Abstract
T-cell-based immunotherapy strategies have profoundly improved the clinical management of several solid tumors and hematological malignancies. A recently developed and promising immunotherapy approach is to redirect polyclonal MHC-unrestricted T lymphocytes toward cancer cells by bispecific antibodies (bsAbs) that engage the CD3 complex and a tumor-associated antigen (TAA). The TNF-related apoptosis-inducing ligand receptor 2 (TRAIL-R2) is an attractive immunotherapy target, frequently expressed by neoplastic cells, that we decided to exploit as a TAA. We found that a TRAIL-R2xCD3 bsAb efficiently activates T cells and specifically redirect their cytotoxicity against cancer cells of different origins in vitro, thereby demonstrating its potential as a pan-carcinoma reagent. Moreover, to mimic in vivo conditions, we assessed its ability to retarget T-cell activity in an ex vivo model of ovarian cancer patients' ascitic fluids containing both effector and target cells—albeit with a suboptimal effector-to-target ratio—with remarkable results.
Highlights
Tcell-based immunotherapy strategies have profoundly improved the clinical management of several solid tumors and hematological malignancies [1]
To exploit the unique pattern of TRAIL-R2 expression, we developed a bispecific antibody (bsAb) able to simultaneously bind TRAIL-R2 in an agonistic manner on cancer cells and the CD3triggering molecule on T lymphocytes and demonstrated that this reagent could efficiently redirect their cytotoxicity against tumor cells in vitro
The single-chain diabody (scDb) used in this paper was previously selected from a library in order to obtain a small molecule able to simultaneously bind TRAIL-R2 on tumor cells and the CD3 molecule on T lymphocytes [19]
Summary
Tcell-based immunotherapy strategies have profoundly improved the clinical management of several solid tumors and hematological malignancies [1]. The membrane receptor TNF-related apoptosis-inducing ligand receptor 2 (TRAIL-R2 or DR5), due to its up-regulation in many tumors compared to normal tissues [4, 5], could be considered a particular tumor-associated antigen (TAA) whose stimulation by its ligand (TRAIL) is able to DR5/CD3 BsAb for Cancer Immunotherapy transmit a death signal to the apoptotic machinery [6]. The differential expression of the receptor along with its capacity to induce apoptosis in tumor cells and preserve normal cells [7] opened a therapeutic window for the development of new cancer therapeutics [8,9,10]. To exploit the unique pattern of TRAIL-R2 expression, we developed a bsAb able to simultaneously bind TRAIL-R2 in an agonistic manner on cancer cells and the CD3triggering molecule on T lymphocytes and demonstrated that this reagent could efficiently redirect their cytotoxicity against tumor cells in vitro
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