  
Alina Baum ◽  
Christos A. Kyratsous
Keyword(s):  
Infectious Diseases ◽  
Viral Vector ◽  
Vice President ◽  
Spike Protein ◽  
Therapeutic Antibodies ◽  
Antibody Therapeutics ◽  
Associate Director

Christos Kyratsous, Vice President of Research, Infectious Diseases, and Viral Vector Technologies at Regeneron Pharmaceuticals, and Alina Baum, Associate Director, Infectious Diseases Associate at Regeneron Pharmaceuticals, discuss the development of antibody therapeutics targeting the spike protein of SARS-CoV-2.

scholarly journals Engineering therapeutic antibodies to combat infectious diseases

2018 ◽  
Vol 19 ◽  
pp. 131-141 ◽  
Author(s):  
Ellen K Wagner ◽  
Jennifer A Maynard
Keyword(s):  
Infectious Diseases ◽  
Therapeutic Antibodies

scholarly journals Development of humanized tri-specific nanobodies with potent neutralization for SARS-CoV-2

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Jianbo Dong ◽  
Betty Huang ◽  
Bo Wang ◽  
Allison Titong ◽  
Sachith Gallolu Kankanamalage ◽  
...  
Keyword(s):  
Computer Aided Design ◽  
Treatment Options ◽  
Unmet Need ◽  
Spike Protein ◽  
Therapeutic Antibodies ◽  
Human Igg1 ◽  
Vhh Antibodies ◽  
Phage Libraries ◽  
Aided Design ◽  
Potent Neutralization

Abstract SARS-CoV-2 is a newly emergent coronavirus, which has adversely impacted human health and has led to the COVID-19 pandemic. There is an unmet need to develop therapies against SARS-CoV-2 due to its severity and lack of treatment options. A promising approach to combat COVID-19 is through the neutralization of SARS-CoV-2 by therapeutic antibodies. Previously, we described a strategy to rapidly identify and generate llama nanobodies (VHH) from naïve and synthetic humanized VHH phage libraries that specifically bind the S1 SARS-CoV-2 spike protein, and block the interaction with the human ACE2 receptor. In this study we used computer-aided design to construct multi-specific VHH antibodies fused to human IgG1 Fc domains based on the epitope predictions for leading VHHs. The resulting tri-specific VHH-Fc antibodies show more potent S1 binding, S1/ACE2 blocking, and SARS-CoV-2 pseudovirus neutralization than the bi-specific VHH-Fcs or combination of individual monoclonal VHH-Fcs. Furthermore, protein stability analysis of the VHH-Fcs shows favorable developability features, which enable them to be quickly and successfully developed into therapeutics against COVID-19.

Problems Associated with the Production and Use of Wrought Aluminium Alloys

1956 ◽  
Vol 60 (550) ◽  
pp. 635-658 ◽  
Author(s):  
G. Forrest ◽  
K. Gunn
Keyword(s):  
Aluminium Alloys ◽  
Vice President ◽  
National Physical Laboratory ◽  
Great Pleasure ◽  
Physical Laboratory ◽  
Technical Department ◽  
Structural Engineer ◽  
President Elect ◽  
Wilbur Wright ◽  
Associate Director

