Biology subjects

Wesch, D.

Publications and source records attributed to Wesch, D..

3 recordsLinked to original sources

bioRxiv2026

L1CAMxCD3 bispecific antibodies exert potent anti-tumor effects in preclinical pancreatic cancer models with representation of the complex tumor microenvironment

Pancreatic ductal adenocarcinoma (PDAC) is characterized by an immunosuppressive tumor microenvironment (TME) with pancreatic myofibroblasts (PMF) and macrophages being two prominent cell populations essentially impairing tumor responses to (immuno)therapies. L1 cell adhesion molecule (L1CAM) is upregulated in PDAC cells in primary and metastatic tissues and associated with tumor progression and therapy resistance. Using L1CAM as tumor-associated antigen, two bispecific antibodies (bsAB) targeting L1CAM and CD3 were developed in the IgG-(L)-ScFv format and their anti-tumorigenic activity was investigated in different preclinical PDAC models. In 2D models, both L1-bsAB exerted L1CAM-specific anti-PDAC cell activity when co-cultured with activated CD8+ T cells. Strong anti-PDAC cell effects along with elevated release of T cell effector molecules were also observed upon co-culture with peripheral blood mononuclear cells (PMBC) from healthy donors and PDAC patients. Of note, both L1-bsAB were also effective in 3D PDAC cell spheroids and neither impaired by PMF nor macrophages. Finally, application of L1-bsAB on organotypic tissue slice cultures from PDAC tissues comprising the entire complex TME also induced PDAC cell apoptosis and release of T cell effector molecules. Overall, our results highlight relevant anti-PDAC cell activity of L1-bsAB in immunosuppressive contexts supporting their potential as immunotherapeutic strategy for PDAC.

cancer biology↗

bioRxiv2026

A Novel Natural Killer Cell Expansion Technology for the Development of Cellular Immunotherapies

Adoptive cell therapy based on Natural Killer (NK) cells holds great promise for the treatment of cancer. For all approaches aiming at utilizing NK cells in immunotherapy, efficient ex vivo expansion technologies for the generation on of cytotoxic NK cells are a prerequisite for clinical translation. In this study, a novel multifunctional fusion protein consisting of a CD20-directed Fab-fragment, an agonistic anti-4-1BB single-chain Fragment variable (scFv), the Sushi domain of the interleukin (IL)-15 receptor and human IL-15 was generated. This molecule triggered strong NK cell expansion when bound to co-cultivated autologous B cells, due to trans-presentation of IL-15 and binding to 4-1BB/CD137. Expansion rates of up to 7,500-fold were achieved and the NK cells showed high cytotoxic capacity against a panel of tumor cell lines representing various tumor entities. Importantly, the activated NK cells did not show cytolytic activity against non-malignant B cells indicating that NK cells amplified by our novel approach were still physiologically regulated. The cytotoxic activity of the expanded NK cells was further enhanced by combination with therapeutic antibodies. Our molecule was additionally able to trigger efficient proliferation of NK cells from cord blood as well as multiple myeloma (MM) and acute myeloid leukemia (AML) patients. In conclusion, our novel platform technology provides ex vivo expansion of NK cells by using a single multifunctional fusion protein and may be well-suited for the development of NK cell-based immunotherapies. Key pointsA novel fusion protein that enables NK cell expansion from different sources including peripheral blood, bone marrow and cord blood

immunology↗

bioRxiv2025

Blinatumomab-driven T-cell activation in αβ and γδ T-cell subsets: Insights from in vitro assays

Blinatumomab (BLN) is a bispecific T-cell engager that has revolutionized the treatment of B-cell precursor acute lymphoblastic leukemia (BCP-ALL), significantly improving outcomes in both adults and children. By simultaneously binding to CD19 on B cells and CD3 on T cells, BLN triggers target cell-dependent T-cell activation, resulting in the cytolysis of CD19+ BCP-ALL cells. Despite the remarkable clinical advancements achieved with BLN, the immunological mechanisms underlying treatment response or failure remain poorly characterized. {gamma}{delta} T cells are attractive candidates for adoptive T-cell therapy due to potent cytotoxicity, capacity to present antigens, broad lysis of different tumor entities, and low alloreactivity. Because {gamma}{delta} T cells can also be redirected by BLN, we systematically studied BLN-driven effector functions of conventional {beta} and unconventional {gamma}{delta} T cells. We evaluated cytotoxicity and cytokine/effector release in freshly isolated and in vitro-expanded {beta} and {gamma}{delta} T cells from healthy adults against CD19 BCP-ALL lines (NALM-6, HAL-01), and profiled dynamic phenotypic alterations by multiparametric flow cytometry. CD19 targets were consistently reduced in the presence of BLN. Freshly isolated {beta}, especially CD8, displayed superior BLN-mediated cytotoxicity as compared to {gamma}{delta} T cells, with donor-dependent variability in {gamma}{delta} killing. Notably, zoledronate-expanded V{gamma}9V{delta}2 {gamma}{delta} T-cell lines achieved cytotoxicity comparable to PHA-expanded {beta} cells. However, {gamma}{delta} T-cell-killing benefited from higher BLN concentration when challenged with high tumor load. BLN induced CD3 down-modulation in {beta} T cells but not in {gamma}{delta} T cells, alongside higher soluble Fas ligand in {beta} cultures, consistent with stronger early activation, preceding activation-induced cell death. {gamma}{delta} T cells showed no such changes, suggesting reduced susceptibility to activation-induced cell death. Single-cell RNA and flow analyses corroborated these findings, showing robust activation/exhaustion programs in {beta} T cells and a stable effector-memory state with low checkpoint expression in {gamma}{delta} T cells. Together, these data reveal subset-specific BLN responses and support expanded V{gamma}9V{delta}2 {gamma}{delta} T cells as a rational adoptive partner to BLN -- particularly in settings of favorable antigen density/low tumor burden -- providing complementary cytotoxicity with potentially reduced inflammatory liability. These findings provide a framework for combining {gamma}{delta} T-cell-based therapies in BLN-treated patients for improving BLN efficacy in BCP-ALL patients.

immunology↗