scholarly journals Clinical grade ACE2 effectively inhibits SARS-CoV-2 Omicron infections

2021 ◽  
Author(s):  
Vanessa Monteil ◽  
Stephanie Devignot ◽  
Jonas Klingstroem ◽  
Charlotte Thalin ◽  
Max J Kellner ◽  
...  
Keyword(s):  
Neutralizing Antibody ◽  
Therapeutic Strategies ◽  
Clinical Development ◽  
Drug Candidate ◽  
Clinical Grade ◽  
Structural Modelling ◽  
Antibody Therapeutics ◽  
Recent Emergence ◽  
Considerable Concern ◽  
Proof Of Principle

The recent emergence of the SARS-CoV-2 variant Omicron has caused considerable concern due to reduced vaccine efficacy and escape from neutralizing antibody therapeutics. Omicron is spreading rapidly around the globe and is suspected to account for most new COVID-19 cases in several countries, though the severity of Omicron-mediated disease is still under debate. It is therefore paramount to identify therapeutic strategies that inhibit the Omicron SARS-CoV-2 variant. Here we report using 3D structural modelling that Spike of Omicron can still associate with human ACE2. Sera collected after the second mRNA-vaccination did not exhibit a protective effect against Omicron while strongly neutralizing infection of VeroE6 cells with the reference Wuhan strain, confirming recent data by other groups on limited vaccine and convalescent sera neutralization efficacy against Omicron. Importantly, clinical grade recombinant human soluble ACE2, a drug candidate currently in clinical development, potently neutralized Omicron infection of VeroE6 cells with markedly enhanced potency when compared to reference SARS-CoV-2 isolates. These data show that SARS-CoV-2 variant Omicron can be readily inhibited by soluble ACE2, providing proof of principle of a viable and effective therapeutic approach against Omicron infections.

scholarly journals Clinical grade ACE2 as a universal agent to block SARS-CoV-2 variants

2021 ◽  
Author(s):  
Gerald Wirnsberger ◽  
Vanessa Monteil ◽  
Brett Eaton ◽  
Elena Postnikova ◽  
Michael Murphy ◽  
...  
Keyword(s):  
Human Lung ◽  
Neutralizing Antibody ◽  
Lung Epithelial Cells ◽  
Clinical Grade ◽  
Phase 2 ◽  
Antibody Therapeutics ◽  
Recent Emergence ◽  
Lung Epithelial ◽  
Effective Inhibition ◽  
Considerable Concern

AbstractThe recent emergence of multiple SARS-CoV-2 variants has caused considerable concern due to reduced vaccine efficacy and escape from neutralizing antibody therapeutics. It is therefore paramount to develop therapeutic strategies that inhibit all known and future SARS-CoV-2 variants. Here we report that all SARS-CoV-2 variants analyzed, including variants of concern (VOC) Alpha, Beta, Gamma, and Delta, exhibit enhanced binding affinity to clinical grade and phase 2 tested recombinant human soluble ACE2 (APN01). Importantly, soluble ACE2 neutralized infection of VeroE6 cells and human lung epithelial cells by multiple VOC strains with markedly enhanced potency when compared to reference SARS-CoV-2 isolates. Effective inhibition of infections with SARS-CoV-2 variants was validated and confirmed in two independent laboratories. These data show that SARS-CoV-2 variants that have emerged around the world, including current VOC and several variants of interest, can be inhibited by soluble ACE2, providing proof of principle of a pan-SARS-CoV-2 therapeutic.

scholarly journals An Overview of Several Inhibitors for Alzheimer’s Disease: Characterization and Failure

2021 ◽  
Vol 22 (19) ◽  
pp. 10798
Author(s):  
Subramanian Boopathi ◽  
Adolfo B. Poma ◽  
Ramón Garduño-Juárez
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Close Contact ◽  
Cellular Membrane ◽  
Therapeutic Strategies ◽  
Conformational Space ◽  
Disordered Proteins ◽  
Drug Candidate ◽  
Aβ Oligomers ◽  
Intrinsically Disorder

