Atacicept (TACI-Ig) inhibits growth of TACI(high) primary myeloma cells in SCID-hu mice and in coculture with osteoclasts.
APRIL (a proliferation-inducing Ligand) and BLyS/BAFF (B-lymphocyte stimulator/B-cell-activating factor of the TNF (tumor necrosis factor) family have been shown to be the survival factors for certain myeloma cells in vitro. BAFF binds to the TNF-related receptors such as B-cell maturation antigen (BCMA), transmembrane activator and CAML interactor (TACI) and BAFFR, whereas APRIL binds to TACI and BCMA and to heparan sulfate proteoglycans (HSPG) such as syndecan-1. TACI gene expression in myeloma reportedly can distinguish tumors with a signature of microenvironment dependence (TACI(high)) versus a plasmablastic signature (TACI(low)). We tested the effect of atacicept (formerly TACI-Ig, which blocks APRIL and BAFF) and BAFFR-Ig (which blocks BAFF only) on primary myeloma growth in the SCID-hu model and in coculture with osteoclasts. With only few exceptions, atacicept and to a lesser extent BAFFR-Ig, inhibited growth of TACI(high) but not TACI(low) myeloma samples in vivo and ex vivo, and the response rate was inversely correlated with TACI expression. Most TACI(high) myeloma cells were molecularly classified as being low risk with our recently described 70-gene model. APRIL and BAFF were highly expressed by osteoclasts and were upregulated in myeloma cells after coculture with osteoclasts. Our findings suggest that APRIL plays an essential role in the survival of TACI(high) bone marrow-dependent myeloma cells and TACI gene expression may be a useful predictive marker for patients who could benefit from atacicept treatment.
Yaccoby
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S
Myeloma Institute for Research and Therapy, Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. yaccobyshmuel@uams.edu
Pennisi
A
A
Li
X
X
Dillon
S R
SR
Zhan
F
F
Barlogie
B
B
Shaughnessy
J D
JD
D000818:Animals; D053264:B-Cell Activating Factor; D049109:Cell Proliferation / Q000187:drug effects*; D018920:Coculture Techniques; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology*; D010010:Osteoclasts / Q000737:chemistry* / Q000166:cytology; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D053303:Transmembrane Activator and CAML Interactor Protein / Q000032:analysis*; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13 / Q000502:physiology*
D053264:B-Cell Activating Factor; D011993:Recombinant Fusion Proteins; C114631:TNFSF13 protein, human; C505719:TNFSF13B protein, human; D053303:Transmembrane Activator and CAML Interactor Protein; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13; C524618:TACI receptor-IgG Fc fragment fusion protein