- Email: [email protected]
B-Cell Activating Factor and a Proliferation-Inducing Ligand in Hematologic Malignancies
Mini-Review Targeting B-Lymphocyte Stimulator/B-Cell Activating Factor and a Proliferation-Inducing Ligand in Hematologic Malignancies Latha Shivakumar,1 Stephen Ansell2 Abstract B-lymphocyte stimulator/B-cell activating factor (BLyS/BAFF) and a proliferation-inducing ligand (APRIL), members of the tumor necrosis family of ligands, are expressed by monocytes, macrophages, and dendritic cells, and increased expression of these ligands is noted in lymphomas and plasma cell malignancies. BLyS and APRIL are essential for the survival of normal and malignant B lymphocytes, and altered expression of BLyS or APRIL or the receptors B-cell maturation, transmembrane activator and calcium-modulating cyclophilin ligand interactor, or BAFF-R have been reported in various B-cell malignancies, including B-cell nonHodgkin’s lymphoma, chronic lymphocytic leukemia, Hodgkin’s lymphoma, multiple myeloma, and Waldenström’s macroglobulinemia. Levels of BLyS (in the tumor and in the serum) increased with the transformation of the tumors to a more aggressive phenotype. A high BLyS level inversely correlated with a poor median overall survival, presence of constitutional symptoms, and increased levels of lactate dehydroge1CIG
Media Group, LP, Dallas, TX of Hematology/Division of Hematology Research, Mayo Clinic, Rochester, MN
2Division
Key words: Belimumab, Chronic lymphocytic leukemia, Hodgkin’s lymphoma, Multiple myeloma, Non-Hodgkin’s lymphoma, Waldenström’s macroglobulinemia Address for correspondence: Stephen M. Ansell, MD, PhD, Division of Hematology, Mayo Clinic, 200 First St SW, Rochester, MN 55905 Fax: 507-266-4972; e-mail: [email protected]
nase in patients with non-Hodgkin’s lymphoma. Additionally, patients who responded to therapy had a lower BLyS level than those with progressive disease. Several agents targeting BLyS and APRIL are currently being pursued in phase I clinical studies in patients with B-cell malignancies.
Figure 1: BLyS and APRIL and Their Receptors4 APRIL BLyS
TACI BCMA BAFF-R
Introduction B-lymphocyte stimulator/B-cell activating factor (BLyS/BAFF) and a proliferation-inducing ligand (APRIL) belong to the tumor necrosis factor (TNF) family of ligands and are essential for the survival of normal and malignant B lymphocytes.1,2 BLyS and APRIL are expressed by monocytes, macrophages, and dendritic cells, and increased expression is noted in lymphomas and plasma cell malignancies. Levels of BLyS (in the tumor and in the serum) increase with the transformation of the tumors to a more aggressive phenotype.3 A high BLyS level correlated with a poor median overall survival, presence of constitutional symptoms, and increased levels of lactate dehydrogenase in patients with non-Hodgkin’s lymphoma (NHL). Additionally, patients who responded to therapy tended to have lower BLyS levels than those who did not exhibit a complete response. BLyS and APRIL bind to 2 TNF receptors (TNF-Rs) belonging to the TNF-R superfamily, one called transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI) and the other called B-cell maturation antigen (BCMA; Figure 1).4 Additionally,
B-Cell
B-Cell B-Cell Antibody Ig Class Differentiation Survival Production Switch
BLyS and APRIL can bind specifically to other receptors—BLyS to BAFF-R/ BR3, another receptor belonging to the TNF-R superfamily—and APRIL to heparin sulfate proteoglycans such as syndecan-1.
Preclinical Studies The biologic role of BLyS and APRIL in vivo was further elucidated in studies of transgenic and knockout mice.5-8 In BLyS and APRIL transgenic mice, increased B-lymphocyte counts and increased levels of immunoglobulins (including autoantibodies) were reported.5,6 BLyS knockout mice have defects in B-cell development with a loss of mature B cells after transitional 1 (T1) stage, decreased levels of circulating immunoglobulins, and impaired antibody response to antigenic challenge.7 APRIL-deficient mice had a decrease in the levels of circulat-
Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #1557-9190, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.
