Peripheral and central biodistribution of (111)In-labeled anti-beta-amyloid autoantibodies in a transgenic mouse model of Alzheimer's disease.
Identifieur interne : 001D20 ( Main/Exploration ); précédent : 001D19; suivant : 001D21Peripheral and central biodistribution of (111)In-labeled anti-beta-amyloid autoantibodies in a transgenic mouse model of Alzheimer's disease.
Auteurs : RBID : pubmed:18786612English descriptors
- KwdEn :
- Alzheimer Disease (genetics), Alzheimer Disease (metabolism), Alzheimer Disease (pathology), Amyloid beta-Peptides (immunology), Amyloid beta-Protein Precursor (genetics), Amyloid beta-Protein Precursor (metabolism), Animals, Antibodies, Monoclonal (metabolism), Antibodies, Monoclonal (pharmacokinetics), Antibodies, Monoclonal, Murine-Derived, Autoantibodies (metabolism), Brain (drug effects), Brain (metabolism), Disease Models, Animal, Humans, Indium (pharmacokinetics), Mice, Mice, Inbred C57BL, Mice, Transgenic, Mutation (genetics), Time Factors.
- MESH :
- chemical , genetics : Amyloid beta-Protein Precursor.
- chemical , immunology : Amyloid beta-Peptides.
- drug effects : Brain.
- genetics : Alzheimer Disease, Mutation.
- metabolism : Alzheimer Disease, Amyloid beta-Protein Precursor, Antibodies, Monoclonal, Autoantibodies, Brain.
- pathology : Alzheimer Disease.
- chemical , pharmacokinetics : Antibodies, Monoclonal, Indium.
- Animals, Antibodies, Monoclonal, Murine-Derived, Disease Models, Animal, Humans, Mice, Mice, Inbred C57BL, Mice, Transgenic, Time Factors.
Abstract
Active as well as passive immunization against beta-amlyoid (Abeta) has been proposed as a treatment to lower cerebral amyloid burden and stabilize cognitive decline in Alzheimer's disease (AD). To clarify the mechanism of action underlying passive immunization, the in vivo distribution (and sites of degradation) of peripherally administered radiolabeled human and mouse anti-Abeta antibodies were analyzed in a transgenic mouse model of AD. In APP23 mice, a model in which mutated human amyloid precursor protein is overexpressed, the biodistribution of intravenously applicated (111)indium-conjugated affinity-purified human polyclonal autoantibodies (NAbs-Abeta) was compared to that of monoclonal anti-Abeta(1-17) (6E10), anti-Abeta(17-24) antibodies (4G8) and anti-CD-20 (Rituximab), a non-Abeta targeting control. Blood clearance half-lives were 50+/-6h for Rituximab, 20-30h for NAbs-Abeta, 29+/-5h for 4G8 and 27+/-3h for 6E10. Blood activity was higher for 6E10 at 4h as compared to 4G8, Rituximab and NAbs-Abeta. At the 96h time point, Rituximab had the highest blood activity among the antibodies tested. As expected, all antibodies displayed hepatobiliary clearance. Additionally, NAbs-Abeta was excreted in the urinary tract. Liver and kidney uptake of NAbs-Abeta increased over time and was higher than in the monoclonal antibodies at 48h/96h. The brain-to-blood radioactivity ratio for NAbs-Abeta at later time points (>48h) was higher than that of 6E10, 4G8 and Rituximab. In addition, the distribution varied, with highest values found in the hippocampus. Our data indicate a cerebral accumulation of human NAbs-Abeta in the APP23 model. Further studies with human immunoglobulins and particularly with those that recognize different Abeta-epitopes are required in order to delineate in more detail the mode of action of NAbs-Abeta.