Amyloid beta (Aβ) oligomers are the most neurotoxic aggregates causing neuronal death and cognitive damage. A detailed elucidation of the aggregation pathways from oligomers to fibril formation is crucial to develop therapeutic strategies for Alzheimer’s disease (AD). Although experimental techniques rely on the measure of time- and space-average properties, they face severe difficulties in the investigation of Aβ peptide aggregation due to their intrinsically disorder character. Computer simulation is a tool that allows tracing the molecular motion of molecules; hence it complements Aβ experiments, as it allows to explore the binding mechanism between metal ions and Aβ oligomers close to the cellular membrane at the atomic resolution. In this context, integrated studies of experiments and computer simulations can assist in mapping the complete pathways of aggregation and toxicity of Aβ peptides. Aβ oligomers are disordered proteins, and due to a rapid exploration of their intrinsic conformational space in real-time, they are challenging therapeutic targets. Therefore, no good drug candidate could have been identified for clinical use. Our previous investigations identified two small molecules, M30 (2-Octahydroisoquinolin-2(1H)-ylethanamine) and Gabapentin, capable of Aβ binding and inhibiting molecular aggregation, synaptotoxicity, intracellular calcium signaling, cellular toxicity and memory losses induced by Aβ. Thus, we recommend these molecules as novel candidates to assist anti-AD drug discovery in the near future. This review discusses the most recent research investigations about the Aβ dynamics in water, close contact with cell membranes, and several therapeutic strategies to remove plaque formation.

Prophylactic and therapeutic strategies for Epstein–Barr virus-associated diseases: emerging strategies for clinical development

2019 ◽  
Vol 18 (5) ◽  
pp. 457-474 ◽  
Author(s):  
Vijayendra Dasari ◽  
Debottam Sinha ◽  
Michelle A. Neller ◽  
Corey Smith ◽  
Rajiv Khanna
Keyword(s):  
Epstein Barr Virus ◽  
Therapeutic Strategies ◽  
Clinical Development ◽  
Barr Virus ◽  
Associated Diseases ◽  
Epstein Barr

scholarly journals Defective neutralizing antibody response to SARS-CoV-2 in vaccinated dialysis patients

2021 ◽  
Author(s):  
Jessica Bassi ◽  
Olivier Giannini ◽  
Chiara Silacci-Fregni ◽  
Laura Pertusini ◽  
Paolo Hitz ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Therapeutic Strategies ◽  
Affinity Maturation ◽  
Plasma Samples ◽  
Igg Antibodies ◽  
Dialysis Patients ◽  
Antibody Avidity ◽  
Neutralizing Activity ◽  
Frail Population

Patients on dialysis are at risk of severe course of SARS-CoV-2 infection. Understanding the neutralizing activity and coverage of SARS-CoV-2 variants of vaccine-elicited antibodies is required to guide prophylactic and therapeutic COVID-19 interventions in this frail population. By analyzing plasma samples from 130 hemodialysis (HD) and 13 peritoneal dialysis patients after two doses of BNT162b2 or mRNA-1273 vaccines, we found that 35% of the patients had low-level or undetectable IgG antibodies to SARS-CoV-2 Spike (S). Neutralizing antibodies against the vaccine-matched SARS-CoV-2 and Delta variant were low or undetectable in 49% and 77% of patients, respectively, and were further reduced against other emerging variants. The fraction of non-responding patients was higher in SARS-CoV-2-naive HD patients immunized with BNT162b2 (66%) than those immunized with mRNA-1273 (23%). The reduced neutralizing activity correlated with low antibody avidity, consistent with a delayed affinity maturation of SARS-CoV-2 S-specific B cells. These data indicate that dialysis patients should be considered for an additional boost and other therapeutic strategies, including early immunotherapy with monoclonal antibodies.