The 988th Lecture to be given before the Society and the 25th Main Lecture to be held at a Branch of the Society, “ Problems Associated with the Production and Use of Wrought Aluminium Alloys,” by G. Forrest, B.SC, A.M.I.Mech.E., A.F.R.Ae.S., and K. Gunn, B.Sc, A.R.S.M., was held under the auspices of the Belfast Branch on 5th April 1956. Mr. D. Keith-Lucas, F.R.Ae.S., Chairman of the Belfast Branch, opened the proceedings, and Mr. E. T. Jones, C.B., O.B.E, M.Eng., F.R.Ae.S., presided for the rest of the meeting.Mr. Keith-Lucas (Branch Chairman): This was a great occasion for the Belfast Branch because for the third time they were honoured to be the hosts of the parent Society, the Royal Aeronautical Society. It was with great pleasure that he welcomed their guests. First of all, Mr. E. T. Jones, the President-elect of the Royal Aeronautical Society, Dr. Ballantyne, the Secretary, and Mr. Dunsby and Mr. Simmons, both of the Technical Department, of the Society. The President, Mr. N. E. Rowe, and the Chairman of the Branches Committee, Mr. Handel Davies, had both sent their sincere apologies that they were unable to be present.He would also like to extend a special welcome to three members of the Preston Branch, Mr. Turner, Mr. Swales and Mr. Dyson. They were rather “ out on a limb” in Belfast, rather far from other Branches and they did appreciate this neighbourly gesture from the Preston Branch. He would also like to welcome their own President of the Belfast Branch, Sir Matthew Slattery, and their Vice-President, Mr. C. P. T. Lipscomb.But this was essentially a Royal Aeronautical Society function and not a Belfast Branch function. Therefore he would invite Mr. E. T. Jones, the President-elect of the Royal Aeronautical Society, to take the Chair and to conduct the meeting.Mr. E. T. Jones: It was a great pleasure and honour to be in Belfast that evening deputising for Mr. Rowe. They had already heard from Mr. Keith-Lucas that Mr. Rowe was unable to be present and he had asked him also to express his regrets.People working in aeronautics were sometimes liable to overlook the fact that materials had played a tremendous part in the advancement that they had achieved. They knew that the aerodynamicist, the structural engineer, the propulsion engineer, had all made their mark on the progress of aviation but they must not forget that materials had forged a very great key towards the progress which had been made. Indeed he recollected that Sir Harry Garner, in his Wilbur Wright Lecture in 1952, made the statement that he doubted whether the Aircraft Industry today could make a much more forward aeroplane than the Wright Brothers did in 1903 if they were confined to the use of the same materials and to the same stalling speed. He thought that statement would have been a very profound one even if stalling speed had been left out. If one considered the materials that people in those days had to work on it was wonderful that they flew at all. Thus he thought it was fitting that they should have a lecture of the kind Mr. Forrest and Mr. Gunn were to give.He had a pleasant duty to introduce the lecturers. Mr. Forrest was educated at London University and joined the National Physical Laboratory in 1925, or thereabouts, in the Engineering Division. In 1936 he joined the Northern Aluminium Company and he later transferred to the Aluminium Laboratories Ltd. He was now an Associate Director of Research in the Aluminium Laboratories Ltd. at Banbury. Mr. Forrest had impressed upon him that he should make a point of saying Banbury because there were three Laboratories of the firm. Mr. Gunn was educated at the Royal School of Mines. He joined the Northern Aluminium Company in 1944 and he too transferred to the Aluminium Laboratories in 1946. He did not know quite how they proposed to deal with the Lecture, but he thought that Mr. Forrest would read it and both would be available to reply to the questions.

scholarly journals RAPPID: a platform of ratiometric bioluminescent sensors for homogeneous immunoassays

2020 ◽  
Author(s):  
Yan Ni ◽  
Bas J.H.M. Rosier ◽  
Eva A. van Aalen ◽  
Eva T.L. Hanckmann ◽  
Lieuwe Biewenga ◽  
...  
Keyword(s):  
Target Recognition ◽  
Point Of Care ◽  
Low Cost ◽  
Digital Camera ◽  
Spike Protein ◽  
Therapeutic Antibodies ◽  
Protein Biomarkers ◽  
External Calibration ◽  
Quantitative Measurements ◽  
Clinical Laboratories

AbstractHeterogeneous immunoassays such as ELISA have become indispensable in modern bioanalysis, yet translation into easy-to-use point-of-care assays is hindered by their dependence on external calibration and multiple washing and incubation steps. Here, we introduce RAPPID (Ratiometric Plug-and-Play Immunodiagnostics), a “mix-and-measure” homogeneous immunoassay platform that combines highly specific antibody-based detection with a ratiometric bioluminescent readout that can be detected using a basic digital camera. The concept entails analyte-induced complementation of split NanoLuc luciferase fragments, photoconjugated to an antibody sandwich pair via protein G adapters. We also introduce the use of a calibrator luciferase that provides a robust ratiometric signal, allowing direct in-sample calibration and quantitative measurements in complex media such as blood plasma. We developed RAPPID sensors that allow low-picomolar detection of several protein biomarkers, anti-drug antibodies, therapeutic antibodies, and both SARS-CoV-2 spike protein and anti-SARS-CoV-2 antibodies. RAPPID combines ratiometric bioluminescent detection with antibody-based target recognition into an easy-to-implement standardized workflow, and therefore represents an attractive, fast, and low-cost alternative to traditional immunoassays, both in an academic setting and in clinical laboratories for point-of-care applications.

scholarly journals Key substitutions in the spike protein of SARS-CoV-2 variants can predict resistance to monoclonal antibodies, but other substitutions can modify the effects

2021 ◽  
Author(s):  
Sabrina Lusvarghi ◽  
Wei Wang ◽  
Rachel Herrup ◽  
Sabari Nath Neerukonda ◽  
Russell Vassell ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Receptor Binding ◽  
Clinical Stage ◽  
Binding Domain ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
Therapeutic Antibodies ◽  
Epistatic Interactions ◽  
Neutralization Activity ◽  
Virus Susceptibility

