BACKGROUND: The spread of tau pathology closely correlates with the disease course and cognitive decline in Alzheimer's disease (AD). Tau-targeting immunotherapies are being developed to stop the spread of tau pathology and thus halt disease progression. In this post hoc analysis of the ADAMANT clinical trial, we examined the performance of AADvac1, an active immunotherapy targeting the microtubule-binding region (MTBR) of tau, in a subgroup of participants with elevated plasma p-tau217, indicating AD-related neuropathological changes. METHODS: ADAMANT was a 24-month, randomized, placebo-controlled, parallel-group, double-blinded, multicenter, phase 2 clinical trial in subjects with mild AD. The trial participants were randomized 3:2 to receive six doses of AADvac1 or placebo at 4-week intervals, followed by five booster doses at 14-week intervals. The primary outcome was safety. The secondary outcomes were the Clinical Dementia Rating-Sum of Boxes (CDR-SB), the Alzheimer's Disease Cooperative Study - Activities of Daily Living score for Mild Cognitive Impairment 18-item version (ADCS-ADL-MCI-18), and immunogenicity. Volumetric MRI, plasma neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) were exploratory outcomes. The inclusion criterion for this post-hoc analysis was a baseline plasma p-tau217 level above the cutoff for AD. RESULTS: Among 196 ADAMANT participants, 137 were positive for plasma p-tau217 (mean age 71.4 years, 59% women). AADvac1 was safe and well tolerated in this subgroup. AADvac1 reduced the rate of accumulation of log-plasma NfL by 56% and that of GFAP by 73%. The treatment differences in the CDR-SB and ADCS-ADL-MCI-18 scores favored AADvac1 but were not statistically significant. AADvac1 had no effect on whole-brain volume but nonsignificantly reduced the loss of brain cortical tissue in several regions. Importantly, the impact on the study outcomes was more pronounced in participants with higher anti-tau antibody levels. CONCLUSIONS: These results suggest that AADvac1 tau immunotherapy can reduce plasma biomarkers of neurodegeneration and neuroinflammation. These findings and possible observations on brain atrophy and cognition are hypothesis-generating and warrant further evaluation in a larger clinical trial. TRIAL REGISTRATION: EudraCT 2015-000630-30 (primary) and NCT02579252.
- MeSH
- aktivní imunoterapie metody MeSH
- Alzheimerova nemoc * krev terapie imunologie MeSH
- biologické markery krev MeSH
- dvojitá slepá metoda MeSH
- lidé středního věku MeSH
- lidé MeSH
- proteiny tau * krev MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- testy pro posouzení mentálních funkcí a demence MeSH
- výsledek terapie MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze II MeSH
- multicentrická studie MeSH
- randomizované kontrolované studie MeSH
BACKGROUND: The emergence of new SARS-CoV-2 variants of concern B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma) and B.1.617.2 (Delta) that harbor mutations in the viral S protein raised concern about activity of current vaccines and therapeutic antibodies. Independent studies have shown that mutant variants are partially or completely resistant against some of the therapeutic antibodies authorized for emergency use. METHODS: We employed hybridoma technology, ELISA-based and cell-based S-ACE2 interaction assays combined with authentic virus neutralization assays to develop second-generation antibodies, which were specifically selected for their ability to neutralize the new variants of SARS-CoV-2. FINDINGS: AX290 and AX677, two monoclonal antibodies with non-overlapping epitopes, exhibit subnanomolar or nanomolar affinities to the receptor binding domain of the viral Spike protein carrying amino acid substitutions N501Y, N439K, E484K, K417N, and a combination N501Y/E484K/K417N found in the circulating virus variants. The antibodies showed excellent neutralization of an authentic SARS-CoV-2 virus representing strains circulating in Europe in spring 2020 and also the variants of concern B.1.1.7 (Alpha), B.1.351 (Beta) and B.1.617.2 (Delta). In addition, AX677 is able to bind Omicron Spike protein just like the wild type Spike. The combination of the two antibodies prevented the appearance of escape mutations of the authentic SARS-CoV-2 virus. Prophylactic administration of AX290 and AX677, either individually or in combination, effectively reduced viral burden and inflammation in the lungs, and prevented disease in a mouse model of SARS-CoV-2 infection. INTERPRETATION: The virus-neutralizing properties were fully reproduced in chimeric mouse-human versions of the antibodies, which may represent a promising tool for COVID-19 therapy. FUNDING: The study was funded by AXON Neuroscience SE and AXON COVIDAX a.s.
