CN1359301A - 致淀粉样病的预防和治疗 - Google Patents
致淀粉样病的预防和治疗 Download PDFInfo
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- CN1359301A CN1359301A CN00808117A CN00808117A CN1359301A CN 1359301 A CN1359301 A CN 1359301A CN 00808117 A CN00808117 A CN 00808117A CN 00808117 A CN00808117 A CN 00808117A CN 1359301 A CN1359301 A CN 1359301A
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Abstract
Description
未处理 | PBS | AN1792 | |
月龄 | Aβ Aβ42 (n) | 总Aβ Aβ42 (n) | Aβ Aβ42 (n) |
121518 | 1,600 1300 (10)8,700 8,300 (10)22,200 18,500 (10) | 8,600 7,200 (9)19,000 15,900 (12) | 1,600 1,300* (10)5,200** 4,000** (9) |
未治疗 | PBS | AN1792 | |
月龄 | 总Aβ Aβ42 (n) | 总Aβ Aβ42 (n) | Aβ Aβ42 (n) |
121518 | 15,500 11,100 (10)51,500 44,400 (10)80,800 64,200 (10) | 40,100 35,70 (9)65,400 57,10 (12) | 24,50 22,100 (10)50,90* 38,900** (9) |
未治疗 | PBS | AN1792 | |
月龄 | 总Aβ (n) | 总Aβ (n) | 总Aβ (n) |
121518 | 15.6 (10)27.7 (10)35.0 (10) | 20.8 (9)43.1 (12) | 21.7 (10)24.8* (9) |
表5 | |||
免疫原 | 共轭物 | Aβ氨基酸 | 应答数 |
Aβ1-5 | 是 | 5-聚体 | 0/7 |
Aβ1-12 | 是 | 12-聚体 | 1/8 |
Aβ13-28 | 是 | 16-聚体 | 1/9 |
Aβ25-35 | 11-聚体 | 1/9 | |
Aβ33-42 | 是 | 10-聚体 | 0/10 |
Aβ1-40 | 40-聚体 | 5/8 | |
Aβ1-42 | 42-聚体 | 9/9 | |
rAβ1-42 | 42-聚体 | 8/8 | |
pBx6 | 0/8 | ||
PBS | 0-聚体 | 0/8 |
抗体 | 表位 |
2H3 | Aβ1-12 |
10D5 | Aβ1-12 |
266 | Aβ13-28 |
21F12 | Aβ33-42 |
小鼠多克隆抗人Aβ42 | 抗聚集态Aβ42 |
实验设计 | |||||
组 | Na | 佐剂b | 剂量 | 抗原 | 剂量(μg) |
1 | 10 | MPL | 12.5μg | AN1792 | 33 |
2 | 10 | MPL | 25μg | AN1792 | 33 |
3 | 10 | MPL | 50μg | AN1792 | 33 |
4 | 13 | MPL | 125μg | AN1792 | 33 |
5 | 13 | MPL | 50μg | AN1792 | 150 |
6 | 13 | MPL | 50μg | AN1528 | 33 |
7 | 10 | PBS | AN1792 | 33 | |
8 | 10 | PBS | 无 | ||
9 | 10 | 角鲨烯乳化 | 5% | AN1792 | 33 |
10 | 10 | 角鲨烯混合 | 5% | AN1792 | 33 |
11 | 10 | 明矾 | 2mg | AN1792 | 33 |
12 | 13 | MPL+明矾 | 50μg/2mg | AN1792 | 33 |
13 | 10 | QS-21 | 5μg | AN1792 | 33 |
14 | 10 | QS-21 | 10μg | AN1792 | 33 |
15 | 10 | QS-21 | 25AN1792 | AN1792 | 33 |
16 | 13 | QS-21 | 25AN1792 | AN1792 | 150 |
17 | 13 | QS-21 | 25AN1792 | AN1528 | 33 |
18 | 13 | QS-21+MPL | 25μg/50μg | AN1792 | 33 |
