Harnessing Long-Lived Bispecific Antibodies for Potent T Cell-Mediated Elimination of Human B Cell Malignancies: Preclinical Insights

CD20 is a common target for antibody treatments in B cell malignancies, though existing therapies like rituximab lack the ability to trigger T cell-mediated destruction of CD20+ cells. To address this, we've developed new bispecific antibodies that can bind to both CD20+ B cells and CD3+ T cells, utilizing a mechanism termed "redirected T cell-cytotoxicity" (RTCC). This allows for T cell activation and cytotoxicity without reliance on T cell receptor specificity. These engineered antibodies feature a complete Fc region, forming stable heterodimers and are manufactured easily. The Fc region has been modified to prevent binding to Fcγ receptors, reducing off-target T cell activation, while still binding to human FcRn, which helps in maintaining a long serum half-life.

We created a series of optimized bispecific antibodies and selected two, XmAb13676 and XmAb13677, for further testing based on their RTCC performance against the CD20+ Ramos B cell line. These antibodies demonstrated potent T cell activation and B cell killing with respective EC50 values of approximately 53 ng/ml and 2 ng/ml. In vivo studies in mice showed that these antibodies had a prolonged serum half-life of around 6.7 days.

Further efficacy studies were conducted in cynomolgus monkeys using different doses of the antibodies. Post-treatment, there was a significant activation of T cells and a substantial depletion of CD40+ B cells, with the high-dose groups showing the most pronounced effect. The depletion was sustained over the study period, and T cell activation markers indicated a sustained response. Additionally, the antibodies induced a rapid redistribution of T cells from the blood, with populations returning to normal levels within days post-treatment. Depletion of CD40+ cells in lymph nodes and bone marrow was substantial and, in some cases, did not recover even after 29 days.

These findings indicate that the bispecific antibodies are effective in activating and directing T cells to eliminate CD20+ B cells in both the blood and lymphoid tissues. The results from the primate studies support the potential of these antibodies for clinical trials in patients with CD20+ B cell leukemias and lymphomas.