Mutations in the spike protein of SARS-CoV-2 variants can compromise the effectiveness of therapeutic antibodies. Most clinical-stage therapeutic antibodies target the spike receptor binding domain (RBD), but variants often have multiple mutations in several spike regions. To help predict antibody potency against emerging variants, we evaluated 25 clinical-stage therapeutic antibodies for neutralization activity against 60 pseudoviruses bearing spikes with single or multiple substitutions in several spike domains, including the full set of substitutions in B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma), B.1.429 (Epsilon), B.1.526 (Iota), A.23.1 and R.1 variants. We found that 14 of 15 single antibodies were vulnerable to at least one RBD substitution, but most combination and polyclonal therapeutic antibodies remained potent. Key substitutions in variants with multiple spike substitutions predicted resistance, but the degree of resistance could be modified in unpredictable ways by other spike substitutions that may reside outside of the RBD. These findings highlight the importance of assessing antibody potency in the context of all substitutions in a variant and show that epistatic interactions in spike can modify virus susceptibility to therapeutic antibodies.

scholarly journals Vaccines against SARS CoV 2 and the vaccination campaign in Italy

2021 ◽  
Vol 24 (2) ◽  
pp. 137
Author(s):  
Ponziani, M.C.
Keyword(s):  
Viral Genome ◽  
Viral Vector ◽  
Vaccination Campaign ◽  
Spike Protein ◽  
Effective Vaccine ◽  
Efficacy And Safety ◽  
Thrombotic Risk ◽  
Safety Studies ◽  
Key Words Vaccination ◽  
Number Of Individuals

The SARS COV 2 pandemic has created an unprecedented need to manufacture and distribute a safe and effective vaccine to immunize an exceptionally large number of individuals planning diversified vaccination approaches quickly. A few weeks have passed since the sequencing of the viral genome for the design of the first vaccines and a few months for the implementation of the efficacy and safety studies. The article analyzes the types of vaccines available by examining their characteristics, efficacy and safety, also examining some debated issues such as the thrombotic risk of viral vector vaccines. The second part deals with the issue of the vaccination campaign in our country. KEY WORDS vaccination; COVID-19; spike protein; efficacy; safety.

scholarly journals Multi-specific DARPin® therapeutics demonstrate very high potency against mutated SARS-CoV-2 variants in vitro

2021 ◽  
Author(s):  
Sylvia Rothenberger ◽  
Marcel Walser ◽  
Francesca Malvezzi ◽  
Jennifer Mayor ◽  
Sarah Ryter ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
South African ◽  
Spike Protein ◽  
Antibody Therapeutics ◽  
Virus Inhibition ◽  
High Production ◽  
The Individual ◽  
Very High ◽  
Potent Protection

AbstractThe SARS-CoV-2 virus responsible for the COVID-19 pandemic has so far infected more than 100 million people globally, and continues to undergo genomic evolution. Emerging SARS-CoV-2 variants show increased infectivity and may lead to resistance against immune responses of previously immunized individuals or existing therapeutics, especially antibody-based therapies.Several monoclonal antibody therapeutics authorized for emergency use or in development start to lose potency against various SARS-CoV-2 variants. Cocktails of two different monoclonal antibodies constitute a promising approach to protect against such variants as long as both antibodies are potent, but come with increased development complexity and therefore cost. As an alternative, we developed two multi-specific DARPin® therapeutics, each combining three independent DARPin® domains binding the SARS-CoV-2 spike protein in one molecule, to potently neutralize the virus and overcome virus escape.Here, we show in a panel of in vitro studies that both multi-specific DARPin® therapeutics, ensovibep (MP0420) and MP0423, are highly potent against the new circulating SARS-CoV-2 variants B.1.1.7 (UK variant) and B.1.351 (South African variant) and the most frequent emerging mutations in the spike protein. Additionally, viral passaging experiments show potent protection by ensovibep and MP0423 against development of escape mutations. Furthermore, we demonstrate that the cooperative binding of the individual modules in a multi-specific DARPin® antiviral is key for potent virus inhibition and protection from escape variants. These results, combined with the relatively small size and high production yields of DARPin® molecules, suggests ensovibep and MP0423 as superior alternatives to monoclonal antibody cocktails for global supply and demonstrate the strength of the DARPin® platform for achieving potent and lasting virus inhibition for SARS-CoV-2 and possibly other viruses.

scholarly journals Can ChAdOx1, a replication-deficient adenoviral (Ad) vector used to deliver SARS-Cov2 spike protein as a vaccine, recombine with the homologous human Ad to generate a novel Ad+Spike virus?

