The immunogenicity of protein aggregates: Studies on a murine monoclonal antibody in wild-type mice:
Gespeichert in:
| 1. Verfasser: | |
|---|---|
| Format: | Abschlussarbeit Buch |
| Sprache: | English |
| Veröffentlicht: |
München
Dr. Hut
2013
|
| Ausgabe: | 1. Aufl. |
| Schriftenreihe: | Pharmazeutische Technologie
|
| Schlagworte: | |
| Online-Zugang: | Inhaltstext Volltext https://nbn-resolving.org/urn:nbn:de:bvb:19-157400 Inhaltsverzeichnis |
| Beschreibung: | 176, IX S. graph. Darst. 210 mm x 148 mm, 296 g |
| ISBN: | 9783843908177 3843908176 |
Internformat
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| 245 | 1 | 0 | |a The immunogenicity of protein aggregates: Studies on a murine monoclonal antibody in wild-type mice |c Angelika Juliane Freitag |
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| 264 | 1 | |a München |b Dr. Hut |c 2013 | |
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Datensatz im Suchindex
| _version_ | 1807955369010397184 |
|---|---|
| adam_text |
IMAGE 1
ANGELIKA FREITAG
DISSERTATION TABLE OF CONTENTS
TABLE OF CONTENTS
1 OBJECTIVES OF THE THESIS 1
2 INTRODUCTION 3
2.1.1 STABILITY OF THERAPEUTIC PROTEIN FORMULATIONS 4
2.2.1 MECHANISMS OF PROTEIN AGGREGATION 4
2.2.2 FACTORS INDUCING PROTEIN AGGREGATION 6
2.2.3 CLASSIFICATION AND CONFORMATION OF PROTEIN AGGREGATES 7
2.3.1 DETECTION OF INSOLUBLE PROTEIN AGGREGATES 9
2.3.1.1 LIGHT OBSCURATION 9
2.3.1.2 MICROSCOPIC METHODS 10
2.3.1.3 LIGHT SCATTERING METHODS 11
2.3.2 DETECTION OF SOLUBLE PROTEIN AGGREGATES 11
2.3.2.1 HIGH PERFORMANCE SIZE EXCLUSION CHROMATOGRAPHY 12
2.3.2.2 ASYMMETRICAL FLOW FIELD-FLOW FRACTIONATION 12
2.3.2.3 SODIUM DODECYL SULFATE - POLYACRYLAMIDE GEL ELECTROPHORESIS 15
2.3.2.4 DYNAMIC LIGHT SCATTERING 15
2.4.1 FACTORS INFLUENCING IMMUNOGENICITY 16
2.4.2 RESPONSES OF THE IMMUNE SYSTEM TO THERAPEUTIC PROTEINS 17
2.4.3 IMPACT OF ANTIBODY INDUCTION 19
2.5.1 STRUCTURE OF MONOCLONAL ANTIBODIES 20
2.5.2 THE PHARMACOKINETICS OF MONOCLONAL ANTIBODIES 21
2.5.3 THE MARKET OF MONOCLONAL ANTIBODIES 22
3 AGGREGATION STUDIES ON A HUMAN MONOCLONAL ANTIBODY 33
3.1.1 TEMPERATURE 33
3.1.2 MECHANICAL STRESS 34
3.1.3 FREEZE-THAW STRESS 34
3.1.4 LIGHT EXPOSURE 35
3.2.1 MATERIALS 36
3.2.1.1 HUMAN LGG1 ANTIBODY (HUAB) 36
3.2.2 METHODS TO PROVOKE PROTEIN INSTABILITY 36
HTTP://D-NB.INFO/1030510482
IMAGE 2
ANGELIKA FRERTAG
DISSERTATION TABLE OF CONTENTS
3.2.2.1 STIRRING STRESS 36
3.2.2.2 SHAKING STRESS 36
3.2.2.3 FREEZE-THAW STRESS 36
3.2.2.4 LIGHT EXPOSURE 37
3.2.2.5 TEMPERATURE STRESS 37
3.2.3 METHODS TO DETERMINE PROTEIN STABILITY 37
3.2.3.1 LIGHT OBSCURATION 37
3.2.3.2 DYNAMIC LIGHT SCATTERING 37
