A microfluidic bone marrow chip for the safety profiling of biologics in pre-clinical drug development
Abstract Hematologic adverse events are common dose-limiting toxicities in drug development. Classical animal models for preclinical safety assessment of immunotherapies are often limited due to insufficient cross-reactivity with non-human homologous proteins, immune system differences, and ethical...
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Nature Portfolio
2025-05-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-025-08137-1 |
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| author | Leopold Koenig Laurent Juglair Thi Phuong Tao Susanne Fischer Inga Clausen Sabine Imhof-Jung Niels Janssen Robert Mader Daniel Marbach Jens Niewoehner Annika Winter Desirée Schubert |
| author_facet | Leopold Koenig Laurent Juglair Thi Phuong Tao Susanne Fischer Inga Clausen Sabine Imhof-Jung Niels Janssen Robert Mader Daniel Marbach Jens Niewoehner Annika Winter Desirée Schubert |
| author_sort | Leopold Koenig |
| collection | DOAJ |
| description | Abstract Hematologic adverse events are common dose-limiting toxicities in drug development. Classical animal models for preclinical safety assessment of immunotherapies are often limited due to insufficient cross-reactivity with non-human homologous proteins, immune system differences, and ethical considerations. Therefore, we evaluate a human bone marrow (BM) microphysiological system (MPS) for its ability to predict expected hematopoietic liabilities of immunotherapeutics. The BM-MPS consists of a closed microfluidic circuit containing a ceramic scaffold covered with human mesenchymal stromal cells and populated with human BM-derived CD34+ cells in chemically defined growth factor-enriched media. The model supports on-chip differentiation of erythroid, myeloid and NK cells from CD34+ cells over 31 days. The hematopoietic lineage balance and output is responsive to pro-inflammatory factors and cytokines. Treatment with a transferrin receptor-targeting IgG1 antibody results in inhibition of on-chip erythropoiesis. The immunocompetence of the chip is established by the addition of peripheral blood T cells in a fully autologous setup. Treatment with T cell bispecific antibodies induces T cell activation and target cell killing consistent with expected on-target off-tumor toxicities. In conclusion, this study provides a proof-of-concept that this BM-MPS is applicable for in vitro hematopoietic safety profiling of immunotherapeutics. |
| format | Article |
| id | doaj-art-258f04be037d4130be3bc912af198aaa |
| institution | OA Journals |
| issn | 2399-3642 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj-art-258f04be037d4130be3bc912af198aaa2025-08-20T02:25:12ZengNature PortfolioCommunications Biology2399-36422025-05-018111910.1038/s42003-025-08137-1A microfluidic bone marrow chip for the safety profiling of biologics in pre-clinical drug developmentLeopold Koenig0Laurent Juglair1Thi Phuong Tao2Susanne Fischer3Inga Clausen4Sabine Imhof-Jung5Niels Janssen6Robert Mader7Daniel Marbach8Jens Niewoehner9Annika Winter10Desirée Schubert11TissUse GmbHRoche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F.Hoffmann-La Roche LtdTissUse GmbHRoche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F.Hoffmann-La Roche LtdRoche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F.Hoffmann-La Roche LtdRoche Pharma Research and Early Development, Therapeutic Modalities Large Molecule ResearchRoche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F.Hoffmann-La Roche LtdRoche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F.Hoffmann-La Roche LtdRoche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F.Hoffmann-La Roche LtdRoche Pharma Research and Early Development, Therapeutic Modalities Large Molecule ResearchTissUse GmbHRoche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F.Hoffmann-La Roche LtdAbstract Hematologic adverse events are common dose-limiting toxicities in drug development. Classical animal models for preclinical safety assessment of immunotherapies are often limited due to insufficient cross-reactivity with non-human homologous proteins, immune system differences, and ethical considerations. Therefore, we evaluate a human bone marrow (BM) microphysiological system (MPS) for its ability to predict expected hematopoietic liabilities of immunotherapeutics. The BM-MPS consists of a closed microfluidic circuit containing a ceramic scaffold covered with human mesenchymal stromal cells and populated with human BM-derived CD34+ cells in chemically defined growth factor-enriched media. The model supports on-chip differentiation of erythroid, myeloid and NK cells from CD34+ cells over 31 days. The hematopoietic lineage balance and output is responsive to pro-inflammatory factors and cytokines. Treatment with a transferrin receptor-targeting IgG1 antibody results in inhibition of on-chip erythropoiesis. The immunocompetence of the chip is established by the addition of peripheral blood T cells in a fully autologous setup. Treatment with T cell bispecific antibodies induces T cell activation and target cell killing consistent with expected on-target off-tumor toxicities. In conclusion, this study provides a proof-of-concept that this BM-MPS is applicable for in vitro hematopoietic safety profiling of immunotherapeutics.https://doi.org/10.1038/s42003-025-08137-1 |
| spellingShingle | Leopold Koenig Laurent Juglair Thi Phuong Tao Susanne Fischer Inga Clausen Sabine Imhof-Jung Niels Janssen Robert Mader Daniel Marbach Jens Niewoehner Annika Winter Desirée Schubert A microfluidic bone marrow chip for the safety profiling of biologics in pre-clinical drug development Communications Biology |
| title | A microfluidic bone marrow chip for the safety profiling of biologics in pre-clinical drug development |
| title_full | A microfluidic bone marrow chip for the safety profiling of biologics in pre-clinical drug development |
| title_fullStr | A microfluidic bone marrow chip for the safety profiling of biologics in pre-clinical drug development |
| title_full_unstemmed | A microfluidic bone marrow chip for the safety profiling of biologics in pre-clinical drug development |
| title_short | A microfluidic bone marrow chip for the safety profiling of biologics in pre-clinical drug development |
| title_sort | microfluidic bone marrow chip for the safety profiling of biologics in pre clinical drug development |
| url | https://doi.org/10.1038/s42003-025-08137-1 |
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