Author interview: Dr. Arindam Ghosh is a Biophysicist by training. He develops cutting-edge fluorescence imaging and spectroscopy tools to answer questions in cancer immunology and cell membrane biophysics.
Lab: Prof. Markus Sauer, University of Würzburg, Germany
Research Summary: We developed a fast volumetric superresolution fluorescence imaging technology for elucidating the molecular binding mechanisms of immunotherapeutic monoclonal antibodies (mAbs) and their target receptor CD20.
What was the core problem you aimed to solve with this research?
Therapeutic monoclonal antibodies (mAbs) are used in the treatment of hematological malignancies. Binding of mAbs to target antigens triggers the activation of downstream cytotoxic pathways. CD20 is a surface marker on B cells targeted by mAbs, such as Rituximab (RTX), Ofatumumab (OFA), and Obinutuzumab (OBZ), for treating chronic lymphocytic leukemia (CLL). mAb-CD20 interaction alters the nanoscale organization of the latter, consequently leading to an immune response. However, the molecular interplay of mAb-CD20 and binding-induced reorganization of CD20 on the plasma membrane remains poorly understood. To decode such interactions, three-dimensional (3D) volumetric super-resolution fluorescence imaging methods are needed that provide a high spatiotemporal resolution.
How did you go about solving this problem?
To address the technological limitation, we developed a speed-optimized advanced variant of the single-molecule imaging modality DNA-points accumulation for imaging in nanoscale topography (DNA-PAINT). This new module, two-dye imager (TDI)-DNA-PAINT enabled ~15 fold faster imaging, compared to classical DNA-PAINT. For fast 3D imaging of B cell volumes at virtually molecular resolution, we combined TDI-DNA-PAINT with lattice light-sheet (LLS) microscopy. Utilizing 3D LLS-TDI-DNA-PAINT, we visualized the whole-cell nanoscale distribution of endogenous CD20 labeled by RTX, OFA, and OBZ. Moreover, we exploited 4D live-cell LLS imaging to elucidate the real-time binding interactions of mAbs and CD20.
“We can now observe how effectively the antibodies work and thus contribute to the development of improved therapies,”, Markus Sauer, PI.
How would you explain your research outcomes (Key findings) to the non-scientific community?
Immunotherapies are a new generation advanced line of treatments against blood cancers and many other malignancies. At the molecular scale, immunotherapies, such as engineered T cells (CAR T therapy), mAbs, bispecific antibodies, etc., rely on specific interactions between proteins residing on the membrane of cancer and immune cells. Our work provides a state-of-the-art technological platform to characterize and investigate such interactions in situ with high resolution in space and time. The findings also demonstrate that both type I (RTX, OFA) and type II (OBZ) mAbs can crosslink CD20 and polarize B cells at different molar concentrations, thus disproving the current classification of therapeutic mAbs based on their cross-linking efficiency.
What are the potential implications of your findings for the field and society?
This work, we believe, will open up a new interdisciplinary research direction, where clinical researchers and medical doctors can access these cutting-edge technologies for the design and characterization of next generation refined immunotherapies. As a result, patients will benefit from improved therapies in the future.
What was the exciting moment during your research?
There are in vitro studies existing that claim type II mAbs do not cross-link CD20. But these studies were on purified CD20. In our experiments, when I observed that type II mAbs can also crosslink endogenous CD20 on B cell membrane, this was surprising and super-exciting at the same time.
Paper reference: Ghosh, A.*#, Meub, M.#, Helmerich, D.A., Weingart, J., Eiring, P., Nerreter, T., Kortüm, K.M., Doose, S. and Sauer, M.*, 2025. Decoding the molecular interplay of CD20 and therapeutic antibodies with fast volumetric nanoscopy. Science, 387(6730), p.eadq4510. https://www.science.org/doi/10.1126/science.adq4510
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