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Aggregated insoluble tau is one of two defining features of Alzheimer’s disease. Because clinical symptoms are strongly correlated with tau aggregates, drug development and clinical diagnosis need cost-effective and accessible specific fluid biomarkers of tau aggregates; however, recent studies suggest that the fluid biomarkers currently available cannot specifically track tau aggregates. We show that the microtubule-binding region (MTBR) of tau containing the residue 243 (MTBR-tau243) is a new cerebrospinal fluid (CSF) biomarker specific for insoluble tau aggregates and compared it to multiple other phosphorylated tau measures (p-tau181, p-tau205, p-tau217 and p-tau231) in two independent cohorts (BioFINDER-2, n  = 448; and Knight Alzheimer Disease Research Center, n  = 219). MTBR-tau243 was most strongly associated with tau-positron emission tomography (PET) and cognition, whereas showing the lowest association with amyloid-PET. In combination with p-tau205, MTBR-tau243 explained most of the total variance in tau-PET burden (0.58 ≤  R 2  ≤ 0.75) and the performance in predicting cognitive measures (0.34 ≤  R 2  ≤ 0.48) approached that of tau-PET (0.44 ≤  R 2  ≤ 0.52). MTBR-tau243 levels longitudinally increased with insoluble tau aggregates, unlike CSF p-tau species. CSF MTBR-tau243 is a specific biomarker of tau aggregate pathology, which may be utilized in interventional trials and in the diagnosis of patients. Based on these findings, we propose to revise the A/T/(N) criteria to include MTBR-tau243 as representing insoluble tau aggregates (‘T’). CSF MTBR-tau243 is more related to tau tangles and clinical cognitive impairment in Alzheimer’s disease than phospho-tau biomarkers, which are more related to amyloid plaques.

INTRODUCTION Incorporating blood‐based Alzheimer's disease biomarkers such as tau and amyloid beta (Aβ) into screening algorithms may improve screening efficiency. METHODS Plasma Aβ, phosphorylated tau (p‐tau)181, and p‐tau217 concentration levels from AHEAD 3–45 study participants were measured using mass spectrometry. Tau concentration ratios for each proteoform were calculated to normalize for inter‐individual differences. Receiver operating characteristic (ROC) curve analysis was performed for each biomarker against amyloid positivity, defined by > 20 Centiloids. Mixture of experts analysis assessed the value of including tau concentration ratios into the existing predictive algorithm for amyloid positron emission tomography status. RESULTS The area under the receiver operating curve (AUC) was 0.87 for Aβ42/Aβ40, 0.74 for phosphorylated variant p‐tau181 ratio (p‐tau181/np‐tau181), and 0.92 for phosphorylated variant p‐tau217 ratio (p‐tau217/np‐tau217). The Plasma Predicted Centiloid (PPC), a predictive model including p‐tau217/np‐tau217, Aβ42/Aβ40, age, and apolipoprotein E improved AUC to 0.95. DISCUSSION Including plasma p‐tau217/np‐tau217 along with Aβ42/Aβ40 in predictive algorithms may streamline screening preclinical individuals into anti‐amyloid clinical trials. ClinicalTrials.gov Identifier: NCT04468659 Highlights The addition of plasma phosphorylated variant p‐tau217 ratio (p‐tau217/np‐tau217) significantly improved plasma biomarker algorithms for identifying preclinical amyloid positron emission tomography positivity. Prediction performance at higher NAV Centiloid levels was improved with p‐tau217/np‐tau217. All models generated for this study are incorporated into the Plasma Predicted Centiloid (PPC) app for public use.

