Biokine (Israel)

Primary sclerosing cholangitis (PSC) is a rare, progressive disease, characterized by inflammation and fibrosis of the bile ducts, lacking reliable prognostic biomarkers for disease activity. Machine learning applied to broad proteomic profiling of sera allowed for the discovery of markers of disease presence, severity, and cirrhosis and the exploration of the involvement of CCL24, a chemokine with fibro-inflammatory activity. Sera from 30 healthy controls and 45 PSC patients were profiled with proximity extension assay, quantifying the expression of 2870 proteins, and used to train an elastic net model. Proteins that contributed most to the model were tested for correlation to enhanced liver fibrosis (ELF) score and used to perform pathway analysis. Statistical modeling for the presence of cirrhosis was performed with principal component analysis (PCA), and receiver operating characteristics (ROC) curves were used to assess the useability of potential biomarkers. The model successfully predicted the presence of PSC, where the top-ranked proteins were associated with cell adhesion, immune response, and inflammation, and each had an area under receiver operator characteristic (AUROC) curve greater than 0.9 for disease presence and greater than 0.8 for ELF score. Pathway analysis showed enrichment for functions associated with PSC, overlapping with pathways enriched in patients with high levels of CCL24. Patients with cirrhosis showed higher levels of CCL24. This data-driven approach to characterize PSC and its severity highlights potential serum protein biomarkers and the importance of CCL24 in the disease, implying its therapeutic potential in PSC.

Abstract NTX1088, a first-in-class anti-PVR (CD155) monoclonal antibody (mAb), is currently evaluated in a Phase 1, open-label, multi-center study (NCT05378425), initiated at MD Anderson Cancer center. Study objectives are safety, dose-finding, and efficacy with focus on pharmacokinetics, pharmacodynamics, and biomarker discovery. NTX1088 will be investigated as a single agent and combined with the anti-PD1 mAb, pembrolizumab (Keytruda) in patients with locally advanced and metastatic solid malignancies. NTX1088 is a humanized, IgG4-S228P mAb that binds PVR with sub-nM affinity and blocks all known interacting receptors with a single nM EC50. PVR, is a membranal protein, highly upregulated on tumor cells, across multiple cancer types. PVR expression has been associated with worse patient outcomes, due to its role in immune suppression. PVR’s impact on immune cells is mediated through interaction with the key stimulatory receptor, DNAM1 (CD226), on T and NK cells, leading to internalization and degradation of DNAM1. Additionally, PVR is the ligand for the inhibitory immune checkpoint receptors, TIGIT, CD96 and KIR2DL5A. Blocking PVR by NTX1088, therefore, has a multi-faceted immune-stimulating role, through restoration of DNAM1 expression and its immune activation function, while simultaneously neutralizing TIGIT, CD96 and KIR2DL5A inhibitory signals in immune cells. Importantly, DNAM1 downmodulation was recently identified as a key resistance mechanism to approved immune checkpoint inhibitors (ICIs), and its restoration by NTX1088 is a novel MoA, not demonstrated by other therapies. In vitro, as a monotherapy, NTX1088 significantly increased immune cell activation, and was superior to TIGIT, CD112R, and PD1 antibody blockade, leading to greater immune-mediated tumor cell killing, IFNγ secretion, and CD137 induction. Importantly, only NTX1088 was able to restore DNAM1 to the surface of immune cells in all experimental settings. Synergy was observed when NTX1088 was combined with PD1 blockers, or with the anti-CD112R mAb, NTX2R13, in line with the restoration of DNAM1 expression. Numerous humanized murine xenograft models were investigated. NTX1088 exhibited robust tumor growth inhibition as a standalone and in combination with PD1 blockade. Syngeneic models of PVRK.O resulted in complete immune-mediated tumor regression, including hard to treat colorectal tumors. In conclusion, PVR blockade by NTX1088 has a remarkable pre-clinical efficacy, suggesting a potential clinical breakthrough, based on the ability of simultaneously overcome multiple tumor escape mechanisms. First-in-human (FIH) trial is currently ongoing and biomarker data is analyzed to assess clinical impact of the drug and prepare for patient stratification. Citation Format: Anas Atieh, Akram Obiedat, Alon Vitenshtein, Guy Cinamon, Keren Paz, Tihana lenac, Paola Kucan, Marija Mazor, Ofer Mandelboim, Stipan Jonji, Pini Tsukerman. Phase I trial of first-in-class anti-PVR mAb NTX1088: Restoration of DNAM1 expression as MOA for enhanced antitumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6657.

