TY - JOUR
KW - Biologics
KW - drug safety
KW - Haematopoiesis
KW - Lab-on-a-chip
AU - Leopold Koenig
AU - Laurent Juglair
AU - Thi Phuong Tao
AU - Susanne Fischer
AU - Inga Clausen
AU - Sabine Imhof-Jung
AU - Niels Janssen
AU - Robert Mader
AU - Daniel Marbach
AU - Jens Niewoehner
AU - Annika Winter
AU - Desirée Schubert
AB - 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.
BT - Communications Biology
DA - 2025-05-15
DO - 10.1038/s42003-025-08137-1
IS - 1
LA - en
N2 - 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.
PY - 2025
EP - 754
T2 - Communications Biology
TI - A microfluidic bone marrow chip for the safety profiling of biologics in pre-clinical drug development
UR - https://www.nature.com/articles/s42003-025-08137-1
VL - 8
Y2 - 2026-08-11
SN - 2399-3642
ER -