ライフサイエンスコーパス: BCMA

1 BCMA and TACI additionally bind APRIL (a proliferation-i

2 BCMA antibodies were only found in post-DLI responders a

3 BCMA expression in murine splenic B cells can be induced

4 BCMA has been implicated as a receptor for both a prolif

5 BCMA, TACI, and B lymphocyte stimulator receptor 3 (BR3)

6 BCMA-Fc also inhibits production of antibodies against k

7 A BCMA-targeted bispecific antibody presents a promising t

8 n algorithm FoldX to successfully generate a BCMA-specific variant of APRIL, APRIL-R206E, and two TAC

9 geting BCMA alone resulted in outgrowth of a BCMA-negative tumor.

10 sing both BCMA and TACI in the presence of a BCMA-targeting antibody.

11 Based on these results, a BCMA-Fc fusion with the single I22K mutation was produce

12 We demonstrate that a BCMA deficiency combined with the lpr mutation or the mu

13 B cell maturation Ag (BCMA) is a receptor for BAFF that, under nonautoimmune c

14 pression of BAFF-R and B cell maturation Ag (BCMA) is also highly regulated and we demonstrate that B

15 B cell maturation Ag (BCMA), a member of the TNFR superfamily expressed on B c

16 and interactor (TACI), B cell maturation Ag (BCMA), and BAFF-R.

17 eptors of this system, B cell maturation Ag (BCMA), transmembrane activator and CAML interactor, and

18 interactor (TACI) and B cell maturation Ag (BCMA), which bind both BAFF and APRIL.

19 and interactor (TACI); B cell maturation Ag (BCMA); and BAFF-R.

20 Although BCMA was previously localized to the Golgi apparatus, BC

21 have also been shown to bind BAFF, although BCMA has significantly higher affinity for APRIL than BA

22 icate that BCMA is a receptor for TALL-1 and BCMA activates NF-kappaB through a TRAF5-, TRAF6-, NIK-,

23 Thus, APRIL-TALL-I and BCMA-TACI form a two ligands-two receptors pathway invol

24 d immunohistochemistry identified BAFF-R and BCMA mRNA and proteins in vCTB cells but essentially no

25 mulating CLL cells through TACI, BAFF-R, and BCMA receptors.

26 ne APRIL and two BAFF (ABB) bind to TACI and BCMA and weakly to BAFFR in accordance with the analysis

27 ndogenous BAFF and APRIL by soluble TACI and BCMA decoy receptors attenuates the survival of NHL B ce

28 zation of BAFF and APRIL by soluble TACI and BCMA decoy receptors could be useful to dampen the accum

29 delivering nonredundant signals via TACI and BCMA receptors through both autocrine and paracrine path

30 Also, mice lacking both TACI and BCMA simultaneously exhibit no B cell loss, thus confirm

31 cells lacked BAFF-R, but expressed TACI and BCMA, a phenotype similar to that of plasmacytoid B cell

32 r factor-kappaB (NF-kappaB) through TACI and BCMA, and each ligand stimulated immunoglobulin M (IgM)

33 family member, binds two receptors, TACI and BCMA, and regulates humoral immune responses [1-7].

34 r is unique in that, in contrast to TACI and BCMA, BR3 only binds BLyS.

35 ysically interacting and inhibiting TACI and BCMA, members of the tumor necrosis factor (TNF) recepto

36 ed two TNF receptor family members, TACI and BCMA, that bind zTNF4.

37 BLyS and APRIL share two receptors, TACI and BCMA, whereas a third receptor, BAFF-R, specifically bin

38 es two TNF receptor family members, TACI and BCMA, with another TNF homolog, BLyS/BAFF.

39 known TNF receptor family members, TACI and BCMA.

40 diated tumor clearance of BCMA(+)TACI(-) and BCMA(-)TACI(+) cells, and a single-chain variable fragme

41 The results from TACI(-/-) and BCMA(-/-) mice suggest the existence of additional recep

42 fering RNAs targeting BAFF, APRIL, TACI, and BCMA inhibited HRS cell accumulation in vitro and might

43 ugh cell-surface receptors BAFF-R, TACI, and BCMA.

