scholarly journals Epitope classification and RBD binding properties of neutralizing antibodies against SARS-CoV-2 variants of concern

2021 ◽  
Author(s):  
Ashlesha Deshpande ◽  
Bethany D. Harris ◽  
Luis Martinez-Sobrido ◽  
James J. Kobie ◽  
Mark R Walter
Keyword(s):  
Neutralizing Antibodies ◽  
Therapeutic Option ◽  
Binding Studies ◽  
Binding Properties ◽  
Viral Attachment ◽  
Naturally Occurring ◽  
Short And Long Term ◽  
Brazil Strain ◽  
Major Target

Severe acute respiratory syndrome coronavirus-2 (SAR-CoV-2) causes coronavirus disease 2019 (COVID19) that is responsible for short and long-term disease, as well as death, in susceptible hosts. The receptor binding domain (RBD) of the SARS-CoV-2 Spike (S) protein binds to cell surface angiotensin converting enzyme type-II (ACE2) to initiate viral attachment and ultimately viral pathogenesis. The SARS-CoV-2 S RBD is a major target of neutralizing antibodies (NAbs) that block RBD - ACE2 interactions. In this report, NAb-RBD binding epitopes in the protein databank were classified as C1, C1D, C2, C3, or C4, using a RBD binding profile (BP), based on NAb-specific RBD buried surface area and used to predict the binding epitopes of a series of uncharacterized NAbs. Naturally occurring SARS-CoV-2 RBD sequence variation was also quantified to predict NAb binding sensitivities to the RBD-variants. NAb and ACE2 binding studies confirmed the NAb classifications and determined whether the RBD variants enhanced ACE2 binding to promote viral infectivity, and/or disrupted NAb binding to evade the host immune response. Of 9 single RBD mutants evaluated, K417T, E484K, and N501Y disrupted binding of 65% of the NAbs evaluated, consistent with the assignment of the SARS-CoV-2 P.1 Japan/Brazil strain as a variant of concern (VoC). RBD variants E484K and N501Y exhibited ACE2 binding equivalent to a Wuhan-1 reference SARS-CoV-2 RBD. While slightly less disruptive to NAb binding, L452R enhanced ACE2 binding affinity. Thus, the L452R mutant, associated with the SARS-CoV-2 California VoC (B.1.427/B.1.429-California), has evolved to enhance ACE2 binding, while simultaneously disrupting C1 and C2 NAb classes. The analysis also identified a non-overlapping antibody pair (1213H7 and 1215D1) that bound to all SARS-CoV-2 RBD variants evaluated, representing an excellent therapeutic option for treatment of SARS-CoV-2 WT and VoC strains.

scholarly journals Epitope Classification and RBD Binding Properties of Neutralizing Antibodies Against SARS-CoV-2 Variants of Concern

2021 ◽  
Vol 12 ◽  
Author(s):  
Ashlesha Deshpande ◽  
Bethany D. Harris ◽  
Luis Martinez-Sobrido ◽  
James J. Kobie ◽  
Mark R. Walter
Keyword(s):  
Neutralizing Antibodies ◽  
Therapeutic Option ◽  
Binding Studies ◽  
Binding Properties ◽  
Viral Attachment ◽  
Naturally Occurring ◽  
Short And Long Term ◽  
Brazil Strain ◽  
Major Target

