Biology subjects

Keenan, B.

Publications and source records attributed to Keenan, B..

5 recordsLinked to original sources

bioRxiv2026

Statistical Methodology for Qualification of a Non-Clinical Risk Assessment Peptide:T Cell Proliferation Assay to Support Decision Making

Antibody- and cell-mediated immune responses against biologics, should they occur, can impact treatment efficacy and potentially pose severe risks to patient safety. Therefore, developers have focused on advancing strategies to mitigate such unwanted immunogenicity. Opportunities to address immunogenicity early in the development process, particularly during the drug design phase, have been identified. In vitro and in silico tools that facilitate the identification and removal of sequence liabilities have been established. For example, human cell-based in vitro T cell assays can be used to identify and remove CD4+ T cell epitopes, which are known to play a critical role in the development of anti-drug antibodies against recombinant proteins products as well as the transgenes of gene and therapy. Despite their widespread use in the industry, most of these assays lack thorough characterization, which undermines confidence in the results and comparability across laboratories. In this study, concepts of immunogenicity bioanalytical assay validation for study design and analysis were applied to characterize an internal CD4+ T cell proliferation assay as fit-for-purpose. A statistical path was applied to establish data acceptance criteria for handling of replicates, positivity and negativity of a signal, and donor cohort size. A Bayesian analysis was also performed and is proposed as an approach for sequence de-risking decision making. The in-depth characterization of the CD4+ T cell proliferation assay described here allows for accurate interpretation of the assay outcomes, thereby enhancing confidence in using this approach for mitigating the immunogenicity of biologics by design.

immunology↗

bioRxiv2025

LONGITUDINAL CHANGES IN WHITE MATTERMICROSTRUCTURAL STATUS FOLLOWING QUANTIFIEDHEAD-BALL IMPACTS IN SOCCER: A PRELIMINARY,PROSPECTIVE STUDY.

Repetitive, sub-concussive head impacts have been associated with increased chronic traumatic encephalopathy (CTE) incidence. CTE diagnosis traditionally relies on post-mortem examination, which limits precise correlation between cause- and-effect. This prospective study embraced innovative diffusion magnetic resonance imaging, which enables in vivo quantification of acute, sub-acute and chronic changes in brain tissue microstructure. This approach was used to evaluate changes in white matter microstructural status at intervals up to 180 days following a specified soccer heading protocol. This study was approved by the university ethics panel. Twelve males (21 - 23 years) were recruited to the study and gave signed, informed consent. Six Intervention participants were university-level soccer players, with 6 Control participants drawn from university-level non-contact sports. Multi-shell diffusion-weighted MRI data were acquired on a 3T Siemens Connectom (300mT/m) scanner using the HARDI protocols. Baseline measures of fractional anisotropy, mean diffusivity and mean kurtosis were acquired at day 0. The Intervention cohort then performed 10 soccer headers in a laboratory, with acceleration-time data captured using an instrumented mouthguard and post-processed to report common metrics. The Intervention group was then re-scanned at day 1 (n = 6), day 90 (n = 5) and day 180 (n = 4). The Control group was re-scanned at day 1 (n = 6) and day 180 (n = 3). Many brain tracts were identified as having significant (p < 0.05) changes in white matter microstructural changes at day 90, which correlated strongly with the magnitude of head impact. A smaller number of tracts had changes at day 1 and day 180. These results indicate that, within this pilot population, the magnitude of repeated soccer headers appears to correlate with the magnitude of white matter microstructural change. Additional investigation is required to determine whether the effect of such an intervention influences long-term brain health risk.

bioengineering↗

bioRxiv2024

HLAIIPred: Cross-Attention Mechanism for Modeling the Interaction of HLA Class II Molecules with Peptides

