CN101688200B - 单链抗体的基于序列的改造和优化 - Google Patents
单链抗体的基于序列的改造和优化 Download PDFInfo
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- CN101688200B CN101688200B CN200880021937XA CN200880021937A CN101688200B CN 101688200 B CN101688200 B CN 101688200B CN 200880021937X A CN200880021937X A CN 200880021937XA CN 200880021937 A CN200880021937 A CN 200880021937A CN 101688200 B CN101688200 B CN 101688200B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/46—Hybrid immunoglobulins
- C07K16/461—Igs containing Ig-regions, -domains or -residues form different species
- C07K16/464—Igs containing CDR-residues from one specie grafted between FR-residues from another
- C07K16/465—Igs containing CDR-residues from one specie grafted between FR-residues from another with additional modified FR-residues
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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
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P35/00—Antineoplastic agents
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
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- G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
- G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
- G16B15/00—ICT specially adapted for analysing two-dimensional or three-dimensional molecular structures, e.g. structural or functional relations or structure alignment
- G16B15/30—Drug targeting using structural data; Docking or binding prediction
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- 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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- 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
- C07K2317/567—Framework region [FR]
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- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
- C07K2317/62—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
- C07K2317/622—Single chain antibody (scFv)
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- G—PHYSICS
- G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
- G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
- G16B15/00—ICT specially adapted for analysing two-dimensional or three-dimensional molecular structures, e.g. structural or functional relations or structure alignment
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Abstract
Description
Aa# | G<Q(事件的#) | G>Q(事件的#) | X/Y | #hvFR(辛普森<0.4) | G<Q(事件的#) | G>Q(事件的#) | X/Y | |
VL | 108 | 61 | 11 | 5.5 | 16 | 13 | 3 | 4.3 |
VH | 116 | 50 | 18 | 2.8 | 27 | 22 | 5 | 4.4 |
残基 | 结构域 | 暴露于溶剂的表面% | STDE% | rSAS | 序列变异性 | VH/抗原界面 | VH/VL界面 | VH/CH界面 |
2 | VH | 23.06 | 19.26 | 10-25% | 10-25% | >0-20% | >0-20% | 0 |
4 | VH | 0.66 | 1.26 | 0-10% | 0-10% | 0 | 0 | |
5 | VH | 61.85 | 12.96 | 50-75% | 10-25% | 0 | >0-20% | 0 |
12 | VH | 70.27 | 9.17 | 50-75% | 10-25% | 0 | 0 | 60-80% |
103 | VH | 35.85 | 5.85 | 25-50% | 10-25% | 0 | >0-2% | >0-2% |
144 | VH | 62.17 | 7.82 | 50-75% | 10-25% | 0 | 0 | >0-2% |
15 | VL | 49.59 | 9.77 | 25-50% | 10-25% | 0 | 0 | 0 |
147 | VL | 31.19 | 23.32 | 25-50% | 10-25% | 0 | 0 | 60-80% |
残基 | VH4 | VH 12 | VH 103 | VH 144 | VL 15 | VL 147 |
A | 0.23046215 | 0 | 0 | 0 | 3.8647343 | 0.176821923 |
C | 0 | 0 | 0 | 0 | 0 | 0 |
D | 0 | 0 | 0 | 0 | 0 | 0 |
E | 0 | 0 | 0 | 0 | 0 | 0 |
F | 0.483091787 | 0 | 0.483091787 | 0 | 0 | 0 |
G | 0 | 0 | 0 | 0 | 0 | 0 |
H | 0 | 0 | 0 | 0 | 0 | 0 |
I | 0 | 2.415458937 | 9.661835749 | 0 | 5.314009662 | 70.38834951 |
K | 0 | 0 | 0 | 0 | 0 | 0 |
L | 96.61835749 | 89.85507246 | 7.246376812 | 27.0531401 | 45.89371981 | 15.53398058 |
M | 0 | 0 | 10.62801932 | 1.93236715 | 0 | 0.970873786 |
N | 0 | 0 | 0 | 0 | 0 | 0 |