<div>AbstractPurpose:<p>Pancreatic ductal adenocarcinoma (PDAC) is largely unresponsive to checkpoint inhibitors. Blockade of the CXCR4/CXCL12 axis increases intratumoral trafficking of activated T cells while restraining immunosuppressive elements. This study evaluates dual blockade of CXCR4 and PD1 with chemotherapy in PDAC.</p>Patients and Methods:<p>Multicenter, single-arm, phase II study to evaluate the safety and efficacy of motixafortide and pembrolizumab combined with chemotherapy in patients with <i>de novo</i> metastatic PDAC and disease progression on front-line gemcitabine-based therapy (NCT02826486). Subjects received a priming phase of motixafortide daily on days 1–5, followed by repeated cycles of motixafortide twice a week; pembrolizumab every 3 weeks; and nanoliposomal irinotecan, fluorouracil, and leucovorin every 2 weeks (NAPOLI-1 regimen). The primary objective was objective response rate (ORR). Secondary objectives included overall survival (OS), progression-free survival (PFS), disease control rate (DCR), safety, and tolerability.</p>Results:<p>A total of 43 patients were enrolled. The ORR according to RECISTv1.1 was 21.1% with confirmed ORR of 13.2%. The DCR was 63.2% with median duration of clinical benefit of 5.7 months. In the intention-to-treat population, median PFS was 3.8 months and median OS was 6.6 months. The triple combination was safe and well tolerated, with toxicity comparable with the NAPOLI-1 regimen. Notably, the incidence of grade 3 or higher neutropenia and infection was 7%, lower than expected for this chemotherapy regimen.</p>Conclusions:<p>Triple combination of motixafortide, pembrolizumab, and chemotherapy was safe and well tolerated, and showed signs of efficacy in a population with poor prognosis and aggressive disease.</p></div>

Impaired motor learning in individuals with Parkinson's disease is often attributed to deficits in executive function, which serves as an important cognitive process supporting motor learning. However, less is known about the role of other cognitive domains and its association with motor learning in Parkinson's disease. The objective of this study was to investigate the associations between motor learning and multiple domains of cognitive performance in individuals with Parkinson's disease. Twenty-nine participants with Parkinson's disease received comprehensive neuropsychological testing, followed by practice of a bimanual finger sequence task. A retention test of the finger sequence task was completed 24 h later. Hierarchical linear regressions were used to examine the associations between motor learning (acquisition rate and retention) and cognitive performance in five specific cognitive domains, while controlling for age, sex, and years of Parkinson's disease diagnosis. We found that a higher acquisition rate was associated with better episodic memory, specifically better recall in visual episodic memory, in individuals with Parkinson's disease. No significant associations were observed between retention and cognitive performance in any domains. The association between motor acquisition and episodic memory indicates an increased dependency on episodic memory as a potential compensatory cognitive strategy used by individuals with Parkinson's disease during motor learning.

The ability to successfully navigate obstacles in our environment requires integration of visual information about the environment with estimates of our body's state. Previous studies have used partial occlusion of the visual field to explore how information about the body and impending obstacles are integrated to mediate a successful clearance strategy. However, because these manipulations often remove information about both the body and obstacle, it remains to be seen how information about the lower extremities alone is utilized during obstacle crossing. Here, we used an immersive virtual reality (VR) interface to explore how visual feedback of the lower extremities influences obstacle crossing performance. Participants wore a head-mounted display while walking on treadmill and were instructed to step over obstacles in a virtual corridor in four different feedback trials. The trials involved: (1) No visual feedback of the lower extremities, (2) an endpoint-only model, (3) a link-segment model, and (4) a volumetric multi-segment model. We found that the volumetric model improved success rate, placed their trailing foot before crossing and leading foot after crossing more consistently, and placed their leading foot closer to the obstacle after crossing compared to no model. This knowledge is critical for the design of obstacle negotiation tasks in immersive virtual environments as it may provide information about the fidelity necessary to reproduce ecologically valid practice environments.

CXCR4 is a key player in the retention and survival of human acute myeloid leukemia (AML) blasts in the bone marrow (BM) microenvironment. We studied the effects of the CXCR4 antagonist BL-8040 on the survival of AML blasts, and investigated the molecular mechanisms by which CXCR4 signaling inhibition leads to leukemic cell death. Treatment with BL-8040 induced the robust mobilization of AML blasts from the BM. In addition, AML cells exposed to BL-8040 underwent differentiation. Furthermore, BL-8040 induced the apoptosis of AML cells in vitro and in vivo. This apoptosis was mediated by the upregulation of miR-15a/miR-16-1, resulting in downregulation of the target genes BCL-2, MCL-1 and cyclin-D1. Overexpression of miR-15a/miR-16-1 directly induced leukemic cell death. BL-8040-induced apoptosis was also mediated by the inhibition of survival signals via the AKT/ERK pathways. Importantly, treatment with a BCL-2 inhibitor induced apoptosis and act together with BL-8040 to enhance cell death. BL-8040 also synergized with FLT3 inhibitors to induce AML cell death. Importantly, this combined treatment prolonged the survival of tumor-bearing mice and reduced minimal residual disease in vivo. Our results provide a rationale to test combination therapies employing BL-8040 and BCL-2 or FLT3 inhibitors to achieve increased efficacy of these agents.

Human pelvic floor muscles have been shown to operate synergistically with a wide variety of muscles, which has been suggested to be an important contributor to continence and pelvic stability during functional tasks. However, the neural mechanism of pelvic floor muscle synergies remains unknown. Here, we test the hypothesis that activation in motor cortical regions associated with pelvic floor activation are part of the neural substrate for such synergies. We first use electromyographic recordings to extend previous findings and demonstrate that pelvic floor muscles activate synergistically during voluntary activation of gluteal muscles, but not during voluntary activation of finger muscles. We then show, using functional magnetic resonance imaging (fMRI), that a region of the medial wall of the precentral gyrus consistently activates during both voluntary pelvic floor muscle activation and voluntary gluteal activation, but not during voluntary finger activation. We finally confirm, using transcranial magnetic stimulation, that the fMRI-identified medial wall region is likely to generate pelvic floor muscle activation. Thus, muscle synergies of the human male pelvic floor appear to involve activation of motor cortical areas associated with pelvic floor control.