19 | 13 | QS-21+明矾 | 25μg/2mg | AN1792 | 33 |
抗体的几何平均效价 | |||||
取血周数 | |||||
治疗组 | 2.9 | 5.0 | 8.7 | 12.9 | 16.7 |
1 | 248 | 1797 | 2577 | 6180 | 4177 |
2 | 598 | 3114 | 3984 | 5287 | 6878 |
3 | 1372 | 5000 | 7159 | 12333 | 12781 |
4 | 1278 | 20791 | 14368 | 20097 | 25631 |
5 | 3288 | 26242 | 13229 | 9315 | 23742 |
6 | 61 | 2536 | 2301 | 1442 | 4504 |
7 | 37 | 395 | 484 | 972 | 2149 |
8 | 25 | 25 | 25 | 25 | 25 |
9 | 25 | 183 | 744 | 952 | 1823 |
10 | 25 | 89 | 311 | 513 | 817 |
11 | 29 | 708 | 2618 | 2165 | 3666 |
12 | 198 | 1458 | 1079 | 612 | 797 |
13 | 38 | 433 | 566 | 1080 | 626 |
14 | 104 | 541 | 3247 | 1609 | 838 |
15 | 212 | 2630 | 2472 | 1224 | 1496 |
16 | 183 | 2616 | 6680 | 2085 | 1631 |
17 | 28 | 201 | 375 | 222 | 1540 |
18 | 31699 | 15544 | 23095 | 6412 | 9059 |
19 | 63 | 243 | 554 | 299 | 441 |
抗体的几何平均效价a | |||||
取血周数 | |||||
治疗 | 3.3 | 5.0 | 9.0 | 13.0 | 17.0 |
明矾/AN1792 | 102(12/21)b | 1,081(17/20) | 2,366(21/21) | 1,083(19/21) | 572(18/21) |
MPL/AN1792 | 6241(21/21) | 28,867(21/21) | 1,1242(21/21) | 5,665(20/20) | 8,204(20/20) |
QS-21/AN1792 | 30(1/20) | 227(10/19) | 327(10/19) | 1,511(17/18) | 1,188(14/18) |
CFA/AN1792 | 10,076(15/15) | 61,279(15/15) | 75,386(15/15) | 41,628(15/15) | 30,574(15/15) |
明矾/AN1528 | 25(0/21) | 33(1/21) | 39(3/20) | 37(1/20) | 31(2/20) |
MPL/AN1528 | 184(15/21) | 2,591(20/21) | 1,653(21/21) | 1,156(20/20) | 3,099(20/20) |
QS-21/AN1528 | 29(1/22) | 221(13/22) | 51(4/22) | 820(20/22) | 2,994(21/22) |
PBS+硫柳汞 | 25(0/16) | 33(2/16) | 39(4/16) | 37(3/16) | 47(4/16) |
PBS | 25(0/16) | 25(0/16) | 25(0/15) | 25(0/12) | 25(0/16) |
佐剂 | 免疫原 | 稀释缓冲液 | 给药方式 | |
组1 | MPL-SE | AN1792-GCS(75μg) | PBS | SC(250μl) |
组2 | ISA51 | AN1792-GCS(75μg) | PBS | IP(400μl) |
组3 | QS21 | AN1792-GCS(75μg) | PBS | SC(250μl) |
组4 | QS21(简) | AN1792-GCS(75μg) | PBS | SC(250μl) |
组5 | PBS | ------- | ------- | SC(250μl) |
PBS | MPL-SE | ISA | QS-21 | QS-21(4) | |
平均值(纳克/克组织) | 7,335 | 1,236 | 3,026 | 2,389 | 2,996 |
范围(纳克/克组织) | 550-18,358 | 70-3,977 | 23-9,777 | 210-11,167 | 24-16,834 |
P值 | --- | <0.0001 | <0.0001 | <0.0001 | <0.0001 |
N | 38 | 29 | 36 | 34 | 40 |
