Citations of BMS286INST
Therapeutic targeting of CD70 and CD27-CD70 interactions with the monoclonal antibody SGN-70 in Waldenstrom's Macroglobulinemia (WM)
Ho,A.W.; Hatjiharissi,E.; Branagan,A.; Hunter,Z.; McEarchern,J.; Law,C.; Grewal,I.S.; Santos,D.; Tai,Y.; Treon,S.P.; Bing Center for Waldenstrom's Macroglobulinemia,
ASCO Meeting Abstracts 2006;24:2509› Link
Abstract
2509 Background: WM represents a lymphoplasmacytic lymphoma characterized by a monoclonal IgM gammopathy and possesses a mast cell component that may contribute to its pathogenesis. The tumor necrosis factor (TNF) receptor family member, CD27, is a transmembrane co-stimulatory molecule that is also secreted in a soluble form (sCD27). Recent evidence has suggested that interactions between CD27 and its TNF-like ligand, CD70, play a critical role in regulating B-cell activation and survival, and therefore, may provide a viable therapeutic target for the treatment of WM. Methods: Patients with the consensus panel diagnosis of WM who provided written consent were evaluated. ELISA assay kits were obtained from Bender MedSystems. Flow cytometric analysis, RT-PCR, and calcein ADCC assays were performed as previously described (Santos et al, in press). Results: By ELISA, WM patients displayed dramatically higher levels of sCD27 in their sera (median 7.45, range 0-19.42 U/ml) versus healthy donors (median 0, range 0-2.78 U/ml; p = 2.5 x 10-7). CD27 was expressed in 7/7 patients using RT-PCR analysis, and on the tumor cell surface of 5/12 patients. CD70, the target for CD27, was widely expressed on tumor cells (6/6) and mast cells (10/11) using flow cytometric analysis. To define the functional role of sCD27 in WM, we cultured BCWM.1 (CD27-CD70+) WM cells, LAD1 (CD27-CD70+) mast cells, and primary tumor and mast cells (CD70+) isolated from WM patients with sCD27 (0.1-50 ug/mL), and observed no effect on their proliferation or induction of apoptosis. However, culture of LAD1 and primary WM mast cells (10/10) with sCD27 resulted in marked upregulation of two TNF family ligands which support the growth and survival of WM cells: CD40L (CD154) and a proliferation induction ligand (APRIL). Importantly, the anti-CD70 mAb SGN-70 (1 ug/ml) inhibited this upregulation by sCD27, establishing the specificity of the CD27-CD70 interaction. In addition, SGN-70 demonstrated significant ADCC against BCWM.1 WM cells at dose levels up to 20 ug/ml. Conclusions: Taken together, these studies suggest a novel functional role for sCD27 in the pathogenesis of WM, and demonstrate the feasibility of targeting CD70 and sCD27-CD70 interactions with the SGN-70 monoclonal antibody. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Seatlle Genetics
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CD27-CD70 interactions in the pathogenesis of Waldenstrom macroglobulinemia
Ho,Allen W.; Hatjiharissi,Evdoxia; Ciccarelli,Bryan T.; Branagan,Andrew R.; Hunter,Zachary R.; Leleu,Xavier; Tournilhac,Olivier; Xu,Lian; O'Connor,Kelly; Manning,Robert J.; Santos,Daniel Ditzel; Chemaly,Mariana; Patterson,Christopher J.; Soumerai,Jacob D.; Munshi,Nikhil C.; McEarchern,Julie A.; Law,Che Leung; Grewal,Iqbal S.; Treon,Steven P.
Blood 2008;112:4683-4689.
› Link
Abstract
Waldenstrom macroglobulinemia (WM) is a B-cell malignancy characterized by an IgM monoclonal gammopathy and bone marrow (BM) infiltration with lymphoplasmacytic cells (LPCs). Excess mast cells (MCs) are commonly present in WM, and provide growth and survival signals to LPCs through several TNF family ligands (CD40L, a proliferation-inducing ligand [APRIL], and B-lymphocyte stimulator factor [BLYS]). As part of these studies, we demonstrated that WM LPCs secrete soluble CD27 (sCD27), which is elevated in patients with WM (P < .001 vs healthy donors), and serves as a faithful marker of disease. Importantly, sCD27 stimulated expression of CD40L on 10 of 10 BM MC samples and APRIL on 4 of 10 BM MC samples obtained from patients with WM as well as on LAD2 MCs. Moreover, the SGN-70 humanized monoclonal antibody, which binds to CD70 (the receptor-ligand partner of CD27), abrogated sCD27 mediated up-regulation of CD40L and APRIL on WM MCs. Last, treatment of severe combined immunodeficiency-human (SCID-hu) mice with established WM using the SGN-70 antibody blocked disease progression in 12 of 12 mice, whereas disease progressed in all 5 untreated mice. The results of these studies demonstrate a functional role for sCD27 in WM pathogenesis, along with its utility as a surrogate marker of disease and a target in the treatment of WM
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