According to the NIH “Biomarkers and Surrogate Endpoint Working Group”, biomarkers can be classified into three types:
Type 0 biomarkers are markers of the natural history of a disease and correlate longitudinally with known clinical indices (stratifying markers).
Type I biomarkers capture the effects of a therapy/intervention in accordance with the mode-of-action of the drug (response markers).
Type II biomarkers are considered surrogate endpoints because a change in that markers predicts clinical benefit (intend to substitute for a clinical endpoint).
The opportunities for biomarker-driven IS and IS drug/strategy development are exiting, offering a more personalized treatment after transplantation. If the roadmap is visible, why did we not move forward so far (no biomarker-driven IS so far), what are the road blocking issues ? The risks associated with this approach are considerable as well. The analytical validation is a precondition before biomarker-associated or even biomarker–driven clinical trials begin to develop cut-off values and establish performance of the assay technology. An invalid biomarker, a suboptimal technology to assess the biomarker, a technically difficult assay (including sensitive pre-analytics) that provides inconclusive or unreliable results can each confound the clinical trial interpretation. To validate a biomarker-driven therapy strategy, it requires enormous and costly efforts. These challenges can only be solved by closed collaboration between experienced academic groups, SMEs, and industry in multinational networks, as realized in this consortium, BIODrIM.
Below there is a list of some recent research achievements of key persons of the BIO-DrIM consortium:
first description of a molecular signature and the particular expansion of a B cell subset in operationally tolerant kidney transplant patients (S. Brouard)
first blinded cross-over validated molecular signature in operationally kidney transplant patients (M Hernandez-Fueyo, B.Sawitzki, S.Brouard, H.-D.Volk – IOT/RISET consortia)
first description of a molecular signature in blood and liver of operationally tolerant liver transplant patients, and validation by analyzing the outcome of IS withdrawal according to the tolerance pattern (A. Sanchez-Fuerto)
key insights into the mechanisms of transplantation tolerance in preclinical models and development of tolerance success/failure-associated biomarkers suitable for monitoring in patients (K.Wood, B.Sawitzki, H.-D.Volk, P.Reinke)
development of a novel technology platform for analyzing antigen-specific T cells in a HLA/ epitope-independent way by using whole protein-spanning overlapping peptide libraries (P.Reinke, H.-D.Volk)
PoC trials of adoptive T cell therapy in transplant patients (P.Reinke, H.-D.Volk)
Establishment of a “humanized” scid mouse model for testing immunoregulatory principles using human T cells (K.Wood)
Role of immature dendritic cells in inducing tolerance (C.Cuturi)
Revealing the role of donor-specific memory T cells as “bad guys” in transplantation (P.Reinke, O.Bestard)
The clinical partners of the BIO-DrIM consortium are well recognized as experts in designing and performing novel investigator-driven and industry-sponsored clinical trials (J.Grinyo, B.Nashan, B.Banas, R.I.M. ten Berge, S.Brouard, O.Bestard, O. Viklicky, A. Pascher, P.Reinke). They contributed significantly to the approval of novel drugs and combinatory approaches.
- WO002008081039: Methods and kits for diagnosis and/or prognosis of the tolerant state in liver transplantation (2008) – P4 Sanchez-Fueyo et al.
- WO002010000320: In vitro diagnosis/prognosis method and kit for assessment tolerance in liver transplantation (2010) – P4 Sanchez-Fueyo et al.
- WO002011138609: Method for determining kidney transplant tolerance (2011) P4+P1 Hernandez-Fuentes/Sawitzki/Volk et al.
- WO002007138011: Methods for diagnosing and treating graft rejection and inflammatory conditions (2007) – P2 Brouard et al.
- WO002002084567: Method for analysing T lymphocytes with the aid of T lymphocyte receptors of an organism (2002) – P2 Sollilou/Brouard et al.
- WO002005070086: Mehods and compositions for determining a graft tolerant phenotype in a subject (2005) – P2 Sollilou/Brouard et al.
- WO002006131537: Diagnostic of immune graft tolerance (2006) – P2 Brouard/Sollilou et al.
- WO002008138928: Diagnostic of immune graft tolerance (2008) – P4 Brouard et al.
- WO002009101083: PSMB10: A diagnosis marker and therapeutic target of chronic rejection (2009) – P4 Brouard et al.
- WO002004018504: Immune markers used for diagnosis and therapy in connection with transplant rejection (2004) – P1+P3 Sawitzki/Volk/Wood et al.
- WO002001063286: Method for antigen-specific stimulation of T-lymphocytes with synthetic peptide libraries (2001) - P1 Volk/Reinke et al.
- WO002007125362: Production and use of regulatory T cells (2007) – P3 Wood et al.
The Business Development of the Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Berlin, a joined translational center of Charité and Helmholtz-Center Gesthaacht, performed a patent search on biomarkers in transplantation. About 80 patent families were found, but much less in relation to tolerance and IS minimization strategies. Most of the latter belong to members of the consortium (core labs).
Some key patent families (each family consists of several files) are:
Additional patents were filed by consortium members within the last months (not yet published).