实验设计 | ||||
处理组 | Na | 处理抗体 | 抗体特异性 | 抗体同种型 |
1 | 9 | 无,仅PBS | NAb | NA |
2 | 10 | 多克隆 | Aβ1-42 | 混合的 |
3 | 0 | mAbc2H3 | Aβ1-12 | IgG1 |
4 | 8 | MAb 10D5 | Aβ1-16 | IgG1 |
5 | 6 | MAb 266 | Aβ13-28 | IgG1 |
6 | 8 | MAb 21F12 | Aβ33-42 | IgG2a |
皮层 | |||||||||
处理组 | Na | 中值 | 平均数 | ||||||
总Aβ | Aβ42 | 总Aβ | Aβ42 | ||||||
ELISA值b | P值c | %变化 | ELISA值 | P值 | %变化 | ELISA值 | ELISA值 | ||
PBS | 9 | 17818 | NAd | NA | 13802 | NA | NA | 16150+/-7456e | 12621+/-5738 |
多克隆抗Aβ42抗体 | 10 | 6160 | 0.0055 | -65 | 4892 | 0.0071 | -65 | 5912+/-4492 | 4454+/-3347 |
mAb 10D5 | 8 | 7915 | 0.1019 | -56 | 6214 | 0.0433 | -55 | 9695+/-6929 | 6943+/-3351 |
mAb 266 | 6 | 9144 | 0.1255 | -49 | 8481 | 0.1255 | -39 | 9204+/-9293 | 7489+/-6921 |
mAb 21F12 | 8 | 15158 | 0.2898 | -15 | 13578 | 0.7003 | -2 | 12481+/-7082 | 11005+/-6324 |
海马 | |||||||||
处理组 | Na | 中值 | 平均数 | ||||||
总Aβ | Aβ42 | 总Aβ | Aβ42 | ||||||
ELISA值b | P值c | %变化 | ELISA值 | P值 | %变化 | ELISA值 | ELISA值 | ||
PBS | 9 | 63389 | NAd | NA | 54429 | NA | NA | 58351+/-13308e | 52801+/-14701 |
多克隆抗Aβ42抗体 | 10 | 31706 | 0.0055 | -50 | 27127 | 0.0025 | -50 | 30058+/-22454 | 24853+/-18262 |
MAb 10D5 | 8 | 46779 | 0.0675 | -26 | 36290 | 0.0543 | -33 | 44581+/-18632 | 36465+/-17146 |
MAb 266 | 6 | 48689 | 0.0990 | -23 | 43034 | 0.0990 | -21 | 36419+/-27304 | 32919+/-25372 |
MAb 21F12 | 8 | 51563 | 0.7728 | -19 | 47961 | 0.8099 | -12 | 57327+/-28927 | 50305+/-23927 |
小脑 | |||||
处理组 | Na | 中值 | 平均数 | ||
总Aβ | 总Aβ | ||||
ELISA值 | P值 | %变化 | ELISA值 | ||
PBS | 9 | 30.64 | NAd | NA | 40.00+/-31.89e |
多克隆抗Aβ42抗体 | 10 | 17.61 | 0.0033 | -43 | 18.15+/-4.36 |
mAb 10D5 | 8 | 21.68 | 0.0675 | -29 | 27.29+/-19.43 |
mAb 266 | 6 | 16.59 | 0.0184 | -46 | 19.59+/-6.59 |
mAb21F12 | 8 | 29.80 | >0.9999 | -3 | 32.88+/-9.90 |
N-末端单克隆抗体3D610D522C86E1014A813-2818G1126622D12C-末端2G316C1121F12免疫血清兔(CFA)鼠(CFA)鼠(QS-21)猴(QS-21)鼠(MAP1-7) | 抗体 | 染色+++++------+++++ | 吞噬++++-------+++++ | |
表位1-53-63-75-104-1010-1816-2418-21-40-40/-42-421-63-73-71-5 | 同种型IgG2bIgG1IgG2aIgG1大鼠IgG1大鼠IgG1IgG1IgG2bIgG1IgG1IgG2a |
抗体 | 同种型 | 对聚集态Aβ的亲和力(pM) | 对β淀粉样斑的结合 | 离体的效率 | 体内效率 | |