Severe acute respiratory syndrome coronavirus-2 (SAR-CoV-2) causes coronavirus disease 2019 (COVID19) that is responsible for short and long-term disease, as well as death, in susceptible hosts. The receptor binding domain (RBD) of the SARS-CoV-2 Spike (S) protein binds to cell surface angiotensin converting enzyme type-II (ACE2) to initiate viral attachment and ultimately viral pathogenesis. The SARS-CoV-2 S RBD is a major target of neutralizing antibodies (NAbs) that block RBD - ACE2 interactions. In this report, NAb-RBD binding epitopes in the protein databank were classified as C1, C1D, C2, C3, or C4, using a RBD binding profile (BP), based on NAb-specific RBD buried surface area and used to predict the binding epitopes of a series of uncharacterized NAbs. Naturally occurring SARS-CoV-2 RBD sequence variation was also quantified to predict NAb binding sensitivities to the RBD-variants. NAb and ACE2 binding studies confirmed the NAb classifications and determined whether the RBD variants enhanced ACE2 binding to promote viral infectivity, and/or disrupted NAb binding to evade the host immune response. Of 9 single RBD mutants evaluated, K417T, E484K, and N501Y disrupted binding of 65% of the NAbs evaluated, consistent with the assignment of the SARS-CoV-2 P.1 Japan/Brazil strain as a variant of concern (VoC). RBD variants E484K and N501Y exhibited ACE2 binding equivalent to a Wuhan-1 reference SARS-CoV-2 RBD. While slightly less disruptive to NAb binding, L452R enhanced ACE2 binding affinity. Thus, the L452R mutant, associated with the SARS-CoV-2 California VoC (B.1.427/B.1.429-California), has evolved to enhance ACE2 binding, while simultaneously disrupting C1 and C2 NAb classes. The analysis also identified a non-overlapping antibody pair (1213H7 and 1215D1) that bound to all SARS-CoV-2 RBD variants evaluated, representing an excellent therapeutic option for treatment of SARS-CoV-2 WT and VoC strains.

Outcomes of interventional electrophysiology in children under 2 years of age

2011 ◽  
Vol 22 (5) ◽  
pp. 499-506 ◽  
Author(s):  
Christian J. Turner ◽  
Kai C. Lau ◽  
Gary F. Sholler
Keyword(s):  
Therapeutic Option ◽  
Early Recurrence ◽  
Efficacy And Safety ◽  
Older Children ◽  
Pharmacological Agents ◽  
Interventional Electrophysiology ◽  
Short And Long Term ◽  
Few Data ◽  
Repeat Procedures

AbstractBackgroundDespite the increasing utilisation of interventional electrophysiology in adults and older children with arrhythmias, there are few data reflecting the safety and efficacy of this procedure in the age group under 2 years.AimWe describe our experience in assessing the efficacy and safety with this group of children.MethodsWe undertook a retrospective review of all infants under 2 years of age who underwent an interventional electrophysiology procedure between 1995 and 2009 to determine indications, procedural details, short- and long-term success, and complication rate.ResultsA total of 23 interventional electrophysiology procedures were performed in 17 patients initially under 2 years of age. Of these, three patients had congenital heart disease. The most common indication was arrhythmia resistant to pharmacological agents (59%), with the remaining cases being arrhythmia complicated by cardiovascular instability (41%). There was initial success in 15 patients after the first procedure, with early recurrence in four. Following six repeat procedures, there was long-term success in 15 patients (88%), with three repeat procedures being performed after 2 years of age. There was one non-procedural death related to persisting arrhythmia. There were three minor complications. In one patient, cryotherapy was used successfully.ConclusionsThe interventional electrophysiology procedure is a viable therapeutic option in infants under 2 years with arrhythmia resistant to other conventional medical management.

Long-Term Dosing of AMG 531 in Thrombocytopenic Patients with Immune Thrombocytopenic Purpura: 48-Week Update.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 476-476 ◽  
Author(s):  
David Kuter ◽  
James Bussel ◽  
James George ◽  
Louis Aledort ◽  
Alan Lichtin ◽  
...  
Keyword(s):  
Platelet Count ◽  
Neutralizing Antibodies ◽  
Sinus Thrombosis ◽  
Therapeutic Option ◽  
Subcutaneous Administration ◽  
Transverse Sinus ◽  
Platelet Response ◽  
Open Label ◽  
The Mean

