Targeting B Cell Malignancies: The Promise of Long-Lived Bispecific Antibody Therapy in Preclinical Models

Researchers have developed a new class of bispecific antibodies targeting both CD20+ B cells and CD3+ T cells, aiming to enhance T cell-mediated killing of malignant B cells. These antibodies are designed to overcome the limitations of existing anti-CD20 therapies, which do not stimulate this immune response. The antibodies were engineered to have a full Fc domain, forming stable heterodimers and maintaining a long serum half-life without binding to Fcγ receptors to prevent nonspecific T cell activation.

After optimizing the affinity of the antibodies, two candidates, XmAb13676 and XmAb13677, were selected for study. They showed high efficacy in stimulating T cell killing of CD20+ B cells in vitro and had an extended serum half-life in mice. Efficacy was further evaluated in cynomolgus monkeys, where the antibodies induced strong T cell activation and depletion of over 97% of circulating CD40+ B cells. The treatment also led to a sustained activation of CD4+ and CD8+ T cells and a rapid but temporary decrease in blood T cell populations.

The study suggests that these bispecific antibodies can effectively recruit and activate T cells to target CD20+ B cells in both the bloodstream and lymphoid organs. The findings support the potential of these antibodies for clinical trials in patients with CD20+ B cell leukemias and lymphomas. The authors are affiliated with Xencor, Inc., and hold employment and equity ownership positions in the company.