106 • Clinical Lymphoma & Myeloma September 2006
ing immunoglobulin (Ig)–A, increased levels of effector memory T cells, and an increased IgG response to T-dependent antigens.8 These results suggest a role for BLyS and APRIL in B-cell differentiation, B-cell survival, and also in antibody production. Additionally, APRIL might play a role in costimulation of T cells. Interestingly, as BLyS transgenic mice age, they develop a secondary pathology, Sjögren syndrome, which is associated with intense B-cell activity and a predisposition to development of B-cell NHLs.9-11 Furthermore, when BLyS transgenic mice are crossed with TNF–/– mice, 35% of the mice develop B-cell lymphomas.12 Furthermore, approximately 40% of aged APRIL transgenic mice develop a B-1 cell-associated neoplasm reminiscent of lymphoma.13
BLyS and APRIL in B-Cell Malignancies Altered expression of BLyS or APRIL or the receptors, BCMA, TACI, or BAFF-R, have been reported in various B-cell malignancies, including B-cell NHL, chronic lymphocytic leukemia (CLL), Hodgkin’s lymphoma (HL), multiple myeloma (MM), and Waldenström’s macroglobulinemia (WM).14-18 Signaling through the BCMA and TACI receptors is required for survival of the lymphoma cells, as seen by the induction of apoptosis of lymphoma cells by blocking the binding of BLyS and APRIL to the receptors with soluble BCMA and TACI. Blocking the BCMA and TACI receptors results in downregulation of antiapoptotic proteins Bcl-2 and Bcl-XL and upregulation of the proapoptotic protein Bax. Increased levels of BLyS and APRIL in the sera of patients with CLL were found to protect the tumor cells from apoptosis.19,20 BLyS and APRIL also played a role in the pathogenesis of HL by promoting survival of the ReedSternberg cells of HL.16 BLyS plays an important role in the biology of MM.15,21,22 The bone marrow microenvironment is crucial for the pathogenesis of MM. Bone marrow stromal cells (BMSCs) from established cell lines and isolated from patients were found to express very high levels of
BLyS (3-10–fold higher than MM cells). Multiple myeloma cells express high levels of the receptors for BLyS, BCMA, TACI, and BAFF-R.15 In vitro studies have shown that adhesion of MM cells to BMSCs resulted in increased secretion of BLyS from the BMSCs.23 Adhesion of MM cells to the BMSCs also resulted in activation of nuclear factor–gB signaling, which led to further secretion of BLyS. Binding of BLyS to TACI and BCMA activated various signaling cascades in the MM cells, leading to proliferation and survival of the MM cells. BLyS levels were increased in the serum and bone marrow of patients with WM and were shown to stimulate Ig production and promote survival of the malignant cells. In previous studies, serum BLyS levels were found to be increased upon transformation of the tumors to a more aggressive phenotype.3,24 Serum BLyS levels have also been shown to correlate with clinical characteristics and prognosis. Serum BLyS levels were increased in patients with large-cell NHL, and high BLyS levels were associated with an inferior overall survival.3 Similarly, serum BLyS levels were higher in relapsed HL and were associated with poor prognosis in these patients.
