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http://dx.doi.org/10.18419/opus-13111
Autor(en): | Sapski, Sabrina Beha, Nadine Kontermann, Roland E. Müller, Dafne |
Titel: | Influence of antigen density and immunosuppressive factors on tumor-targeted costimulation with antibody-fusion proteins and bispecific antibody-mediated T cell response |
Erscheinungsdatum: | 2020 |
Dokumentart: | Zeitschriftenartikel |
Seiten: | 2291-2303 |
Erschienen in: | Cancer immunology, immunotherapy 69 (2020), S. 2291-2303 |
URI: | http://nbn-resolving.de/urn:nbn:de:bsz:93-opus-ds-131303 http://elib.uni-stuttgart.de/handle/11682/13130 http://dx.doi.org/10.18419/opus-13111 |
ISSN: | 0340-7004 1432-0851 |
Zusammenfassung: | 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. |
Enthalten in den Sammlungen: | 04 Fakultät Energie-, Verfahrens- und Biotechnik |
Dateien zu dieser Ressource:
Datei | Beschreibung | Größe | Format | |
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s00262-020-02624-6.pdf | 1,6 MB | Adobe PDF | Öffnen/Anzeigen |
Diese Ressource wurde unter folgender Copyright-Bestimmung veröffentlicht: Lizenz von Creative Commons