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Monoclonal Antibody Blocks B-Cell Receptor and Eases Leukemia Burden in Mouse Model

By BiotechDaily International staff writers
Posted on 26 May 2014
Blocking the B-cell-activating factor receptor (BAFF-R) on leukemia cells has been suggested as a new approach for treating an acute, chemotherapy-resistant form of childhood leukemia.

Acute lymphoblastic leukemia (ALL) is characterized by an excessive amount of white blood cell precursors (B-cell lymphoblasts) in the blood and bone marrow. B-cell lineage ALL (pre-B ALL) accounts for 80% to 85% of childhood ALL.

BAFF-R is encoded in humans by the TNFRSF13C (tumor necrosis factor receptor superfamily member 13C) gene. BAFF enhances B-cell survival in vitro and is a regulator of the peripheral B-cell population. Overexpression of BAFF in mice results in mature B-cell hyperplasia and symptoms of systemic lupus erythematosus (SLE). Also, some SLE patients have increased levels of BAFF in their serum. Therefore, it has been proposed that abnormally high levels of BAFF may contribute to the pathogenesis of autoimmune diseases by enhancing the survival of autoreactive B cells. The protein encoded by the TNFRSF13C gene is a receptor for BAFF and is a type III transmembrane protein containing a single extracellular cysteine-rich domain.

It is thought that BAFF-R is the principal receptor required for BAFF-mediated mature B-cell survival. Since BAFF-R is expressed on precursor pre-B ALL cells but not on their pre-B normal counterparts, selective killing of ALL cells is possible by targeting this receptor.

Investigators at the University of Southern California (USA) tested a novel humanized anti–BAFF-R monoclonal antibody in a study carried out on leukemia cell cultures and in an immunodeficient mouse transplant model.

They reported in the May 13, 2014, online edition of the journal Molecular Cancer Therapeutics that the antibodies significantly stimulated natural killer 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 the immunodeficient transplant model, mice that were treated with the antibody had a significantly decreased leukemia burden in bone marrow and spleen.

"We have now demonstrated that BAFF-R is a strong potential therapeutic target for treating chemotherapy-resistant leukemia cells, without damaging healthy cells," said senior author Dr. Nora Heisterkamp, professor of research, pediatrics, and pathology at the University of Southern California. "We found that human pre-B ALL cells could be even further reduced when the anti-BAFF-R antibody was combined with chemotherapy or another therapeutic agent. We are looking at a potential one, two punch."

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University of Southern California



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Image: representation of a protein (blue), which contains three zinc fingers in complex with DNA (orange). The coordinating amino acid residues and zinc ions (green) are highlighted (Photo courtesy of Wikimedia Commons).

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