44 ilin ligand-interactor CD267, TNFRSF13B) and BCMA (B cell maturation antigen, CD269, TNFRSF13C).

45 sequent treatment with APRIL or agonist anti-BCMA to similarly induce Ag presentation.

46 humanized and afucosylated antagonistic anti-BCMA antibody-drug conjugate via a noncleavable linker.

47 f BiFab-BCMA are comparable to those of anti-BCMA chimeric antigen receptor T cell therapy (CAR-T-BCM

48 of ELL2, including B-cell maturation antigen BCMA, a receptor with a defined role in plasma cell surv

49 This mAb targets B-cell maturation antigen (BCMA) and has considerable preclinical activity, thus ho

50 nds the receptors B-cell maturation antigen (BCMA) and TACI with high affinity; both of these recepto

51 for BAFF, namely B-cell maturation antigen (BCMA) and the transmembrane activator and calcium modula

52 nt TNF receptors, B cell maturation antigen (BCMA) and transmembrane activator and cylclophilin ligan

53 B-cell maturation antigen (BCMA) is a promising therapeutic target for multiple mye

54 B cell maturation antigen (BCMA) is a tumor necrosis factor receptor family member

55 B-cell maturation antigen (BCMA) is expressed in most cases of MM.

56 We find that B cell maturation antigen (BCMA), a predicted member of the TNF receptor family exp

57 these studies was B-cell maturation antigen (BCMA), a transmembrane receptor of the tumor necrosis fa

58 The B-cell maturation antigen (BCMA), an essential membrane protein for maintaining the

59 ned expression of B cell maturation antigen (BCMA), and lowered expression of transmembrane activator

60 ractor (TACI) and B-cell maturation antigen (BCMA), has been shown to be important in B-cell biology,

61 B-cell maturation antigen (BCMA), highly expressed on malignant plasma cells in hum

62 ractor (TACI) and B cell maturation antigen (BCMA), on B cells.

63 to the receptors B cell maturation antigen (BCMA), transmembrane activator and CAML interactor (TACI

64 family receptors (B-cell maturation antigen (BCMA), transmembrane activator and CAML-interactor (TACI

65 decoy receptor of B-cell maturation antigen (BCMA), which can bind both BAFF and APRIL, but not with

66 previously localized to the Golgi apparatus, BCMA was found to be expressed on the surface of transfe

67 Modeling of the APRIL-BCMA complex shows the resulting interface is in agreeme

68 rystal structures of APRIL.TACI_d2 and APRIL.BCMA complexes that together reveal the mechanism by whi

69 Our data, therefore, identify a novel APRIL/BCMA signaling pathway in HCC and suggest that APRIL cou

70 and may serve as a model for specific APRIL/BCMA actions.

71 eceptors BCMA and BAFFR, but not TACI; APRIL/BCMA is enhanced in HCC, compared with normal liver tiss

72 se in NZM.Br3-/- mice demonstrates that BAFF-BCMA and/or BAFF-TACI interactions contribute to SLE, an

73 BiFab-BCMA lysed target BCMA-positive cell lines up to 20-fold

74 ody against B cell maturation antigen (BiFab-BCMA), which potently and specifically redirects T cells

75 Further, BiFab-BCMA robustly activated T cells in vitro and mediated ra

76 The in vitro and in vivo activities of BiFab-BCMA are comparable to those of anti-BCMA chimeric antig

77 prevented APRIL, but not BAFF, from binding BCMA, their shared receptor.

78 d cytolysis of primary tumor expressing both BCMA and TACI in the presence of a BCMA-targeting antibo

79 n and tolerance, binds three receptors: BR3, BCMA, and TACI.

80 t the specific B cell responses regulated by BCMA remain unclear.

81 ings demonstrate antimyeloma activity of CAR-BCMA T cells.

82 Twelve patients received CAR-BCMA T cells in this dose-escalation trial.

83 -eight weeks after this patient received CAR-BCMA T cells, bone marrow plasma cells were undetectable

84 ls expressing the CAR used in this work (CAR-BCMA) specifically recognized BCMA-expressing cells.