Therapies That Target BLyS, APRIL, or Their Receptors Several agents targeting BLyS, APRIL, or their receptors, TACI and BAFF-R, are currently being pursued in clinical studies (Table 1).25-27 Inhibition of BLyS and APRIL using a soluble fusion
protein of the extracellular domain of TACI and the Fc portion of a human IgG (TACI-Ig) inhibited signaling from the BLyS and APRIL pathways and induced apoptosis of myeloma cells in vitro.28 A phase I/II study of TACI-Ig in heavily pretreated patients with MM or WM to evaluate the safety, biologic activity, pharmacodynamics, and pharmacokinetics of TACI-Ig reported no dose-limiting toxicities up to the highest dose of TACI-Ig tested (10 mg/kg).25 Treatment with TACI-Ig was associated with some antitumor activity, with disease stabilization noted in 2 of the 6 patients with MM and 1 of the 3 patients with WM. TACI-Ig treatment was also associated with biologic activity as seen by the decrease in polyclonal Ig in 6 of 9 patients and soluble syndecan-1 in 2 of 5 patients with MM during the treatment. In a phase I trial of a radiolabeled recombinant BLyS protein, 10 patients with relapsed/refractory follicular non-Hodgkin’s lymphoma received an imaging/dosimetric dose of 5-7 mCi of LR131, radioconjugated BLyS protein, followed by the therapeutic dose (0.35-1.7 mCi/kg) 1-2 weeks later.26 Fluorodeoxyglucose positron emission tomography and computed tomography imaging were performed before and after LR131 treatment to evaluate tumor response to the treatment. LR131 was specifically targeted to the tumor site and was rapidly cleared from blood and normal organs. Of the 8 evaluable patients, 2 complete responses were reported at 12 weeks, and follow-up fluorodeoxyglucose positron emission tomography scanning was negative in all areas of previous
Table 1: Agents Targeting BLyS, APRIL, or Their Receptors25-27 Mechanism of Action
Stage of Clinical Study
TACI-Ig
Soluble fusion protein of the extracellular domain of TACI and the Fc portion of a human IgG
Phase I/II trial in heavily pretreated patients with MM or WM. Additional phase I trials in NHL, CLL, and autoimmune diseases.
LR131
Radiolabeled recombinant BLyS protein
Phase I trials in relapsed/ refractory NHL and MM
Belimumab
Fully human monoclonal antibody against BLyS
Preclinical studies in monkeys. Phase II trials in autoimmune diseases.
AMG 623
Antagonistic monoclonal antibody to BLyS
Phase I trial in CLL
Anti-BR3
Antagonistic monoclonal antibody to BAFF-R
Preclinical studies
Targeted Agent
Clinical Lymphoma & Myeloma September 2006 • 107
activity. No dose-limiting toxicities were reported in this study, and only mild to moderate reversible toxicities were reported at the doses of LR131 tested. A fully human monoclonal antibody against BLyS, belimumab, was tested in cynomolgus monkeys. Peripheral blood B-lymphocyte populations were significantly decreased after 13 weeks of treatment, and a decrease in spleen and lymph node B lymphocytes was seen after 13-26 weeks of treatment with belimumab.27 Another antagonistic monoclonal antibody against BLyS, AMG 623, is currently being evaluated in a phase I study in patients with CLL. Furthermore, an anti-BR3 antibody is currently in development, and phase I clinical trials with this agent in B-cell malignancies are planned.
Conclusion BLyS and APRIL are overexpressed in B-cell malignancies and promote survival of the malignant B lymphocytes. Serum BLyS levels are increased in patients with B-cell malignancies and are associated with poor prognosis in these patients. Several agents targeting BLyS and APRIL are currently being pursued in phase I clinical studies in patients with B-cell malignancies.
References 1. Moore PA, Belvedere O, Orr A, et al. BLyS: member of the tumor necrosis factor family and B lymphocyte stimulator. Science 1999; 285:260-263.