- MeSH
- angiotensin-konvertující enzym 2 chemie genetika metabolismus MeSH
- antigenní drift a shift MeSH
- COVID-19 virologie MeSH
- farmakoterapie COVID-19 MeSH
- glykoprotein S, koronavirus genetika imunologie metabolismus MeSH
- imunodominantní epitopy imunologie MeSH
- kinetika MeSH
- lidé MeSH
- modely nemocí na zvířatech MeSH
- monoklonální protilátky imunologie terapeutické užití MeSH
- mutace MeSH
- myši MeSH
- neutralizační testy MeSH
- plíce patologie MeSH
- protinádorové látky imunologicky aktivní imunologie terapeutické užití MeSH
- SARS-CoV-2 genetika imunologie izolace a purifikace MeSH
- vazba proteinů MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Vyšetrovanie prípadov náhlych úmrtí je často predmetom súdnolekárskej praxe. V mnohých prípadoch ide o úmrtia z kardiovaskulárnych príčin. Stanoviť diagnózu náhlej srdcovej smrti len na základe morfologických nálezov môže byť niekedy veľmi obtiažne až nemožné. V diagnostike poškodenia myokardu u živých pacientov sa bežne využívajú biochemické markery kardiálny troponín I (cTnI) a atriálny natriuretický peptid (pro-ANP). Cieľ: Cieľom práce bolo overiť využitie biochemických markerov cTnI a pro-ANP v diagnostike náhlej srdcovej smrti. Pacienti a metódy: Predmetom štúdie bolo 89 nekroptických prípadov. V 53 prípadoch išlo o náhlu srdcovú smrť, 36 prípadov s inou ako kardiálnou príčinou smrti slúžilo ako kontrolný súbor. Koncentrácie markerov boli stanovené v krvi z ľavej komory srdca a pravej femorálnej vény. Bola zisťovaná závislosť medzi výsledkami biochemického vyšetrenia a príčinami smrti, morfologickými nálezmi v myokarde, časovým intervalom medzi smrťou a odberom vzoriek biologických materiálov a údajmi o resuscitácii. Výsledky: Koncentrácie cTnI zistené vo vzorkách krvi z ľavej komory srdca v prevažnej väčšine prípadov mnohonásobne prevyšovali cutoff hodnoty, podobne ako koncentrácie pro-ANP. Hodnoty obidvoch parametrov boli významne nižšie v periférnej krvi. Neboli zistené signifikantné vzťahy medzi hodnotami sledovaných markerov a príčinou smrti, histopatologickými nálezmi v myokarde, časovým intervalom medzi smrťou a odberom vzoriek a údajmi o resucitácii. Záver: Na základe získaných výsledkov je možné konštatovať, že krv nie je vhodný materiál na stanovenie biochemických markerov kardiálneho troponínu I a atriálneho natriuretického peptidu pre stanovenie diagnózy náhlej srdcovej smrti podobne ako pri zisťovaní poškodenia myokardu u klinických pacientov.
Introduction: Medical examiners frequently examine victims of sudden death. Most often sudden deaths have a cardiovascular cause. To determine the diagnosis of sudden cardiac death based only on morphological findings may be often very difficult. Measurement of blood concentrations of cardiac troponin I (cTnI) and atrial natriuretic peptide (pro-ANP) is now in clinical use in adult patients with heart failure caused by myocardial damage. Aim: The aim of the study was the estimation wheather cTnI and/or pro-ANP could be markers of sudden cardiac death. Patients and methods: The study was carried out on 89 necroptic cases, of which 53 were concluded as cardiac-related sudden death, and 36 cases were used as a control group being other than cardiac death cases. Concentrations of markers were determined in blood taken from the left cardiac ventricle and from the right femoral vein. The dependence between the results of biochemical studies and death causes, results of histopathological examination of myocardium, time interval between the death and taking of samples, and resuscitation data was investigated. Results: Concentrations of cTnI as determined in blood samples from the left ventricle were in most cases very high, largely exceeding the cut-off level, and so were concentrations of pro-ANP. The values of both parameters were significantly lower in peripheral blood. No statistically significant dependences were found between the levels of the studied markers and the cause of death, myocardial histopathological findings, time interval between the death and taking of samples, and resuscitation data. Conclusion: Based on the results obtained, the study can be concluded that blood is not a suitable medium for determination of biochemical markers of cardial troponin I and atrial natriuretic peptide for post-mortem diagnostics of myocardial damage and for determining the diagnosis of sudden cardiac death in a manner similar to diagnostics of myocardium damage in living patients.
- MeSH
- biologické markery krev MeSH
- dieta vegetariánská MeSH
- finanční podpora výzkumu jako téma MeSH
- hyperhomocysteinemie etiologie metabolismus MeSH
- lidé MeSH
- nedostatek vitaminu B12 komplikace prevence a kontrola MeSH
- oxidace-redukce MeSH
- produkty pokročilé glykace krev MeSH
- proteiny metabolismus MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- MeSH
- albuminy MeSH
- cystatiny krev metabolismus MeSH
- dialýza ledvin MeSH
- dospělí MeSH
- hodnoty glomerulární filtrace MeSH
- kreatinin krev MeSH
- lidé středního věku MeSH
- lidé MeSH
- referenční hodnoty MeSH
- renální insuficience diagnóza MeSH
- senioři MeSH
- sérový albumin MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- senioři MeSH
- MeSH
- biologické markery MeSH
- C-reaktivní protein krev MeSH
- dítě MeSH
- kalcitonin MeSH
- kojenec MeSH
- lidé MeSH
- neopterin krev MeSH
- novorozenec s velmi nízkou porodní hmotností MeSH
- novorozenec MeSH
- referenční hodnoty MeSH
- sepse diagnóza krev MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- novorozenec MeSH
- Publikační typ
- srovnávací studie MeSH