85 nes (e.g., CLEC12B, ILT4, galectin-3, CD160, BCMA, FGL2, LAG3, GPNMB).

86 Circulating human pDCs contained BCMA protein without displaying it on the cell surface.

87 s) in its extracellular region; in contrast, BCMA and BR3, the other known high affinity receptors fo

88 CAR), which killed targets expressing either BCMA or TACI (P < .01 and P < .05, respectively, cf. con

89 with human pDCs, murine pDCs did not express BCMA, not even after TLR9 activation.

90 both tonsil and bone marrow tissues, express BCMA.

91 All cases tested expressed BCMA, and 39 (78%) of them also expressed TACI.

92 Using transfected cells expressing BCMA, antibodies in patient serum were found to react wi

93 d cells and primary myeloma cells expressing BCMA.

94 nced B cell generation in mice deficient for BCMA or TACI, respectively, suggested that the interacti

95 ggest that APRIL is the preferred ligand for BCMA and show that specificity can be further modified t

96 APRIL) is a natural high-affinity ligand for BCMA and transmembrane activator and calcium-modulator a

97 ctional role for BR3 and a redundant one for BCMA in B cell function.

98 nt for determining binding specificities for BCMA, TACI and BAFF-R.

99 ion between BLyS and another TNFR homologue, BCMA (B cell maturation antigen) [7] [8].

100 mouse models deficient in BCMA, we identify BCMA as an important factor in regulating peripheral B c

101 ferent lupus-prone mouse models deficient in BCMA, we identify BCMA as an important factor in regulat

102 sults predicted four amino acid positions in BCMA (Tyr13, Ile22, Gln25, and Arg27) that could impart

103 MA in PC survival was provided by studies in BCMA-/- mice in which the survival of long-lived bone ma

104 TALL-1 has three receptors, including BCMA, TACI, and BAFF-R, which are mostly expressed by B

105 tion of the Q25D and R27Y substitutions into BCMA produced a dual specificity variant, since it has c

106 In contrast, mice lacking BCMA had normal-appearing B lymphocyte compartments.

107 actor (TACI) and B cell maturation molecule (BCMA)-on B cells play an important role in the humoral i

108 actor (TACI) and B cell maturation molecule (BCMA).

109 racterized the binding affinity of monomeric BCMA for its ligands; BAFF binding affinity (IC50 = 8 +/

110 Binding of the I22K mutant of monomeric BCMA to BAFF was undetectable (IC50 > 100 microm), but a

111 contrast to monovalent BAFF-R-Fc, monovalent BCMA does not form stable complexes with BAFF.

112 Moreover, BCMA-mediated NF-kappaB activation is inhibited by domin

113 We found that signaling through BR3, but not BCMA or TACI, activated the alternative nuclear factor o

114 emonstrating tumor control in the absence of BCMA, we maintained cytolysis of primary tumor expressin

115 erein provide a dual perspective analysis of BCMA binding to both APRIL and BAFF.

116 terminal sialylation, assists the binding of BCMA with ligands in an in vitro binding assay.

117 as complete ACAR-mediated tumor clearance of BCMA(+)TACI(-) and BCMA(-)TACI(+) cells, and a single-ch

118 The display of BCMA on the surface of human pDCs was accompanied by rel

119 The single cysteine-rich domain of BCMA and BAFF-R both have saddle-like architectures, whi

120 eptor containing the extracellular domain of BCMA blocks the binding of TALL-1 to its receptor on the

121 in consisting of the extracellular domain of BCMA fused to the hinge and CH1 and CH2 domains of human

122 und to react with the cell-surface domain of BCMA.

123 complexed with the extracellular domains of BCMA and BAFF-R at 2.6 and 2.5 A, respectively.

124 ELL2 enhances the expression of BCMA (also known as Tnfrsf17), which is important for lo

125 mma-secretase enhanced surface expression of BCMA and reduced the release of sBCMA by pDCs.

