scholarly journals Implementing a method for engineering multivalency to substantially enhance binding of clinical trial anti-SARS-CoV-2 antibodies to wildtype spike and variants of concern proteins

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Adam Leach ◽  
Ami Miller ◽  
Emma Bentley ◽  
Giada Mattiuzzo ◽  
Jemima Thomas ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Severe Acute Respiratory Syndrome ◽  
Clinical Investigation ◽  
Spike Protein ◽  
Therapeutic Antibodies ◽  
Methodological Development ◽  
Virus Variant ◽  
Tetramerization Domain ◽  
Spike Proteins

AbstractInfection by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes COVID-19 disease. Therapeutic antibodies are being developed that interact with the viral spike proteins to limit viral infection of epithelium. We have applied a method to dramatically improve the performance of anti-SARS-CoV-2 antibodies by enhancing avidity through multimerization using simple engineering to yield tetrameric antibodies. We have re-engineered six anti-SARS-CoV-2 antibodies using the human p53 tetramerization domain, including three clinical trials antibodies casirivimab, imdevimab and etesevimab. The method yields tetrameric antibodies, termed quads, that retain efficient binding to the SARS-CoV-2 spike protein, show up to two orders of magnitude enhancement in neutralization of pseudovirus infection and retain potent interaction with virus variant of concern spike proteins. The tetramerization method is simple, general and its application is a powerful methodological development for SARS-CoV-2 antibodies that are currently in pre-clinical and clinical investigation.

scholarly journals Application of a Method for Engineering Multivalent Antibodies to Substantially Enhance Functional affinity of Clinical Trial Anti-SARS-CoV-2 Antibodies

2021 ◽  
Author(s):  
Adam Leach ◽  
Ami Miller ◽  
Emma Bentley ◽  
Giada Mattiuzzo ◽  
Jemima Thomas ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Severe Acute Respiratory Syndrome ◽  
Viral Infection ◽  
Clinical Investigation ◽  
Spike Protein ◽  
Therapeutic Antibodies ◽  
Methodological Development ◽  
Tetramerization Domain ◽  
Spike Proteins

Abstract Infection by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes COVID-19 disease. Therapeutic antibodies are being developed that interact with the viral spike proteins to limit viral infection of epithelium. We have applied a method to dramatically improve the performance of anti-SARS-CoV-2 antibodies by enhancing avidity through multimerization using simple engineering to yield tetrameric antibodies. We have re-engineered six anti-SARS-CoV-2 antibodies using the human p53 tetramerization domain, including three clinical trials antibodies casirivimab, imdevimab and etesevimab. The method yields tetrameric antibodies, termed Quads, that retain efficient binding to the SARS-CoV-2 spike protein and show up to two orders of magnitude enhancement in neutralization of pseudovirus infection. The tetramerization method is simple and general and its application is a powerful methodological development for SARS-CoV-2 antibodies that are currently in pre-clinical and clinical investigation.

scholarly journals Clinical trial endpoints for patients with gliomas

2017 ◽  
Vol 4 (4) ◽  
pp. 201-208 ◽  
Author(s):  
Jennie W Taylor ◽  
Annette M Molinaro ◽  
Nicholas Butowski ◽  
Michael Prados
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Trial Design ◽  
Clinical Investigation ◽  
Clinical Trial Design ◽  
Therapeutic Agents ◽  
Survival Outcomes ◽  
Clinical Trial Endpoints ◽  
Primary Glioma ◽  
Trial Endpoints

Abstract Malignant glioma represents a diverse set of molecularly heterogeneous diseases. Few therapeutic agents have been approved despite decades of clinical trials research and pre-clinical investigation. Attempts to refine neuroimaging criteria and recent discovery of the genomic profiles linking tumor subsets to survival outcomes have spurred discussion on a variety of new approaches in clinical trial design and relevant endpoints. Here we focus on those endpoints in clinical trial design for patients with primary glioma and related issues still to be resolved.