Background This phase 1 study examined the safety, maximum-tolerated dose (MTD) and antitumour activity of E7449, a novel PARP 1/2 and tankyrase 1/2 inhibitor. Methods E7449 was orally administered once daily in 28-day cycles to patients with advanced solid tumours (50–800-mg doses). Archival tumour samples from consenting patients were evaluated for the expression of 414 genes in a biomarker panel (2X-121 drug-response predictor [DRP]) found to be predictive of the response to E7449 in cell lines. Results Forty-one patients were enrolled (13 pancreatic, 5 ovarian, 4 each with breast, lung or colorectal cancer and 11 with other tumour types). The most common grade ≥3 treatment-related adverse event was fatigue ( n  = 7, 17.1%). Five patients experienced a dose-limiting toxicity (fatigue, n  = 4, 800 mg; anaphylaxis, n  = 1, 600 mg) for an MTD of 600 mg. E7449 exhibited antitumour activity in solid tumours, including 2 partial responses (PRs), and stable disease (SD) in 13 patients, which was durable (>23 weeks) for 8 patients. In 13 patients, the 2X-121 DRP identified those achieving PR and durable SD. E7449 showed good tolerability, promising antitumour activity and significant concentration-dependent PARP inhibition following 50–800-mg oral dosing. Conclusion The results support further clinical investigation of E7449 and its associated biomarker 2X-121 DRP. Clinical trial registration www.ClinicalTrials.gov code: NCT01618136.

Background No biomarkers have been established to predict treatment efficacy in renal cell carcinoma (RCC). In an exploratory retrospective analysis of a Phase 2 study, we constructed composite biomarker scores (CBSs) to predict progression-free survival (PFS) and overall survival (OS) in patients with metastatic RCC randomised to receive lenvatinib-plus-everolimus. Methods Of 40 biomarkers tested, the 5 most strongly associated with PFS (HGF, MIG, IL-18BP, IL-18, ANG-2) or OS (TIMP-1, M-CSF, IL-18BP, ANG-2, VEGF) were used to make a 5-factor PFS-CBS or OS-CBS, respectively. A 2-factor CBS was generated with biomarkers common to PFS-CBS and OS-CBS. Patients were divided into groups accordingly (5-factor-CBS high: 3−5, CBS-low: 0–2; 2-factor-CBS high: 1–2, CBS-low: 0). Results PFS/OS with lenvatinib-plus-everolimus were significantly longer in the 5-factor CBS-high group versus the CBS-low group ( P  = 0.0022/ P  < 0.0001, respectively). In the CBS-high group, PFS/OS were significantly longer with lenvatinib-plus-everolimus versus everolimus ( P  < 0.001/ P  = 0.0079, respectively); PFS was also significantly longer with lenvatinib-plus-everolimus versus lenvatinib ( P  = 0.0046). The 5-factor-CBS had a predictive role in PFS and OS after multivariate analysis. Similar trends were observed with the 2-factor-CBS for PFS (i.e., lenvatinib-plus-everolimus versus everolimus). Conclusions The 5-factor CBS may identify patients with metastatic RCC who would benefit from lenvatinib-plus-everolimus versus everolimus; additional validation is required. Clinical trial registration The clinical trial registration number is NCT01136733.

The G protein-coupled receptor (GPCR), chemokine CXC-type receptor 4 (CXCR4), and its ligand, CXCL12, mediate the retention of polymorphonuclear neutrophils (PMNs) and hematopoietic stem and progenitor cells (HSPCs) in the bone marrow. Agents that disrupt CXCL12-mediated chemoattraction of CXCR4-expressing cells mobilize PMNs and HSPCs into the peripheral circulation and are therapeutically useful for HSPC collection before autologous bone marrow transplantation (ABMT). Our aim was to develop unique CXCR4-targeted therapeutics using lipopeptide GPCR modulators called pepducins. A pepducin is a synthetic molecule composed of a peptide derived from the amino acid sequence of one of the intracellular (IC) loops of a target GPCR coupled to a lipid tether. We prepared and screened a small CXCR4-targeted pepducin library and identified several pepducins with in vitro agonist activity, including ATI-2341, whose peptide sequence derives from the first IC loop. ATI-2341 induced CXCR4-and G protein-dependent signaling, receptor internalization, and chemotaxis in CXCR4-expressing cells. It also induced dose-dependent peritoneal recruitment of PMNs when administered i.p. to mice. However, when administered systemically by i.v. bolus, ATI-2341 acted as a functional antagonist and dose-dependently mediated release of PMNs from the bone marrow of both mice and cynomolgus monkeys. ATI-2341-mediated release of granulocyte/macrophage progenitor cells from the bone marrow was confirmed by colony-forming assays. We conclude that ATI-2341 is a potent and efficacious mobilizer of bone marrow PMNs and HSPCs and could represent a previously undescribed therapeutic approach for the recruitment of HSPCs before ABMT.

