Anti-BR3 antibodies: A new class of B-cell immunotherapy combining cellular depletion and survival blockade

Department of Immunology, Genentech, South San Francisco, CA 94080, USA.
Blood (Impact Factor: 10.45). 01/2008; 110(12):3959-67. DOI: 10.1182/blood-2007-04-088088
Source: PubMed


Removal of pathogenic B lymphocytes by depletion of monoclonal antibodies (mAbs) or deprivation of B-cell survival factors has demonstrated clinical benefit in both oncologic and immunologic diseases. Partial clinical responses and emerging data demonstrating incomplete B-cell depletion after immunotherapy fuels the need for improved therapeutic modalities. Lessons from the first generation of therapeutics directed against B-cell-specific antigens (CD20, CD22) are being applied to develop novel antibodies with additional functional attributes. We describe the generation of a novel class of B-cell-directed therapy (anti-BR3 mAbs) that combines the depleting capacity of a therapeutic mAb and blockade of B-cell-activating factor (BAFF)-BR3 B-cell survival. In mice, treatment with antagonistic anti-BR3 antibodies results in quantitatively greater reduction in some B-cell subsets and qualitatively different effects on bone marrow plasma cells compared with BR3-Fc BAFF blockade or with anti-CD20 treatment. Comparative analysis of BR3-Fc and anti-BR3 mAb reveals a lower B-cell dependence for BAFF-mediated survival in nonhuman primates than in mice. This novel class of B-cell-targeted therapies shows species characteristics in mice and primates that will guide translation to treatment of human disease.

37 Reads
  • Source
    • "The first is an anti-BAFF neutralizing antibody (LymphoStat-B, Belimumab) [158]. The second is anti-BAFF-R [159], which blocks the interaction of BAFF with the BAFF-R and also kills BAFF-R expressing cells. The third is the decoy receptor BR3-Fc, which is a humanized fusion protein of the extracellular domain of human BAFF-R with the Fc portion of human IgG1 [160]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: BAFF is a potent B-cell survival factor, and it plays an essential role in B-cell homeostasis and B-cell function in the periphery. Both normal and autoreactive B cells are BAFF dependent; however, excess BAFF promotes the survival, growth, and maturation of autoreactive B cells. When overexpressed, BAFF protects B cells from apoptosis, thereby contributing to autoimmunity. Three independent studies have shown higher BAFF levels in the circulation of MG patients. BAFF may play an important role in the pathogenesis of MG. BAFF antagonists may well provide new treatment options for MG patients, particularly those patients with thymic lymphoid follicular hyperplasia.
    11/2011; 2011(1):939520. DOI:10.4061/2011/939520
  • Source
    • "Since BAFF is the only known ligand for BAFF-R these studies strongly suggest that peripheral B cells require BAFF for their survival. In one of these studies a more detailed analysis of the extent of depletion of the various mature B cell subpopulations is reported [25]. This analysis revealed that after such a treatment the B-2 and MZB compartments were largely reduced whereas the B-1 cell numbers were practically not affected. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Defects in the expression of either BAFF (B cell activating factor) or BAFF-R impairs B cell development beyond the immature, transitional type-1 stage and thus, prevents the formation of follicular and marginal zone B cells, whereas B-1 B cells remain unaffected. The expression of BAFF-R on all mature B cells might suggest a role for BAFF-R signaling also for their in vivo maintenance. Here, we show that, 14 days following a single injection of an anti-BAFF-R mAb that prevents BAFF binding, both follicular and marginal zone B cell numbers are drastically reduced, whereas B-1 cells are not affected. Injection of control, isotype-matched but non-blocking anti-BAFF-R mAbs does not result in B cell depletion. We also show that this depletion is neither due to antibody-dependent cellular cytotoxicity nor to complement-mediated lysis. Moreover, prevention of BAFF binding leads to a decrease in the size of the B cell follicles, an impairment of a T cell dependent humoral immune response and a reduction in the formation of memory B cells. Collectively, these results establish a central role for BAFF-BAFF-R signaling in the in vivo survival and maintenance of both follicular and marginal zone B cell pools.
    PLoS ONE 02/2009; 4(5):e5456. DOI:10.1371/journal.pone.0005456 · 3.23 Impact Factor
  • Source
    • "TACI-Ig is being evaluated in RA and SLE, and preliminary studies suggest that there is a significant decrease in serum immunoglobulins. Anti-BR3 antibodies with cell depletion activity and BR3-Fc are being developed for similar indications [21,23]. The respective merits of strategies involving BLyS and APRIL are difficult to compare because their respective roles in humans are not yet fully understood. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Advances in our understanding of the cellular and molecular mechanisms in rheumatic disease fostered the advent of the targeted therapeutics era. Intense research activity continues to increase the number of potential targets at an accelerated pace. In this review, examples of promising targets and agents that are at various stages of clinical development are described. Cytokine inhibition remains at the forefront with the success of tumor necrosis factor blockers, and biologics that block interleukin-6 (IL-6), IL-17, IL-12, and IL-23 and other cytokines are on the horizon. After the success of rituximab and abatacept, other cell-targeted approaches that inhibit or deplete lymphocytes have moved forward, such as blocking BAFF/BLyS (B-cell activation factor of the tumor necrosis factor family/B-lymphocyte stimulator) and APRIL (a proliferation-inducing ligand) or suppressing T-cell activation with costimulation molecule blockers. Small-molecule inhibitors might eventually challenge the dominance of biologics in the future. In addition to plasma membrane G protein-coupled chemokine receptors, small molecules can be designed to block intracellular enzymes that control signaling pathways. Inhibitors of tyrosine kinases expressed in lymphocytes, such as spleen tyrosine kinase and Janus kinase, are being tested in autoimmune diseases. Inactivation of the more broadly expressed mitogen-activated protein kinases could suppress inflammation driven by macrophages and mesenchymal cells. Targeting tyrosine kinases downstream of growth factor receptors might also reduce fibrosis in conditions like systemic sclerosis. The abundance of potential targets suggests that new and creative ways of evaluating safety and efficacy are needed.
    Arthritis research & therapy 02/2009; 11(1):206. DOI:10.1186/ar2556 · 3.75 Impact Factor
Show more