Abstract
An enhanced expression of human epidermal growth factor receptor 2 (HER2, ErbB2) often occurs in an advanced stage of breast, ovarian, gastric or esophageal cancer, and pancreatic ductal adenocarcinoma (PDAC). Commonly, HER2 expression is associated with poor clinical outcome or chemoresistance in ovarian and breast cancer patients. Treatment with humanized anti-HER2 monoclonal antibodies, such as trastuzumab or pertuzumab, has improved the outcome of patients with HER2-positive metastatic gastric or breast cancer, but not all patients benefit. In this study, the bispecific antibody [(HER2)2xCD16] in the tribody format was employed to re-direct CD16-expressing γδ T lymphocytes as well as natural killer (NK) cells to the tumor-associated cell surface antigen HER2 to enhance their cytotoxic anti-tumor activity. Tribody [(HER2)2xCD16] comprises two HER2-specific single chain fragment variable fused to a fragment antigen binding directed to the CD16 (FcγRIII) antigen expressed on γδ T cells and NK cells. Our results revealed the superiority of tribody [(HER2)2xCD16] compared to trastuzumab in triggering γδ T cell and NK cell-mediated lysis of HER2-expressing tumor cells, such as PDAC, breast cancer, and autologous primary ovarian tumors. The increased efficacy of [(HER2)2xCD16] can be explained by an enhanced degranulation of immune cells. Although CD16 expression was decreased on γδ T cells in several PDAC patients and the number of tumor-infiltrating NK cells and γδ T cells was impaired in ovarian cancer patients, [(HER2)2xCD16] selectively enhanced cytotoxicity of cells from these patients. Here, unique anti-tumor properties of tribody [(HER2)2xCD16] are identified which beyond addressing HER2 overexpressing solid tumors may allow to treat with similar immunoconstructs combined with the adoptive transfer of γδ T cells and NK cells refractory hematological malignancies. A major advantage of γδ T cells and NK cells in the transplant situation of refractory hematological malignancies is given by their HLA-independent killing and a reduced graft-versus-host disease.
Highlights
The human epidermal growth factor receptor 2 [(HER2), ErbB2] stimulates tumor cell proliferation via the Ras-MAP-kinase pathway and its expression is often associated with an aggressive tumor phenotype, advanced stage diseases, and poor clinical outcome [1, 2]
In order to analyze trastuzumabmediated lysis of HER2-expressing cancer cells by inhibition of HER2 signaling after its homodimerization and antibody-dependent cell-mediated cytotoxicity (ADCC)-mediated lysis by FcγRIII (CD16)-expressing cells, such as natural killer (NK) cells or γδ T cells, we applied a Real-Time Cell Analyzer (RTCA)-assay
The combination of trastuzumab and peripheral blood lymphocytes (PBL) enhanced lysis of all applied tumor cells (Figure 1A) compared to trastuzumab alone. This effect was more pronounced in MCF7- and OC1-cells than in PancTu-I cells and other pancreatic ductal adenocarcinoma (PDAC) cells such as Panc1 co-cultured with allogeneic PBL from healthy donor (HD) (Figure S1A in Supplementary Material, upper figure)
Summary
The human epidermal growth factor receptor 2 [(HER2), ErbB2] stimulates tumor cell proliferation via the Ras-MAP-kinase pathway and its expression is often associated with an aggressive tumor phenotype, advanced stage diseases, and poor clinical outcome [1, 2]. A dysfunction of cardiomyocytes, which is induced in 4% of the cancer patients receiving anti-HER2 therapy, is reversible [4]. The antibody-drug conjugate (ADC) trastuzumab emtansine (T-DM-1) consisting of the antiHER2 mAb trastuzumab linked to the cytotoxic agent emtansine (DM-1), which enters and destroys the HER2-overexpressing cells by binding to tubulin, was successful in patients with advanced breast cancer [13, 14]. Trastuzumab and pertuzumab induce antibody-dependent cell-mediated cytotoxicity (ADCC) and/or cell death of tumor cells by inhibition of HER2 signaling [15,16,17]. Regarding γδ T cells, Capietto and colleagues recently reported that adoptive transfer of human Vγ9Vδ2-expressing γδ T lymphocytes from healthy donors (HDs) together with trastuzumab reduced growth of HER2-expressing breast cancer tumors grafted into immunocompromised mice. Γδ T cells bound to mAb-labeled breast cancer tumors via FcγRIII (CD16) and thereby exerted ADCC [21]
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