Co-stimulatory bispecific antibodies induce enhanced T cell activation and tumor cell killing in breast cancer models

• Verfasst von: Warwas, Karsten M. [VerfasserIn]
• Verfasst von: Meyer, Marten [VerfasserIn]
• Verfasst von: Gonçalves, Márcia [VerfasserIn]
• Verfasst von: Moldenhauer, Gerhard [VerfasserIn]
• Verfasst von: Bulbuc, Nadja [VerfasserIn]
• Verfasst von: Knabe, Susanne [VerfasserIn]
• Verfasst von: Luckner-Minden, Claudia [VerfasserIn]
• Verfasst von: Ziegelmeier, Claudia [VerfasserIn]
• Verfasst von: Heußel, Claus Peter [VerfasserIn]
• Verfasst von: Zörnig, Inka [VerfasserIn]
• Verfasst von: Jäger, Dirk [VerfasserIn]
• Verfasst von: Momburg, Frank [VerfasserIn]
• Titel: Co-stimulatory bispecific antibodies induce enhanced T cell activation and tumor cell killing in breast cancer models
• Verf.angabe: Karsten M. Warwas, Marten Meyer, Márcia Gonçalves, Gerhard Moldenhauer, Nadja Bulbuc, Susanne Knabe, Claudia Luckner-Minden, Claudia Ziegelmeier, Claus Peter Heussel, Inka Zörnig, Dirk Jägera and Frank Momburg
• E-Jahr: 2021
• Jahr: 16 August 2021
• Umfang: 22 S.
• Fussnoten: Gesehen am 12.11.2021
• Titel Quelle: Enthalten in: Frontiers in immunology
• Ort Quelle: Lausanne : Frontiers Media, 2010
• Jahr Quelle: 2021
• Band/Heft Quelle: 12(2021), Artikel-ID 3240, Seite 1-22
• ISSN Quelle: 1664-3224
• DOI: doi:10.3389/fimmu.2021.719116
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1777332745

Abstract

Although T cell-recruiting CD3-binding bispecific antibodies (BiMAb) have been proven to be clinically effective for hematologic malignancies, the success of BiMAb targeting solid tumor-associated antigens (TAA) in carcinomas so far remains poor. We reasoned that provision of co-stimulatory BiMAb in combination with αTAA-αCD3 BiMAb would boost T cell activation and proliferative capacity, and thereby facilitate the targeting of weakly or heterogeneously expressed tumor antigens. Various αTAA-αCD3 and αTAA-αCD28 BiMAb in a tetravalent IgG1-Fc based format have been analyzed, targeting multiple breast cancer antigens including HER2, EGFR, CEA, and EpCAM. Moreover, bifunctional fusion proteins of αTAA-tumor necrosis factor ligand (TNFL) superfamily members including 4-1BBL, OX40L, CD70 and TL1A have been tested. The functional activity of BiMAb was assessed using co-cultures of tumor cell lines and purified T cells in monolayer and tumor spheroid models. Only in the presence of tumor cells, αTAA-αCD3 BiMAb activated T cells and induced cytotoxicity in vitro, indicating a strict dependence on cross-linking. Combination treatment of αTAA-αCD3 BiMAb and co-stimulatory αTAA-αCD28 or αTAA-TNFL fusion proteins drastically enhanced T cell activation in terms of proliferation, activation marker expression, cytokine secretion and tumor cytotoxicity. Furthermore, BiMAb providing co-stimulation were shown to reduce the minimally required dose to achieve T cell activation by at least tenfold. Immuno-suppressive effects of TGF-β and IL-10 on T cell activation and memory cell formation could be overcome by co-stimulation. BiMAb-mediated co-stimulation was further augmented by immune checkpoint-inhibiting antibodies. Effective co-stimulation could be achieved by targeting a second breast cancer antigen, or by targeting fibroblast activation protein (FAP) expressed on another target cell. In tumor spheroids derived from pleural effusions of breast cancer patients, co-stimulatory BiMAb were essential for the activation tumor-infiltrating lymphocytes and cytotoxic anti-tumor responses against breast cancer cells. Taken together we showed that co-stimulation significantly potentiated the tumoricidal activity of T cell-activating BiMAb while preserving the dependence on TAA recognition. This approach could provide for a more localized activation of the immune system with higher efficacy and reduced peripheral toxicities.