126 We quantified surface tumor expression of BCMA and TACI on primary MM cells (n = 50).

127 Increased expression of BCMA, a weak TNFSF receptor for B lymphocyte stimulator

128 A soluble form of BCMA, which inhibited the binding of BAFF to a B cell li

129 effect of N-glycosylation on the function of BCMA and found that the dexamethasone-induced apoptosis

130 The identification of BCMA as a NF-kappaB-activating receptor for TALL-1 sugge

131 Affirmation of the importance of BCMA in PC survival was provided by studies in BCMA-/- m

132 differentiation inhibited both induction of BCMA expression and loss of BAFF-R.

133 Overexpression of BCMA activates NF-kappaB, and this activation is potenti

134 expression is variable, and early reports of BCMA targeting chimeric antigen receptors (CARs) suggest

135 ated with the increased surface retention of BCMA, leading to its elevated level on cell surface.

136 to resting B cells suggests a vital role of BCMA in PC survival.

137 Second, shotgun alanine scanning of BCMA was used to map critical residues for either APRIL

138 In this study, we extend the spectrum of BCMA expression to human pDCs.

139 BCMA activates the JNK pathway conferring on BCMA the specific ability to activate this Ag presentati

140 ghlight the importance of N-glycosylation on BCMA in the regulation of ligand binding and functions o

141 an bind more than one BAFF-R-Fc but only one BCMA-Fc.

142 eptors can trigger NF-kappaB signaling, only BCMA activates the JNK pathway conferring on BCMA the sp

143 ains of APRIL/BAFF receptors found that only BCMA, but not transmembrane activator and calcium-modula

144 essing a mutant BR3 gene, but not in TACI or BCMA null B cells.

145 ell line assays specific for BAFFR, TACI, or BCMA.

146 0-fold selectivity for binding to BAFFR over BCMA.

147 Here we show that B cell maturation protein (BCMA), a member of the TNF receptor family that is expre

148 Antibodies to the receptors BAFF-R, BCMA, and TACI were used to define expression of the ind

149 y shown that the TNFR family member receptor BCMA (B cell maturation Ag) is a critical survival recep

150 , BLyS and APRIL, and a homologous receptor, BCMA, that similarly binds both ligands.

151 ) family member APRIL binds to the receptors BCMA on B cells and TACI on B and T cells.

152 s express APRIL and BAFF and their receptors BCMA and BAFFR, but not TACI; APRIL/BCMA is enhanced in

153 expressed one or more of 3 known receptors (BCMA, TACI, and BAFF-R) for BLyS; however, the pattern o

154 cell survival and binds to three receptors (BCMA, TACI, and the recently described BAFF-R).

155 NF) ligand TALL-1 and its cognate receptors, BCMA, TACI and BAFF-R, were recently identified as membe

156 Fc fusion decoy receptors, BCMA-Fc and BAFF-R-Fc, are therapeutic candidates for bl

157 as been reported to bind to three receptors, BCMA (B cell maturation protein), TACI (transmembrane ac

158 F is known to interact with three receptors, BCMA, TACI and BAFF-R, that have distant similarities wi

159 nd with different affinity to two receptors, BCMA and TACI, and induce cell survival and/or prolifera

160 BAFF is already known to bind two receptors, BCMA and TACI, we have identified a third receptor for B

161 this work (CAR-BCMA) specifically recognized BCMA-expressing cells.

162 Soluble BCMA and TACI specifically prevent binding of APRIL and

163 n pDCs was accompanied by release of soluble BCMA (sBCMA); inhibition of gamma-secretase enhanced sur

164 Antibody responses to cell-surface BCMA may contribute directly to tumor rejection in vivo.

165 mation by MM cells while sparing surrounding BCMA-negative normal cells.

166 meric antigen receptor T cell therapy (CAR-T-BCMA), for which two clinical trials have recently been

167 producing BAFF and APRIL, which engage TACI, BCMA, and BAFF-R receptors on the B cells.

168 xamined B cells from mice deficient in TACI, BCMA, and BAFF-R.

