ライフサイエンスコーパス: CTLA4-Ig

1 CTLA4-Ig demonstrated no efficacy when used in combinati

2 CTLA4-Ig did not induce IDO expression in macrophages or

3 CTLA4-Ig is a fusion protein that blocks this pathway an

4 CTLA4-Ig is an Fc fusion protein containing the extracel

5 CTLA4-Ig modulates T cell costimulatory signals by block

6 CTLA4-Ig reduced CD4(+) central memory and effector memo

7 CTLA4-Ig therapy significantly increased the susceptibil

8 CTLA4-Ig treatment blocks CD28 costimulation and resulta

9 CTLA4-Ig treatment of mdx bone marrow cells diminished t

10 CTLA4-Ig treatment of Treg-depleted mice almost complete

11 CTLA4-Ig treatment reduced mdx sarcolemma lesions and re

12 CTLA4-Ig was also significantly less effective in older

13 CTLA4-Ig was clearly less effective in the complete mism

14 CTLA4-Ig/abatacept dampens activation of naive T cells b

15 isease settings may lead to development of a CTLA4-Ig molecule with improved efficacy and safety prof

16 Abatacept (CTLA4-Ig), etanercept (anti-TNF), or phosphate-buffered

17 Abatacept (CTLA4-Ig), the first selective T-cell costimulation modu

18 cribe the mechanisms of action of abatacept (CTLA4-Ig) and summarize the evidence of its efficacy and

19 Co-stimulation blockade with abatacept (CTLA4-Ig) will soon be licensed for the treatment of rhe

20 B ODNs and rAd vectors encoding CTLA4-Ig (Ad CTLA4-Ig) to generate stably immature murine myeloid DCs

21 Furthermore, administration of Ad CTLA4-Ig ODN-treated donor DCs (C57BL10; B10(H-2b)) befo

22 These Ad CTLA4-Ig-transduced ODN DCs exhibit markedly impaired al

23 Recipients were administered CTLA4-Ig at 2 mg/kg per day (alternate days) in combinat

24 n the level of the Th2 cytokine, IL-4, after CTLA4-Ig treatment either before sensitization or before

25 or fludarabine and immunosuppressive agents CTLA4-Ig + anti-CD40L or anti-(murine)thymocyte serum (A

26 ade consisting of MR1 (250 mug/ip day 0) and CTLA4-Ig (200 mug/ip day 2), we administered low-dose IL

27 treated control cells, anti-caCD28 (1C6) and CTLA4-Ig equivalently inhibited cytotoxic T lymphocyte-m

28 one and one animal treated with both 5C8 and CTLA4-Ig experienced late, biopsy-proven rejection, but

29 py with cyclophosphamide, anti-CD40L Ab, and CTLA4-Ig is associated with the abrogation of germinal c

30 increased expression of CD28 with aging and CTLA4-Ig treatment in old recipients resulted in reduced

31 Finally, an anti-CD22/cal and CTLA4-Ig-based combination therapy displayed remarkable

32 We studied the effect of anti-CD154 and CTLA4-Ig on diabetes development, and the requirements t

33 eric mAb against the B cell antigen CD20 and CTLA4-Ig, which blocks the CD28/B7 interaction.

34 eatment with a combination of mIL-21R.Fc and CTLA4-Ig (an inhibitor of the early alloimmune response)

35 y, a short course of combination TACI-Ig and CTLA4-Ig prolonged life and even reversed proteinuria in

36 The combination of TACI-Ig and CTLA4-Ig resulted in a temporary decrease in serum IgG l

37 mune-suppressive molecules such as PD-L1 and CTLA4-Ig.

38 When anti-gp39 mAb and CTLA4-Ig were given together, the effect was additive, l

39 s in donor hearts of untreated wild-type and CTLA4-Ig- or anti-CTLA4 mAb-treated CD28-deficient mice.

40 In contrast to CD80/86 antagonists (CTLA4-Ig), FR104 selectively blunts CD28 costimulation w

41 In contrast to CD80/86 antagonists (CTLA4-Ig), selective CD28 antagonists blunt T cell costi

42 However, because CTLA4-Ig has been suspected to interfere with T regulato

43 ies demonstrate a powerful synergism between CTLA4-Ig and tofacitinib and suggest their combined use

44 Mice receiving costimulation blockade (CTLA4-Ig and anti-CD40 ligand) alone or in combination w

45 w-dose busulfan) and costimulation blockade (CTLA4-Ig and anti-CD40L) to produce mixed chimerism and

46 Whereas EL4-B7.1 cells bound both CTLA4-Ig and CD28-Ig, EL4-B7.2 transfectants preferentia

47 Expression of both CTLA4-Ig, which disrupts T cell costimulatory pathways,

48 EL4-B7.2 transfectants preferentially bound CTLA4-Ig, but not CD28-Ig.

49 res in that it was only partially blocked by CTLA4 Ig and was dependent upon both CD4+ and CD8+ T cel

50 these hypertensive stimuli were abrogated by CTLA4-Ig.

