Target-to-B!

B cells exert multiple essential functions in our immune system: production of protective antibodies, immunomodulatory cytokines, and antigen-presentation to T cells. Dysregulated activation of B cells forms the basis of a wide variety of B-immune-mediated diseases (B-IMD) characterized by production of disease-causing pathogenic autoantibodies or oncogenic transformation of B cells in various malignancies (B-ONC). The crucial role of B-cells and antibodies in B-IMD/B-ONC pathology is evident from the clinical observation that B-cell and IgG-targeted therapies can be highly effective. Therefore, B cell dysfunction is the central theme of our ‘out-of-balance’ research program, whereby we take the parallels in pathogenesis and treatment strategies across different B-IMDs as well as between B-IMDs and B-ONCs as a critical starting point.

At present, the underlying pathogenic mechanisms in B-IMDs and B-ONCs, their commonalities and differences in cellular functionality, remain unknown. Moreover, functional consequences of structural characteristics of antibodies, e.g. the extent and role of antibody glycosylation, in immune activation are undefined. A coherent pathophysiological underpinning of why, where, and when B cell or antibody-targeting strategies are effective is missing.

Our consortium

Our B cell consortium includes both clinical, translational and fundamental research groups and companies, together with various patient organisations. We are thus combining our strength in immunology, hemato-oncology, diagnostics and clinical experience. Patients from various B-IMD/B-ONC cohorts of ongoing studies will be studied over a longer period of time for clinical (outcome measures) and state-of-the-art immunological, biochemical and molecular parameters. Clinical data and materials collected longitudinally in the past and from current inclusions will be available for our network.
Our joint expertise in both relatively common (e.g. rheumatoid arthritis, pemphigus-like disorders, chronic lymphatic leukemia) and rare (e.g. idiopathic thrombocytopenic purpura, autoimmune-encephalitis, multiple sclerosis, autoimmune nephritis, follicular lymphoma) diseases enables a better definition of common principles and pathways operative to improve disease-specific and/or patient-tailored treatment outcomes.
Our ambition is (i) to integrate and expand current knowledge on these diseases, (ii) to establish a harmonized immune monitoring platform and (iii) to provide mechanistic understanding to predict outcome and develop innovative treatment modalities.
This should lead to major advances of our insight into B-IMD/B-ONC pathogenesis and to significant improvement of therapy efficacy for these serious diseases.

The T2B program aims to provide disease-overarching underpinnings and to create a solid basis for targeted and effective treatment protocols. For example, novel ‘biologicals’ or small-molecule inhibitors targeting BCR-signaling (inhibitors of BTK, PI3K) or B-cell survival show clinically proven efficacy in B-ONCs (1-3). It is currently not clear in which B-IMDs or at which disease-stage these compounds could also be therapeutically applied. By introduction of B-cell oncology expertise into the B-IMD field , novel therapeutic targets in B-IMD could be uncovered. Conversely, development of improved therapeutic options for B-ONC patients will benefit from harmonized immunomonitoring, and increased fundamental insight into B-cell biology.
Early therapy tailoring for non-responder patients would greatly enhance therapy efficacy. Moreover, alternative B-cell-targeting strategies are needed in B-IMD/B-ONC to secure the best outcome with least side-effects.