scholarly journals Pharmacokinetics and target attainment of SQ109 in plasma and human-like tuberculosis lesions in rabbits

2021 ◽  
Author(s):  
Oluwaseun Egbelowo ◽  
Jansy P. Sarathy ◽  
Kamunkhwala Gausi ◽  
Matthew D. Zimmerman ◽  
Han Wang ◽  
...  
Keyword(s):  
Rabbit Model ◽  
Multidrug Resistant ◽  
Clinical Development ◽  
Drug Candidate ◽  
Parameter Estimates ◽  
Drug Resistant ◽  
Drug Resistant Tuberculosis ◽  
Bacterial Populations ◽  
Resistant Tuberculosis

SQ109 is a novel well-tolerated drug candidate in clinical development for the treatment of drug resistant tuberculosis (TB). It is the only inhibitor of the MmpL3 mycolic acid transporter in clinical development. No SQ109 resistant mutant has been directly isolated thus far, in vitro, in mice or in patients, tentatively attributed to its multiple targets. It is considered as a potential replacement for poorly tolerated components of multidrug-resistant TB regimens. To prioritize SQ109-containing combinations with best potential for cure and treatment shortening, one must understand its contribution against different bacterial populations in pulmonary lesions. Here we have characterized the pharmacokinetics of SQ109 in the rabbit model of active TB and its penetration at the sites of disease: lung tissue, cellular and necrotic lesions, and caseum. A two-compartment model with first-order absorption and elimination described the plasma pharmacokinetics. At the human-equivalent dose, parameter estimates fell within the ranges published for preclinical species. Tissue concentrations were modelled using an "effect" compartment, showing high accumulation in lung and cellular lesion areas with penetration coefficients in excess of 1,000, and lower passive diffusion in caseum after 7 daily doses. These results, together with the hydrophobic nature and high non-specific caseum binding of SQ109, suggest that multi-week dosing would be required to reach steady state in caseum and poorly vascularized compartments, similar to bedaquiline. Linking lesion pharmacokinetics to SQ109 potency in assays against replicating, non-replicating, and intracellular M. tuberculosis showed SQ109 concentrations markedly above pharmacokinetic-pharmacodynamic targets in lung and cellular lesions throughout the dosing interval. IMPORTANCE Drug-resistant tuberculosis (TB) accounts for over 20% of all fatalities due to drug-resistant pathogens. With recently approved drugs and a promising drug candidate pipeline, the challenge faced by clinical developers is prioritization of drug combinations with the best potential to improve cure rates and shorten treatment duration. To this end, one must understand the contribution of each partner drug against different bacterial populations in pulmonary TB lesions. SQ109 is a safe drug candidate in clinical development for the treatment of multidrug resistant TB. It is active against replicating and non-replicating Mycobacterium tuberculosis persisters in vitro, in mouse models and in patients. SQ109 exhibits extremely low frequency of resistance, unprecedented among all TB drugs so far. Here we characterize the pharmacokinetics and activity of SQ109 at the site of TB disease to inform the selection of drug regimens that account for its lesion-centric pharmacokinetic-pharmacodynamic parameters and best leverage its contribution to efficient disease cure.

scholarly journals Infection and vaccine-induced neutralizing antibody responses to the SARS-CoV-2 B.1.617.1 variant

2021 ◽  
Author(s):  
Venkata-Viswanadh Edara ◽  
Lilin Lai ◽  
Malaya Sahoo ◽  
Katharine Floyd ◽  
Mamdouh Sibai ◽  
...  
Keyword(s):  
Protective Immunity ◽  
Neutralizing Antibody ◽  
Antibody Responses ◽  
Live Virus ◽  
Global Pandemic ◽  
Virus Assay ◽  
Recent Emergence ◽  
The World ◽  
Antibody Resistance ◽  
Second Wave

