CN1935260A - 结合人TNFα的人抗体 - Google Patents
结合人TNFα的人抗体 Download PDFInfo
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- CN1935260A CN1935260A CNA2006101018258A CN200610101825A CN1935260A CN 1935260 A CN1935260 A CN 1935260A CN A2006101018258 A CNA2006101018258 A CN A2006101018258A CN 200610101825 A CN200610101825 A CN 200610101825A CN 1935260 A CN1935260 A CN 1935260A
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- tnf
- aminoacid sequence
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- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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- C—CHEMISTRY; METALLURGY
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- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
- C07K2317/565—Complementarity determining region [CDR]
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- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S424/00—Drug, bio-affecting and body treating compositions
- Y10S424/80—Antibody or fragment thereof whose amino acid sequence is disclosed in whole or in part
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y10S424/81—Drug, bio-affecting and body treating compositions involving autoimmunity, allergy, immediate hypersensitivity, delayed hypersensitivity, immunosuppression, immunotolerance, or anergy
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S530/00—Chemistry: natural resins or derivatives; peptides or proteins; lignins or reaction products thereof
- Y10S530/868—Chemistry: natural resins or derivatives; peptides or proteins; lignins or reaction products thereof involving autoimmunity, allergy, immediate hypersensitivity, delayed hypersensitivity, immunosuppression, or immunotolerance
Abstract
Description
抗体 | Koffsec-1 | KonM-1sec-1 | KdM | 化学计量 |
D2E7 IgG1 | 8.81×10-5 | 1.91×105 | 6.09×10-10 | 1.2 |
2SD4 IgG4 | 8.4×10-3 | 4.20×105 | 2.00×10-8 | 0.8 |
MAK195 F(ab’)2 | 8.70×10-5 | 1.90×105 | 4.60×10-10 | 1.4 |
抗体 | [Ab],nM | 结合的rhTNFα,RUs | 结合的Ab,RUs | rhTNFα/Ab | Koff,sec-1,(Avg) |
D2E7 | 267 | 373 | 1215 | 1.14 | 8.45×10-5 |
133 | 420 | 1569 | 1.30 | 5.42×10-5 | |
67 | 434 | 1633 | 1.31 | 4.75×10-5 | |
33 | 450 | 1532 | 1.19 | 4.46×10-5 | |
17 | 460 | 1296 | 0.98 | 3.47×10-5 | |
8 | 486 | 936 | 0.67 | 2.63×10-5 | |
4 | 489 | 536 | 0.38 | 2.17×10-5 | |
2 | 470 | 244 | 0.18 | 3.68×10-5 | |
(4.38×10-5) | |||||
MAK195 | 400 | 375 | 881 | 1.20 | 5.38×10-5 |
200 | 400 | 1080 | 1.38 | 4.54×10-5 | |
100 | 419 | 1141 | 1.39 | 3.54×10-5 | |
50 | 427 | 1106 | 1.32 | 3.67×10-5 | |
25 | 446 | 957 | 1.09 | 4.41×10-5 | |