DOI: 10.1016/j.neulet.2008.08.083
PubMed: 18786612
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Peripheral and central biodistribution of (111)In-labeled anti-beta-amyloid autoantibodies in a transgenic mouse model of Alzheimer's disease.</title><author><name sortKey="Bacher, Michael" uniqKey="Bacher M">Michael Bacher</name><affiliation wicri:level="3"><nlm:affiliation>Department of Neurology, Philipps University, Rudolf-Bultmann-Str. 8, 35033 Marburg, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Neurology, Philipps University, Rudolf-Bultmann-Str. 8, 35033 Marburg</wicri:regionArea><placeName><region type="land" nuts="1">Hesse (Land)</region><region type="district" nuts="2">District de Giessen</region><settlement type="city">Marbourg</settlement></placeName></affiliation></author><author><name sortKey="Depboylu, Candan" uniqKey="Depboylu C">Candan Depboylu</name></author><author><name sortKey="Du, Yansheng" uniqKey="Du Y">Yansheng Du</name></author><author><name sortKey="Noelker, Carmen" uniqKey="Noelker C">Carmen Noelker</name></author><author><name sortKey="Oertel, Wolfgang H" uniqKey="Oertel W">Wolfgang H Oertel</name></author><author><name sortKey="Behr, Thomas" uniqKey="Behr T">Thomas Behr</name></author><author><name sortKey="Henriksen, Gjermund" uniqKey="Henriksen G">Gjermund Henriksen</name></author><author><name sortKey="Behe, Martin" uniqKey="Behe M">Martin Behe</name></author><author><name sortKey="Dodel, Richard" uniqKey="Dodel R">Richard Dodel</name></author></titleStmt><publicationStmt><date when="2009">2009</date><idno type="doi">10.1016/j.neulet.2008.08.083</idno><idno type="RBID">pubmed:18786612</idno><idno type="pmid">18786612</idno><idno type="wicri:Area/Main/Corpus">002238</idno><idno type="wicri:Area/Main/Curation">002238</idno><idno type="wicri:Area/Main/Exploration">001D20</idno></publicationStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Alzheimer Disease (genetics)</term><term>Alzheimer Disease (metabolism)</term><term>Alzheimer Disease (pathology)</term><term>Amyloid beta-Peptides (immunology)</term><term>Amyloid beta-Protein Precursor (genetics)</term><term>Amyloid beta-Protein Precursor (metabolism)</term><term>Animals</term><term>Antibodies, Monoclonal (metabolism)</term><term>Antibodies, Monoclonal (pharmacokinetics)</term><term>Antibodies, Monoclonal, Murine-Derived</term><term>Autoantibodies (metabolism)</term><term>Brain (drug effects)</term><term>Brain (metabolism)</term><term>Disease Models, Animal</term><term>Humans</term><term>Indium (pharmacokinetics)</term><term>Mice</term><term>Mice, Inbred C57BL</term><term>Mice, Transgenic</term><term>Mutation (genetics)</term><term>Time Factors</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Amyloid beta-Protein Precursor</term></keywords><keywords scheme="MESH" type="chemical" qualifier="immunology" xml:lang="en"><term>Amyloid beta-Peptides</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Brain</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Alzheimer Disease</term><term>Mutation</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Alzheimer Disease</term><term>Amyloid beta-Protein Precursor</term><term>Antibodies, Monoclonal</term><term>Autoantibodies</term><term>Brain</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Alzheimer Disease</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacokinetics" xml:lang="en"><term>Antibodies, Monoclonal</term><term>Indium</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Antibodies, Monoclonal, Murine-Derived</term><term>Disease Models, Animal</term><term>Humans</term><term>Mice</term><term>Mice, Inbred C57BL</term><term>Mice, Transgenic</term><term>Time Factors</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Active as well as passive immunization against beta-amlyoid (Abeta) has been proposed as a treatment to lower cerebral amyloid burden and stabilize cognitive decline in Alzheimer's disease (AD). To clarify the mechanism of action underlying passive immunization, the in vivo distribution (and sites of degradation) of peripherally administered radiolabeled human and mouse anti-Abeta antibodies were analyzed in a transgenic mouse model of AD. In APP23 mice, a model in which mutated human amyloid precursor protein is overexpressed, the biodistribution of intravenously applicated (111)indium-conjugated affinity-purified human polyclonal autoantibodies (NAbs-Abeta) was compared to that of monoclonal anti-Abeta(1-17) (6E10), anti-Abeta(17-24) antibodies (4G8) and anti-CD-20 (Rituximab), a non-Abeta targeting control. Blood clearance half-lives were 50+/-6h for Rituximab, 20-30h for NAbs-Abeta, 29+/-5h for 4G8 and 27+/-3h for 6E10. Blood activity was higher for 6E10 at 4h as compared to 4G8, Rituximab and NAbs-Abeta. At the 96h time point, Rituximab had the highest blood activity among the antibodies tested. As expected, all antibodies displayed hepatobiliary clearance. Additionally, NAbs-Abeta was excreted in the urinary tract. Liver and kidney uptake of NAbs-Abeta increased over time and was higher than in the monoclonal antibodies at 48h/96h. The brain-to-blood radioactivity ratio for NAbs-Abeta at later time points (>48h) was higher than that of 6E10, 4G8 and Rituximab. In addition, the distribution varied, with highest values found in the hippocampus. Our data indicate a cerebral accumulation of human NAbs-Abeta in the APP23 model. Further studies with human immunoglobulins and particularly with those that recognize different Abeta-epitopes are required in order to delineate in more detail the mode of action of NAbs-Abeta.