51 ion, bone marrow infusion, or B7 blockade by CTLA4-Ig have been tried, and synergistic effects for to

52 CD28-B7 blockade by CTLA4-Ig inhibited IFN-gamma production in C57BL/6 recip

53 to ICOS-B7h blockade, because B7 blockade by CTLA4-Ig prolongs graft survival in CD8-deficient mice a

54 ce, blockade of B7-mediated costimulation by CTLA4-Ig treatment of +/+ mice also resulted in a 2-fold

55 imulation, as proliferation was inhibited by CTLA4-Ig and by anti-B7-2 mAbs.

56 n of CD28/CTLA4(-/-) T cells is inhibited by CTLA4-Ig and by the use of antigen-presenting cells lack

57 ion of CD3-CD56+ cells was also inhibited by CTLA4-Ig, indicating a role for CD80/86.

58 This effect was potentiated markedly by CTLA4-Ig, administered 1 day after the AADC.

59 tion, whereas IL-2 secretion is modulated by CTLA4-Ig, but not ICOS-Ig.

60 d by anti-CD154mAb-based (P<0.05) but not by CTLA4-Ig-based IS.

61 ained by a combination of these agents or by CTLA4-Ig.

62 tibody (mAb), by an anti-TNFalpha mAb, or by CTLA4-Ig.

63 vival induced by anti-CD45RB is prevented by CTLA4-Ig, which interferes with B7:CTLA-4 interactions.

64 owed that 46% of the genes down-regulated by CTLA4-Ig were genes up-regulated in macrophages by the p

65 l phenotype, which was partially reversed by CTLA4-Ig therapy.

66 rolongation of cardiac allograft survival by CTLA4-Ig is STAT4-independent but, at least in part, STA

67 ession or given costimulatory blockade (CoB; CTLA4-Ig+anti-CD154 mAb).

68 In contrast, CTLA4-Ig, which targets B7 on allogeneic cells, promotes

69 can be inhibited by a soluble form of CTLA4 (CTLA4-Ig) that binds to both B7.1 and B7.2.

70 Only high-dose CTLA4-Ig attenuates both IgG2a and IgG3 autoantibody pro

71 After treatment with low dose CTLA4-Ig, PI3Kgamma (-/-) , but not PI3Kappadelta (D910A

72 duction can be dissociated by using low-dose CTLA4-Ig.

73 aft survival in combination with single-dose CTLA4-Ig or in CD28 knockout recipients.

74 obtained from recipients treated with either CTLA4-Ig or anti-CD40L monoclonal antibody alone exhibit

75 e of NF-kappaB ODNs and rAd vectors encoding CTLA4-Ig (Ad CTLA4-Ig) to generate stably immature murin

76 To engineer CTLA4-Ig variants with altered binding affinity to CD80

77 First, we engineered CTLA4-Ig to enhance binding to ICOSL while retaining aff

78 ed knockin hESCs that constitutively express CTLA4-Ig and PD-L1 before and after differentiation, den

79 s of autophagosome formation, while DCs from CTLA4-Ig-treated rheumatoid arthritis patients displayed

80 tes harvested on day 145 posttransplant from CTLA4-Ig-treated rejecting STAT6(-/-) recipients were tr

81 In contrast, when splenocytes from CTLA4-Ig-treated wild-type or nonrejecting STAT6(-/-) mi

82 pression of an immunosuppressive gene (e.g., CTLA4-Ig).

83 nces in activity between cCTLA4-Ig and human CTLA4-Ig.

84 nation with hu5C8 were as effective as human CTLA4-Ig plus hu5C8.

85 The human XMLR was attenuated by human CTLA4-Ig and anti-human CD154 (hu5C8), and the combinati

86 HIRPE genomic DNA, a recombinant gene human CTLA4-Ig, and the dhfr gene as a positive selection mark

87 tein 4 fused to a modified fragment of IgG1 (CTLA4-Ig) fusion protein that blocks costimulatory signa

88 to MHC class II or by CTLA4 immunoglobulin (CTLA4-Ig).