13 | 464 | 708 | 0.78 | 3.66×10-5 | |
6 | 474 | 433 | 0.47 | 7.37×10-5 | |
3 | 451 | 231 | 0.26 | 6.95×10-5 | |
(4.94×10-5) |
实验 | Kd(s-1) |
1 | 9.58×10-5 |
2 | 9.26×10-5 |
3 | 7.60×10-5 |
平均 | 8.81±1.06×10-5 |
实验 | Ka(M-1,s-1) |
1 | 1.33×105 |
2 | 1.05×105 |
3 | 3.36×105 |
平均 | 1.91±1.26×105 |
实验 | Ka(M-1,s-1) | Kd(s-1) | Kd(M) |
1 | 1.33×105 | 9.58×10-5 | 7.20×10-10 |
2 | 1.05×105 | 9.26×10-5 | 8.82×10-10 |
3 | 3.36×105 | 7.60×10-5 | 2.26×10-10 |
平均 | 1.91±1.26×105 | 8.81±1.06×10-5 | 6.09±3.42×10-10 |
VH | VL | K off( sec -1) |
D2E7VH | D2E7VL | 9.65×10-5 |
HD2E7*.A1 | D2E7VL | 1.4×10-4 |
HD2E7*.A2 | D2E7VL | 4.6×10-4 |
HD2E7*.A3 | D2E7VL | 8.15×10-4 |
HD2E7*.A4 | D2E7VL | 1.8×10-4 |
HD2E7*.A5 | D2E7VL | 2.35×10-4 |
HD2E7*.A6 | D2E7VL | 2.9×10-4 |
HD2E7*.A7 | D2E7VL | 1.0×10-4 |
HD2E7*.A8 | D2E7VL | 3.1×10-4 |
HD2E7*.A9 | D2E7VL | 8.1×10-4 |
D2E7VH | LD2E7*.A1 | 6.6×10-5 |
D2E7VH | LD2E7*.A3 | NOT DETECTABLE |
D2E7VH | LD2E7*.A4 | 1.75×10-4 |
D2E7VH | LD2E7*.A5 | 1.8×10-4 |
D2E7VH | LD2E7*.A7 | 1.4×10-4 |
D2E7VH | LD2E7*.A8 | 3.65×10-4 |
HD2E7*.A9 | LD2E7*.A1 | 1.05×10-4 |
VH | VL | 形式 | K off( sec -1) |
D2E7VH | D2E7VL | IgG1/IgG4 | 9.65×10-5 |
VH1-D2 | LOE7 | IgG1/IgG4 | 7.7×10-5 |
VH1-D2 | LOE7 | scFv | 4.6×10-4 |
VH1-D2.N | LOE7.T | IgG4 | 2.1×10-5 |
VH1-D2.Y | LOE7.A | IgG4 | 2.7×10-5 |
VH1-D2.N | LOE7.A | IgG4 | 3.2×10-5 |
VH1-D2 | EP B12 | scFv | 8.0×10-4 |
VH1-D2 | 2SD4VL | scFv | 1.94×10-3 |
3C-H2 | LOE7 | scFv | 1.5×10-3 |
2SD4VH | LOE7 | scFv | 6.07×10-3 |
2SD4VH | 2SD4VL | scFv | 1.37×10-2 |
VH1A11 | 2SD4VL | scFv | 1.34×10-2 |
VH1B12 | 2SD4VL | scFv | 1.01×10-2 |
VH1B11 | 2SD4VL | scFv | 9.8×10-3 |
VH1E4 | 2SD4VL | scFv | 1.59×10-2 |
VH1F6 | 2SD4VL | scFv | 2.29×10-2 |
VH1D8 | 2SD4VL | scFv | 9.5×10-3 |
VH1G1 | 2SD4VL | scFv | 2.14×10-2 |
2SD4VH | EPB12 | scFv | 6.7×10-3 |
2SD4VH | VL10E4 | scFv | 9.6×10-3 |
2SD4VH | VL100A9 | scFv | 1.33×10-2 |
2SD4VH | VL100D2 | scFv | 1.41×10-2 |
2SD4VH | VL10F4 | scFv | 1.11×10-2 |
2SD4VH | VLLOE5 | scFv | 1.16×10-2 |
2SD4VH | VLL0F9 | scFv | 6.09×10-3 |
2SD4VH | VLL0F10 | scFv | 1.34×10-2 |
2SD4VH | VLLOG7 | scFv | 1.56×10-2 |
2SD4VH | VLLOG9 | scFv | 1.46×10-2 |
2SD4VH | VLLOH1 | scFv - | 1.17×10-2 |
2SD4VH | VLLOH10 | scFv | 1.12×10-2 |
2SD4VH | VL1B7 | scFv | 1.3×10-2 |
2SD4VH | VL1C1 | scFv | 1.36×10-2 |
2SD4VH | VL1C7 | scFv | 2.0×10-2 |
2SD4VH | VL0.1F4 | scFv | 1.76×10-2 |
2SD4VH | VL0.1H8 | scFv | 1.14×10-2 |
VH | VL | 结构 | IC 50 .M |
D2E7 | D2E7 | scFv | 1.1×10-10 |
D2E7 | D2E7 | IgG4 | 4.7×10-11 |
2SD4 | 2SD4 | seFv/IgG1/IgG4 | 3.0×10-7 |
2SD4 | LOE7 | scFv | 4.3×10-8 |
VH1-D2 | 2SD4 | scFv | 1.0×10-8 |
