Bi20 (fBTA05), a novel trifunctional bispecific antibody (anti‐CD20 × anti‐CD3), mediates efficient killing of B‐cell lymphoma cells even with very low CD20 expression levels

Abstract

Trifunctional bispecific antibodies can efficiently mediate tumor cell killing by redirecting T cells and immune accessory cells to the tumor cell. Here, we describe the new trifunctional antibody, Bi20 (FBTA05, anti-CD20 3 anti-CD3), that connects B cells and T cells via its variable regions and recruits FccRI 1 accessory immune cells via its Fc region. Bi20 mediated efficient and specific lysis of B-cell lines and of B cells with low CD20 expression levels that were derived from CLL patients. Remarkably, T-cell activation and tumor cell killing occurred in an entirely autologous setting without additional effector cells in 5 of 8 samples. In comparison, rituximab, a chimeric monoclonal CD20 antibody, demonstrated a significantly lower B-cell eradication rate. Additionally, Bi20, but not rituximab, upregulated the activation markers CD25 and CD69 on both CD41 and CD8 1 T cells in the presence of accessory immune cells. CD141 accessory cells and the monocyte cell line THP-1 were activated via binding of the Fc region of Bi20, given that T cells were simultaneously engaged by the antibody. Bi20 induced a strong Th1 cytokine pattern characterized by high IFN-c and very low IL-4 secretion. In conclusion, Bi20 may offer new immunotherapeutic options for the treatment of B-cell lymphomas. '

The Trifunctional Antibody Ertumaxomab Destroys Tumor Cells That Express Low Levels of Human Epidermal Growth Factor Receptor 2

“…This observed superiority of ertumaxomab over trastuzumab is based on the particular mode of action that all members of the trifunctional antibody family (e.g., ertumaxomab, catumaxomab, Bi20/FBTA05, BiLu, and BiUII) have in common. These therapeutic antibodies induce a simultaneous recruitment and activation of T cells and accessory cells, leading to the destruction of targeted tumor cells by different killer mechanisms (9,12,13,15,23). .…”

Immunotherapy of recurrent B-cell malignancies after allo-SCT with Bi20 (FBTA05), a trifunctional anti-CD3 × anti-CD20 antibody and donor lymphocyte infusion

“…26,27 Interestingly, a significant release of IL-10 was already observed in context with in vitro studies using the trifunctional antibodies catumaxomab (antiEpCAM Â anti-CD3), TRBs02/07 (anti-GD2/GD3 Â anti-CD3) and Bi20. 14,28 However, so far, the therapeutic consequences are not well understood and need to be investigated further.…”

“…13 Here we report on the use of Bi20 (FBTA05), a trifunctional heterodimeric anti-CD3 (rat IgG2b) Â anti-CD20 (mouse IgG2a) antibody, already shown to kill lymphoma cells very effectively even at very low expression levels in vitro. 14 In a pilot study, we treated six patients with recurrent B-cell malignancies, CLL and highly malignant lymphoma after allo-SCT. Escalating doses of Bi20 were followed by DLI or mobilized PBSCT.…”

Effector mechanisms of anti-CD20 monoclonal antibodies in B cell malignancies

“…There is still no conclusive evidence for the pivotal role of CDC, ADCC, attempts to introduce additional modifications resulting in multifunctional activities 93,94 .…”