Lenvatinib is a multikinase inhibitor of VEGFR1, VEGFR2, and VEGFR3, and other receptor tyrosine kinases. Pembrolizumab, an antibody targeting PD-1, has moderate efficacy in biomarker-unselected endometrial cancer. We aimed to assess the combination of lenvatinib plus pembrolizumab in patients with advanced endometrial carcinoma, after establishing the maximum tolerated dose in a phase 1b study. In this open-label, single-arm, phase 2 study done at 11 centres in the USA, eligible patients were aged 18 years or older and had metastatic endometrial cancer (unselected for microsatellite instability or PD-L1), had an Eastern Cooperative Oncology Group performance status of 0 or 1, had received no more than two previous systemic therapies, had measurable disease according to the immune-related Response Evaluation Criteria In Solid Tumors (irRECIST), and had a life expectancy of 12 weeks or longer. Patients received 20 mg oral lenvatinib daily plus 200 mg intravenous pembrolizumab every 3 weeks. Treatment continued until disease progression, development of unacceptable toxic effects, or withdrawal of consent. The primary endpoint of this interim analysis was the proportion of patients with an objective response at week 24 as assessed by investigators according to irRECIST in the per-protocol population. This trial is registered with ClinicalTrials.gov, number NCT02501096. Between Sept 10, 2015, and July 24, 2017, 54 patients were enrolled, 53 of whom were included in the analysis. At the cutoff date for anti-tumour activity data (Dec 15, 2017), median study follow-up was 13·3 months (IQR 6·7–20·1). 21 (39·6% [95% CI 26·5–54·0]) patients had an objective response at week 24. Serious treatment-related adverse events occurred in 16 (30%) patients, and one treatment-related death was reported (intracranial haemorrhage). The most frequently reported any-grade treatment-related adverse events were hypertension (31 [58%]), fatigue (29 [55%]), diarrhoea (27 [51%]), and hypothyroidism (25 [47%]). The most common grade 3 treatment-related adverse events were hypertension (18 [34%]) and diarrhoea (four [8%]). No grade 4 treatment-related adverse events were reported. Five (9%) patients discontinued study treatment because of treatment-related adverse events. Lenvatinib plus pembrolizumab showed anti-tumour activity in patients with advanced recurrent endometrial cancer with a safety profile that was similar to those previously reported for lenvatinib and pembrolizumab monotherapies, apart from an increased frequency of hypothyroidism. Lenvatinib plus pembrolizumab could represent a new potential treatment option for this patient population, and is being investigated in a randomised phase 3 study. Eisai and Merck.