VH1-D2 | LOE7 | scFv/IgG1/IgG4 | 3.4×10-10 |
VH1.D2.Y | LOE7.T | IgG4 | 8.1×10-11 |
VH1-D2.N | LOE7.T | IgG4 | 1.3×10-10 |
VH1-D2.Y | LOE7.A | IgG4 | 2.8×10-11 |
VH1-D2.N | LOE7.A | IgG4 | 6.2×10-11 |
MAK195 | MAK195 | scFv | 1.9×10-8 |
MAK195 | MAK195 | F(ab′)2 | 6.2×10-11 |
实验 | IC50[M] |
1 | 1.26×10-10 |
2 | 1.33×10-10 |
3 | 1.15×10-10 |
平均 | 1.25±0.01×10-10 |
实验 | IC50[M] |
1 | 1.70×10-10 |
2 | 1.49×10-10 |
3 | 1.50×10-10 |
平均 | 1.56±0.12×10-10 |
IC50[M] | ||
试剂 | p55TNFR | p75TNFR |
D2E7 | 1.47×10-9 | 1.26×10-9 |
rhTNF | 2.31×10-9 | 2.70×10-9 |
实验 | IC50[M] |
1 | 1.95×10-10 |
2 | 1.69×10-10 |
3 | 1.90×10-10 |
平均 | 1.85±0.14×10-10 |
ICAM-1抑制 | IC50[M] | ||
实验 | IC50[M] | 实验 | IC50[M] |
1 | 1.84×10-10 | 1 | 1.03×10-10 |
2 | 2.49×10-10 | 2 | 9.26×10-10 |
3 | 1.06×10-10 | ||
平均 | 2.17±0.46×10-10 | 平均 | 1.01±0.01×10-10 |
组 | 存活率(生存/总数) | 存活率(%) |
1(无抗体) | 0/7 | 0 |
2(1μg) | 1/7 | 14 |
3(2.6μg) | 5/7 | 71 |
4(5.2μg) | 6/7 | 86 |
5(26μg) | 6/7 | 86 |
6(26μg;无rhTNF) | 7/7 | 100 |
7(25μg Hu IgG1) | 1/7 | 14 |
温度上升*,℃ | 摩尔比 | 峰值温度 | |||
D2E7剂量(μg/kg) | rhTNF | rhTNF+D2E7 | 抑制%** | D2E7∶rhTNF | rhTNF后分钟 |
14 | 0.53 | 0.25 | 53 | 1 | 60 |
24 | 0.43 | 0.13 | 70 | 1.6 | 40 |
48 | 0.53 | 0.03 | 94 | 3.3 | 50 |
137 | 0.53 | 0.00 | 100 | 9.5 | 60 |
792 | 0.80 | 0.00 | 1001 | 55 | 60 |
组别 | 治疗 | 组织病理学计分 | 关节炎计分 |
1 | 无 | 3(7/70 | +++(7/7) |
2 | 盐水 | 3(8/8) | +++(8/8) |
6 | IgG1对照 | 3(9/9) | +++(7/9) |
3 | 1.5μg/g的D2E7 | 0(6/8) | 0(8/8) |
4 | 15μg/g的D2E7 | 0(7/8) | 0(8/8) |
5 | 30μg/g的D2E7 | 0(8/8) | 0(8/8) |
TNFα* | 来源 | D2E7中和的IC 50(M)** |
人 | 重组 | 7.8×10-11 |
黑猩猩 | LPS刺激的PBMC | 5.5×10-11 |
狒狒 | 重组 | 6.0×10-11 |
狨 | LPS刺激的PBMC | 4.0×10-10 |
猕猴 | LPS刺激的PBMC | 8.0×10-11 |
恒河猴 | LPS刺激的PBMC | 3.0×10-11 |
犬 | LPS刺激的WBC | 2.2×10-10 |
猪 | 重组 | 1.0×10-7 |
鼠 | 重组 | >1.0×10-7 |
SEQ ID NO: | 抗体链 | 区 | 序列类型 |
1 | D2E7 | VL | 氨基酸 |
2 | D2E7 | VH | 氨基酸 |
3 | D2E7 | VL CDR3 | 氨基酸 |
4 | D2E7 | VH CDR3 | 氨基酸 |
5 | D2E7 | VL CDR2 | 氨基酸 |
6 | D2E7 | VH CDR2 | 氨基酸 |
7 | D2E7 | VL CDR1 | 氨基酸 |
8 | D2E7 | VH CDR1 | 氨基酸 |
9 | 2SD4 | VL | 氨基酸 |
10 | 2SD4 | VH | 氨基酸 |
11 | 2SD4 | VL CDR3 | 氨基酸 |
12 | EP B12 | VL CDR3 | 氨基酸 |
13 | VL10E4 | VL CDR3 | 氨基酸 |
14 | VL100A9 | VL CDR3 | 氨基酸 |
15 | VLL100D2 | VL CDR3 | 氨基酸 |
16 | VLL0F4 | VL CDR3 | 氨基酸 |
17 | LOE5 | VL CDR3 | 氨基酸 |
18 | VLLOG7 | VL CDR3 | 氨基酸 |
19 | VLLOG9 | VL CDR3 | 氨基酸 |
20 | VLLOH1 | VL CDR3 | 氨基酸 |
21 | VLLOH10 | VL CDR3 | 氨基酸 |
22 | VL1B7 | VL CDR3 | 氨基酸 |
23 | VL1C1 | VL CDR3 | 氨基酸 |
24 | VL0.1F4 | VL CDR3 | 氨基酸 |
25 | VL0.1H8 | VL CDR3 | 氨基酸 |
26 | LOE7.A | VL CDR3 | 氨基酸 |
27 | 2SD4 | VH CDR3 | 氨基酸 |