Remdesivir (GS-5734) in COVID-19 Therapy: The Fourth Chance

2020 ◽  
Vol 21 ◽  
Author(s):  
Dinesh Singh Moirangthem ◽  
Laishram Surbala
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Severe Acute Respiratory Syndrome ◽  
Mechanism Of Action ◽  
World Health ◽  
Viral Agent ◽  
Compassionate Use ◽  
Rna Dependent Rna Polymerase ◽  
Nucleotide Analog ◽  
Health Organization

Background: Since its initial start on December 2019 at Wuhan, China, the coronavirus disease 2019 (COVID19) has been rapidly spreading and labelled as pandemic by World Health Organization. The rate of human to human transmission of COVID-19 is far higher than severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome coronavirus (MERS). With no drugs or vaccines approved for the treatment of the disease, physicians have been using the pre-existing drugs to curb the disease. One potential anti-viral agent currently undergoing numerous clinical trial is remdesivir, a nucleotide analog that inhibits RNA-dependent RNA polymerase of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Objective: In this mini-review, we provide an overview of remdesivir’s journey, mechanism of action, pharmacokinetics, used in patients with COVID-19 under compassionate use principle and clinical trials to understand the effect of remdesivir in the treatment of patients with COVID-19. Conclusion: In this mini-review, we provide an overview of remdesivir’s journey, mechanism of action, pharmacokinetics, used in patients with COVID-19 under compassionate use principle and clinical trials to understand the effect of remdesivir in the treatment of patients with COVID-19.

scholarly journals Emerging SARS-CoV-2 variants of concern and potential intervention approaches

Critical Care ◽  
2021 ◽  
Vol 25 (1) ◽  
Author(s):  
Jasmin Khateeb ◽  
Yuchong Li ◽  
Haibo Zhang
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Clinical Outcome ◽  
Therapeutic Strategies ◽  
Spike Protein ◽  
Host Responses ◽  
Structural Protein ◽  
Potential Intervention ◽  
Viral Virulence ◽  
Protein Mutations ◽  
Spike Proteins

AbstractThe major variant of concerns (VOCs) have shared mutations in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike proteins, mostly on the S1 unit and resulted in higher transmissibility rate and affect viral virulence and clinical outcome. The spike protein mutations and other non-structural protein mutations in the VOCs may lead to escape approved vaccinations in certain extend. We will discuss these VOC mutations and discuss the need for combination therapeutic strategies targeting viral cycle and immune host responses.

scholarly journals Unapproved clinical trials in Russia: exception or norm?

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Petr Talantov ◽  
Ravil Niyazov ◽  
Galina Viryasova ◽  
Margarita Dranitsyna ◽  
Ilya Yasny
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Medicinal Product ◽  
Clinical Investigation ◽  
Randomised Trial ◽  
Well Being ◽  
Russian Language ◽  
Full Description ◽  
Medical Journals ◽  
Administration Method

Abstract Background In modern Russia, any clinical investigation of a pharmaceutical for use in humans is subject to prior evaluation and approval by the Ministry of Health and its Central Ethics Committee. Despite this, some researchers and trial sponsors fail to comply, this is particularly true in case of the studies initiated by domestic sponsors or sponsor-investigators and published in Russian language medical journals. This exploratory research aims to discover whether it is a sporadic non-compliance with regulations or a common practice. Methods We searched the Russian language database eLIBRARY for the phrase ‘results of a randomised trial’. We selected publications reporting clinical trials and conducted in Russia. For each of the selected studies, we searched the state register of the approved clinical trials. We assessed whether (1) the investigational medicinal product was approved for marketing in Russia; (2) the therapeutic indications, posology, and administration method in the clinical trial were consistent with the approved labelling; (3) the issue of the journal included an advertisement of the medicinal product in question; and (4) the full description of the methodology corroborated that the clinical trial was randomised, as was stated in the title or abstract. Results Of the 26 selected articles, 22 reported the results of unauthorised clinical trials. Three of those trials were conducted in children. Twenty-one studies reported on data from unauthorised trials for investigational products approved for marketing in Russia. However, in nine cases, the therapeutic indications, posology, or administration method did not match the conditions indicated in the labelling. Moreover, in one case, the unauthorised trial included a drug therapy intervention where the active substance was not approved for use in any medicinal product marketed in Russia. In 14 of the 26 articles, the issue of the journal or the article itself contained an advertisement for the same medicinal product or, in one case, its manufacturer. All publications accompanied by advertisements claimed that the medicinal product in question was efficacious. Conclusions A substantial fraction of the clinical trials initiated by domestic sponsors and reported in Russian medical journals failed to obtain the mandatory prior evaluation and approval from the regulator. This can affect the rights and well-being of the study participants and the scientific validity of the studies.

scholarly journals The V-BRCH Project: building clinical trial research capacity for HIV and noncommunicable diseases in Nigeria