BackgroundE7046 is a highly selective, small-molecule antagonist of the E-type prostanoid receptor 4 (EP4) for prostaglandin E2, an immunosuppressive mediator of the tumor immune microenvironment. This first-in-human phase 1 study assessed the safety, tolerability, pharmacokinetics, pharmacodynamics, maximum tolerated dose (MTD) and recommended phase 2 dose of E7046.MethodsThis first-in-human study enrolled 30 patients with advanced tumors of cancer types associated with high levels of myeloid infiltrates. E7046 was administered orally once-daily in sequential escalating dose cohorts (125, 250, 500, and 750 mg) with ≥6 patients per cohort. Tumor assessments were performed every 6 weeks. Paired tumor biopsies and blood samples, before and on treatment, were collected for pharmacokinetic and pharmacodynamic characterization of the treatment.ResultsNo dose-limiting toxicities were observed, and the MTD was not reached. E7046 had an elimination half-life (t1/2) of 12 hours, and drug exposure increased dose-dependently from 125 to 500 mg. Target modulation by E7046 was supported by changes in genes downstream of EP4 with concurrent enhanced antitumoral immune responses. A best response of stable disease (per irRECIST) was reported in 23% of patients treated with E7046 (n=30) (125 mg: n=2; 250 mg: n=2; 750 mg: n=3). Over half (4/7) of the patients with stable disease had treatment duration of 18 weeks or more, and three patients (3/15; 20%) achieved metabolic responses.ConclusionsIn this first-in-human study, E7046 administered orally once daily demonstrated manageable tolerability, immunomodulatory effects, and a best response of stable disease (≥18 weeks) in several heavily pretreated patients with advanced malignancies. The 250 and 500 mg doses are proposed for further development in the combination setting.Trial registration number NCT02540291.

Background Single analyte blood‐based biomarkers such as p‐tau181 and p‐tau217 are promising biomarkers for identifying Alzheimer's disease (AD) pathology. However, multi‐analyte blood‐based biomarker panels are needed to further improve the detection, differential diagnosis, and screening of AD and to predict disease progression and assess response to therapy. The Alamar NULISASeq CNS Disease Panel (“NULISASeq”) simultaneously profiles 120 proteins associated with neurodegeneration, synaptic, and inflammatory pathways to support these goals. Multiplexed panels also maximize the potential of precious clinical trial biospecimens while also providing the sensitivity required to measure low abundant analytes. Methods Plasma samples were collected during screening from a Phase 3 program for elenbecestat (MissionAD) in early AD and analyzed using NULISASeq. Data normalization was performed using the vendor protocol to form NULISA Protein Quantification (NPQ) units, used for statistical analysis. Analysis of Variance (ANOVA) was used to determine statistical significance of the difference in each target protein level between amyloid+ and amyloid‐ subjects as determined by PET visual read. p‐values were adjusted for multiplicity. Cohen's D was calculated to show the effect size of difference in target protein levels. The correlation of overlapping target protein levels between NULISASeq and other assays was evaluated. Results A total of 124 subjects were included in the statistical analysis (74 amyloid+ and 50 amyloid‐). Statistical significance was observed in 7 plasma proteins (GFAP, MAPT, NEFH, SNAP25, pTau‐181, pTau‐217, pTau‐231) between amyloid+ and amyloid‐ subjects. pTau‐217 showed the largest effect size. In predicting amyloid status, using pTau‐217 alone also resulted in the highest AUC (0.87). Combining these proteins did not result in much improvement in prediction. NULISASeq protein levels of common ATN biomarkers showed high correlation with that of other assays in both plasma and CSF. Conclusion Targeted multiplexed panels such as NULISASeq quantifies multiple analytes in a single run thereby reducing the amount of precious input material and the time required for analysis. This offers advantage over fluid and neuroimaging‐based measurements tailored to singular targets. We have demonstrated the utility of a multiplexed panel for reliable detection of amyloid status as well as highlighted the potential of discovering novel biomarkers associated with AD.