89 We tested immunoregulatory CTLA4-Ig explicitly for its effect on Treg cell numbers,

90 effector transcripts were largely intact in CTLA4-Ig + bone marrow-treated recipients as they showed

91 The presentation of chronic rejection in CTLA4-Ig-treated LysM(C)(re) Traf6 (fl/fl) mice was simi

92 ow were irradiated before transplantation in CTLA4-Ig-treated recipients.

93 ton that were reversed by the B7-1 inhibitor CTLA4-Ig.

94 erent settings confirmed that prolonged mATG+CTLA4-Ig treatment is a clinically relevant strategy to

95 hyperglycemic NOD mice under prolonged mATG+CTLA4-Ig treatment showed a pronounced delay in allograf

96 cific T cells in anti-gp39 mAb-treated mice, CTLA4-Ig treated mice, and in mice given control hamster

97 ockade (500 microg anti-CD40L and 500 microg CTLA4-Ig, days 0, 2, 4, 6) treated recipients.

98 hypothesis in a relevant preclinical model, CTLA4-Ig and the CD40L-specific monoclonal antibody 5C8

99 ied to express the immunoregulatory molecule CTLA4-Ig.

100 t protocols were tested: Chi220 monotherapy, CTLA4-Ig monotherapy, Chi220 combined with CTLA4-Ig, and

101 , treatment with costimulation blockade (MR1/CTLA4-Ig) resulted in attenuated FBXO3, preserved FBXL2,

102 In separate experiments, injection of murine CTLA4-Ig completely blocked the primary response to fact

103 of the following treatment protocols: murine CTLA4-Ig, L-6 control Ig, sirolimus, cyclosporine, ALS,

104 LEA29Y (BMS-224818), a mutant CTLA4-Ig molecule with increased binding activity, was e

105 pment of EAG using native CTLA4-Ig or mutant CTLA4-Ig (Y100F-Ig), which selectively blocks B7.1.

106 Native CTLA4-Ig treatment ameliorated EAG by several measures,

107 ckade on the development of EAG using native CTLA4-Ig or mutant CTLA4-Ig (Y100F-Ig), which selectivel

108 ICOS-Ig, but not CTLA4-Ig, uniquely regulates SAg-induced TNF-alpha produ

109 CD40L, and was blocked by administration of CTLA4 Ig.

110 However, 14% of CTLA4-Ig-treated STAT6(-/-) mice rejected their grafts b

111 ly slightly reduced (20%) by the addition of CTLA4-Ig.

112 Transient administration of CTLA4-Ig and anti-CD40L mAb to SIV-infected rhesus macaq

113 Administration of CTLA4-Ig either before Ag sensitization or before pulmon

114 hese data demonstrate that administration of CTLA4-Ig is effective in ablating allergen-induced airwa

115 Finally, administration of CTLA4-Ig to CD28/CTLA4(-/-) cardiac allograft recipients

116 Administration of CTLA4-Ig to SCID mice infected with T. gondii inhibited

117 hat equally affected the binding affinity of CTLA4-Ig for both ligands as well as those that differen

118 sing a library approach, binding affinity of CTLA4-Ig to human ICOSL was increased significantly from

119 splenic dendritic cells, and coinjection of CTLA4-Ig, which is known to block B7 function in vivo, c

120 In vivo, the combination of CTLA4-Ig and tofacitinib induced long-term survival of h

121 secondary skin grafts using a combination of CTLA4-Ig plus donor bone marrow.

122 LEW animals followed by a single low dose of CTLA4-Ig, T cells were rendered unresponsive to indirect

123 Brief induction doses of CTLA4-Ig or 5C8 alone significantly prolonged rejection-

124 rse of TACI-Ig with and without six doses of CTLA4-Ig to 18- to 20-wk-old NZB/NZW F(1) mice and evalu

125 efficacy testing, we examined the effect of CTLA4-Ig and rapamycin on DSA-mediated cytolysis.

126 inib restored the immunomodulatory effect of CTLA4-Ig on mouse alloreactive T cells in the presence o

127 s caused by a selective inhibitory effect of CTLA4-Ig on proliferating conventional T cells, whereas

128 study was to determine the effectiveness of CTLA4-Ig, a novel immunosuppressive agent, in augmenting

129 Here, we assessed age-specific effects of CTLA4-Ig (cytotoxic T-lymphocyte antigen 4-Ig), a fusion

130 nable contributor to the limited efficacy of CTLA4-Ig.

131 atopoietic chimerism in the establishment of CTLA4-Ig-induced transplantation tolerance was investiga

132 Furthermore, injection of CTLA4-Ig to block CD28-B7 interactions substantially imp

133 a single injection or multiple injections of CTLA4-Ig and anti-CD40L monoclonal antibody resulted in

134 a single injection or multiple injections of CTLA4-Ig fusion protein (200 microg/dose i.p.) and/or an

135 The presence of CTLA4-Ig in mixed leukocyte reactions-while dampening th

136 hich was inhibited by 90% in the presence of CTLA4-Ig, an antagonist of B7 stimulation.