2. Hahne M, Kataoka T, Shroter M, et al. APRIL, a new ligand of the tumor necrosis factor family, stimulates tumor cell growth. J Exp Med 1998; 188:1185-1190. 3. Novak AJ, Grote DM, Stenson M, et al. Expression of BLyS and its receptors in B-cell non-Hodgkin lymphoma: correlation with disease activity and patient outcome. Blood 2004; 104:2247-2253. 4. Dillon SR, Gross JA, Ansell SM, et al. An APRIL to remember: novel TNF ligands as therapeutic targets. Nat Rev Drug Discov 2006; 5:235-246. Review. 5. Mackay F, Woodcock SA, Lawton P, et al. Mice transgenic for BAFF develop lymphocytic disorders along with autoimmune manifestations. J Exp Med 1999; 190:1697-1610. 6. Stein JV, Lopez-Fraga M, Elustondo FA, et al. APRIL modulates B and T cell immunity. J Clin Invest 2002; 109:1587-1598. 7. Schiemann B, Gommerman JL, Vora K, et al. An essential role for BAFF in the normal development of B cells through a BCMA-independent pathway. Science 2001; 293:2111-2114. 8. Varfolomeev E, Kischkel F, Martin F, et al. APRILdeficient mice have normal immune system development. Mol Cell Biol 2004; 24:997-1006. 9. Groom J, Kalled SL, Cutler AH, et al. Association of BAFF/BLyS overexpression and altered B cell differentiation with Sjogren’s syndrome. J Clin Invest 2002; 109:59-68. 10. Royer B, Cazals-Hatem D, Sibilia J, et al. Lymphomas in patients with Sjogren’s syndrome are marginal zone b-cell neoplasms, arise in diverse extranodal and nodal sites, and are not associated with viruses. Blood 1997; 90:766-775. 11. Zulman J, Jaffe R, Talal N. Evidence that the malignant lymphoma of Sjogren’s syndrome is a monoclonal B-cell neoplasm. N Engl J Med 1978; 299:1215-1220. 12. Batten M, Groom J, Cachero TG, et al. BAFF mediates survival of peripheral immature B lymphocytes. J Exp Med 2000; 192:1453-1466. 13. Planelles L, Carvalho-Pinto CE, Hardenberg G, et al. APRIL promotes B-1 cell-associated neoplasm. Cancer Cell 2004; 6:399-408. 14. He B, Chadburn A, Jou E, et al. Lymphoma B cells evade apoptosis through the TNF family members BAFF/ BLyS and APRIL. J Immunol 2004; 172:33683379. 15. Raje N, Kumar S, Hideshima T, et al. The role of B cell-activating factor (BAFF) in the biology of multiple myeloma (MM). Blood 2005; 106:944a (Abstract #3380). 16. Chiu A, Xu W, He B, et al. Hodgkin lymphoma cells express TACI and BCMA receptors and generate survival and proliferation signals in response to BAFF
108 • Clinical Lymphoma & Myeloma September 2006
and APRIL. Blood 2006. Epub ahead of print. 17. Elsawa SF, Novak AJ, Grote DM, et al. B-lymphocyte stimulator (BlyS) stimulates immunoglobulin production and malignant B-cell growth in Waldenstrom macroglobulinemia. Blood 2006; 107:2882-2888. 18. Briones J, Timmerman JM, Hilbert DM, et al. BLyS and BLyS receptor expression in non-Hodgkin’s lymphoma. Exp Hematol 2002; 30:135-141. 19. Nishio M, Endo T, Tsukada N, et al. Nurselike cells express BAFF and APRIL, which can promote survival of chronic lymphocytic leukemia cells via a paracrine pathway distinct from that of SDF-1alpha. Blood 2005; 106:1012-1020. 20. Novak AJ, Bram RJ, Kay NE, et al. Aberrant expression of B-lymphocyte stimulator by B chronic lymphocytic leukemia cells: a mechanism for survival. Blood 2002; 100:2973-2979. 21. Novak AJ, Darce JR, Arendt BK, et al. Expression of BCMA, TACI, and BAFF-R in multiple myeloma: a mechanism for growth and survival. Blood 2004; 103:689-694. 22. Moreaux J, Legouffe E, Jourdan E, et al. BAFF and APRIL protect myeloma cells from apoptosis induced by interleukin 6 deprivation and dexamethasone. Blood 2004; 103:3148-3157. 23. Tai Y-T, Li X-F, Coffey R, et al. Role of BAFF in adhesion and growth of human multiple myeloma cells in the bone marrow environment. Proc Amer Assoc Cancer Res 2006; 47:1132 (Abstract #4823). 24. Oki Y, Georgakis GV, Migone T-S, et al. Serum BLyS level as a prognostic marker in patients with lymphoma. Blood 2005; 106:546a (Abstract #1926). 25. Rossi J-F, Borghini-Fuhrer I, Moreaux J, et al. A phase I/II study of TACI-Ig to neutralize APRIL and BLyS in patients with refractory or relapsed multiple myeloma or previously-treated Waldenstrom’s macroglobulinemia. Blood 2005; 106:721a (Abstract #2566). 26. Belch A, McEwan A, Hewitt J, et al. Tumor targeting, dosimetry and clinical response data for lymphorad-131 (LR131; I-131 labeled B-lymphocyte stimulator) in patients with relapsed/refractory non-Hodgkin’s lymphoma. Blood 2004; 104:214a (Abstract #750). 27. Halpern WG, Lappin P, Zanardi T, et al. Chronic administration of belimumab, a BLyS antagonist, decreases tissue and peripheral blood B-lymphocyte populations in cynomolgus monkeys: pharmacokinetics, pharmacodynamics and toxicologic effects. Toxicol Sci 2006; 91:586-599. 28. Gross JA, Dillon SR, Mudri S, et al. TACI-Ig neutralizes molecules critical for B cell development and autoimmune disease. Immunity 2001; 15:289-302.