3.2.3.3 TURBIDITY 38
3.2.3.4 SIZE EXCLUSION CHROMATOGRAPHY 38
3.2.3.5 INTRINSIC PROTEIN FLUORESCENCE SPECTROSCOPY 38
3.2.3.6 EXTRINSIC PROTEIN FLUORESCENCE SPECTROSCOPY 38
3.2.3.7 FOURIER TRANSFORM INFRARED SPECTROSCOPY (FTIR) 39
3.2.3.8 HIGH RESOLUTION UV ABSORBANCE SPECTROSCOPY 39
3.3.1 MECHANICAL STABILITY OF HUMAN LGG1 ANTIBODY (HUAB) 40
3.3.2 STABILITY OF HUAB AGAINST FREEZE-THAWING 47
3.3.3 STABILITY OF HUAB AGAINST LIGHT EXPOSURE 49
3.3.4 STABILITY OF HUAB AGAINST STORAGE AT ELEVATED TEMPERATURES 56
4 AGGREGATION STUDIES ON A MURINE MONOCLONAL ANTIBODY 71
4.2.1 MATERIALS 72
4.2.1.1 MURINE LGG2C ANTIBODY (MUAB) SAMPLES 72
4.2.2 METHODS TO PROVOKE PROTEIN INSTABILITY 72
4.2.2.1 STIRRING STRESS 72
4.2.2.2 SHAKING STRESS 72
4.2.2.3 LIGHT EXPOSURE 73
4.2.2.4 TEMPERATURE STRESS 73
4.2.3 METHODS TO DETERMINE PROTEIN STABILITY 73
4.2.3.1 LIGHT OBSCURATION 73
4.2.3.2 TURBIDITY 73
4.2.3.3 SIZE EXCLUSION CHROMATOGRAPHY 74
4.2.3.4 INTRINSIC PROTEIN FLUORESCENCE SPECTROSCOPY 74
4.2.3.5 EXTRINSIC PROTEIN FLUORESCENCE SPECTROSCOPY 74
IMAGE 3
ANGELIKA FREITAG DISSERTATION TABLE OF CONTENTS
4.2.3.6 FOURIER TRANSFORM INFRARED SPECTROSCOPY (FTIR) 74
4.2.3.7 HIGH RESOLUTION UV ABSORBANCE SPECTROSCOPY 74
4.3.1 FORMATION OF SUBVISIBLE PARTICLES OF THE MURINE LGG2C ANTIBODY
(MUAB) 74
4.3.2 FORMATION OF SOLUBLE AGGREGATES OF THE MURINE LGG2C ANTIBODY
(MUAB) 76
4.3.3 MODIFICATIONS IN THE STRUCTURE OF THE MURINE LGG2C ANTIBODY (MUAB)
80
4.3.3.1 STRUCTURAL MODIFICATIONS OF MUAB AFTER STIRRING AND SHAKING 80
4.3.3.2 STRUCTURAL MODIFICATIONS OF MUAB AFTER STORAGE AT 50C 81
4.3.3.3 STRUCTURAL MODIFICATIONS OF MUAB AFTER LIGHT EXPOSURE 81
5 FRACTIONATION OF PROTEIN AGGREGATES OF A HUMAN MONOCLONAL ANTIBODY BY
AF4 87
5.1.1 THE USE OF ASYMMETRICAL FLOW FIELD-FLOW FRACTIONATION (AF4) TO
SEPARATE PROTEIN
AGGREGATES 87
5.2.1 SAMPLE PREPARATION 89
5.2.2 ASYMMETRICAL FLOW FIELD-FLOW FRACTIONATION 89
5.2.3 PROTEIN CONCENTRATION BY CENTRIFUGATION 91
5.2.4 MICRO BCA* PROTEIN ASSAY KIT 91
5.2.5 SODIUM DODECYL SULFATE - POLYACRYLAMIDE GEL ELECTROPHORESIS 92
5.2.6 SIZE EXCLUSION CHROMATOGRAPHY 92
5.3.1 CHARACTERIZATION OF THE SAMPLES 92
5.3.2 COLLECTION OF PROTEIN SPECIES AFTER FIELD-FLOW FRACTIONATION 96
5.3.3 INCREASING PROTEIN CONCENTRATION WITHIN THE FRACTIONS 98
6 THE PREPARATIVE USE OF AF4 TO OBTAIN ENDOTOXLN-FREE PROTEIN SPECIES
109
6.2.2 ASYMMETRICAL FLOW FIELD-FLOW FRACTIONATION 111
6.2.3 PROTEIN CONCENTRATION BY CENTRIFUGATION 111
6.2.4 DETERMINATION OF ENDOTOXIN LEVEL 112
6.3.1 PREPARATION OF INSTRUMENT, SAMPLES AND BUFFER SOLUTIONS 112
6.3.2 FIELD-FLOW FRACTIONATION OF MOUSE LGG2C 113