Abstract AMG 531 is a novel thrombopoiesis-stimulating peptibody that increases platelet production by targeting the TPO receptor. The study described here is an ongoing, open-label extension assessing the safety and efficacy of long-term, weekly, subcutaneous administration of AMG 531 in ITP patients who have completed a previous AMG 531 study. Patients previously treated with AMG 531 receive the same starting dose as the final dose given in the previous study; placebo-treated patients begin the extension with a 1 μg/kg dose. Doses may be skipped, decreased, maintained, or increased based on platelet response. Patients who achieve a stable dose for at least 3 weeks (later amended to 4 weeks) may be allowed to self-administer the drug. A total of 104 patients have been enrolled; the longest AMG 531 treatment duration is 96 weeks. This planned interim analysis includes 36 patients (safety subset) whose previous study was a phase 2 trial. Data for patients previously enrolled in a phase 3 trial are still blinded. The 25 women and 11 men have a mean age of 50±13 (SD) years; 30 (83%) have had a splenectomy. Twelve patients entered the study using concurrent corticosteroids, which were tapered when the platelet count was >50x109/L. Adverse event (AE) profiles were similar for the intervals of weeks 1–24 vs 25–48 and beyond. The most frequent were headache (incidence of 2.0 per 100 weeks of subject exposure for weeks 1–24 vs 1.7 for weeks 25–48), upper respiratory infection (1.3 vs 0.8), and fatigue (0.9 vs 1.0). Four patients had serious treatment-related AEs: vaginal hemorrhage/anemia (withdrawn from treatment), diffuse reticulin formation in the bone marrow (withdrawn), bone pain (continues on treatment), and transverse sinus thrombosis with papilledema and temporary decrease in visual acuity (64-year-old patient with diabetes mellitus and a platelet count of 293x109/L at the time of the AE; this patient continues on treatment). No neutralizing antibodies have been detected to date. The efficacy subset consists of 27 patients who completed week 48 or beyond. Both the mean platelet count and the mean dose of AMG 531 have remained stable between weeks 24–48. The mean platelet count was 100x109/L ± 4.4 (SE) during weeks 1–24 and 131x109/L ± 5.3 (SE) during weeks 25–48. Eleven patients (41%) have had at least one platelet count >450x109/L, excluding counts associated with ITP rescue medication. Six of 12 patients were able to discontinue concurrent corticosteroids, and 2 had a >25% dose reduction. Individualized weekly doses of AMG 531 provide a therapeutic option for ITP. Most patients have been able to maintain a safe platelet count and to decrease or discontinue concurrent corticosteroid therapy.

Long-Term Dosing of AMG 531 in Thrombocytopenic Patients with Immune Thrombocytopenic Purpura: 2-Year Update.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 568-568 ◽  
Author(s):  
James B. Bussel ◽  
D.J. Kuter ◽  
J.Th.M de Wolf ◽  
T.H. Guthrie ◽  
A. Newland ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Platelet Count ◽  
Neutralizing Antibodies ◽  
Drug Exposure ◽  
Therapeutic Option ◽  
Platelet Response ◽  
Initial Report ◽  
Chronic Itp ◽  
Long Term Treatment

Abstract AMG 531, a novel thrombopoiesis-stimulating peptibody, increases platelet production by stimulating the TPO receptor. This study is an ongoing, open-label extension assessing the safety and efficacy of long-term, weekly, SC administration of AMG 531 in patients with chronic ITP who completed a previous AMG 531 study. Patients previously treated with AMG 531 received the same starting dose as the final dose given in the previous study; placebo-treated patients began the extension at 1μg/kg. Doses could be adjusted based on platelet response. As of an April 2007 analysis, 137 patients were enrolled and 136 had received AMG 531. The longest treatment duration was 122 weeks; 22 patients were followed for 96 weeks or longer. At baseline, 91 women and 46 men had a mean age of 53±15(SD) years and a median (range) platelet count of 18(1–50)x109/L; 82 patients (60%) had undergone splenectomy. The most frequently reported adverse events (AEs) were headache (overall incidence 31%), contusion (27%), fatigue (24%), diarrhea (24%), epistaxis (23%), nasopharyngitis (21%), and arthralgia (20%). Exposure-adjusted analysis showed no trend for AEs to increase in frequency with increased drug exposure (table). Eleven patients had serious AEs judged by investigators as treatment-related including 3 withdrawn from study (vaginal hemorrhage, increased reticulin in the bone marrow reported as myelofibrosis, and initial report of multiple myeloma later reclassified as monoclonal gammopathy of undetermined significance - 1 report each) and 8 who continued on-study (bone marrow disorder/reticulin fibrosis - 3, unacceptably high platelet count - 2, thrombosis - 2, and cerebral thrombosis/papilloedema/temporary blindness - 1). One patient developed neutralizing antibodies to AMG 531 (absent on retesting 4 months after drug cessation), with no clinical sequelae and no cross-reactive antibodies to TPO. Overall, 112 patients (82%) achieved a platelet response (≥50x109/L and doubling of baseline). From week 4 onward, weekly incidence of platelet response ranged from 52–73% (figure). Median number of weeks to first response was 2 (median dose 3μg/kg). Of 30 patients with baseline use of concurrent ITP therapies, 13 were able to discontinue them and 6 additional patients had a >25% dose reduction. Individualized weekly doses of AMG 531 provide a therapeutic option for long-term treatment of chronic ITP. The safety profile has been acceptable, and most patients have been able to maintain a platelet response and discontinue or reduce concurrent ITP therapies. Exposure-Adjusted incidence of AEs with Overall Incidence ≥ 20% Platelet Response (≥ 50x109/L and Doubling of Baseline) by Study Week Platelet Response (≥ 50x109/L and Doubling of Baseline) by Study Week