Media Group, LP, Dallas, TX of Hematology/Division of Hematology Research, Mayo Clinic, Rochester, MN
2Division
Key words: Belimumab, Chronic lymphocytic leukemia, Hodgkin’s lymphoma, Multiple myeloma, Non-Hodgkin’s lymphoma, Waldenström’s macroglobulinemia Address for correspondence: Stephen M. Ansell, MD, PhD, Division of Hematology, Mayo Clinic, 200 First St SW, Rochester, MN 55905 Fax: 507-266-4972; e-mail: [email protected]
nase in patients with non-Hodgkin’s lymphoma. Additionally, patients who responded to therapy had a lower BLyS level than those with progressive disease. Several agents targeting BLyS and APRIL are currently being pursued in phase I clinical studies in patients with B-cell malignancies.
Figure 1: BLyS and APRIL and Their Receptors4 APRIL BLyS
TACI BCMA BAFF-R
Introduction B-lymphocyte stimulator/B-cell activating factor (BLyS/BAFF) and a proliferation-inducing ligand (APRIL) belong to the tumor necrosis factor (TNF) family of ligands and are essential for the survival of normal and malignant B lymphocytes.1,2 BLyS and APRIL are expressed by monocytes, macrophages, and dendritic cells, and increased expression is noted in lymphomas and plasma cell malignancies. Levels of BLyS (in the tumor and in the serum) increase with the transformation of the tumors to a more aggressive phenotype.3 A high BLyS level correlated with a poor median overall survival, presence of constitutional symptoms, and increased levels of lactate dehydrogenase in patients with non-Hodgkin’s lymphoma (NHL). Additionally, patients who responded to therapy tended to have lower BLyS levels than those who did not exhibit a complete response. BLyS and APRIL bind to 2 TNF receptors (TNF-Rs) belonging to the TNF-R superfamily, one called transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI) and the other called B-cell maturation antigen (BCMA; Figure 1).4 Additionally,
B-Cell
B-Cell B-Cell Antibody Ig Class Differentiation Survival Production Switch
BLyS and APRIL can bind specifically to other receptors—BLyS to BAFF-R/ BR3, another receptor belonging to the TNF-R superfamily—and APRIL to heparin sulfate proteoglycans such as syndecan-1.
Preclinical Studies The biologic role of BLyS and APRIL in vivo was further elucidated in studies of transgenic and knockout mice.5-8 In BLyS and APRIL transgenic mice, increased B-lymphocyte counts and increased levels of immunoglobulins (including autoantibodies) were reported.5,6 BLyS knockout mice have defects in B-cell development with a loss of mature B cells after transitional 1 (T1) stage, decreased levels of circulating immunoglobulins, and impaired antibody response to antigenic challenge.7 APRIL-deficient mice had a decrease in the levels of circulat-
Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #1557-9190, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.
