Quint, W. H. | Search bioRxiv

bioRxiv2024

DNA methylation database for gynecological cancer detection, classification and assay development

Changes in the genome wide DNA methylation landscape are hallmarks of cancer cells and precursor lesions of cancers. To capitalize on utilizing DNA methylation for detection and classification of cancer, we generated a DNA methylation database of gynecological cancers and associated healthy tissues using Methylated DNA sequencing (MeD-seq). We show that target cell enrichment to generate the database is crucial for marker discovery and report a wide range of novel biomarkers for classification and tissue of origin determination of gynecological cancers. We developed a subset of these novel biomarkers, both intragenic and intergenic, into a qMSP assays that detect all gynecological cancers at once or specific gynecological cancer subtypes, as well as cancers that are not part of our database. The database generated in this study not only provides the foundation for cancer detection, classification and biomarker discovery, but also for treatment monitoring of cancers using MeD-seq on liquid biopsies.

cancer biology↗

bioRxiv2020

Bispecific tau antibodies with additional binding to C1q or alpha-synuclein

BackgroundAlzheimers disease (AD) and other tauopathies are neurodegenerative disorders characterized by cellular accumulation of aggregated tau protein. Tau pathology within these disorders is accompanied by chronic neuroinflammation, such as activation of the classical complement pathway by complement initiation factor C1q. Additionally, about half of the AD cases present with inclusions composed of aggregated alpha-synuclein called Lewy bodies. Lewy bodies in disorders such as Parkinsons disease and Lewy body dementia also frequently occur together with tau pathology. Immunotherapy is currently the most promising treatment strategy for tauopathies. However, the presence of multiple pathological processes within tauopathies makes it desirable to simultaneously target more than one disease pathway. MethodsHerein, we have developed three bispecific antibodies based on published antibody binding region sequences. One bispecific antibody binds to tau plus alpha-synuclein and two bispecific antibodies bind to tau plus C1q. ResultsThe affinity of the bispecific antibodies to their targets compared to their monospecific counterparts ranged from nearly identical to one order of magnitude lower. All bispecific antibodies retained binding to aggregated protein in patient-derived brain sections. The bispecific antibodies also retained their ability to inhibit aggregation of recombinant tau, regardless of whether the tau binding sites were in IgG or scFv format. Mono- and bispecific antibodies inhibited cellular seeding induced by AD-derived pathological tau with similar efficacy. Finally, both Tau-C1q bispecific antibodies completely inhibited the classical complement pathway. ConclusionBispecific antibodies that bind to multiple pathological targets may therefore present a promising approach to treat tauopathies and other neurodegenerative disorders.

neuroscience↗