scholarly journals Regenerative Role of Stem Cell-Derived Extracellular Vesicles in Acute Kidney Injury

Nephron ◽  
2020 ◽  
Vol 144 (12) ◽  
pp. 638-643
Author(s):  
Davide Medica ◽  
Sergio Dellepiane ◽  
Vincenzo Cantaluppi
Keyword(s):  
Acute Kidney Injury ◽  
Clinical Trials ◽  
Extracellular Vesicles ◽  
Therapeutic Option ◽  
Kidney Injury ◽  
Glomerular Injury ◽  
Paracrine Factors ◽  
Short And Long Term

Acute kidney injury (AKI) is a frequent complication of hospital admission and worsens short- and long-term patients’ prognosis. Currently, AKI treatment remains supportive and no therapy has proven significant benefit in clinical trials. Stem cells (SCs) are a promising therapeutic option, but their translation to the clinical setting is limited by the risk of rejection or aberrant differentiation. Numerous studies have shown how SC effects are mediated by paracrine factors such as extracellular vesicles (EVs). In this review, we describe the preclinical evidence about EV efficacy in acute tubular and glomerular injury and the recently generated clinical data.

scholarly journals Fourteen-Year Long-Term Results after Gastric Banding

2011 ◽  
Vol 2011 ◽  
pp. 1-6 ◽  
Author(s):  
Christine Stroh ◽  
Ulrich Hohmann ◽  
Harald Schramm ◽  
Frank Meyer ◽  
Thomas Manger
Keyword(s):  
Weight Loss ◽  
Gastric Banding ◽  
Therapeutic Option ◽  
Reoperation Rate ◽  
Long Term Results ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Short And Long Term

Background. Gastric banding (GB) is a common bariatric procedure that is performed worldwide. Weight loss can be substantial after this procedure, but it is not sufficient in a significant portion of patients. Long-term rates for associated complications increase with every year of follow up, and only a few long-term studies have been published that examine these rates. We present our results after 14 years of postoperative follow up.Methods. Two hundred patients were operated upon form 01.02.1995 to 31.01.2009. Data collection was performed prospectively. In retrospective analysis, we analyzed weight loss, short- and long-term complications, amelioration of comorbidities and long-term outcome.Results. The mean postoperative follow up time was 94.4 months (range 2–144). The follow up rate was 83.5%. The incidence of postoperative complications for slippage was 2.5%, for pouch dilatation was 9.5%, for band migration was 5.5% and 12.0% for overall band removal. After 14 years, the reoperation rate was 30.5% with a reoperation rate of 2.2% for every year of follow up. Excess weight loss was 40.2% after 1 year, 46.3% after 2 years, 45.9% after 3 years, 41.9% after five years, 33.3% after 8 years, 30.8% after 10 years, 33.3% after 12 years and 15.6% after 14 years of follow up.Conclusion. The complication and reoperation rate after GB is high. Nevertheless, GB is still a therapeutic option in morbid obese patients, but the criteria for patient selection should be carefully evaluated.

l-Triiodothyronine acutely increases Ca2+ uptake in the isolated, perfused rat heart. Changes in l-type Ca2+ channels and β-receptors during short- and long-term hyper- and hypothyroidism