Background Long non‐coding RNAs (lncRNAs) play a significant role in the pathogenesis of Alzheimer's disease (AD). They modulate various cellular processes such as amyloid production, Tau hyperphosphorylation, neuroinflammation, and the impairment of mitochondrial and synaptic functions. Emerging studies have revealed that certain lncRNAs can encode small open reading frame‐derived peptides. However, the identification and understanding of the role of lncRNA‐encoded peptides in AD remain largely unexplored due to the inherent low abundance and small sizes of these peptides. Here, we leveraged the de novo peptide sequencing algorithm and a custom database to identify lncRNA‐encoded peptides in cerebrospinal fluid (CSF) of demented subjects Method We developed an innovative strategy to identify lncRNA‐encoded peptides in biofluids. A custom database of hypothetical peptides was generated by six‐frame translation of all lncRNAs from LNCipedia (www.lncipedia.org) and integrated to human SwissProt protein entries. MS data (PRIDE archive PXD016278) from CSF of demented subjects with (n = 29) or without (n = 31) amyloid positivity were analyzed. Peptide raw peak area intensities were quantile normalized and log2 transformed to reduce technical variation and ensure distribution symmetry. Differentially expressed peptides were identified via analysis of covariance after adjusting for age and gender, with the significant criteria based on 20% false discovery rate (FDR). Result The de novo‐assisted search of MS spectra identified 32,191 peptides at 0.1% global peptide‐level FDR. Mapping of de novo peptides to our custom database identified 99 lncRNA‐encoded peptides in CSF of demented subjects. 7/99 significantly (q<0.2; Cohens >0.8) altered lncRNA‐encoded peptides were linked to amyloid positivity. These peptides were translated from non‐coding regions of six lncRNA genes involved in the cellular processes relevant to AD, including tau protein aggregation and glutamatergic synapse plasticity. Conclusion This is the first study identifying differentially regulated lncRNA‐encoded peptides in the CSF of Ab+ (AD) and Ab‐ (non‐AD) dementia. Further investigation of novel lncRNA‐derived peptides lights a new beacon to explore their promising applications in AD diagnosis, staging, and future treatment strategies.

Background Existing copathologies, such as Lewy body (LB) disease, can introduce heterogeneity to AD pathogenesis and presentation of symptoms and likely influence disease progression. A seed amplification assay (SAA) that detects aggregated, misfolded α‐synuclein (α‐syn) can detect LB. Incorporation of SAA can characterize disease heterogeneity in AD and potentially predict disease progression. Methods A validated SAA was used to characterize α‐syn SAA status (Amprion Clinical Laboratory) in baseline CSF samples collected from a Phase 3 program for elenbecestat in subjects with MCI or mild dementia due to AD (NCT02956486). Samples were selected by PET visual read status. The sample set was enriched using subjects considered to be progressors or non‐progressors based on change in cognition (CDR‐SB) at 18 months, before assessment of SAA status. Results of α‐syn status were reported as Detected, Not Detected, or Indeterminate. The proportion of samples defined as Detected and Not Detected were summarized by amyloid status. Cognition, at baseline and longitudinally, was summarized by amyloid and α‐syn status. Available baseline A/T/N biomarkers were also summarized and compared. Results Among the 201 samples that were included in the analyses, 15% of amyloid+ and 8% of amyloid‐ MCI/early AD subjects were determined to be SAA+ and hence determined to have LB copathology. In comparison, in ADNI, 17% of cognitively unimpaired (CU) subjects; 20% of MCI subjects and 39% of AD subjects had synuclein copathology (Tosun et al Alzheimer's Dement. 2024). In BioFinder2, synuclein copathology was detected in 8%, 17% and 23% of CU, MCI, and AD subjects, respectively (Palmqvist et al and Quadalti et al Nature Medicine 2023). The longitudinal trajectory of amyloid positive subjects with α‐syn copathology seemed to have faster cognitive decline in natural history studies. In the Phase 3 samples, the longitudinal cognitive trajectory showed trend towards faster decline over 18 months in the amyloid+ subjects with α‐syn copathology; however, this did not appear significant. Conclusion LB, a common copathology of AD, may be a source of heterogeneity. Incorporation of SAA, a specific biomarker of LB‐pathology, can help account for disease heterogeneity and potentially improve assessment of treatment response in amyloid and synuclein status confirmed AD target population.