Effector-Mediated Eradication of Precursor B Acute Lymphoblastic Leukemia with a Novel Fc-Engineered Monoclonal Antibody Targeting the BAFF-R

Abstract

B-cell activating factor receptor (BAFF-R) is expressed on precursor B acute lymphoblastic leukemia ALL (pre-B ALL) cells but not on their pre-B normal counterparts. Thus, selective killing of ALL cells is possible by targeting this receptor. Here we have further examined therapeutic targeting of pre-B ALL based on the presence of the BAFF-R. Mouse pre-B ALL cells lacking BAFF-R function had comparable viability and proliferation to wild type cells but were more sensitive to drug treatment. Viability of human pre-B ALL cells was further reduced when antibodies to the BAFF-R were combined with other drugs, even in the presence of stromal protection. This indicates that inhibition of BAFF-R function reduces fitness of stressed pre-B ALL cells. We tested a novel humanized anti-BAFF-R monoclonal antibody optimalized for FcRγIII mediated, antibody-dependent cell killing by effector cells. Antibody binding to human ALL cells was inhibitable, in a dose-dependent manner, by recombinant human BAFF. There was no evidence for internalization of the antibodies. The antibodies significantly stimulated NK cell-mediated killing of different human patient-derived ALL cells. Moreover, incubation of such ALL cells with these antibodies stimulated phagocytosis by macrophages. When this was tested in an immunodeficient transplant model, mice that were treated with the antibody had a significantly decreased leukemia burden in bone marrow and spleen. In view of the restricted expression of the BAFF-R on normal cells and the multiple anti-pre-B ALL activities stimulated by this antibody, a further examination of its use for treatment of pre-B ALL is warranted.

Real world data of the impact of first cycle daratumumab on multiple myeloma and AL amyloidosis services

“…Recently our group reported the preservation of TNFRSF13C expression during early drug treatment and at relapse, further supporting its importance in B-ALL blasts survival (Fazio et al, 2017). Targeting the TNFSF13B/TNFRSF13C (BAFF/BAFFR) axis by monoclonal antibodies has long been suggested, with TNFSF13B also detected within the leukaemic niche promoting tumour survival, proliferation and chemoresistance (Parameswaran et al, 2014). Here we propose, for the first time to our knowledge, an additional modality to target TNFRSF13C exploiting a CAR-based approach.…”

Combination Therapy for Treating Advanced Drug-Resistant Acute Lymphoblastic Leukemia

“…ALL cell killing by NK cells was analyzed using calcein-AM assay purchased from Life Technologies (17). Target tumor cells (10 Â 10 6 ) were labeled with (0.5 mmol/L) calcein-AM for 30 minutes at 37 C. Following staining, cells were washed with PBS, counted using Trypan blue (Sigma), and 2 Â 10 6 /mL cells were incubated with VAY736 (20 mg/mL) for 2 hours.…”

“…The indicated ALL cells were plated at a density of 1 Â 10 6 cells per mL in different conditions in an irradiated OP9 bone marrow stroma cells (16,17). OP9 cells were purchased from ATCC.…”

“…Drug-resistant patient cells developed resistance to vincristine (ph À ) or tyrosine kinase inhibitor nilotinib (phþ; Supplementary Fig. S1C) in a coculture OP9 stromal system (16,17). Both relapse and drug-resistant ALL cells expressed surface BAFF-R (Fig.…”

“…We and others have previously shown that B-ALL cells express surface BAFF-R, making it an attractive antigen for therapeutic targeting (13,14), and also report potential therapeutic approaches targeting BAFF-R, which include the fusion toxin rGel/BLyS and an antibody-dependent cellular cytotoxicity (ADCC) optimized anti-BAFF-R, B1239 (15)(16)(17). Antibody to a tumor-specific antigen can be used to target cancer cells through ADCC and is mediated mainly by CD16 (FcRgIII), a major triggering receptor on natural killer (NK) cells.…”