The BlyS Ligand/Receptor Family
Three receptors, TACI (transmembrane activator or CAML-interactor), BCMA (B-cell maturation antigen) and BAFF-R (receptor for B-cell activating factor, belonging to the TNF family), have been identified that have unique binding affinities for the two growth factors BlyS (B-lymphocyte stimulator) and APRIL (a proliferation-inducing ligand) (Marsters et al. Curr Biol 2000; 10(13):785-788; Thompson et al. Science 2001; 293-21 08-2111). TACI and BCMA bind both BLyS and APRIL, while BAFF-R appears capable of binding only BLyS with high affinity (Marsters et al. Curr Biol 2000; 10(13):785-788; Thompson et al. Science 2001; 293:2108-2111). As a result, BLyS is able to signal through all three receptors, while APRIL only appears capable of signaling through TACI and BCMA. In addition, circulating heterotrimer complexes of BLyS and APRIL (groupings of three proteins, containing one or two copies each of BLyS and APRIL) have been identified in serum samples taken from patients with systemic immune-based rheumatic diseases, and have been shown to induce B-cell proliferation in vitro (Roschke et al. J Immunol 2002; 169:4314-4321).
BLyS and APRIL are potent stimulators of B-cell maturation, proliferation and survival (Moore et al. Science 1999; 285(5425): 260-263; Schneider et al. J Exp Med 1999; 189(11): 1747-1756; Do et al. J Exp Med 2000; 192(7):953-964). BLyS and APRIL may be necessary for persistence of autoimmune diseases, especially those involving B-cells. Transgenic mice engineered to express high levels of BLyS exhibit immune cell disorders and display symptoms similar to those seen in patients with Systemic Lupus Erythematosus (Gross et al. Nature 2000; 404:995-999; Mackay et al. J Exp Me 1999; 190(11); 1697-1710). Similarly, increased levels of BLyS/APRIL have been measured in serum samples taken from Systemic Lupus Erythematosus patients and other patients with various autoimmune diseases like Rheumatoid Arthritis (Roschke et al. J Immunol 2002; 169:4314-4321; Cheema et al. Arthritis Rheum 2001; 44(6): 1313-1319; Groom et al. J Clin Invest 2002; 109(1):59-68; Mariette X, Ann Rheum Dis 2003; 62(2):168-171), extending the association of BLyS and/or APRIL and B-cell mediated diseases from animal models to humans.
Multiple Myeloma
Multiple myeloma (MM) is a plasma cell neoplasm characterized by the accumulation of monoclonal plasma cells in the bone marrow, associated with the synthesis of a monoclonal immunoglobulin and a high incidence of osteolytic bone lesions. Overgrowth of MM cells usually leads to immunodeficiency and destruction of the bone cortex at multiple tumor sites. Although traditionally, MM is a disease of the elderly, it is increasingly being detected in younger patients. Diagnosed patients generally have a short life expectancy. The median survival of patients treated with conventional chemotherapy is about 42 months. The use of high-dose therapy with autologous stem cell transplantation increases the median survival to 60 months in younger patients. However, the disease remains incurable.
The cause of multiple myeloma is unknown. There are approximately 74,000 new cases of MM each year worldwide, with an overall incidence of 4.5 per 100,000 per year in most Western industrialized countries. Male to female ratio is 3 to 2 and the incidence is about 2-fold higher in American blacks than in Caucasians. The median age of diagnosis is 68 years. MM accounts for 1% of all malignancies.