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Muktar H. Aliyu ◽  
Mahmoud U. Sani ◽  
Donna J. Ingles ◽  
Fatimah I. Tsiga-Ahmed ◽  
Baba M. Musa ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Clinical Investigation ◽  
Evidence Synthesis ◽  
Research Capacity ◽  
Noncommunicable Diseases ◽  
Grant Writing ◽  
Double Burden ◽  
High Quality Research ◽  
Clinical Trial Research

AbstractAntiretroviral therapy has turned HIV into a chronic condition, with morbidity from HIV-associated noncommunicable diseases (NCDs) becoming more common as HIV-infected individuals live longer. In Nigeria, the additional challenge of an under-capacitated health system highlights the need for skilled clinical investigators who can generate evidence to tackle the double burden of HIV and NCDs. The Vanderbilt-Nigeria Building Research Capacity in HIV and Non-communicable Diseases (V-BRCH) programme is a training platform to create a cohort of skilled Nigerian investigators with the capacity to lead independent clinical trial research focused on the intersection of HIV and NCDs. V-BRCH will solidify an atmosphere of continuous mentoring and skills acquisition for physician faculty at the Aminu Kano Teaching Hospital via short- and medium-term learning opportunities, paired mentoring arrangements, and mentored research projects. Trainees will attend an annual faculty enrichment programme in Nashville, in addition to on-site workshops in Nigeria on HIV-associated NCD epidemiology, clinical trials methodology, evidence synthesis, qualitative research methods, stakeholder engagement, knowledge translation, and grant writing. Research-oriented junior faculty will undergo focused training in clinical trials administration and regulatory oversight. Scholars will share best practices through mentoring panels, regular ‘Works in Progress’ meetings, and monthly career development seminars. Competitive seed grants will be provided to mentor–mentee teams to promote targeted in-country pilot studies focused on HIV-associated NCDs. For long-term training, physician scientists will be supported to undergo enhanced Master of Public Health (MPH) training at Bayero University in Nigeria and Master of Science in Clinical Investigation (MSCI) training at Vanderbilt. Short-term regional courses, staff development workshops, and MPH curriculum refinement will help to strengthen institutional capacity in HIV-associated NCD clinical trial research. V-BRCH will create a cohort of skilled Nigerian scientists who will be able to compete for independent funding and design and implement high quality research that will generate evidence to inform policy and practice and lead to improved outcomes for Nigerians impacted by HIV-associated NCDs.

COVID-19 infection: A review of summarized Clinical trials study for the treatment

Coronaviruses ◽  
2020 ◽  
Vol 01 ◽  
Author(s):  
Afzal Hussain ◽  
Ashfaq Hussain ◽  
Chandan Kumar Verma
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Severe Acute Respiratory Syndrome ◽  
Viral Infection ◽  
Rna Virus ◽  
Antiviral Treatment ◽  
Pharmaceutical Drugs ◽  
The World ◽  
Amoxicillin Clavulanate ◽  
Bevacizumab Injection

Background: Coronavirus Disease 2019 (COVID-19) is a widely infectious and pathogenic viral infection due to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) that has arisen in Wuhan, China, and spread throughout the world. Coronavirus is indeed an enveloped RNA virus of the genus Betacoronavirus, which is transmitted to birds, humans as well as other mammals. The fastest human to human transition has been generally established. On July 19, 2020, WHO has been reported total confirmed cases: 1,40, 43,176, total confirmed new cases: 1,66,735, total deaths: 5,97,583, total new deaths: 4,496 globally. Material & Methods: In this review, the Clinical trial database is analyzed and systematically summarized drugs which are in the recruiting phase and the completion phase of the clinical trial. Results: Total 383 clinical trials are listed, involving more than 350 medicines such as Deferoxamine, Favipiravir, DAS181, Tocilizumab Injection, Sarilumab, Placebo, Sildenafil citrate tablets, Sargramostim, Lopinavir/ritonavir, Remdesivir, Bevacizumab, Tetrandrine, Fingolimod, Methylprednisolone, Plaquenil, Tocilizumab, Hydroxychloroquine, Abidol hydrochloride, Bevacizumab Injection, Methylprednisolone, Amoxicillin-clavulanate, Moxifloxacin, Sarilumab, Darunavir, and Cobicistat, etc. Conclusion: There is no commercially authorized antiviral treatment or vaccine suitable for use against COVID-19. However, Clinical trials represent an effective approach because they facilitate the development of new types of pharmaceutical drugs.