106 • Clinical Lymphoma & Myeloma September 2006
ing immunoglobulin (Ig)–A, increased levels of effector memory T cells, and an increased IgG response to T-dependent antigens.8 These results suggest a role for BLyS and APRIL in B-cell differentiation, B-cell survival, and also in antibody production. Additionally, APRIL might play a role in costimulation of T cells. Interestingly, as BLyS transgenic mice age, they develop a secondary pathology, Sjögren syndrome, which is associated with intense B-cell activity and a predisposition to development of B-cell NHLs.9-11 Furthermore, when BLyS transgenic mice are crossed with TNF–/– mice, 35% of the mice develop B-cell lymphomas.12 Furthermore, approximately 40% of aged APRIL transgenic mice develop a B-1 cell-associated neoplasm reminiscent of lymphoma.13
BLyS and APRIL in B-Cell Malignancies Altered expression of BLyS or APRIL or the receptors, BCMA, TACI, or BAFF-R, have been reported in various B-cell malignancies, including B-cell NHL, chronic lymphocytic leukemia (CLL), Hodgkin’s lymphoma (HL), multiple myeloma (MM), and Waldenström’s macroglobulinemia (WM).14-18 Signaling through the BCMA and TACI receptors is required for survival of the lymphoma cells, as seen by the induction of apoptosis of lymphoma cells by blocking the binding of BLyS and APRIL to the receptors with soluble BCMA and TACI. Blocking the BCMA and TACI receptors results in downregulation of antiapoptotic proteins Bcl-2 and Bcl-XL and upregulation of the proapoptotic protein Bax. Increased levels of BLyS and APRIL in the sera of patients with CLL were found to protect the tumor cells from apoptosis.19,20 BLyS and APRIL also played a role in the pathogenesis of HL by promoting survival of the ReedSternberg cells of HL.16 BLyS plays an important role in the biology of MM.15,21,22 The bone marrow microenvironment is crucial for the pathogenesis of MM. Bone marrow stromal cells (BMSCs) from established cell lines and isolated from patients were found to express very high levels of
BLyS (3-10–fold higher than MM cells). Multiple myeloma cells express high levels of the receptors for BLyS, BCMA, TACI, and BAFF-R.15 In vitro studies have shown that adhesion of MM cells to BMSCs resulted in increased secretion of BLyS from the BMSCs.23 Adhesion of MM cells to the BMSCs also resulted in activation of nuclear factor–gB signaling, which led to further secretion of BLyS. Binding of BLyS to TACI and BCMA activated various signaling cascades in the MM cells, leading to proliferation and survival of the MM cells. BLyS levels were increased in the serum and bone marrow of patients with WM and were shown to stimulate Ig production and promote survival of the malignant cells. In previous studies, serum BLyS levels were found to be increased upon transformation of the tumors to a more aggressive phenotype.3,24 Serum BLyS levels have also been shown to correlate with clinical characteristics and prognosis. Serum BLyS levels were increased in patients with large-cell NHL, and high BLyS levels were associated with an inferior overall survival.3 Similarly, serum BLyS levels were higher in relapsed HL and were associated with poor prognosis in these patients.
Therapies That Target BLyS, APRIL, or Their Receptors Several agents targeting BLyS, APRIL, or their receptors, TACI and BAFF-R, are currently being pursued in clinical studies (Table 1).25-27 Inhibition of BLyS and APRIL using a soluble fusion
protein of the extracellular domain of TACI and the Fc portion of a human IgG (TACI-Ig) inhibited signaling from the BLyS and APRIL pathways and induced apoptosis of myeloma cells in vitro.28 A phase I/II study of TACI-Ig in heavily pretreated patients with MM or WM to evaluate the safety, biologic activity, pharmacodynamics, and pharmacokinetics of TACI-Ig reported no dose-limiting toxicities up to the highest dose of TACI-Ig tested (10 mg/kg).25 Treatment with TACI-Ig was associated with some antitumor activity, with disease stabilization noted in 2 of the 6 patients with MM and 1 of the 3 patients with WM. TACI-Ig treatment was also associated with biologic activity as seen by the decrease in polyclonal Ig in 6 of 9 patients and soluble syndecan-1 in 2 of 5 patients with MM during the treatment. In a phase I trial of a radiolabeled recombinant BLyS protein, 10 patients with relapsed/refractory follicular non-Hodgkin’s lymphoma received an imaging/dosimetric dose of 5-7 mCi of LR131, radioconjugated BLyS protein, followed by the therapeutic dose (0.35-1.7 mCi/kg) 1-2 weeks later.26 Fluorodeoxyglucose positron emission tomography and computed tomography imaging were performed before and after LR131 treatment to evaluate tumor response to the treatment. LR131 was specifically targeted to the tumor site and was rapidly cleared from blood and normal organs. Of the 8 evaluable patients, 2 complete responses were reported at 12 weeks, and follow-up fluorodeoxyglucose positron emission tomography scanning was negative in all areas of previous
Table 1: Agents Targeting BLyS, APRIL, or Their Receptors25-27 Mechanism of Action
Stage of Clinical Study
TACI-Ig
Soluble fusion protein of the extracellular domain of TACI and the Fc portion of a human IgG
Phase I/II trial in heavily pretreated patients with MM or WM. Additional phase I trials in NHL, CLL, and autoimmune diseases.