169 reterm neonatal B cells expressed less TACI, BCMA, and BAFF-R compared with adult B cells and had sig

170 Inhibition of TACI, BCMA, and BAFF-R expression on CLL cells; abrogation of

171 he binding of BLyS to its 3 receptors, TACI, BCMA, and BLyS receptor 3/BAFF-R.

172 BAFF binds three receptors, TACI, BCMA, and BR3, with signaling through BR3 being essentia

173 BLyS binds to 3 TNF-R receptors, TACI, BCMA, BAFF-R, to regulate B-cell survival, differentiati

174 It binds three receptors: TACI, BCMA, and BR3.

175 with the TNF family receptors (TNFRs) TACI, BCMA, and BAFF-R are crucial to TI antibody responses, w

176 BiFab-BCMA lysed target BCMA-positive cell lines up to 20-fold more potently tha

177 single-chain variable fragment CAR targeting BCMA alone resulted in outgrowth of a BCMA-negative tumo

178 ric antigen receptor (CAR) T cells targeting BCMA.

179 Further, therapeutic trials targeting BCMA in patients with multiple myeloma should consider p

180 found that BAFF-R-Fc is more effective than BCMA-Fc for blocking BAFF binding to its receptors.

181 w BAFF-R-Fc is 10-fold more efficacious than BCMA-Fc for blocking BAFF-induced B cell proliferation i

182 nd can function through receptors other than BCMA.

183 lso highly regulated and we demonstrate that BCMA expression is only acquired in MB cells and in a ma

184 These results demonstrate that BCMA is a target of donor B-cell immunity in patients wi

185 ted human immune cell subsets, we found that BCMA was transcribed in plasmacytoid dendritic cells (pD

186 These data indicate that BCMA is a receptor for TALL-1 and BCMA activates NF-kapp

187 This study unexpectedly reveals that BCMA works to control B cell homeostasis and self-tolera

188 ver, we have used these ligands to show that BCMA and TACI have a distinct role in APRIL-induced B ce

189 We here show that BCMA is universally expressed on the MM cell surface and

190 al effects are driven by duplications in the BCMA (branched-chain methionine allocation) loci control

191 imilar to the BAFF knockout mouse, while the BCMA knockout mouse has no discernible B cell phenotype.

192 hway in CLL cells, whereas signaling through BCMA/TACI induced activation of the canonical NF-kappaB

193 After engagement of TLR7/8 or TLR9, BCMA was detected also on the cell surface of pDCs.

194 rkers CD319 (SLAMF7/CS1) and CD269 (TNFRSF17/BCMA) are considerably more robust than CD138 and enable

195 the functional significance of antibodies to BCMA in vivo.

196 Binding of BAFF to BCMA-Fc, a bivalent fusion protein consisting of the ext

197 APRIL functions via binding to BCMA (B cell maturation antigen) and TACI (transmembrane

198 ntrast to previous reports, APRIL binding to BCMA decreases cell proliferation by inducing G(2)/M cel

199 elected sequences inhibited APRIL binding to BCMA with IC(50) values of 0.49-27 microM.

200 L shows the opposite selectivity, binding to BCMA with K(D) approximately 16 nM while showing no dete

201 related TNF family ligand that also binds to BCMA and TACI, but not BAFF-R.

202 [9], a close relative of BLyS, also bound to BCMA and TACI.

203 or binding to APRIL was similar to wild-type BCMA.

204 he high selectivity of BAFF for BAFFR versus BCMA is thus partly obscured in these multivalent assays

205 how that the effect of APRIL is mediated via BCMA, which does not activate the classical NF-kappaB pa

206 ating that APRIL and/or TALL-I signaling via BCMA and/or TACI are required for generation of humoral

207 Whereas BCMA is restricted to B cells, TACI is also expressed on

208 itory role for this receptor [11, 12], while BCMA null mice have no discernable phenotype [13].

209 ds BAFF with K(D) approximately 16 nM, while BCMA binds with K(D) approximately 1.6 microM, indicatin

210 hat ligation of A20 B cells transfected with BCMA induces the expression of CD40, CD80/B7-1, CD86/B7-

211 lasma cells can be rescued by treatment with BCMA ligands, such as a proliferation-inducing ligand (A