137 Additionally, in the presence of CTLA4-Ig, the frequency of apoptosis was decreased in th

138 on of this gene may be a molecular target of CTLA4-Ig therapy.

139 e) Traf6 (fl/fl) mice was similar to that of CTLA4-Ig-treated wild-type B6 recipients.

140 L-6 control Ig had no effect whereas use of CTLA4-Ig alone resulted in a doubling of the median graf

141 ationally designed, high affinity variant of CTLA4-Ig, LEA29Y (belatacept), in a nonhuman primate mod

142 finity- and stability-engineered variants of CTLA4-Ig fusion molecules with enhanced pharmacokinetic

143 function, recently, substantial concerns on CTLA4-Ig's potentially antitolerogenic effects have been

144 y reduced by anti-CD154mAb-based (P<0.01) or CTLA4-Ig-based (P<0.01) IS.

145 a combination of anti-B7-1 and anti-B7-2 or CTLA4-Ig.

146 n (IS; n=3), or anti-CD154mAb-based (n=5) or CTLA4-Ig-based (n=5) IS.

147 y, a subtherapeutic dose of anti-CD154 Ab or CTLA4-Ig, which was not sufficient to prevent cardiac al

148 riectomized mice with either antioxidants or CTLA4-Ig, an inhibitor of the CD80/CD28 pathway.

149 , co-stimulatory blockade with anti-CD154 or CTLA4-Ig induced long-term survival for wild-type heart

150 regimens based on a calcineurin inhibitor or CTLA4-Ig have proved unsuccessful, the regimen we admini

151 treating SLE in mice using anti-CD4 mAb's or CTLA4-Ig and anti-CD154 mAb's have proven to be effectiv

152 were rejected at ~30 days in MR1-treated or CTLA4-Ig-treated recipients selectively deficient in C5a

153 ere administered 25 million untransfected or CTLA4-Ig-transfected D2SC/1 cells i.v. on the day of isl

154 a 17.5-fold improved off-rate over parental CTLA4-Ig binding to CD86.

155 otocol based on prolonged low-dose mATG plus CTLA4-Ig.

156 lternative transplant survival outcomes post CTLA4-Ig treatment.

157 ulation using the B7-specific fusion protein CTLA4-Ig has been shown to induce long-term allograft su

158 e inoculation of the chimeric fusion protein CTLA4-Ig virtually abrogated the therapeutic effects of

159 toxic T-Lymphocyte Antigen 4 fusion protein (CTLA4-Ig) synergized with the DRAK2 deficiency and led t

160 stimulation pathway with the fusion protein, CTLA4-Ig, has been shown to prolong allograft survival i

161 CTLA-4 immunoglobulin fusion proteins (CTLA4-Ig) suppress immune reactions by blocking the T-ce

162 ed to the synthetic immunomodulatory reagent CTLA4-Ig.

163 Mice receiving CTLA4-Ig therapy had lower serum levels of interleukin 4

164 Mice receiving CTLA4-Ig treatment had more-severe septic arthritis, com

165 n peritoneal macrophages from mice receiving CTLA4-Ig, compared with expression in the anti-TNF group

166 CI-Ig had a beneficial effect on murine SLE; CTLA4-Ig potentiated this effect.

167 We conclude that CTLA4-Ig and 5C8 can both prevent and reverse acute allo

168 Our findings unequivocally demonstrate that CTLA4-Ig does not negatively affect Treg cell frequencie

169 These findings show that CTLA4-Ig is a promising immunotherapeutic for DMD, and m

170 In vitro data showed that CTLA4-Ig acts directly on bone marrow cells and macropha

171 cing analysis of mdx macrophages showed that CTLA4-Ig reduced expression of genes associated with leu

172 These data suggest that CTLA4-Ig may be effective clinically in combination with

173 de of the T cell costimulatory signal by the CTLA4-Ig synthetic protein (abatacept) could prevent SEB

174 ntenance of transplantation tolerance in the CTLA4-Ig plus bone marrow murine cardiac allograft model

175 s model of T cell-dependent Ab response, the CTLA4-Ig variant MEDI5265 could be formulated at >100 mg

176 ition of either sirolimus or cyclosporine to CTLA4-Ig increased graft survival over that achieved wit

177 nical response of LRBA-deficient patients to CTLA4-Ig therapy.

178 cells as a correlate of clinical response to CTLA4-Ig therapy.