单克隆 | 3D6 | IgG2b | 470 | + | + | + |
10D5 | IgG1 | 43 | + | + | + | |
16C11 | IgG1 | 90 | - | - | - | |
21F12 | IgG2a | 500 | - | - | - | |
TM2a | IgG1 | - | - | - | - | |
多克隆 | 1-42 | 混合 | 600 | + | + | + |
佐剂 | 免疫原 | 稀释缓冲液 | 给药方式 | |
组1 | CFA/IFA | MAP(Aβ1-7:TT)(100μg) | PBS | IP(400μl) |
组2 | QS21 | AN1792-GCS(75μg) | PBS | SC(250μl) |
组3 | PBS | ------ | --- | SC(250μl) |
PBS | MAP | QS-21 | |
平均值(纳克/克组织) | 7,335 | 3,692 | 2,389 |
范围(纳克/克组织) | 550-18,358 | 240-10,782 | 210-11,167 |
P值 | --- | 0.0003 | <0.0001 |
N | 38 | 30 | 34 |
组 | 实验设计a | 猴(M/F) | AN1792剂量(μg/剂) | QS21剂量(μg/剂) | 途径 |
1b | 1 | 4/4 | 0 | 0 | IM |
2 | 1 | 4/4 | 载体c | 50 | IM |
3 | 1 | 4/4 | 载体 | 100 | IM |
4 | 1 | 4/4 | 75 | 50 | IM |
5 | 1 | 4/4 | 300 | 50 | IM |
6 | 1 | 4/4 | 75 | 100 | IM |
7 | 1 | 4/4 | 300 | 100 | IM |
8 | 2 | 4/4 | 75 | 100 | IM |
9 | 2 | 4/4 | 300 | 100 | IM |
10 | 3 | 4/4 | 75 | 100 | IM |
11 | 3 | 4/4 | 300 | 100 | IM |
表1 | |||||||||
50%最大光密度时的效价 | |||||||||
聚集态Aβ注射的小鼠 | |||||||||
PDAPP的月龄 | 小鼠100 | 小鼠101 | 小鼠102 | 小鼠103 | 小鼠104 | 小鼠105 | 小鼠106 | 小鼠107 | 小鼠108 |
4 | 70000 | 150000 | 15000 | 120000 | 1000 | 15000 | 50000 | 80000 | 100000 |
6 | 15000 | 65000 | 30000 | 55000 | 300 | 15000 | 15000 | 50000 | 60000 |
8 | 20000 | 55000 | 50000 | 50000 | 400 | 15000 | 18000 | 50000 | 60000 |
10 | 40000 | 20000 | 60000 | 50000 | 900 | 15000 | 50000 | 20000 | 40000 |
12 | 25000 | 30000 | 60000 | 40000 | 2700 | 20000 | 70000 | 25000 | 20000 |
两种免疫原的PBS注射小鼠 | |||||||||
效价为1/100 | |||||||||
PDAPP的月龄 | 小鼠113 | 小鼠114 | 小鼠115 | 小鼠116 | 小鼠117 | ||||
6 | <4x bkg | <4x bkg | <4x bkg | <4x bkg | <4x bkg | ||||
10 | 5x bkg | <4x bkg | <4x bkg | <4x bkg | <4x bkg | ||||
12 | <4x bkg | <4x bkg | <4x bkg | <4x bkg | <4x bkg |
Claims (109)
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US09/322,289 US7964192B1 (en) | 1997-12-02 | 1999-05-28 | Prevention and treatment of amyloidgenic disease |
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CN104122400A (zh) * | 2014-07-01 | 2014-10-29 | 上海依科赛生物制品有限公司 | 一种人体β淀粉样蛋白检测试剂盒及其用途 |
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