2020 ◽  
Author(s):  
Sandeep Chakraborty
Keyword(s):  
Viral Vector ◽  
Rna Virus ◽  
Human Adenovirus ◽  
Cell Receptor ◽  
Spike Protein ◽  
Transcriptional Unit ◽  
Human Virus ◽  
Dna And Rna ◽  
Host Cell Receptor ◽  
Weakened Version

The development of a vaccine for Covid19 is being expedited [1]. The underlying technology for the vaccines are varied: ‘nucleic acid (DNA and RNA), virus-like particle, peptide, viral vector (replicating and non- replicating), recombinant protein, live attenuated virus and inactivated virus’ [2]. Among these, ChAdOx1, a genetically modified, weakened version of a common cold virus (adenovirus) is now in human clinical trials [3]. The ChAd vector (Chimpanzee adenovirus) was introduced in 2012 Chimpanzee adenovirus Y25 [4]. A large proportion of human adults possess significant titres of neutralising antibodies to human Adv, hence the requirement for a different adenovirus. The deletion of a single transcriptional unit, E1, ensures these viruses cant replicate. Other genes like the E3 region may also be deleted. Now, in the Covid19 vaccine ChAdOx1, the spike protein gene from MERS-CoV strain Camel/Qatar/2/2014 ‘was inserted into the E1 locus of a genomic clone of ChAdOx1 using site-specific recombination’ [5].One of the theories about the genesis of SARS-Cov2 is recombination with coronaviruses from pan- golins [6]. Whether or not it happened in SARS-Cov2, there is no denying that such recombinations do happen.How do we know that the spike protein wont be inserted into a human adenovirus using recombination?Human adenovirus shares 95% homology to ChAd. The spike protein may be inserted after the E1 protein in a viable human virus. What will happen after that to the virus is anyone’s guess. Note, that there is precedence for such recombinant adenoviruses - using ‘ping-pong” zoonosis and anthroponosis’, where the genome of a promiscuous pathogen is ‘embedded with evidence of unprecedented multiple, multidirectional, stable, and reciprocal cross-species infections of hosts from three species (human, chimpanzee, and bonobo)’ [7].Another critique - co-stimulation in host cellsA spike protein from SARS-Cov2, which is supposed to bind to ACE2 and CD147 [8], has been inserted in an adenovirus. The adenovirus has its own host-cell receptor preferences [9] - what will be the consequences of co-stimulation in those cells in which both these receptors are expressed?

scholarly journals SARS-CoV-2 Delta Variant Displays Moderate Resistance to Neutralizing Antibodies and Spike Protein Properties of Higher Soluble ACE2 Sensitivity, Enhanced Cleavage and Fusogenic Activity

Viruses ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2485
Author(s):  
Sabari Nath Neerukonda ◽  
Russell Vassell ◽  
Sabrina Lusvarghi ◽  
Richard Wang ◽  
Fernando Echegaray ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Neutralization Assay ◽  
Spike Protein ◽  
Therapeutic Antibodies ◽  
Partial Loss ◽  
Fusogenic Activity ◽  
Fold Reduction ◽  
Protein Properties ◽  
Moderate Resistance ◽  
Second Wave

The SARS-CoV-2 B.1.617 lineage variants, Kappa (B.1.617.1) and Delta (B.1.617.2, AY) emerged during the second wave of infections in India, but the Delta variants have become dominant worldwide and continue to evolve. Here, we compared B.1.617 variants for neutralization resistance by convalescent sera, mRNA vaccine-elicited sera, and therapeutic neutralizing antibodies using a pseudovirus neutralization assay. B.1.617.1, B.1.617.2, and AY.1 pseudoviruses showed a modest 1.5- to 4.4-fold reduction in neutralization by convalescent sera and vaccine-elicited sera. In comparison, similar modest reductions were also observed for C.37, P.1, R.1, and B.1.526 pseudoviruses, but 7- and 16-fold reductions for vaccine-elicited and convalescent sera, respectively, were seen for B.1.351 pseudoviruses. Among twenty-three therapeutic antibodies tested, four antibodies showed either complete or partial loss of neutralization against B.1.617.2 pseudoviruses and six antibodies showed either complete or partial loss of neutralization against B.1.617.1 and AY.1 pseudoviruses. Our results indicate that the current mRNA-based vaccines will likely remain effective in protecting against B.1.617 variants. Finally, the P681R substitution confers efficient cleavage of B.1.617 variants’ spike proteins and the spike of Delta variants exhibited greater sensitivity to soluble ACE2 neutralization, as well as fusogenic activity, which may contribute to enhanced spread of Delta variants.

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