P | 0.966183575 | 0 | 0 | 0.966183575 | 21.73913043 | 0.485436893 |
Q | 0 | 0 | 0 | 0.483091787 | 0 | 0 |
R | 0 | 0 | 7.246376812 | 0 | 0 | 0 |
S | 0 | 0.966183575 | 0 | 18.84057971 | 0 | 0 |
T | 0 | 0 | 15.4589372 | 50.72463768 | 0.966183575 | 0 |
V | 1.93236715 | 6.763285024 | 49.27536232 | 0 | 22.22222222 | 12.62135922 |
W | 0 | 0 | 0 | 0 | 0 | 0 |
Y | 0 | 0 | 0 | 0 | 0 | 0 |
残基 | 结构域 | 暴露于溶剂的表面% | 亲本残基 | 亲本残基的疏水性 | 可溶性突变 | 突变的疏水性 |
4 | VH | 0.66 | L | 85.2 | A | 42.7 |
12 | VH | 70.27 | V | 73.2 | S | 28 |
103 | VH | 35.85 | V | 73.2 | T | 32.8 |
144* | VH | 62.17 | V | 73.2 | S | 28 |
15 | VL | 49.59 | V | 73.2 | T | 32.8 |
147 | VL | 31.19 | L | 85.2 | A | 42.7 |
蛋白质 | 蛋白质丧失(不溶性聚集物) |
ESBA105 | 1.14% |
ESBA105 Opt 1_0 | 8.17% |
ESBA105 Opt 0_2 | 4.45% |
ESBA105 Opt 1_2 | 46.60% |
ESBA105 VH V103T | -1.95% |
蛋白质 | VL/VH突变 | FTIRTm(℃) | PEG溶解性(mg/ml) | 相对于E105的活性 | kD |
QC7.1D-N-15.2 | VL:D31N;V83EVH:V78A;K43R;F67L | 69.0 | 90 | 1.7 | 9.06×10-10 |
QC7.1D-N-15.2VH V103T | VL:D31N;V83EVH:V78A;K43R;F67L;V103T | 68.9 | 106 | 1.5 | 8.79×10-10 |
QC7.1D-N-15.2Opt 0_2 | VL:D31N;V83EVH:V12S;V78A;K43R;F67L;L144S | 66.6 | 121 | 1.2 | 8.12×10-10 |
QC7.1D-N-15.2VH V103T Opt0_2 | VL:D31N;V83EVH:V12S;V78A;K43R;F67L;V103T;L144S | 67.3 | 186 | 1.5 | 1.34×10-9 |
Claims (13)
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
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US93711207P | 2007-06-25 | 2007-06-25 | |
US60/937,112 | 2007-06-25 | ||
US6905708P | 2008-03-12 | 2008-03-12 | |
US61/069,057 | 2008-03-12 | ||
PCT/CH2008/000284 WO2009000098A2 (en) | 2007-06-25 | 2008-06-25 | Sequence based engineering and optimization of single chain antibodies |
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CN101688200A CN101688200A (zh) | 2010-03-31 |
CN101688200B true CN101688200B (zh) | 2012-08-08 |
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CN200880021937XA Active CN101688200B (zh) | 2007-06-25 | 2008-06-25 | 单链抗体的基于序列的改造和优化 |
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US (1) | US9908945B2 (zh) |
EP (1) | EP2164961B1 (zh) |
JP (2) | JP5506670B2 (zh) |
KR (1) | KR101530723B1 (zh) |
CN (1) | CN101688200B (zh) |
AU (1) | AU2008267733B2 (zh) |
BR (1) | BRPI0813287A2 (zh) |
CA (1) | CA2689064C (zh) |
DK (1) | DK2164961T3 (zh) |
ES (1) | ES2532725T3 (zh) |
HK (1) | HK1137035A1 (zh) |
IL (1) | IL202352A (zh) |
MX (1) | MX2009013327A (zh) |
NZ (1) | NZ581470A (zh) |
PL (1) | PL2164961T3 (zh) |
PT (1) | PT2164961E (zh) |
RU (1) | RU2010102064A (zh) |
SI (1) | SI2164961T1 (zh) |
WO (1) | WO2009000098A2 (zh) |
ZA (1) | ZA200908314B (zh) |
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AU2008267733A1 (en) | 2008-12-31 |
BRPI0813287A2 (pt) | 2014-12-30 |
NZ581470A (en) | 2013-04-26 |
DK2164961T3 (en) | 2015-03-02 |
WO2009000098A2 (en) | 2008-12-31 |
JP2014051508A (ja) | 2014-03-20 |
ES2532725T3 (es) | 2015-03-31 |
CN101688200A (zh) | 2010-03-31 |
PL2164961T3 (pl) | 2015-08-31 |
EP2164961B1 (en) | 2015-01-07 |
JP5506670B2 (ja) | 2014-05-28 |
KR101530723B1 (ko) | 2015-06-22 |
US9908945B2 (en) | 2018-03-06 |
KR20100028053A (ko) | 2010-03-11 |
EP2164961A2 (en) | 2010-03-24 |
CA2689064C (en) | 2018-04-24 |
MX2009013327A (es) | 2010-06-02 |
SI2164961T1 (sl) | 2015-05-29 |
CA2689064A1 (en) | 2008-12-31 |
RU2010102064A (ru) | 2011-07-27 |
JP2010532324A (ja) | 2010-10-07 |
HK1137035A1 (zh) | 2010-07-16 |
AU2008267733B2 (en) | 2013-11-14 |
IL202352A0 (en) | 2011-08-01 |
US20090028848A1 (en) | 2009-01-29 |
ZA200908314B (en) | 2011-02-23 |
IL202352A (en) | 2015-06-30 |
PT2164961E (pt) | 2015-04-08 |
WO2009000098A3 (en) | 2009-04-23 |
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