</div></front></TEI><pubmed><MedlineCitation Owner="NLM" Status="MEDLINE"><PMID Version="1">18786612</PMID><DateCreated><Year>2008</Year><Month>12</Month><Day>16</Day></DateCreated><DateCompleted><Year>2009</Year><Month>04</Month><Day>27</Day></DateCompleted><DateRevised><Year>2013</Year><Month>11</Month><Day>21</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Print">0304-3940</ISSN><JournalIssue CitedMedium="Print"><Volume>449</Volume><Issue>3</Issue><PubDate><Year>2009</Year><Month>Jan</Month><Day>16</Day></PubDate></JournalIssue><Title>Neuroscience letters</Title><ISOAbbreviation>Neurosci. Lett.</ISOAbbreviation></Journal><ArticleTitle>Peripheral and central biodistribution of (111)In-labeled anti-beta-amyloid autoantibodies in a transgenic mouse model of Alzheimer's disease.</ArticleTitle><Pagination><MedlinePgn>240-5</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1016/j.neulet.2008.08.083</ELocationID><Abstract><AbstractText>Active as well as passive immunization against beta-amlyoid (Abeta) has been proposed as a treatment to lower cerebral amyloid burden and stabilize cognitive decline in Alzheimer's disease (AD). To clarify the mechanism of action underlying passive immunization, the in vivo distribution (and sites of degradation) of peripherally administered radiolabeled human and mouse anti-Abeta antibodies were analyzed in a transgenic mouse model of AD. In APP23 mice, a model in which mutated human amyloid precursor protein is overexpressed, the biodistribution of intravenously applicated (111)indium-conjugated affinity-purified human polyclonal autoantibodies (NAbs-Abeta) was compared to that of monoclonal anti-Abeta(1-17) (6E10), anti-Abeta(17-24) antibodies (4G8) and anti-CD-20 (Rituximab), a non-Abeta targeting control. Blood clearance half-lives were 50+/-6h for Rituximab, 20-30h for NAbs-Abeta, 29+/-5h for 4G8 and 27+/-3h for 6E10. Blood activity was higher for 6E10 at 4h as compared to 4G8, Rituximab and NAbs-Abeta. At the 96h time point, Rituximab had the highest blood activity among the antibodies tested. As expected, all antibodies displayed hepatobiliary clearance. Additionally, NAbs-Abeta was excreted in the urinary tract. Liver and kidney uptake of NAbs-Abeta increased over time and was higher than in the monoclonal antibodies at 48h/96h. The brain-to-blood radioactivity ratio for NAbs-Abeta at later time points (>48h) was higher than that of 6E10, 4G8 and Rituximab. In addition, the distribution varied, with highest values found in the hippocampus. Our data indicate a cerebral accumulation of human NAbs-Abeta in the APP23 model. Further studies with human immunoglobulins and particularly with those that recognize different Abeta-epitopes are required in order to delineate in more detail the mode of action of NAbs-Abeta.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Bacher</LastName><ForeName>Michael</ForeName><Initials>M</Initials><Affiliation>Department of Neurology, Philipps University, Rudolf-Bultmann-Str. 8, 35033 Marburg, Germany.</Affiliation></Author><Author ValidYN="Y"><LastName>Depboylu</LastName><ForeName>Candan</ForeName><Initials>C</Initials></Author><Author ValidYN="Y"><LastName>Du</LastName><ForeName>Yansheng</ForeName><Initials>Y</Initials></Author><Author ValidYN="Y"><LastName>Noelker</LastName><ForeName>Carmen</ForeName><Initials>C</Initials></Author><Author ValidYN="Y"><LastName>Oertel</LastName><ForeName>Wolfgang H</ForeName><Initials>WH</Initials></Author><Author ValidYN="Y"><LastName>Behr</LastName><ForeName>Thomas</ForeName><Initials>T</Initials></Author><Author ValidYN="Y"><LastName>Henriksen</LastName><ForeName>Gjermund</ForeName><Initials>G</Initials></Author><Author ValidYN="Y"><LastName>Behe</LastName><ForeName>Martin</ForeName><Initials>M</Initials></Author><Author ValidYN="Y"><LastName>Dodel</LastName><ForeName>Richard</ForeName><Initials>R</Initials></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType>Journal Article</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2008</Year><Month>09</Month><Day>03</Day></ArticleDate></Article><MedlineJournalInfo><Country>Ireland</Country><MedlineTA>Neurosci Lett</MedlineTA><NlmUniqueID>7600130</NlmUniqueID><ISSNLinking>0304-3940</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance>Amyloid 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