The rGel/BLyS fusion toxin specifically targets malignant B cells expressing the BLyS receptors BAFF-R, TACI, and BCMA

Lyu, Mi Ae; Cheung, Lawrence H.; Hittelman, Walter N.; Marks, John W.; Aguiar, Ricardo C.T.; Rosenblum, Michael G.

doi:10.1158/1535-7163.mct-06-0254

Cited by 51 publications

(50 citation statements)

References 37 publications

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“…rGeloninBLyS, a recombinant toxin-BLyS fusion ligand, has been shown to target BAFF-R in LBCL and MCL cell lines. 51 Our recent studies indicate that BAFF-R binds rGelonin-BLyS and migrates to the nucleus resulting not only in lymphoma cell apoptosis in vitro, but also in severe combined immunodeficiency (SCID) mouse LBCL BLOOD, 7 MAY 2009 ⅐ VOLUME 113, NUMBER 19 For personal use only. on May 12, 2018.…”

Section: Discussionmentioning

confidence: 99%

BAFF-R promotes cell proliferation and survival through interaction with IKKβ and NF-κB/c-Rel in the nucleus of normal and neoplastic B-lymphoid cells

Lin-Lee

Pham

et al. 2009

Blood

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BLyS and its major receptor BAFF-R have been shown to be critical for development and homeostasis of normal B lymphocytes, and for cell growth and survival of neoplastic B lymphocytes, but the biologic mechanisms of this ligand/receptor-derived intracellular signaling pathway(s) have not been completely defined. We have discovered that the BAFF-R protein was present in the cell nucleus, in addition to its integral presence in the plasma membrane and cytoplasm, in both normal and neoplastic B cells. BAFF-R interacted IntroductionBAFF-R (also called BR3) is the most unique of the 3 tumor necrosis factor receptors (TNFRs) for BLyS (B-lymphocyte stimulator; also called BAFF). A/WySNJ mice (which have a mutant BAFF-R gene) have a low peripheral blood B-cell fraction that is similar to that seen in BLyS-deficient mice, suggesting that BAFF-R transmits critical B-cell survival signals associated with BLyS stimulation. 1 Downstream mediators of BAFF-R activation include both the canonical (classic, NF-B1) and alternative (noncanonical, NF-B2) NF-B pathways. [2][3][4][5][6][7] Although BLyS/BAFF-R-derived intracellular signaling pathways are still incompletely defined, this ligand/receptor dyad provides key regulatory control of antiapoptotic cell survival and growth stimulation. [8][9][10][11] In this regard, BLyS modulates several antiapoptotic Bcl-2 family members, including Bcl-x L , Mcl-1, A-1, Bcl-2, and Bim, via survival-promoting kinase systems such as Pim 1/2 or Erk 11-14 as well as proteins involved in early cell-cycle progression, including c-myc, p27 Kip1 , cyclin D1, and cyclin D2. 15,16 Most studies of TNFR family receptors have focused on these proteins' function in the cellular plasma membrane and cytoplasm. However, our laboratory recently demonstrated that another TNFR protein, CD40, is present in the nuclei of normal and B-cell non-Hodgkin lymphoma (NHL-B) cells, where it functions as a transcription factor that regulates the expression of several antiapoptotic and proliferation-associated genes. 17,18 The IB kinase (IKK) protein complex is critical for regulating NF-B pathway activation. The IKK complex includes 3 important subunits: the catalytic subunits IKK␣ and IKK␤ (also known as IKK1 and IKK2, respectively) and the regulatory subunit IKK␥ (also known as NEMO). In the cytoplasm, activation of the IKK complex induces processing of precursors p105 and p100 into p50 and p52, respectively, resulting in NF-B subunit dimeric partners that migrate from the cytoplasm into the nucleus. [19][20][21][22][23] In recent studies, IKK␣ has also been identified in the cell nucleus, functioning in histone H3 phosphorylation. 24,25 Although IKK␤ was also previously observed in the cell nucleus, its nuclear function has remained obscure. 24 The second purpose of our study was to elucidate how nuclear BAFF-R interacts with the NF-B pathway to promote B-cell survival and proliferation.In this study, we found that BAFF-R was present in the cell nucleus as well as in the plasma membrane and cytoplasm, in both normal ...

