Journal Article

Immunological synapse formation as a key mechanism in T cell-dependent bispecific antibody-mediated immune activation and cytotoxicity

Anzai, Takahiro, Nakamura, Rikuto, Tsumura, Ryo, Yasunaga, Masahiro, Asano, Ryutaro

2025

Overview

T cell-dependent bispecific antibodies (TDBs) are next-generation antibody therapies that link cancer cells and T cells to achieve potent antitumor effects. Despite the successful development of TDBs for hematological malignancies, their efficacy against solid tumors remains limited. Overcoming this challenge requires a deeper understanding of their mechanisms of action. While the basic process of immunological synapse (IS) formation and T cell activation by TDB is known, the detailed effects of IS on the bystander effect and T cell migration, both crucial for therapeutic efficacy, remain unclear. This study investigated these mechanisms using an EGFR/CD3 TDB (hEx3) and EGFR knockout cancer cells (KO). The results revealed that IS formation by TDB induced a bystander effect, leading to damage in surrounding KO, with the extent depending on the proportion of EGFR-positive wild-type cancer cells (WT) and the duration of co-culture. Furthermore, IS formation significantly enhanced T cell cytokine and chemokine secretion, promoting T cell migration. These findings provide critical insights into TDB efficacy mechanisms and highlight the importance of evaluating IS formation in developing new antibody drugs. Establishing a reliable system for assessing IS formation will be essential for advancing TDBs and other antibody-based therapies, particularly against solid tumors.

• Publisher: Springer Berlin Heidelberg,Springer Nature B.V,Springer
• Subject: Antibodies / Antibodies, Bispecific - immunology / Antibodies, Bispecific - pharmacology / Antibody therapeutics / Antibody-Dependent Cell Cytotoxicity - immunology / Antigens / Antitumor activity / Bispecific antibodies / Bispecific antibody (BsAb) / Cancer / Cancer Research / CD3 antigen / CD3 Complex - immunology / Cell activation / Cell adhesion & migration / Cell culture / Cell Line, Tumor / Cell migration / Cell Movement - immunology / Chemokines / CRISPR / Cytokines / Cytokines - metabolism / Cytotoxicity / Epidermal growth factor receptors / ErbB Receptors - genetics / ErbB Receptors - immunology / FDA approval / Flow cytometry / Humans / Immunological synapse (IS) / Immunological synapses / Immunological Synapses - immunology / Immunology / Immunosuppressive agents / Immunotherapy / Lymphocyte Activation - immunology / Lymphocytes / Lymphocytes T / Malignancy / Medicine / Medicine & Public Health / Neoplasms - immunology / Oncology / Pancreatic cancer / Penicillin / Solid tumors / Stains & staining / T cell-dependent bispecific antibody (TDB) / T-Lymphocytes - immunology