6.3.3 COLLECTION AND CONCENTRATION OF PROTEIN SPECIES AFTER AF4
SEPARATION 114
7 THE NEED FOR IMMUNE COMPLEX DISSOCIATION IN ANTI-DRUG ANTIBODY
DETECTION 121
7.2.1 GENERATION OF PROTEIN AGGREGATE TEST ITEMS 122
7.2.2 SIZE EXCLUSION CHROMATOGRAPHY 123
7.2.3 LIGHT OBSCURATION 123
7.2.4 ENDOTOXIN TESTING 123
IMAGE 4
ANGELIKA FREITAG DISSERTATION TABLE OF CONTENTS
7.2.5 ANIMALS 123
7.2.6 IMMUNIZATION PROTOCOL 124
7.2.7 COLLECTION OF BLOOD SAMPLES 124
7.2.8 DETERMINATION OF ANTI-DRUG ANTIBODIES (ADAS) 124
7.2.8.1 METHOD A 125
7.2.8.2 METHOD B 125
7.2.9 DETERMINATION OF DRUG LEVELS IN SERUM (PHARMACOKINETICS, PK) 126
7.3.1 SEC ANALYSIS OF MURINE LGG2C AFTER LIGHT EXPOSURE 126
7.3.2 ANALYSIS OF ANTI-DRUG ANTIBODY LEVELS USING TWO ELISA FORMATS 127
7.3.3 DETECTION OF SERUM LEVELS OF MUAB - PHARMACOKINETICS 135
8 INVESTIGATIONS ON THE IMMUNOGENICITY OF PROTEIN AGGREGATES OF A MURINE
MONOCLONAL
ANTIBODY IN WILDTYPE MICE 143
8.2.1 MATERIALS 144
8.2.1.1 MURINE LGG2C ANTIBODY (MUAB) 144
8.2.1.2 ANIMALS 144
8.2.2 METHODS 144
8.2.2.1 SAMPLE PREPARATION 144
8.2.2.3 ASYMMETRICAL FLOW FIELD-FLOW FRACTIONATION (AF4) 146
8.2.2.4 LIGHT OBSCURATION (LO) 146
8.2.2.5 TURBIDITY MEASUREMENTS 146
8.2.2.6 ENDOTOXIN TESTING 146
8.2.2.7 FOURIER TRANSFORM INFRARED SPECTROSCOPY (FTIR) 146
8.2.2.8 ULTRAVIOLET (UV) ABSORBANCE SPECTROSCOPY AT 280 NM 146
8.2.2.9 IMMUNIZATION PROTOCOL 146
8.2.2.10 COLLECTION OF BLOOD SAMPLES 147
8.2.2.11 DETERMINATION OF ANTI-DRUG ANTIBODIES (ADAS) 147
8.2.2.12 DETERMINATION OF DRUG LEVELS IN SERUM (PHARMACOKINETICS, PK)
147
8.2.2.13 STATISTICAL ANALYSIS 147
8.3.1 PREPARATION AND ANALYSIS OF AGGREGATES 148
8.3.2 PREPARATION AND ANALYSIS OF THE ADJUVANT SAMPLES 150
8.3.3 TESTING OF THE SAMPLES FOR THE PRESENCE OF ENDOTOXINS 150
8.3.4 DETECTION OF IMMUNE RESPONSE - ANTI-DRUG ANTIBODIES TOWARDS MUAB
150
IMAGE 5
ANGELIKA FREITAG
DISSERTATION TABLE OF CONTENTS
8.3.4.1 ANTI-MUAB ANTIBODIES IN C57BL/6 MICE 151
8.3.4.2 ANTI-MUAB ANTIBODIES IN BALB/C MICE 154
8.3.4.3 COMPARISON OF C57BU6 MICE AND BALB/C MICE 157
8.3.5 DETECTION OF MUAB CIRCULATING IN THE BLOOD STREAM -
PHARMACOKINETICS 159
8.4.1 PHARMACOKINETICS OF MUAB 162
8.4.2 IMMUNOGENICITY OF MUAB IN THE CONTROL GROUPS 163
8.4.3 SOLUBLE AGGREGATES OF MUAB 163
8.4.4 INSOLUBLE AGGREGATES OF MUAB 164
8.4.4.1 AGGREGATION BY LIGHT EXPOSURE 165
8.4.4.2 AGGREGATION BY MECHANICAL STRESS 165
8.4.4.3 AGGREGATION BY ELEVATED TEMPERATURE 166
8.4.5 SPECIES DIFFERENCES 166
9 FINAL SUMMARY AND CONCLUSIONS 171
LIST OF ABBREVIATIONS I
LIST OF PRESENTATIONS AND PUBLICATIONS VII
CURRICULUM VITAE IX |
| any_adam_object | 1 |