LR131
Radiolabeled recombinant BLyS protein
Phase I trials in relapsed/ refractory NHL and MM
Belimumab
Fully human monoclonal antibody against BLyS
Preclinical studies in monkeys. Phase II trials in autoimmune diseases.
AMG 623
Antagonistic monoclonal antibody to BLyS
Phase I trial in CLL
Anti-BR3
Antagonistic monoclonal antibody to BAFF-R
Preclinical studies
Targeted Agent
Clinical Lymphoma & Myeloma September 2006 • 107
activity. No dose-limiting toxicities were reported in this study, and only mild to moderate reversible toxicities were reported at the doses of LR131 tested. A fully human monoclonal antibody against BLyS, belimumab, was tested in cynomolgus monkeys. Peripheral blood B-lymphocyte populations were significantly decreased after 13 weeks of treatment, and a decrease in spleen and lymph node B lymphocytes was seen after 13-26 weeks of treatment with belimumab.27 Another antagonistic monoclonal antibody against BLyS, AMG 623, is currently being evaluated in a phase I study in patients with CLL. Furthermore, an anti-BR3 antibody is currently in development, and phase I clinical trials with this agent in B-cell malignancies are planned.
Conclusion BLyS and APRIL are overexpressed in B-cell malignancies and promote survival of the malignant B lymphocytes. Serum BLyS levels are increased in patients with B-cell malignancies and are associated with poor prognosis in these patients. Several agents targeting BLyS and APRIL are currently being pursued in phase I clinical studies in patients with B-cell malignancies.
References 1. Moore PA, Belvedere O, Orr A, et al. BLyS: member of the tumor necrosis factor family and B lymphocyte stimulator. Science 1999; 285:260-263.
2. Hahne M, Kataoka T, Shroter M, et al. APRIL, a new ligand of the tumor necrosis factor family, stimulates tumor cell growth. J Exp Med 1998; 188:1185-1190. 3. Novak AJ, Grote DM, Stenson M, et al. Expression of BLyS and its receptors in B-cell non-Hodgkin lymphoma: correlation with disease activity and patient outcome. Blood 2004; 104:2247-2253. 4. Dillon SR, Gross JA, Ansell SM, et al. An APRIL to remember: novel TNF ligands as therapeutic targets. Nat Rev Drug Discov 2006; 5:235-246. Review. 5. Mackay F, Woodcock SA, Lawton P, et al. Mice transgenic for BAFF develop lymphocytic disorders along with autoimmune manifestations. J Exp Med 1999; 190:1697-1610. 6. Stein JV, Lopez-Fraga M, Elustondo FA, et al. APRIL modulates B and T cell immunity. J Clin Invest 2002; 109:1587-1598. 7. Schiemann B, Gommerman JL, Vora K, et al. An essential role for BAFF in the normal development of B cells through a BCMA-independent pathway. Science 2001; 293:2111-2114. 8. Varfolomeev E, Kischkel F, Martin F, et al. APRILdeficient mice have normal immune system development. Mol Cell Biol 2004; 24:997-1006. 9. Groom J, Kalled SL, Cutler AH, et al. Association of BAFF/BLyS overexpression and altered B cell differentiation with Sjogren’s syndrome. J Clin Invest 2002; 109:59-68. 10. Royer B, Cazals-Hatem D, Sibilia J, et al. Lymphomas in patients with Sjogren’s syndrome are marginal zone b-cell neoplasms, arise in diverse extranodal and nodal sites, and are not associated with viruses. Blood 1997; 90:766-775. 