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Section: Discussionmentioning

confidence: 99%

BAFF-R promotes cell proliferation and survival through interaction with IKKβ and NF-κB/c-Rel in the nucleus of normal and neoplastic B-lymphoid cells

Lin-Lee

Pham

et al. 2009

Blood

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“…Recently, an alternative approach was developed to target malignant B-cell lines (45) or chronic lymphocytic leukemia (46) by fusing the ligand BlyS (also known as BAFF) with a xenogeneic recombinant protein toxin, gelonin. This ligand-toxin fusion protein, rGel/BlyS, was tested for potency and selectivity on several different B-cell lines that included mantle cell lymphoma, diffuse large B-cell lymphoma, and MM (45).…”

Section: Discussionmentioning

confidence: 99%

“…This ligand-toxin fusion protein, rGel/BlyS, was tested for potency and selectivity on several different B-cell lines that included mantle cell lymphoma, diffuse large B-cell lymphoma, and MM (45). The greatest potency of rGel/BlyS was observed on mantle cell lymphoma and diffuse large B-cell lymphoma cell lines, with IC 50 values of 1 to 5 pmol/L.…”

Section: Discussionmentioning

confidence: 99%

Antibody targeting of B-cell maturation antigen on malignant plasma cells

Ryan

Hering

Peckham

et al. 2007

Molecular Cancer Therapeutics

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B-cell maturation antigen (BCMA) is expressed on normal and malignant plasma cells and represents a potential target for therapeutic intervention. BCMA binds to two ligands that promote tumor cell survival, a proliferation inducing ligand (APRIL) and B-cell activating factor. To selectively target BCMA for plasma cell malignancies, we developed antibodies with ligand blocking activity that could promote cytotoxicity of multiple myeloma (MM) cell lines as naked antibodies or as antibody-drug conjugates. We show that SG1, an inhibitory BCMA antibody, blocks APRIL -dependent activation of nuclear factor-KB in a dose-dependent manner in vitro. Cytotoxicity of SG1 was assessed as a naked antibody after chimerization with and without Fc mutations that enhance Fc;RIIIA binding. The Fc mutations increased the antibody-dependent cellmediated cytotoxicity potency of BCMA antibodies against MM lines by f100-fold with a z2-fold increase in maximal lysis. As an alternative therapeutic strategy, anti-BCMA antibodies were endowed with direct cytotoxic activity by conjugation to the cytotoxic drug, monomethyl auristatin F. The most potent BCMA antibody-drug conjugate displayed IC 50 values of V130 pmol/L for three different MM lines. Hence, BCMA antibodies show cytotoxic activity both as naked IgG and as drug conjugates and warrant further evaluation as therapeutic candidates for plasma cell malignancies.

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“…Although rGel-based immunotoxins have been used in the treatment of malignant cancers for more than 15 years, the actual mechanisms behind the induction of cell death have remained unclear (46,47). In this study, we showed that C6.5/rGel fusions had no effect on apoptosis-related mechanisms (PARP cleavage, TUNEL, and DNA fragmentation) or necrosis-related mechanisms (LDH release).…”

Section: Discussionmentioning

confidence: 59%

Construction and Characterization of Novel, Recombinant Immunotoxins Targeting the Her2/neu Oncogene Product: In vitro and In vivo Studies

Cao

Marks

et al. 2009

Cancer Research

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The goal of this study was to characterize a series of antiHer2/neu immunotoxin constructs to identify how different antibodies and linker choices affect the specificity and cytotoxicity of these proteins. We constructed a series of immunotoxins containing either the human single-chain antibody (scFv) C6.5 or the murine scFv e23 fused to the highly toxic recombinant gelonin (rGel) molecule. Based on the flexible GGGGS linker (L), the fusion construct C6.5-L-rGel was compared with e23-L-rGel to evaluate the specific cytotoxic effects against Her2/neu-positive and Her2/neu-negative tumor cells. Both constructs retained the specificity of the original antibody as well as the biological activity of rGel toxin. The two constructs displayed similar cytotoxicity against different carcinoma cells. We additionally introduced the modified linkers TRHRQPRGWEQL (Fpe) and AGNRVRRSVG (Fdt), which contained furin cleavage sites, to determine the effect of these design changes on stability and cell killing efficiency. The introduction of furin cleavage linkers (Fpe or Fdt) into the molecules resulted in dissimilar sensitivity to protease cleavage compared with the constructs containing the L linker, but very similar intracellular rGel release, cytotoxic kinetics, and induction of autophagic cell death in vitro. Xenograft studies with SKOV3 ovarian tumors were done using various C6.5/rGel constructs. C6.5-L-rGel was more efficient in tumor inhibition than constructs containing furin linkers, attributing to a higher stability in vivo of the L version. Therefore, our studies suggest that human C6.5-L-rGel may be an effective novel clinical agent for therapy of patients with Her2/neuoverexpressing malignancies. [Cancer Res 2009;69(23):8987-95]

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The rGel/BLyS fusion toxin specifically targets malignant B cells expressing the BLyS receptors BAFF-R, TACI, and BCMA

Cited by 51 publications

References 37 publications

BAFF-R promotes cell proliferation and survival through interaction with IKKβ and NF-κB/c-Rel in the nucleus of normal and neoplastic B-lymphoid cells

BAFF-R promotes cell proliferation and survival through interaction with IKKβ and NF-κB/c-Rel in the nucleus of normal and neoplastic B-lymphoid cells

Antibody targeting of B-cell maturation antigen on malignant plasma cells

Construction and Characterization of Novel, Recombinant Immunotoxins Targeting the Her2/neu Oncogene Product: In vitro and In vivo Studies

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