Generation and characterization of LymphoStat‐B, a human monoclonal antibody that antagonizes the bioactivities of B lymphocyte stimulator

TLDR

B lymphocyte stimulator (BLyS) is a TNF‑related cytokine that regulates B‑cell maturation, and its elevated levels are linked to autoimmune disease pathogenesis. The study aimed to identify and characterize a fully human monoclonal antibody that targets BLyS. Using phage display and affinity maturation, the authors produced LymphoStat‑B, a high‑affinity antibody that blocks BLyS binding to its three receptors (TACI, BCMA, BAFF‑R) and was evaluated in vitro and in murine and cynomolgus monkey models. LymphoStat‑B potently inhibited BLyS‑driven B‑cell proliferation, reduced splenic B‑cell numbers and IgA titers in mice, and caused B‑cell depletion in spleen and lymph nodes of cynomolgus monkeys, indicating therapeutic promise for autoimmune diseases.

Abstract

To identify and characterize a fully human antibody directed against B lymphocyte stimulator (BLyS), a tumor necrosis factor-related cytokine that plays a critical role in the regulation of B cell maturation and development. Elevated levels of BLyS have been implicated in the pathogenesis of autoimmune diseases.A human phage display library was screened for antibodies against human BLyS. A human monoclonal antibody, LymphoStat-B, specific for human BLyS was obtained from the library screening and subsequent affinity optimization mutagenesis. The antibody was tested for inhibition of human BLyS in vitro and in an in vivo murine model. Additionally, the consequences of BLyS inhibition were tested in vivo by administration of LymphoStat-B to cynomolgus monkeys.LymphoStat-B bound with high affinity to human BLyS and inhibited the binding of BLyS to its 3 receptors, TACI, BCMA, and BLyS receptor 3/BAFF-R. LymphoStat-B potently inhibited BLyS-induced proliferation of B cells in vitro, and administration of LymphoStat-B to mice prevented human BLyS-induced increases in splenic B cell numbers and IgA titers. In cynomolgus monkeys, administration of LymphoStat-B resulted in decreased B cell representation in both spleen and mesenteric lymph nodes.A fully human monoclonal antibody has been isolated that binds to BLyS with high affinity and neutralizes human BLyS bioactivity in vitro and in vivo. Administration of this antibody to cynomolgus monkeys resulted in B cell depletion in spleen and lymph node. This antibody may prove therapeutically useful in the treatment of autoimmune diseases in humans.