一种CD3×CD20双特异性T细胞衔接器在人源化PBMC小鼠模型中的表征及临床前疗效

Immuno-oncology (IO) therapies aim to harness and amplify the body's immune system to recognize, control, and destroy cancer cells. One key therapeutic goal in IO is to enhance T cell-mediated tumor killing. Currently established strategies include immune checkpoint inhibitors (ICIs), which release inhibitory brakes on T cells; T cell receptor-engineered T cell (TCR-T) therapies, which improve surface and intracellular antigen recognition; and chimeric antigen receptor (CAR) T cell therapies, which provide synthetic tumor antigen specificity. While these approaches have achieved success, they also face challenges such as T cell exhaustion, antigen escape, and safety and toxicity concerns, including cytokine release syndrome. Another emerging class of T cell-redirecting therapies are T cell engagers (TCEs); bi- or tri-specific antibodies that physically link T cells to tumor-associated antigens (TAAs). This interaction triggers robust T cell activation and a cascade of cytotoxic events culminating in tumor cell apoptosis. FDA-approved TCEs, such as Epcoritamab (CD3xCD20) for relapsed or refractory diffuse large B-cell lymphoma (DLBCL), Blinatumomab (CD3×CD19) for acute lymphoblastic leukemia (ALL) and Teclistamab (CD3×BCMA) for multiple myeloma, have demonstrated significant clinical efficacy in these respective diseases. While TCEs have shown success in treating hematologic malignancies, their role in Burkitt's lymphoma, an aggressive B-cell non-Hodgkin lymphoma linked to Epstein-Barr virus and MYC dysregulation, remains unexplored. Burkitt's lymphoma is generally considered highly curable using CD20 antibody-based immunotherapy, however resistance to anti-CD20 therapy is emerging, potentially linked to immune effector depletion and exhaustion from continuous intensive treatment. To investigate the efficacy of TCEs in Burkitt's lymphoma, we characterized a CD3×CD20 TCE using in vitro binding and cytotoxicity assays, and evaluated its therapeutic activity using an in vivo Raji xenograft model (cell line of Burkitt's lymphoma origin, expressing CD19/CD20) in humanized PBMC NOG mice. The CD3×CD20 TCE showed the most potent binding to Raji cells in vitro . Furthermore, in the humanized Raji model, the CD3×CD20 TCE achieved significant tumor regression in the high-dose group, and a partial response was observed in the low-dose group. Furthermore, both low and high doses of TCE resulted in a greater reduction in tumor volume compared to the ICI Toripalimab, a humanized PD-1 monoclonal antibody. Evidence of body weight loss (BWL) was observed in the groups that had PBMCs administered (tumour bearing animals), suggesting that the BWL is linked to the model and PBMC rather that the treatment. These findings highlight the potential of CD3×CD20 TCEs as an alternative strategy for treatment of Burkitt's lymphoma.