Browsing by Author "Müller, Dafne"

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    Influence of antigen density and immunosuppressive factors on tumor-targeted costimulation with antibody-fusion proteins and bispecific antibody-mediated T cell response
    (2020) Sapski, Sabrina; Beha, Nadine; Kontermann, Roland E.; Müller, Dafne
    Target expression heterogeneity and the presence of an immunosuppressive microenvironment can hamper severely the efficiency of immunotherapeutic approaches. We have analyzed the potential to encounter and overcome such conditions by a combinatory two-target approach involving a bispecific antibody retargeting T cells to tumor cells and tumor-directed antibody-fusion proteins with costimulatory members of the B7 and TNF superfamily. Targeting the tumor-associated antigens EpCAM and EGFR with the bispecific antibody and costimulatory fusion proteins, respectively, we analyzed the impact of target expression and the influence of the immunosuppressive factors IDO, IL-10, TGF-β, PD-1 and CTLA-4 on the targeting-mediated stimulation of T cells. Here, suboptimal activity of the bispecific antibody at diverse EpCAM expression levels could be effectively enhanced by targeting-mediated costimulation by B7.1, 4-1BBL and OX40L in a broad range of EGFR expression levels. Furthermore, the benefit of combined costimulation by B7.1/4-1BBL and 4-1BBL/OX40L was demonstrated. In addition, the expression of immunosuppressive factors was shown in all co-culture settings, where blocking of prominent factors led to synergistic effects with combined costimulation. Thus, targeting-mediated costimulation showed general promise for a broad application covering diverse target expression levels, with the option for further selective enhancement by the identification and blockade of main immunosuppressive factors of the particular tumor environment.
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    Mechanosensory feedback loops during chronic inflammation
    (2023) Saha, Sarbari; Müller, Dafne; Clark, Andrew G.
    Epithelial tissues are crucial to maintaining healthy organization and compartmentalization in various organs and act as a first line of defense against infection in barrier organs such as the skin, lungs and intestine. Disruption or injury to these barriers can lead to infiltration of resident or foreign microbes, initiating local inflammation. One often overlooked aspect of this response is local changes in tissue mechanics during inflammation. In this mini-review, we summarize known molecular mechanisms linking disruption of epithelial barrier function to mechanical changes in epithelial tissues. We consider direct mechanisms, such as changes in the secretion of extracellular matrix (ECM)-modulating enzymes by immune cells as well as indirect mechanisms including local activation of fibroblasts. We discuss how these mechanical changes can modulate local immune cell activity and inflammation and perturb epithelial homeostasis, further dysregulating epithelial barrier function. We propose that this two-way relationship between loss of barrier function and altered tissue mechanics can lead to a positive feedback loop that further perpetuates inflammation. We discuss this cycle in the context of several chronic inflammatory diseases, including inflammatory bowel disease (IBD), liver disease and cancer, and we present the modulation of tissue mechanics as a new framework for combating chronic inflammation.
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    Targeting co-stimulatory receptors of the TNF superfamily for cancer immunotherapy
    (2022) Müller, Dafne
    The clinical approval of immune checkpoint inhibitors is an important advancement in the field of cancer immunotherapy. However, the percentage of beneficiaries is still limited and it is becoming clear that combination therapies are required to further enhance the treatment efficacy. The potential of strategies targeting the immunoregulatory network by “hitting the gas pedal” as opposed to “blocking the brakes” is being recognized and intensively investigated. Hence, next to immune checkpoint inhibitors, agonists of co-stimulatory receptors of the tumor necrosis factor superfamily (TNF-SF) are emerging as promising options to expand the immunomodulatory toolbox. In this review the development of different categories of recombinant antibody and ligand-based agonists of 4-1BB, OX40, and GITR is summarized and discussed in the context of the challenges presented by the structural and mechanistical features of the TNFR-SF. An overview of current formats, trends, and clinical studies is provided.
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    Trifunctional antibody-cytokine fusion protein formats for tumor-targeted combination of IL-15 with IL-7 or IL-21
    (2025) Möller, Annika M.; Vettermann, Sarah; Baumann, Felix; Pütter, Max; Müller, Dafne
    Cytokines from the common gamma chain receptor family, such as IL-15, IL-21 and IL-7, show promise for cancer immunotherapy and have been incorporated individually into the immunocytokine approach. However, their efficacy as monotherapy is limited. Here, we investigated the molecular design of tumor-directed trifunctional antibody-cytokine fusion proteins for a combinatorial approach of IL-15 with either IL-7 or IL-21. Various fusion proteins differing in antibody format, cytokine composition and arrangement were generated and cooperative cytokine activity assessed in solution and bound to target cells. Comparative analysis revealed that formats with cytokines positioned at the N- and C-termini of the antibody were more effective than those arranged in series. For the former design, cooperative effects were observed with the scFv-based (IL-15+IL-7) trifunctional fusion protein, primarily enhancing the proliferation of naive T cells, while the scFv/Fab-based (IL-15+IL-21) trifunctional fusion proteins enhanced IFN-y release and the cytotoxic potential of T cells. Combining cytokines in the two-in-one molecule approach was principally advantageous when bound to target cells. Greater potency in inducing JAK-STAT pathway activation highlighted the importance of cytokine colocalization for cooperative receptor activation. Compared to the Fab-based (IL-15+IL-21) format, the scFv-based (IL-15+IL-21) format displayed a tendency towards higher activity in targeted and lower activity in untargeted settings, emphasizing the targeted concept. Thus, this study underscores the importance of molecular design in developing trifunctional immunocytokines and identified the scFv-based trifunctional (IL-15+IL-21) fusion protein, with the antibody in the central position, as a particularly promising candidate for further drug development.