11. Zulman J, Jaffe R, Talal N. Evidence that the malignant lymphoma of Sjogren’s syndrome is a monoclonal B-cell neoplasm. N Engl J Med 1978; 299:1215-1220. 12. Batten M, Groom J, Cachero TG, et al. BAFF mediates survival of peripheral immature B lymphocytes. J Exp Med 2000; 192:1453-1466. 13. Planelles L, Carvalho-Pinto CE, Hardenberg G, et al. APRIL promotes B-1 cell-associated neoplasm. Cancer Cell 2004; 6:399-408. 14. He B, Chadburn A, Jou E, et al. Lymphoma B cells evade apoptosis through the TNF family members BAFF/ BLyS and APRIL. J Immunol 2004; 172:33683379. 15. Raje N, Kumar S, Hideshima T, et al. The role of B cell-activating factor (BAFF) in the biology of multiple myeloma (MM). Blood 2005; 106:944a (Abstract #3380). 16. Chiu A, Xu W, He B, et al. Hodgkin lymphoma cells express TACI and BCMA receptors and generate survival and proliferation signals in response to BAFF
108 • Clinical Lymphoma & Myeloma September 2006
and APRIL. Blood 2006. Epub ahead of print. 17. Elsawa SF, Novak AJ, Grote DM, et al. B-lymphocyte stimulator (BlyS) stimulates immunoglobulin production and malignant B-cell growth in Waldenstrom macroglobulinemia. Blood 2006; 107:2882-2888. 18. Briones J, Timmerman JM, Hilbert DM, et al. BLyS and BLyS receptor expression in non-Hodgkin’s lymphoma. Exp Hematol 2002; 30:135-141. 19. Nishio M, Endo T, Tsukada N, et al. Nurselike cells express BAFF and APRIL, which can promote survival of chronic lymphocytic leukemia cells via a paracrine pathway distinct from that of SDF-1alpha. Blood 2005; 106:1012-1020. 20. Novak AJ, Bram RJ, Kay NE, et al. Aberrant expression of B-lymphocyte stimulator by B chronic lymphocytic leukemia cells: a mechanism for survival. Blood 2002; 100:2973-2979. 21. Novak AJ, Darce JR, Arendt BK, et al. Expression of BCMA, TACI, and BAFF-R in multiple myeloma: a mechanism for growth and survival. Blood 2004; 103:689-694. 22. Moreaux J, Legouffe E, Jourdan E, et al. BAFF and APRIL protect myeloma cells from apoptosis induced by interleukin 6 deprivation and dexamethasone. Blood 2004; 103:3148-3157. 23. Tai Y-T, Li X-F, Coffey R, et al. Role of BAFF in adhesion and growth of human multiple myeloma cells in the bone marrow environment. Proc Amer Assoc Cancer Res 2006; 47:1132 (Abstract #4823). 24. Oki Y, Georgakis GV, Migone T-S, et al. Serum BLyS level as a prognostic marker in patients with lymphoma. Blood 2005; 106:546a (Abstract #1926). 25. Rossi J-F, Borghini-Fuhrer I, Moreaux J, et al. A phase I/II study of TACI-Ig to neutralize APRIL and BLyS in patients with refractory or relapsed multiple myeloma or previously-treated Waldenstrom’s macroglobulinemia. Blood 2005; 106:721a (Abstract #2566). 26. Belch A, McEwan A, Hewitt J, et al. Tumor targeting, dosimetry and clinical response data for lymphorad-131 (LR131; I-131 labeled B-lymphocyte stimulator) in patients with relapsed/refractory non-Hodgkin’s lymphoma. Blood 2004; 104:214a (Abstract #750). 27. Halpern WG, Lappin P, Zanardi T, et al. Chronic administration of belimumab, a BLyS antagonist, decreases tissue and peripheral blood B-lymphocyte populations in cynomolgus monkeys: pharmacokinetics, pharmacodynamics and toxicologic effects. Toxicol Sci 2006; 91:586-599. 28. Gross JA, Dillon SR, Mudri S, et al. TACI-Ig neutralizes molecules critical for B cell development and autoimmune disease. Immunity 2001; 15:289-302.