Mission

TransBioLine aims to qualify protein biomarkers for drug-induced glomerular, liver, pancreatic, vascular and brain damage. We aim for identification of novel glomerular injury biomarkers in patients at risk and demonstrating how a panel of glomerular specific biomarkers can optimize insights to drug-induced renal injury. We aim to facilitate detection of subclinical (without alterations in serum-creatinine and progressive elevations of proteinuria) glomerular injury. We plan to include patients with preeclampsia as well as cancer patients treated with VEGF-inhibitors. Both disorders are associated with a significant degree of glomerular injury as manifested by progressive proteinuria and impairment of kidney function. 

The aim of WP2 is to identify new biomarkers that improve the diagnostic and prognostic assessment of Drug Induced Liver Injury (DILI). Once DILI has occurred in a patient, the subsequent clinical course is often difficult to predict with the use of standard parameters such as the aminotransferases ALT/AST. A new biomarker that assesses the risk of progression to more severe liver injury would be a major advance in the management of DILI. Moreover, new biomarkers may provide insight into the pathogenetic mechanisms and immune components that lead to idiosyncratic adverse hepatic reactions.

The remit of WP3 is to qualify biomarkers to detect and predict prognosis of pancreas injury associated with acute pancreatitis, including when caused by approved or experimental drugs.  Current biomarkers of pancreas injury (e.g. amylase, lipase) lack sufficient sensitivity and specificity to detect early stages of drug-induced pancreas injury or provide valuable prognostic information for the clinical management of acute pancreatitis. Although drug-induced pancreas injury (DIPI) is rare, the consequences can be severe.  Additionally, better safety biomarkers will allow progression of potentially impactful medicines into human clinical trials when pancreas effects are detected in pre-clinical toxicology studies that may or may not predict human pancreas injury.  Recent reports have shown the promise of using circulating micro-RNA (miR) as sensitive and specific biomarkers for DIPI.  Select proteins related to exocrine proteases have also shown utility.  WP3 will investigate both types of markers to determine if they will allow prognostic detection of acute pancreatitis. 

WP4 focusses on the discovery, evaluation and qualification of new biomarkers for drug-induced vascular injury (DIVI). Because this is a rare, but important type of organ injury to mitigate during drug development or evaluation, we take advantage of the strong similarity of tissue changes in DIVI and inflammation of blood vessels in systemic autoimmune diseases called vasculitides, as well as acute transient injury caused by angioplasty procedures. By analyzing blood-based proteins and microRNA biomarkers in systemic vasculitides, we seek to establish a sensitive and specific pattern of response to vascular injury. Ideally, this will allow detection and monitoring of DIVI. Because different organs may be involved in vascular injury, we collaborate with WP1, as kidney is a frequently involved site of vascular injury and detected by a similar set of urinary biomarkers.

The objective of the TransBioLine Drug Induced CNS Injury (DINI) Work Package is to qualify blood-based biomarkers of drug-induced CNS neurotoxicity to enable decisions (e.g. dose selection, termination, etc.) in early clinical trials with neurotoxicity risk.  DINI can lead to severe and irreversible neurological damage. Thus, early detection of DINI is of utmost importance and there is a pressing unmet medical need for safety biomarkers to safeguard healthy volunteers and patients from serious, irreversible CNS injury and to guide decision-making in early clinical trials.

Focusing on the discovery, evaluation and qualification of microRNAs in liquid biopsies as reliable, non-invasive, and sensitive safety biomarkers is the remit of WP6. Since the transcription of certain microRNAs is restricted to specific cell types they can be used as accessible tissue- and mechanism- specific biomarkers enabling an early and precise detection of drug-induced organ injuries. Within TransBioLine WP6 supports other work packages during the qualification of organ- and disease- specific microRNA signatures in 5 organ/disease areas, and to develop systems biology tools that will improve our understanding of the biological mechanisms underlying drug-induced tissue damage.

Work package 7 has two task areas: (i) sample workflow and management (Central Biomaterial Bank Charité, ZeBanC) and (ii) assay development and biomarker analysis (Signatope).

The ZeBanC is responsible for harmonisation of workflows, documents and the coordination of the interfaces within the context of the collection of biosamples. ID management as an important basis for the unique coding and linkage of patient data and samples is a further task of WP7. The ZeBanC guaranties quality-assured biobanking including sample storage, documentation and provision of samples for downstream analyses. In essence, the work of the ZeBanC provides an excellent basis for assay development as performed by the co-lead of WP7, Signatope.

Protein biomarkers have proven valuable in identifying drug safety issues. Certain proteins found in organs or certain cell types are released either actively by a mechanism or by cell death in the event of drug-induced organ injury. TransBioLine aims to qualify protein biomarkers for drug-induced  kidney, liver, pancreatic, vascular and  CNS damage.  Applied assay technologies include novel analytical strategies such as coupling immunoprecipitation with mass spectrometry and ultra-highly sensitive sandwich immunoassays as well as classical sandwich immunoassays. In order to demonstrate and test the translational character of biomarkers from preclinical to clinical studies, the assays can also be used for animal models.

WP8 provides the data management and the underlying infrastructure and tools for efficient data analysis across the consortium. In this context WP8 is leading a cross-WP group ensuring smooth communication and harmonised interaction between project stakeholders as well as information and data flows within the project. Alignments of data structure and semantics as well as general interoperability aspects are here the main focus points.

Objectives

  • Generate exploratory and confirmatory data enabling regulatory qualification of new safety biomarkers for application in drug development.
  • Establish robust datasets on the biomarkers across relevant patient populations to enhance diagnosis and prognosis of disease for application in clinical practice.
  • Implement profiles of circulating microRNAs as tissue- and mechanism- specific diagnostic tools, supported by suitable bioinformatics systems, to facilitate in-depth mechanistic understanding of drug side- effects and disease, and/or to strengthen risk assessment and safety monitoring.
  • Develop and validate assays for new safety biomarkers, suitable for application in drug development and clinical practice.
  • Have key safety biomarkers accepted as qualified drug development tools by EMA, FDA, and PMDA. Support continuous improvement of biomarker qualification methodology and processes in close collaboration with key regulatory agencies.
  • Facilitate sustainability of the consortium’s efforts by establishing and maintaining a European expert and knowledge network for biomarker qualification, the “Safety Biomarker Factory” and “Safety Biomarker Warehouse”, allowing for future continuous feed-in and qualification of new biomarker candidates, as well as access to comprehensive safety biomarker data.

Structure

WP9
Project management

Core Science Cluster

XWP Task Force
Cross-WP alignment
WP1
DIKI
WP2
DILI
WP3
DIPI
WP4
DIVI
WP5
DINI
WP6
LB
WP7
Assay/sample management
WP8
Data management and analysis
WP10
Regulatory interaction
WP11
Communication, dissemination, sustainability

Core Science Cluster

Organ Work Packages

Organ WPs (DIKI, DILI, DIPI, DIVI and DINI) are focused on study design/strategy, timely recruitment of the patients, sample acquisition, statistical analyses, and the selection, evaluation and qualification of respective biomarkers.

Assay and Biobank Work Packages

These WPs develop and provide assays for miRNA and protein biomarkers. WP7 will also be in-charged of sample management–sample shipment, biobanking, and sample data repository.

Data Management and Analysis

WP8 oversee and lead data capture, data management, and data analysis. In particular, setting up eCRFs and the consortium database is the responsibility of this WP.

 

Regulatory interactions

Management

Communication, Dissemunation & Sustainability