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

Abstract

[1][2][3][4] Since approval of a depleting anti-CD20 monoclonal antibody (mAb) (rituximab [Genentech, South San Francisco, CA; Biogen-IDEC, Cambridge, MA; Roche, Basel, Switzerland)] in 1997 for the treatment of non-Hodgkin lymphoma (NHL), almost 1 million patients have been treated with rituximab as a first or second line therapy, either alone or in combination with chemotherapy. In addition, rituximab maintenance therapy significantly prolongs tumor remission and patient survival in patients with indolent B-cell NHL or chronic lymphocytic leukemia (CLL). 5,6 More recently, rituximab has demonstrated clinical benefit in a variety of autoimmune diseases including rheumatoid arthritis, pemphigus vulgaris, immune thrombocytopenia and autoimmune hemolytic anemia. 4,7,8 As a result, understanding the contribution of B lymphocytes to human autoimmune diseases received revived interest, and several mechanisms have been postulated to participate in disease pathogenesis, including autoantibody production, B-cell antigen presentation, cytokine generation, and lymphorganogenesis. 2,3,9,10 Inhibition of different combinations of these mechanisms is probably responsible for clinical benefit.The success of anti-CD20 B-cell immunotherapy spearheaded a large number of preclinical and clinical efforts to understand in vivo mechanisms of drug activity. Direct elimination of malignant B cells through antigen-dependent cell-mediated cytotoxicity (ADCC), complement-mediated cytotoxicity (CDC), and apoptosis have been demonstrated as the main mechanisms of action in a variety of systems including mouse xenotumors and normal mouse and nonhuman primate (NHP) B-cell subsets. 11-15 Two major determinants affecting normal mouse B-cell depletion have been identified. 13,16 First, the kinetics of B-cell recirculation determines the speed and magnitude of anti-CD20 mAb-mediated B-cell depletion. Cells with higher recirculatory kinetics from blood, lymph nodes, and spleen follicular areas are depleted faster and more completely than cells with lower recirculatory kinetics (eg, peritoneal cavity [PEC], marginal zone [MZ], germinal centers [GC]). Second, the local microenvironment influences the extent of B-cell depletion. Marginal zone, Peyer patches (PP), germinal center, memory, and peritoneal cavity B cells exhibit greater resistance to depletion in mice and nonhuman primates. Reduced recruitment of effector mechanisms in the peritoneal cavity as well as intrinsic B1 B cells properties appear to cause the slower kinetics and B-cell reduction after anti-CD20 mAb treatment. 16 Differences across mouse strains and epitopes recognized by anti-CD20 antibodies used for depletion might explain the differential effects seen on mouse splenic marginal zone B cells. 13,16 Small but consistent numbers of residual B cells can be detected in most lymphoid organs in mice and primates treated with anti-CD20 mAbs. One possibility of achieving a more complete B-cell reduction would be to block B-cell survival signals in addition to Submitted April 30, 2007...

Conditional Deletion of NF-κB–Inducing Kinase (NIK) in Adult Mice Disrupts Mature B Cell Survival and Activation

“…Thus, the differences in secondary lymphoid organ phenotypes between our NIK KO/KO mice and NIK aly/aly mice, as well as the other NIK-deficient mouse strain, may arise from Upon acute deletion of NIK in adult mice using our conditional NIK KO allele, we observed the abrogation of noncanonical NF-kB signaling, as assessed by p52 production, and a resulting reduction in B cell numbers in lymph nodes and spleen. These reductions in B cell populations are similar to what was observed upon blockade of BAFF signaling in adult mice (52) produced in BAFF-deficient and BR3/BAFF-R-deficient mice (61), these effects of NIK deletion likely reflect roles for NIK and the noncanonical NF-kB pathway in non-BAFF-driven biology. Given that CD40L/CD40 signaling is required for germinal center formation and the production of germinal center B cells (22,23) and that CD40 signaling activates the noncanonical NF-kB pathway in a NIK-dependent manner, it is likely that the reductions in germinal center B cells upon acute NIK deletion are a result of the abrogation of NIK-mediated noncanonical NF-kB pathway activation downstream of CD40L/CD40 signaling.…”

“…7C, 7D). These effects were specific to B cells, because CD4 + T cell numbers did not change (data not shown) and were very similar to the published effects of BAFF inhibition on B cell populations in adult mice (20,52). Similar effects on B cell populations in the spleen, including marginal zone B cells, also were observed upon acute NIK deletion, although NIK-specific effects at early time points could not be distinguished from nonspecific Cre effects that were observed in Rosa26-CreER T2+ NIK WT/WT control mice (data not shown).…”

Хронічна Запальна Демієлінізуюча Поліневропатія: Від Патогенезу До Діагностики

“…Показано, что TACI-рецепторы оказывают негативное воздействие на популяцию периферических В-клеток [31]. При введении BAFF-R-антител мышам выявляется истощение различных популяций В-клеток путем ингибирования BAFF-сигналов и активации ан-тителозависимой клеточной цитотоксичности [32].…”

Toll-like receptor-9 is involved in the development of B cell stimulating factor-induced systemic lupus erythematosus

“…Animal and clinical studies of SLE pathogenesis have revealed that B lymphocyte stimulating factor (BLyS) may promote the activation and proliferation of B-lymphocytes, which leads to the production of large amounts of immunoglobulins and autoantibodies (12,13). Immunologic injury is caused by formation of immune complexes, complement-mediated cytolysis, opsonophagocytosis and antibody-mediated cell-dependent cytotoxicity (14).…”