SARS-CoV-2 has caused a devastating global pandemic. The recent emergence of SARS-CoV-2 variants that are less sensitive to neutralization by convalescent sera or vaccine-induced neutralizing antibody responses has raised concerns. A second wave of SARS-CoV-2 infections in India is leading to the expansion of SARS-CoV-2 variants. The B.1.617.1 variant has rapidly spread throughout India and to several countries throughout the world. In this study, using a live virus assay, we describe the neutralizing antibody response to the B.1.617.1 variant in serum from infected and vaccinated individuals. We found that the B.1.617.1 variant is 6.8-fold more resistant to neutralization by sera from COVID-19 convalescent and Moderna and Pfizer vaccinated individuals. Despite this, a majority of the sera from convalescent individuals and all sera from vaccinated individuals were still able to neutralize the B.1.617.1 variant. This suggests that protective immunity by the mRNA vaccines tested here are likely retained against the B.1.617.1 variant. As the B.1.617.1 variant continues to evolve, it will be important to monitor how additional mutations within the spike impact antibody resistance, viral transmission and vaccine efficacy.

Implications of retinal effects observed in chronic toxicity studies on the clinical development of a CNS-active drug candidate

2014 ◽  
Vol 69 (2) ◽  
pp. 187-200 ◽  
Author(s):  
G. Eichenbaum ◽  
J. Zhou ◽  
M.F. Kelley ◽  
W. Roosen ◽  
P. Costa-Giomi ◽  
...  
Keyword(s):  
Chronic Toxicity ◽  
Active Drug ◽  
Clinical Development ◽  
Drug Candidate ◽  
Toxicity Studies

scholarly journals Immunogenicity, Safety, and Lot Consistency of a Novel Inactivated Enterovirus 71 Vaccine in Chinese Children Aged 6 to 59 Months

2013 ◽  
Vol 20 (12) ◽  
pp. 1805-1811 ◽  
Author(s):  
Yue-Mei Hu ◽  
Xu Wang ◽  
Jun-Zhi Wang ◽  
Ling Wang ◽  
Yong-Jie Zhang ◽  
...  
Keyword(s):  
Injection Site ◽  
Geometric Mean ◽  
Enterovirus 71 ◽  
Neutralizing Antibody ◽  
Clinical Development ◽  
Phase Iii ◽  
Healthy Children ◽  
The Novel ◽  
Double Blind

ABSTRACTThe determination of lot-to-lot consistency in the manufacturing process is a mandatory step in the clinical development of the novel enterovirus 71 (EV71) vaccine. A phase III, randomized, placebo-controlled, double-blind trial assessed the lot consistency, immunogenicity, and safety of the EV71 vaccine in children aged 6 to 59 months. Healthy children (n= 1,400) received one of three lots of the EV71 vaccine containing 400 U of EV71 antigen or a placebo at days 0 and 28. Blood samples were collected before dose 1 and at 28 days after dose 2 (day 56) for an anti-EV71 neutralizing antibody (NTAb) assay. The geometric mean titer (GMT) and the seropositivity rates (with titers of ≥1:8) were compared at day 56. After each dose, the solicited injection site and general adverse events (AEs) were recorded for 7 days, and unsolicited AEs were recorded for 28 days. At day 56, the seropositivity rates ranged from 99.7% to 100% for the vaccine groups. The NTAb GMTs for the vaccine were 140.3 (95% confidence interval [CI], 117.8 to 167.1), 141.5 (95% CI, 118.0 to 169.6), and 146.6 (95% CI, 122.5 to 175.3). The two-sided 95% CI of the log difference in GMTs between the pairs of lots were between −0.176 and 0.176, therefore meeting the predefined equivalence criteria. The percentages of subjects reporting any injection site AEs, general AEs, or serious AEs were similar across the four vaccination groups. In conclusion, the demonstration of consistency between the manufacturing lots confirms for the purposes of clinical development the reliability of the EV71 vaccine production process. (This study has been registered atClinicalTrials.govunder registration no. NCT01636245.)

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