Osteolytic lesions, anemia, renal insufficiency and recurrent bacterial infections are the most common clinical features of multiple myeloma. All these complications, especially infections and renal insufficiency are also major causes of death. The pathogenesis of these clinical features depends on the interactions between the myeloma cells and the microenvironment of the bone marrow, by means of cell-to-cell contact, adhesion molecules and cytokines or on the direct effects of circulating monoclonal immunoglobulins or light chains. The M-protein is a hallmark of the disease. The M-protein is an overproduced homogenous immunoglobulin or immunoglobulin fragment. Monoclonal protein is used to calculate myeloma tumor burden and kinetics, to stage myeloma patients and to document their response to treatment. The different immunologic subtypes of MM are: IgG (approximately 55% of cases), 19A (approximately 26% of cases), Bence-Jones or free light chain only (approximately 14% of cases) and IgD (2% of cases). Non-secretory myeloma accounts for 1 to 5% of myeloma cases and IgM, IgE or bi-clonal MM are extremely rare. Serum beta-2 microglobulin levels, C-reactive protein levels, serum albumin levels, plasma cell labeling index (PCLI) and the presence of chromosome 13 abnormalities are prognostic factors for multiple myeloma.
The bifunctional alkylating agents like melphalan and cyclophosphamide, have been the foundation of standard therapy in multiple myeloma; the classic combination of melphalan and prednisone is still the standard treatment for most patients (Durie et al. Hematol J 2004; 4:379-398).
The regimen vincristine, doxorubicin and dexamethasone (VAD) or VAD-like regimens are commonly used as induction therapy pre-stem cell collection and transplantation. An alternative therapy is dexamethasone alone or, more recently thalidomide/dexamethasone. Indeed, thalidomide has recently been recognized as an effective agent alone or in combination for patients with MM at various stages of disease (Barlogie et al. Blood 2001; 98:492-494).
High-dose chemotherapy supported by autologous peripheral blood stem cell (PBSC)-transplantation has been accepted as an important treatment modality for patients younger than age 65. Furthermore, the approach of tandem (double) autologous stem cell transplantation is also pursued to attempt to improve Complete Response rates and survival, especially in patients who do not have a Very Good Partial Response after undergoing one transplantation. Autologous stem cell transplantation is now a safe procedure, however, contamination of the autologous graft by myeloma cells remains a concern. Maintenance treatment after transplantation with corticosteroids or IFN-alpha is often prescribed to delay relapse.
Allogeneic transplantation eliminates the problem of tumor cell contamination of the stem cells. Furthermore, there is evidence of graft-versus-myeloma effect with allografting. Standard myeloablative allogeneic transplantation can lead to prolonged disease-free survival in a small percentage of patients, but the high treatment-related mortality and significant toxicity from graft-versus-host disease have limited the role of this procedure in the treatment of myeloma. Positive results have been reported using non-myeloablative regimens (mini-allotransplants) which elicit lower acute toxicity.
The proteasome inhibitor Velcade™ (bortezomib) represents a new class of agents with activity in myeloma that is refractory to multiple lines of standard and high-dose regimen. A 35% overall response rate was reported in the pivotal phase II trial, with a 12 months median duration of response (Richardson et al. N Eng J Med 2003; 348(26):26092617). Furthermore, experimental therapies under investigation for multiple myeloma include thalidomide derivatives, vaccination, monoclonal antibodies and anti-sense drugs. Supportive therapies address the symptoms and complications of the disease. Supportive therapies commonly used in MM include bisphosphonates, growth factors, antibiotics, intravenous immunoglobulin, plasmapheresis and pain control measures. Therefore, there is a long-felt need in the field to develop effective methods for treating or ameliorating multiple myeloma.
Waldenström's Macroglobulinemia
Waldenstrom's macroglobulinemia (WM) is a condition related to MM and is the result of proliferation of lymphocytes and plasma cells which produce monoclonal IgM. The median age at presentation is 63 years and over 60% of patients are male. Many of the clinical features are the result of hyperviscosity of blood due to the raised IgM concentration. WM is characterized by hypersecretion of IgM in the serum; excess lymphoplasmacytoid cells in the bone marrow and involvement of visceral organs including liver and spleen. Primary treatment for patients who require systemic therapy includes alkylating agents or nucleoside analogs, such as cladribine and fludarabine. Steroids can be used alone or in combination with alkylating agents. Plasmapheresis is indicated for treatment of symptomatic hyperviscosity. At present there is no cure for WM patients. Therefore, there is a long-felt need in the field to develop new methods for treating or ameliorating WM.