| author | Freitag, Angelika Juliane 1984- |
| author_GND | (DE-588)103213321X |
| author_facet | Freitag, Angelika Juliane 1984- |
| author_role | aut |
| author_sort | Freitag, Angelika Juliane 1984- |
| author_variant | a j f aj ajf |
| building | Verbundindex |
| bvnumber | BV040806915 |
| collection | ebook |
| ctrlnum | (OCoLC)835406397 (DE-599)DNB1030510482 |
| dewey-full | 615.19 |
| dewey-hundreds | 600 - Technology (Applied sciences) |
| dewey-ones | 615 - Pharmacology and therapeutics |
| dewey-raw | 615.19 |
| dewey-search | 615.19 |
| dewey-sort | 3615.19 |
| dewey-tens | 610 - Medicine and health |
| discipline | Biologie Medizin |
| edition | 1. Aufl. |
| format | Thesis Book |
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| genre_facet | Hochschulschrift |
| id | DE-604.BV040806915 |
| illustrated | Illustrated |
| indexdate | 2024-08-21T00:36:40Z |
| institution | BVB |
| isbn | 9783843908177 3843908176 |
| language | English |
| oai_aleph_id | oai:aleph.bib-bvb.de:BVB01-025786892 |
| oclc_num | 835406397 |
| open_access_boolean | 1 |
| owner | DE-12 DE-19 DE-BY-UBM DE-384 DE-473 DE-BY-UBG DE-703 DE-1051 DE-824 DE-29 DE-91 DE-BY-TUM DE-1049 DE-92 DE-739 DE-898 DE-BY-UBR DE-355 DE-BY-UBR DE-706 DE-20 DE-1102 |
| owner_facet | DE-12 DE-19 DE-BY-UBM DE-384 DE-473 DE-BY-UBG DE-703 DE-1051 DE-824 DE-29 DE-91 DE-BY-TUM DE-1049 DE-92 DE-739 DE-898 DE-BY-UBR DE-355 DE-BY-UBR DE-706 DE-20 DE-1102 |
| physical | 176, IX S. graph. Darst. 210 mm x 148 mm, 296 g |
| psigel | ebook |
| publishDate | 2013 |
| publishDateSearch | 2013 |
| publishDateSort | 2013 |
| publisher | Dr. Hut |
| record_format | marc |
| series2 | Pharmazeutische Technologie |
| spelling | Freitag, Angelika Juliane 1984- Verfasser (DE-588)103213321X aut The immunogenicity of protein aggregates: Studies on a murine monoclonal antibody in wild-type mice Angelika Juliane Freitag 1. Aufl. München Dr. Hut 2013 176, IX S. graph. Darst. 210 mm x 148 mm, 296 g txt rdacontent n rdamedia nc rdacarrier Pharmazeutische Technologie Zugl.: München, Univ., Diss., 2012 Tiermodell (DE-588)4140660-6 gnd rswk-swf Proteine (DE-588)4076388-2 gnd rswk-swf Aggregat Chemie (DE-588)4333754-5 gnd rswk-swf Immunogenität (DE-588)4278029-9 gnd rswk-swf Monoklonaler Antikörper (DE-588)4040094-3 gnd rswk-swf (DE-588)4113937-9 Hochschulschrift gnd-content Proteine (DE-588)4076388-2 s Aggregat Chemie (DE-588)4333754-5 s Monoklonaler Antikörper (DE-588)4040094-3 s Immunogenität (DE-588)4278029-9 s Tiermodell (DE-588)4140660-6 s DE-604 Erscheint auch als Online-Ausgabe urn:nbn:de:bvb:19-157400 X:MVB text/html http://deposit.dnb.de/cgi-bin/dokserv?id=4249336&prov=M&dok_var=1&dok_ext=htm Verlag kostenfrei Inhaltstext http://edoc.ub.uni-muenchen.de/15740/ Verlag kostenfrei Volltext https://nbn-resolving.org/urn:nbn:de:bvb:19-157400 Resolving-System DNB Datenaustausch application/pdf http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=025786892&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA Inhaltsverzeichnis |
