Harnessing the Power of CD20 TCB (RG6026): A Promising "2:1" T Cell Bispecific Antibody in B Cell Malignancy Therapy

Despite recent improvements in anti-CD20 monoclonal antibody treatments, a significant portion of non-Hodgkin's lymphoma (NHL) patients still do not achieve long-lasting responses to standard therapies. This highlights the ongoing demand for safer and more potent cancer treatments. T-cell bispecific antibodies (TCBs) are emerging as a promising class of therapies that leverage a patient's T cells to combat cancer cells.

A novel bispecific antibody, CD20 TCB, has been developed with unique properties that enhance its effectiveness. It features a "2:1" binding structure, which increases the affinity for tumor antigens and boosts T cell engagement and tumor cell destruction compared to other bispecific antibodies. This antibody consists of two CD20 binding sites derived from obinutuzumab, a CD3e binding site connected through a short linker, and a modified Fc region that prevents binding to FcgRs and C1q.

In laboratory tests, CD20 TCB demonstrated a dose-dependent tumor lysis with very low EC50 values, showing significantly higher potency than conventional "1:1" IgG-based TCBs. This resulted in T cell activation, proliferation, and cytokine release, along with an upregulation of the PD-1/PD-L1 pathway following tumor lysis.

Ex vivo studies with bone marrow samples from NHL and CLL patients showed that CD20 TCB was more effective than "1:1" TCBs, with faster and more potent B cell depletion. In vivo studies in stem cell humanized mice with aggressive lymphoma tumors revealed that CD20 TCB not only induced tumor regression but also rapidly depleted peripheral blood B cells and completely eliminated B cells in various organs after a few administrations.

Furthermore, the treatment led to a transient decrease in T cell counts and a peak in cytokine release, followed by a quick recovery. The anti-tumor activity was associated with increased T cell infiltration and upregulation of PD-1 and PD-L1. Combining CD20 TCB with a PD-L1 blocking antibody resulted in even more effective tumor growth inhibition.

The preclinical findings indicate that CD20 TCB is a novel and differentiated CD20-targeting TCB with significant anti-tumor potential and the capacity to alter the tumor microenvironment. It has consistently shown greater potency and efficacy across various tests compared to "1:1" TCBs. Clinical trials for this molecule are expected to commence by the end of 2016.