We introduce HLAIIPred, a deep learning model to predict peptides presented by class II human leukocyte antigens (HLAII) on the surface of antigen presenting cells. HLAIIPred is trained using a Transformer-based neural network and a dataset comprising of HLAII-presented peptides identified by mass spectrometry. In addition to predicting peptide presentation, the model can also provide important insights into peptide-HLAII interactions by identifying core peptide residues that form such interactions. We evaluate the performance of HLAIIPred on three different tasks, peptide presentation in monoallelic samples, immunogenicity prediction of therapeutic antibodies, and neoantigen prioritization for cancer immunotherapy. Additionally, we created a dataset of biotherapeutics HLAII peptides presented by human dendritic cells. This data is used to develop screening strategies to predict the unwanted immunogenic segments of therapeutic antibodies by HLAII presentation models. HLAIIPred demonstrates superior or equivalent performance when compared to the latest models across all evaluated benchmark datasets. We achieve a 16% increase in prediction of presented peptides compared to the second-best model on a set of unseen peptides presented by less frequent alleles. The model improves clinical immunogenicity prediction, identifies epitopes in therapeutic antibodies and prioritize neoantigens with high accuracy. HIGHLIGHTS* We developed a deep learning model to address the shortcomings of existing models for the prediction of peptides presented by HLAII molecules. * The model is end-to-end and context-free, requiring only a peptide sequence and available HLAII alleles as input. * HLAIIPred outperforms the state-of-the-art models on multiple benchmark datasets. * The model is able to predict the core residues of peptides that interact with HLAIIs. * We created experimental data and developed screening strategies to accurately predict the immunogenic hotspots in therapeutic antibodies.

bioinformatics↗

bioRxiv2023

Screening effects of HCN channel blockers on sleep/wake behavior in zebrafish

Hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channels generate electrical rhythmicity in various tissues although primarily heart, retina and brain. The HCN channel blocker compound, Ivabradine (Corlanor), is approved by the US Food and Drug Administration (FDA) as a medication to lower heart rate by blocking hyperpolarization activated inward current in the sinoatrial node. In addition, a growing body of evidence suggests a role for HCN channels in regulation of sleep/wake behavior. Zebrafish larvae are ideal model organisms for high throughput drug screening, drug repurposing and behavioral phenotyping studies. We leveraged this model system to investigate effects of three HCN channel blockers (Ivabradine, Zatebradine Hydrochloride and ZD7288) at multiple doses on sleep/wake behavior in wild type zebrafish. Results of interest included shorter latency to day time sleep at 0.1 M dose of Ivabradine (ANOVA, p:0.02), moderate reductions in average activity at 30 M dose of Zatebradine Hydrochloride (ANOVA, p:0.024) in daytime, and increased nighttime sleep at 4.5 M dose of ZD7288 (ANOVA, p:0.036). These differences support the hypothesis that compounds blocking HCN channels decreases wakefulness. HighlightsO_LIA drug screening study in which effects of HCN channel blocker compounds were tested displayed decreased wakefulwness in zebrafish. C_LIO_LIThere was modest evidence of these drugs on sleep and wake phenotypes including shorter latency to sleep, moderate reductions in average activity and increased sleep at different doses of three compounds compared to DMSO. C_LIO_LIWhile several specific doses of Ivabradine, Zatebradine hydrochloride or ZD7288 demonstrated some differences compared to DMSO, effects of these compounds was smaller than the effect of melatonin, a positive control. C_LI

pharmacology and toxicology↗

bioRxiv2017

The Multiple Sclerosis Genomic Map: Role of peripheral immune cells and resident microglia in susceptibility

AbstractWe assembled and analyzed genetic data of 47,351 multiple sclerosis (MS) subjects and 68,284 control subjects and establish a reference map of the genetic architecture of MS that includes 200 autosomal susceptibility variants outside the major histocompatibility complex (MHC), one chromosome X variant, and 32 independent associations within the extended MHC. We used an ensemble of methods to prioritize up to 551 potentially associated MS susceptibility genes, that implicate multiple innate and adaptive pathways distributed across the cellular components of the immune system. Using expression profiles from purified human microglia, we do find enrichment for MS genes in these brain - resident immune cells. Thus, while MS is most likely initially triggered by perturbation of peripheral immune responses the functional responses of microglia and other brain cells are also altered and may have a role in targeting an autoimmune process to the central nervous system.\n\nOne Sentence SummaryWe report a detailed genetic and genomic map of multiple sclerosis, and describe the role of putatively affected genes in the peripheral immune system and brain resident microglia.

genetics↗