179 (MLR) in a dose-dependent manner similar to CTLA4-Ig, whereas the agonistic antibody to caCD28 enhan

180 he CD28/CTLA4/B7 costimulatory pathway using CTLA4-Ig has great therapeutic potential, and has been s

181 co-stimulation blockade-based strategy using CTLA4-Ig and anti-CD154 antibodies to modulate T-cell ac

182 However, maintenance immunosuppression via CTLA4-Ig monotherapy is characterized by high frequency

183 role for T cells in rheumatoid arthritis was CTLA4-Ig (abatacept), use of this biologic is now expand

184 ic mice following adoptive transfer, whereas CTLA4-Ig treatment did not block T cell clonal expansion

185 eased graft survival over that achieved with CTLA4-Ig alone.

186 54 was reduced to less than 1 pg/mL and with CTLA4-Ig-based IS to 65 pg/mL.

187 st to previous studies targeting APC B7 with CTLA4-Ig, reagents targeting CD28 can block ongoing dise

188 Blockade with CTLA4-Ig had a minimal effect on proliferation and cytok

189 hi 220), either alone or in combination with CTLA4-Ig, on the survival of renal allografts in a nonhu

190 high-dose donor H2-Kd peptides combined with CTLA4-Ig reduced the frequencies of Kd287(+) CD4(+) T ce

191 , CTLA4-Ig monotherapy, Chi220 combined with CTLA4-Ig, and H106 (anti-CD40L) combined with CTLA4-Ig.

192 TLA4-Ig, and H106 (anti-CD40L) combined with CTLA4-Ig.

193 mediated inflammatory diseases compared with CTLA4-Ig alone.

194 54 when administered in vivo in concert with CTLA4-Ig in promoting both allogeneic bone marrow chimer

195 Blockade of B7-dependent costimulation with CTLA4-Ig reduced both angiotensin II- and deoxycorticost

196 lts show that blockade of costimulation with CTLA4-Ig, a fusion protein known to prevent costimulatio

197 amster ovarian cells were cotransfected with CTLA4-Ig vector and a dihydrofolate reductase-containing

198 A or CTLA4 deficiency sharply decreased with CTLA4-Ig therapy in parallel with other markers of immun

199 e sustained inhibition of PC generation with CTLA4-Ig or belatacept (B/B).

200 Treating mdx macrophages with CTLA4-Ig reduced their cytolysis of muscle cells in vitr

201 lants, treatment of IL-6-deficient mice with CTLA4-Ig resulted in graft acceptance.

202 trast, treatment of CD28-deficient mice with CTLA4-Ig, anti-B7-1 plus anti-B7-2 mAbs, or a blocking a

203 n presentation by treating RBP4-Ox mice with CTLA4-Ig, which blocks costimulation of T cells, is suff

204 Also, blocking antigen presentation with CTLA4-Ig improves RBP4-induced insulin resistance and ma

205 t of LysM(C)(re) Mtor(fl/fl) recipients with CTLA4-Ig induced long-term allograft survival (>100 days

206 dependent, shown by inhibition studies with CTLA4-Ig.

207 shown in rodents to act synergistically with CTLA4-Ig.

208 tory markers on T cells, and synergized with CTLA4-Ig to promote long-term acceptance of cardiac allo

209 Positive controls treated with CTLA4-Ig and cyclosporine had significant histological i

210 nificantly decreased in animals treated with CTLA4-Ig before challenge, while there was no significan

211 gh wild-type C57BL/6 recipients treated with CTLA4-Ig rejected fully MHC-mismatched BALB/c heart tran

212 afts in young mice (2-3 months) treated with CTLA4-Ig survived indefinitely, whereas 80% of old recip

213 ntreated diabetic NODs and NODs treated with CTLA4-Ig to block CD28/B7 and with anti-CD154 mAb to inh

214 Human DCs treated with CTLA4-Ig, a fusion protein composed of the Fc region of

215 Mice treated with CTLA4-Ig-transfected D2SC/1 cells demonstrated prolonged

216 Treatment with CTLA4-Ig and anti-CD154 prevented graft destruction in a

217 center response, combination treatment with CTLA4-Ig and ICOS ligand (ICOSL) blocking Ab completely

218 n of membrane lymphotoxin and treatment with CTLA4-Ig inhibited rejection in wild-type mice.

219 Treatment with CTLA4-Ig led to marked reduction of T cell proliferation

220 of diabetic nephropathy, and treatment with CTLA4-Ig prevented increased urinary albumin excretion a

221 how that Tregs can be combined in vitro with CTLA4-Ig (belatacept) to lead to enhanced inhibition of