scholarly journals Sensitivity in Detection of Antibodies to Nucleocapsid and Spike Proteins of Severe Acute Respiratory Syndrome Coronavirus 2 in Patients With Coronavirus Disease 2019

2020 ◽  
Vol 222 (2) ◽  
pp. 206-213 ◽  
Author(s):  
Peter D Burbelo ◽  
Francis X Riedo ◽  
Chihiro Morishima ◽  
Stephen Rawlings ◽  
Davey Smith ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Nucleocapsid Protein ◽  
Spike Protein ◽  
Heat Inactivation ◽  
Cross Sectional ◽  
Quantitative Measurements ◽  
Initial Symptoms ◽  
Antibody Levels ◽  
Immunocompetent Patients ◽  
Spike Proteins

Abstract Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), is associated with respiratory-related disease and death. Assays to detect virus-specific antibodies are important to understand the prevalence of infection and the course of the immune response. Methods Quantitative measurements of plasma or serum antibodies to the nucleocapsid and spike proteins were analyzed using luciferase immunoprecipitation system assays in 100 cross-sectional or longitudinal samples from patients with SARS-CoV-2 infection. A subset of samples was tested both with and without heat inactivation. Results At >14 days after symptom onset, antibodies against SARS-CoV-2 nucleocapsid protein showed 100% sensitivity and 100% specificity, whereas antibodies to spike protein were detected with 91% sensitivity and 100% specificity. Neither antibody levels nor the rate of seropositivity were significantly reduced by heat inactivation of samples. Analysis of daily samples from 6 patients with COVID-19 showed anti-nucleocapsid and spike protein antibodies appearing between days 8 and 14 after initial symptoms. Immunocompromised patients generally had a delayed antibody response to SARS-CoV-2, compared with immunocompetent patients. Conclusions Antibody to the nucleocapsid protein of SARS-CoV-2 is more sensitive than spike protein antibody for detecting early infection. Analyzing heat-inactivated samples with a luciferase immunoprecipitation system assay is a safe and sensitive method for detecting SARS-CoV-2 antibodies.

scholarly journals Evolutionary Arms Race between Virus and Host Drives Genetic Diversity in Bat Severe Acute Respiratory Syndrome-Related Coronavirus Spike Genes

2020 ◽  
Vol 94 (20) ◽  
Author(s):  
Hua Guo ◽  
Bing-Jie Hu ◽  
Xing-Lou Yang ◽  
Lei-Ping Zeng ◽  
Bei Li ◽  
...  
Keyword(s):  
Genetic Diversity ◽  
Severe Acute Respiratory Syndrome ◽  
Binding Affinity ◽  
Arms Race ◽  
Spike Protein ◽  
Content Type ◽  
Evolutionary Arms Race ◽  
Horseshoe Bat ◽  
Key Residues ◽  
Spike Proteins

ABSTRACT The Chinese horseshoe bat (Rhinolophus sinicus), reservoir host of severe acute respiratory syndrome coronavirus (SARS-CoV), carries many bat SARS-related CoVs (SARSr-CoVs) with high genetic diversity, particularly in the spike gene. Despite these variations, some bat SARSr-CoVs can utilize the orthologs of the human SARS-CoV receptor, angiotensin-converting enzyme 2 (ACE2), for entry. It is speculated that the interaction between bat ACE2 and SARSr-CoV spike proteins drives diversity. Here, we identified a series of R. sinicus ACE2 variants with some polymorphic sites involved in the interaction with the SARS-CoV spike protein. Pseudoviruses or SARSr-CoVs carrying different spike proteins showed different infection efficiencies in cells transiently expressing bat ACE2 variants. Consistent results were observed by binding affinity assays between SARS-CoV and SARSr-CoV spike proteins and receptor molecules from bats and humans. All tested bat SARSr-CoV spike proteins had a higher binding affinity to human ACE2 than to bat ACE2, although they showed a 10-fold lower binding affinity to human ACE2 compared with that of their SARS-CoV counterpart. Structure modeling revealed that the difference in binding affinity between spike and ACE2 might be caused by the alteration of some key residues in the interface of these two molecules. Molecular evolution analysis indicates that some key residues were under positive selection. These results suggest that the SARSr-CoV spike protein and R. sinicus ACE2 may have coevolved over time and experienced selection pressure from each other, triggering the evolutionary arms race dynamics. IMPORTANCE Evolutionary arms race dynamics shape the diversity of viruses and their receptors. Identification of key residues which are involved in interspecies transmission is important to predict potential pathogen spillover from wildlife to humans. Previously, we have identified genetically diverse SARSr-CoVs in Chinese horseshoe bats. Here, we show the highly polymorphic ACE2 in Chinese horseshoe bat populations. These ACE2 variants support SARS-CoV and SARSr-CoV infection but with different binding affinities to different spike proteins. The higher binding affinity of SARSr-CoV spike to human ACE2 suggests that these viruses have the capacity for spillover to humans. The positive selection of residues at the interface between ACE2 and SARSr-CoV spike protein suggests long-term and ongoing coevolutionary dynamics between them. Continued surveillance of this group of viruses in bats is necessary for the prevention of the next SARS-like disease.

