Anti-alpha4 integrin antibody suppresses the development of multiple myeloma and associated osteoclastic osteolysis.
Supporting roles of stromal cells in preferential colonization of myeloma cells in bone marrow and development of associated osteoclastic osteolysis through cell-cell interactions have been indicated. Here we examined the effects of a monoclonal antibody to alpha4 integrin (anti-alpha4 Ab) that disrupts myeloma cell-stromal cell interactions mediated via alpha4beta1 integrin and vascular cell adhesion molecule-1 (VCAM-1) on myeloma cell growth in bone marrow and accompanying osteolysis. The anti-alpha4 Ab decreased VCAM-1-stimulated 5TGM1/luc cell growth in culture. The 5TGM1 murine myeloma cells stably transfected with the firefly luciferase (5TGM1/luc) were inoculated from tail vein in bg/xid/nd mice. Preventative administration of the anti-alpha4 Ab suppressed the elevation of serum IgG2b levels, decreased 5TGM1/luc tumor burden with increased apoptosis in bone and spleen, reduced bone destruction with diminished number of osteoclasts, and prolonged survival of 5TGM1/luc-bearing mice. In contrast, therapeutic administration of the antibody failed to show these effects. However, therapeutic administration of the antibody combined with melphalan significantly suppressed serum IgG2b levels and tumor burden in bone. Our results suggest that the interactions with stromal cells via alpha4beta1/VCAM-1 are critical to the development of myeloma and associated osteolysis and that disruption of these interactions using anti-alpha4 Ab is a potential therapeutic approach for myeloma.
Mori
Yoshihisa
Y
Division of Endocrinology and Metabolism, Department of Medicine, The University of Texas Health Science Center at San Antonio, TX 78229-3900, USA.
Shimizu
Nobuaki
N
Dallas
Mark
M
Niewolna
Maryla
M
Story
Beryl
B
Williams
Paul J
PJ
Mundy
Gregory R
GR
Yoneda
Toshiyuki
T
D000818:Animals; D000906:Antibodies / Q000737:chemistry / Q000378:metabolism*; D000911:Antibodies, Monoclonal / Q000737:chemistry; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000378:metabolism; D001842:Bone and Bones / Q000473:pathology; D002450:Cell Communication; D002455:Cell Division; D045744:Cell Line, Tumor; D002470:Cell Survival; D007074:Immunoglobulin G / Q000097:blood / Q000737:chemistry; D039441:Integrin alpha4 / Q000737:chemistry / Q000276:immunology*; D039041:Integrin alpha4beta1 / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D008558:Melphalan / Q000494:pharmacology; D051379:Mice; D009101:Multiple Myeloma / Q000276:immunology*; D010010:Osteoclasts / Q000276:immunology* / Q000378:metabolism; D010014:Osteolysis; D011994:Recombinant Proteins / Q000737:chemistry; D013154:Spleen / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism*
D000906:Antibodies; D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G; D039041:Integrin alpha4beta1; D011994:Recombinant Proteins; D019010:Vascular Cell Adhesion Molecule-1; D039441:Integrin alpha4; D008156:Luciferases; D008558:Melphalan