28 | VH1B11 | VH CDR3 | 氨基酸 |
29 | VH1D8 | VH CDR3 | 氨基酸 |
30 | VH1A11 | VH CDR3 | 氨基酸 |
31 | VH1B12 | VH CDR3 | 氨基酸 |
32 | VH1E4 | VH CDR3 | 氨基酸 |
33 | VH1F6 | VH CDR3 | 氨基酸 |
34 | 3C-H2 | VH CDR3 | 氨基酸 |
35 | VH1-D2.N | VH CDR3 | 氨基酸 |
36 | D2E7 | VL | 核酸 |
37 | D2E7 | VH | 核酸 |
Claims (53)
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/599,226 US6090382A (en) | 1996-02-09 | 1996-02-09 | Human antibodies that bind human TNFα |
US08/599,226 | 1996-02-09 | ||
US3147696P | 1996-11-25 | 1996-11-25 | |
US60/031,476 | 1996-11-25 |
Related Parent Applications (1)
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CNB971936358A Division CN1300173C (zh) | 1996-02-09 | 1997-02-10 | 结合人TNFα的人抗体 |
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CN1935260A true CN1935260A (zh) | 2007-03-28 |
CN1935260B CN1935260B (zh) | 2012-07-18 |
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CN2008101088480A Expired - Lifetime CN101302515B (zh) | 1996-02-09 | 1997-02-10 | 结合人TNFα的人抗体 |
CNA200610058091XA Pending CN1876683A (zh) | 1996-02-09 | 1997-02-10 | 结合人TNFα的人抗体 |
CN200810212687.XA Expired - Lifetime CN101343324B (zh) | 1996-02-09 | 1997-02-10 | 体外抑制人TNFα活性的方法 |
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CN2008101088480A Expired - Lifetime CN101302515B (zh) | 1996-02-09 | 1997-02-10 | 结合人TNFα的人抗体 |
CNA200610058091XA Pending CN1876683A (zh) | 1996-02-09 | 1997-02-10 | 结合人TNFα的人抗体 |
CN200810212687.XA Expired - Lifetime CN101343324B (zh) | 1996-02-09 | 1997-02-10 | 体外抑制人TNFα活性的方法 |
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US (8) | US6090382A (zh) |
EP (9) | EP2930187A1 (zh) |
CN (5) | CN101003573B (zh) |
BR (1) | BRPI9715219C8 (zh) |
CA (2) | CA2596476A1 (zh) |
NZ (4) | NZ598487A (zh) |
RO (1) | RO128628A2 (zh) |
RU (1) | RU2268266C2 (zh) |
UA (2) | UA102988C2 (zh) |
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- 1997-02-10 EP EP15165123.9A patent/EP2933267A1/en not_active Withdrawn
- 1997-02-10 CA CA002596476A patent/CA2596476A1/en not_active Abandoned
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
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CN101003573B (zh) * | 1996-02-09 | 2014-02-26 | 阿布维生物技术有限公司 | 结合人TNFα的人抗体 |
CN103656638A (zh) * | 2008-05-30 | 2014-03-26 | 埃克斯生物科技公司 | 白细胞介素-1α 抗体及使用方法 |
CN103656638B (zh) * | 2008-05-30 | 2016-04-27 | 埃克斯生物科技公司 | 白细胞介素-1α抗体及使用方法 |
CN105646643A (zh) * | 2008-10-29 | 2016-06-08 | 阿布林克斯公司 | 单域抗原结合性分子的纯化方法 |
CN104726393A (zh) * | 2013-12-24 | 2015-06-24 | 江苏省农业科学院 | TNF-α诱导的人脐静脉内皮细胞HUVEC炎症反应模型的制备方法 |
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