scholarly journals Analyses of the Spike Proteins of Severe Acute Respiratory Syndrome-Related Coronaviruses

2020 ◽  
pp. 32-50
Author(s):  
Peramachi Palanivelu
Keyword(s):  
Sequence Analysis ◽  
Severe Acute Respiratory Syndrome ◽  
Receptor Binding ◽  
Spike Protein ◽  
Protein Sequence Analysis ◽  
Conserved Motifs ◽  
Loop Region ◽  
Palm Civet ◽  
Clustal Omega ◽  
Spike Proteins

Aim: To analyze spike proteins of Severe Acute Respiratory Syndrome (SARS)-related coronaviruses (CoVs) for their conserved motifs, Receptor-Binding  Domain (RBD), Receptor Binding Motif (RBM) of SARS-CoV (CoV-1), SARS-CoV-2, Middle East Respiratory Syndrome (MERS)-CoV and their relationship to the bat, pangolin and palm civet-CoVs as possible intermediate hosts. Study Design: Multiple sequence analysis (MSA) of spike proteins of different SARS-CoVs were studied using Clustal Omega and ExPASy tools. Methodology: Bioinformatics, SDM and X-ray crystallographic data of the spike proteins from different CoVs including the current epidemic causing SARS-CoV-2 were analyzed. The advanced version of Clustal Omega was used for protein sequence analysis of different spike proteins from various CoVs and ExPASy tool was used for pI analysis. Results: Spike proteins in coronaviruses play important roles in mediating receptor binding, membrane fusion, and viral entry into human cells. Furthermore, nowadays all the vaccine development programmes are mainly focused on the SARS-CoV-2 spike protein only, as it plays the crucial, first step in the infection process. Therefore, the spike proteins of the SARS-related coronaviruses, the main determinant of coronavirus host specificity, are analyzed for their conserved motifs, RBD, RBM, etc. The recent epidemic causing strain, SARS-CoV-2, showed 2 dipeptide deletions and 4 peptide insertions ranging from tetra- to hepta-peptides in its spike protein as compared to its predecessor CoV-1. Most of the insertions are also found in the bat and pangolin CoVs except one unique tetrapeptide. The RBM region shows that the bats, pangolins and CoV-2 exhibit very similar to identical sequences. The overall analyses show that the latest SARS-CoV-2 is related to bats and more to pangolin-CoVs suggesting that the pangolins could be possibly the intermediate host. On the other hand, it is found that palm civet RBM sequences are highly related to CoV-1 and not CoV-2. Possibly the novel CoV-2 would have taken three insertions from bats and/or pangolins and the fourth insertion –PRRA- which is unique to SARS-CoV-2 is critically placed just in the S1/S2 cleavage region. The recently discovered G614 mutation (D614→G) in CoV-2, the most prevalent form in the global pandemic now, is found near the RBD towards the C-terminal. Placement of the unique tetrapeptide in the S1/S2 loop region and replacement with more positive charges on the spike protein which resulted in marked increase in the basicity of the SARS-CoV-2 spike protein may, possibly result in significant effects on the structure and function of the protein, possibly leading to rapid transmission. Conclusions: RBD and RBM regions of the spike proteins of SARS-CoV-1 and palm civet show very close identity to each other whereas the SARS-CoV-2, pangolin- and bat-CoVs exhibit very close identities in their RBD and RBM regions. The two crucial modifications in the spike protein of SARS-CoV-2, viz. a marked increase in the basicity of the protein and the insertion of a dibasic tetrapeptide (–PRRA-) at the critical S1/S2 cleavage point possibly make it to bind to the ACE2 receptor with higher affinity and get it cleaved by the host proteases more efficiently with subsequent effective internalization of the viral genome.

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