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EGFR-selective activation of CD27 co-stimulatory signaling by a bispecific antibody enhances anti-tumor activity of T cells.

ABSTRACT: A higher density of tumor infiltrating lymphocytes (TILs) in the tumor microenvironment, particularly cytotoxic CD8⁺ T cells, is associated with improved clinical outcome in various cancers. However, local inhibitory factors can suppress T cell activity and hinder anti-tumor immunity. Notably, TILs from various cancer types express the co-stimulatory Tumor Necrosis Factor receptor CD27, making it a potential target for co-stimulation and re-activation of tumor-infiltrated and tumor-reactive T cells. Anti-cancer therapeutics based on exploiting CD27-mediated T cell co-stimulation have proven safe, but clinical responses remain limited. This is likely because current monoclonal antibodies fail to effectively activate CD27 signaling, as this receptor requires higher-order receptor cross-linking. Here, we report on a bispecific antibody, CD27xEGFR, that targets both CD27 and the tumor antigen, epidermal growth factor receptor (EGFR). By targeting EGFR, which is commonly expressed on carcinomas, CD27xEGFR induced cancer cell-localized crosslinking and activation of CD27. The design of CD27xEGFR includes an Fc-silent domain, which is designed to minimize potential toxicity by reducing Fc gamma receptor-mediated binding and activation of immune cells. CD27xEGFR bound to both of its targets simultaneously and triggered EGFR-restricted co-stimulation of T cells as measured by T cell proliferation, T cell activation markers, cytotoxicity and IFN-γ release. Further, CD27xEGFR augmented T cell cytotoxicity in a panel of artificial antigen-presenting carcinoma cell line models, leading to Effector-to-Target ratio-dependent elimination of cancer cells. Taken together, we present the in vitro characterization of a novel bispecific antibody that re-activates T cell immunity in EGFR-expressing cancers through targeted co-stimulation of CD27.

SUBMITTER: Melo V

PROVIDER: S-EPMC10399592 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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EGFR-selective activation of CD27 co-stimulatory signaling by a bispecific antibody enhances anti-tumor activity of T cells.

Melo Vinicio V Nelemans Levi Collin LC Vlaming Martijn M Lourens Harm Jan HJ Wiersma Valerie R VR Bilemjian Vrouyr V Huls Gerwin G de Bruyn Marco M Bremer Edwin E

Frontiers in immunology 20230720

A higher density of tumor infiltrating lymphocytes (TILs) in the tumor microenvironment, particularly cytotoxic CD8<sup>+</sup> T cells, is associated with improved clinical outcome in various cancers. However, local inhibitory factors can suppress T cell activity and hinder anti-tumor immunity. Notably, TILs from various cancer types express the co-stimulatory Tumor Necrosis Factor receptor CD27, making it a potential target for co-stimulation and re-activation of tumor-infiltrated and tumor-re ...[more]

PMID: 37545491

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Project description: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.

Dataset Information

EGFR-selective activation of CD27 co-stimulatory signaling by a bispecific antibody enhances anti-tumor activity of T cells.

Publications

EGFR-selective activation of CD27 co-stimulatory signaling by a bispecific antibody enhances anti-tumor activity of T cells.

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