| spellingShingle | Freitag, Angelika Juliane 1984- The immunogenicity of protein aggregates: Studies on a murine monoclonal antibody in wild-type mice Tiermodell (DE-588)4140660-6 gnd Proteine (DE-588)4076388-2 gnd Aggregat Chemie (DE-588)4333754-5 gnd Immunogenität (DE-588)4278029-9 gnd Monoklonaler Antikörper (DE-588)4040094-3 gnd |
| subject_GND | (DE-588)4140660-6 (DE-588)4076388-2 (DE-588)4333754-5 (DE-588)4278029-9 (DE-588)4040094-3 (DE-588)4113937-9 |
| title | The immunogenicity of protein aggregates: Studies on a murine monoclonal antibody in wild-type mice |
| title_auth | The immunogenicity of protein aggregates: Studies on a murine monoclonal antibody in wild-type mice |
| title_exact_search | The immunogenicity of protein aggregates: Studies on a murine monoclonal antibody in wild-type mice |
| title_full | The immunogenicity of protein aggregates: Studies on a murine monoclonal antibody in wild-type mice Angelika Juliane Freitag |
| title_fullStr | The immunogenicity of protein aggregates: Studies on a murine monoclonal antibody in wild-type mice Angelika Juliane Freitag |
| title_full_unstemmed | The immunogenicity of protein aggregates: Studies on a murine monoclonal antibody in wild-type mice Angelika Juliane Freitag |
| title_short | The immunogenicity of protein aggregates: Studies on a murine monoclonal antibody in wild-type mice |
| title_sort | the immunogenicity of protein aggregates studies on a murine monoclonal antibody in wild type mice |
| topic | Tiermodell (DE-588)4140660-6 gnd Proteine (DE-588)4076388-2 gnd Aggregat Chemie (DE-588)4333754-5 gnd Immunogenität (DE-588)4278029-9 gnd Monoklonaler Antikörper (DE-588)4040094-3 gnd |
| topic_facet | Tiermodell Proteine Aggregat Chemie Immunogenität Monoklonaler Antikörper Hochschulschrift |
| url | http://deposit.dnb.de/cgi-bin/dokserv?id=4249336&prov=M&dok_var=1&dok_ext=htm http://edoc.ub.uni-muenchen.de/15740/ https://nbn-resolving.org/urn:nbn:de:bvb:19-157400 http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=025786892&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA |
| work_keys_str_mv | AT freitagangelikajuliane theimmunogenicityofproteinaggregatesstudiesonamurinemonoclonalantibodyinwildtypemice |