Generation of a humanized afucosylated BAFF-R antibody with broad activity against human B-cell malignancies

Abstract

B-cell activating factor receptor (BAFF-R) is a mature B-cell survival receptor, which is highly expressed in a wide variety of B-cell malignancies but with minimal expression in immature B cells. These properties make BAFF-R an attractive target for therapy of B-cell lymphomas. We generated a novel humanized anti BAFF-R monoclonal antibody (mAb) with high specificity and potent in vitro and in vivo activity against B-cell lymphomas and leukemias. The humanized variants of an original chimeric BAFF-R mAb retained BAFF-R binding affinity and antibody-dependent cellular cytotoxicity (ADCC) against a panel of human cell lines and primary lymphoma samples. Furthermore, 1 humanized BAFF-R mAb clone and its afucosylated version, glycoengineered to optimize the primary mechanism of action, prolonged survival of immunodeficient mice bearing human tumor cell lines or patient-derived lymphoma xenografts in 3 separate models, compared with controls. Finally, the tissue specificity of this humanized mAb was confirmed against a broad panel of normal human tissues. Taken together, we have identified a robust lead-candidate BAFF-R mAb for clinical development.