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 therapy significantly increased the susceptibil

7 CTLA4-Ig treatment blocks CD28 costimulation and resulta

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

40 these hypertensive stimuli were abrogated by CTLA4-Ig.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

86 ied to express the immunoregulatory molecule CTLA4-Ig.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

108 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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

135 lternative transplant survival outcomes post CTLA4-Ig treatment.

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

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

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

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

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

141 ed to the synthetic immunomodulatory reagent CTLA4-Ig.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

160 54 was reduced to less than 1 pg/mL and with CTLA4-Ig-based IS to 65 pg/mL.

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

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

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

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

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

166 54 when administered in vivo in concert with CTLA4-Ig in promoting both allogeneic bone marrow chimer

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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