1994 ◽  
Vol 130 (2) ◽  
pp. 171-179 ◽  
Author(s):  
Liv Bjørn-Hansen Gøtzsche
Keyword(s):  
Rat Heart ◽  
Binding Capacity ◽  
University Hospital ◽  
Inotropic Effect ◽  
Coronary Perfusion ◽  
Binding Studies ◽  
Perfused Rat Heart ◽  
Isolated Perfused Rat Heart ◽  
Short And Long Term

Gøtzsche LB-H. l-Triiodothyronine acutely increases Ca2+ uptake in the isolated, perfused rat heart. Changes in l-type Ca2+ channels and β-receptors during short- and long-term hyper- and hypothyroidism. Eur J Endocrinol 1994;130:171–9. ISSN 0804–4643 Acutely administered triiodothyronine (T3) in supraphysiological doses has been shown to exert an acute positive inotropic effect in vivo a few minutes after intravenous administration. To investigate whether this effect could be explained by an acutely increased Ca2+ uptake in the myocardium, an isolated perfused rat heart model ad modum Langendorff was established. The acute stimulative effect of T3 on myocardial Ca2+ uptake was determined indirectly by measuring changes in Ca2+ concentration in the perfusate following coronary perfusion with 45Ca2+-containing buffer. Perfusion with T3 gave rise to dose-dependent reductions in perfusate Ca2+ within 20 s. Following 10−9 and 10−11 mol/l T3, the effect was small and usually lasted less than 1 min. Perfusion with 10−6 and 10−7 mmol/l T3 resulted in a decrease in perfusate Ca2+, which remained stable throughout 4–6 min of observation. Calcium channel blockade with nifedipine prevented the decrease in perfusate Ca2 +, suggesting that voltage-operated Ca2+ channels are involved in the increased Ca2 + uptake. A washout period with T3-free buffer re-established the Ca2+ concentration in the perfusate, suggesting that the effect is reversible. Calcium channels have been suggested to be regulated directly by T3. Maximum binding capacities for myocardial Ca2+ channels and β-receptors were determined by binding studies with [3H]PN200-110 and [125I]iodocyanopindolol in short-term and long-term hyper- and hypothyroid rats. After 2 and 8 weeks, Ca2+-channel maximum binding capacities were reduced by 25% and 23% in hyperthyroid rats (p<0.05) and increased by 33% and 23% in hypothyroid rats (p<0.05). β-Receptor binding capacities were increased by 33% and 50% in hyperthyroid rats (p<0.05) and reduced by 28% and 47% (p<0.05) in hypothyroid rats. The reduced Ca2+-channel maximum binding capacity during chronic hyperthyroidism is hypothesized to be a secondary event to a T3-induced increase in myocardial Ca2+ uptake in hyperthyroid rats, serving a protective role against Ca2+ overloading of the cell. The acute increase in Ca2+ uptake following T3 administration may explain the reported acute inotropic effect of T3. Liv Bjørn-Hansen Gøtzsche, Medical Department (Diabetes and Endocrinology), Århus Kommunehospital, University Hospital of Århus, DK-8000 Århus C, Denmark

scholarly journals Lipofilling: A New Therapeutic Option for the Treatment of Lupus Panniculitis-Induced Atrophy

2016 ◽  
Vol 8 (3) ◽  
pp. 323-326 ◽  
Author(s):  
Laura Polivka ◽  
Marc Revol ◽  
Maxime Battistella ◽  
Hervé Bachelez
Keyword(s):  
Lupus Erythematosus ◽  
Therapeutic Option ◽  
Cutaneous Lupus Erythematosus ◽  
Efficacy And Safety ◽  
Lupus Panniculitis ◽  
Rare Manifestation ◽  
Short And Long Term ◽  
Pathogenic Process

Lupus panniculitis is a rare manifestation of cutaneous lupus erythematosus, which may lead to major aesthetic sequelae with a severe impact on patients’ quality of life. We report 2 cases supporting the short- and long-term efficacy and safety of lipofilling in the treatment of lupus panniculitis-induced atrophy. These observations pave the way for prospective, larger-scale studies in patients with scarring lupus panniculitis, provided that the autoimmune pathogenic process is in complete, stable remission.

Long-Term Dosing of AMG 531 Is Effective and Well Tolerated in Thrombocytopenic Patients with Immune Thrombocytopenic Purpura.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 220-220 ◽  
Author(s):  
James B. Bussel ◽  
David J. Kuter ◽  
James N. George ◽  
Louis M. Aledort ◽  
Alan E. Lichtin ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Platelet Count ◽  
Neutralizing Antibodies ◽  
Therapeutic Option ◽  
Platelet Response ◽  
Open Label ◽  
Baseline Platelet Count ◽  
First Response ◽  
The Mean

Abstract AMG 531 is a novel platelet-stimulating peptibody that targets the TPO receptor, resulting in increased production of platelets. This ongoing, open-label study assessed the safety and efficacy of long-term AMG 531 dosing in ITP patients. Eligible patients have completed a previous AMG 531 study in ITP, are ≥18 years of age, have a baseline platelet count ≤50 x 109/L, with no recent significant change in medical history. The AMG 531 starting dose is 1μg/kg by SC injection with dose adjustment to an original maximum of 30μg/kg, since reduced to 15μg/kg. Patients are treated weekly unless the platelet count is >400x109/L. Concurrent corticosteroids can be tapered when the platelet count is ≥50x109/L. Preliminary data are available for 26 patients treated for up to 24 weeks: 17 women and 9 men; mean age, 48.4±11.6 (SD) years; mean baseline platelet count, 18.5±12.3 (SD) x109/L. Twenty-one patients (80.8%) had undergone a splenectomy before study entry; 6 (23.1%) were receiving concurrent corticosteroids for ITP. Twenty-one of 26 patients (80.8%) had a protocol-defined platelet response to AMG 531 (doubling of the baseline platelet count and ≥50x109/L). The mean AMG 531 dose at the first response was 3.7±2.7 (SD) μg/kg (at median 5 weeks); the mean dose at week 24 was 7.2±4.2 (SD) μg/kg. Twelve of 26 patients (46.2%) had a durable platelet response (doubling of the baseline count and ≥50x109/L at 6 or more of weeks 17–24). Twenty patients (76.9%) had a platelet count ≥100x109/L at least once; 7 (26.9%) had a platelet count ≥400x109/L. Of 6 patients on concurrent corticosteroids, 3 discontinued treatment and 2 had a ≥25% dose reduction. At least 1 serious adverse event was reported in 4 patients: anal fistula (unrelated to treatment), adverse drug reaction (unrelated), multiple sclerosis relapse (unrelated), bone pain (related), and diffuse reticulin formation in the bone marrow reported as myelofibrosis (related). Reticulin formation is hypothesized as due to excessive accumulation of megakaryocytes in the bone marrow. AMG 531 was discontinued, and a bone marrow 3 months later showed improvement. One patient experienced adverse events (musculoskeletal pain and headache) resulting in withdrawal from the study. No neutralizing antibodies have been detected to date. In summary, repeated exposure to AMG 531 has been generally well tolerated in this ongoing study. A total 80.8% of patients achieved a platelet response, defined as doubling of the baseline count and ≥50x109/L. Individualized weekly doses of AMG 531 may provide a therapeutic option in ITP, potentially enabling patients to taper off long-term corticosteroid therapy.

Cholecystokinin and Gastrin Receptors

2006 ◽  
Vol 86 (3) ◽  
pp. 805-847 ◽  
Author(s):  
Marlène Dufresne ◽  
Catherine Seva ◽  
Daniel Fourmy
Keyword(s):  
Structural Data ◽  
G Protein Coupled Receptors ◽  
Long Term Effects ◽  
Binding Properties ◽  
Cholecystokinin Receptors ◽  
Clinical Disorders ◽  
Short And Long Term ◽  
The Subject ◽  
G Protein Coupled

Cholecystokinin and gastrin receptors (CCK1R and CCK2R) are G protein-coupled receptors that have been the subject of intensive research in the last 10 years with corresponding advances in the understanding of their functioning and physiology. In this review, we first describe general properties of the receptors, such as the different signaling pathways used to exert short- and long-term effects and the structural data that explain their binding properties, activation, and regulation. We then focus on peripheral cholecystokinin receptors by describing their tissue distribution and physiological actions. Finally, pathophysiological peripheral actions of cholecystokinin receptors and their relevance in clinical disorders are reviewed.

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