Enhanced antibody half-life improves in vivo activity
A correlation between drug exposure and efficacy has never been demonstrated for therapeutic antibodies. Zalevsky et al . use a humanized mouse model to show that a reduction in antibody clearance engineered through increased antibody affinity for the neonatal Fc receptor enhances antitumor activity...
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| Veröffentlicht in: | Nature biotechnology 2010-02, Vol.28 (2), p.157-159 |
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| container_title | Nature biotechnology |
| container_volume | 28 |
| creator | Zalevsky, Jonathan Chamberlain, Aaron K Horton, Holly M Karki, Sher Leung, Irene W L Sproule, Thomas J Lazar, Greg A Roopenian, Derry C Desjarlais, John R |
| description | A correlation between drug exposure and efficacy has never been demonstrated for therapeutic antibodies. Zalevsky
et al
. use a humanized mouse model to show that a reduction in antibody clearance engineered through increased antibody affinity for the neonatal Fc receptor enhances antitumor activity.
Improved affinity for the neonatal Fc receptor (FcRn) is known to extend antibody half-life
in vivo
. However, this has never been linked with enhanced therapeutic efficacy. We tested whether antibodies with half-lives extended up to fivefold in human (h)FcRn transgenic mice and threefold in cynomolgus monkeys retain efficacy at longer dosing intervals. We observed that prolonged exposure due to FcRn-mediated enhancement of half-life improved antitumor activity of Fc-engineered antibodies in an hFcRn/Rag1
−/−
mouse model. This bridges the demand for dosing convenience with the clinical necessity of maintaining efficacy. |
| doi_str_mv | 10.1038/nbt.1601 |
| format | Article |
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et al
. use a humanized mouse model to show that a reduction in antibody clearance engineered through increased antibody affinity for the neonatal Fc receptor enhances antitumor activity.
Improved affinity for the neonatal Fc receptor (FcRn) is known to extend antibody half-life
in vivo
. However, this has never been linked with enhanced therapeutic efficacy. We tested whether antibodies with half-lives extended up to fivefold in human (h)FcRn transgenic mice and threefold in cynomolgus monkeys retain efficacy at longer dosing intervals. We observed that prolonged exposure due to FcRn-mediated enhancement of half-life improved antitumor activity of Fc-engineered antibodies in an hFcRn/Rag1
−/−
mouse model. This bridges the demand for dosing convenience with the clinical necessity of maintaining efficacy.</description><identifier>ISSN: 1087-0156</identifier><identifier>EISSN: 1546-1696</identifier><identifier>DOI: 10.1038/nbt.1601</identifier><identifier>PMID: 20081867</identifier><language>eng</language><publisher>New York: Nature Publishing Group US</publisher><subject>631/154/436/1729 ; 631/553/1886 ; 631/61/51/1568 ; Agriculture ; Animals ; Antibodies ; Antibodies, Monoclonal - immunology ; Antibodies, Monoclonal - therapeutic use ; Bioinformatics ; Biomedical and Life Sciences ; Biomedical Engineering/Biotechnology ; Biomedicine ; Biotechnology ; brief-communication ; Cynomolgus ; Fc receptors ; Half-Life ; Life Sciences ; Macaca fascicularis ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Monkeys & apes ; Monoclonal antibodies ; Physiological aspects ; Rodents ; Structure ; Transgenic animals ; Viral antibodies</subject><ispartof>Nature biotechnology, 2010-02, Vol.28 (2), p.157-159</ispartof><rights>Springer Nature America, Inc. 2009</rights><rights>COPYRIGHT 2010 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Feb 2010</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c701t-c794b5adcbf0790ddd515dd7de4feff20a9e0627ebc8e32c4cc84c5403a216513</citedby><cites>FETCH-LOGICAL-c701t-c794b5adcbf0790ddd515dd7de4feff20a9e0627ebc8e32c4cc84c5403a216513</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/nbt.1601$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/nbt.1601$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>230,314,776,780,881,27903,27904,41467,42536,51297</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20081867$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zalevsky, Jonathan</creatorcontrib><creatorcontrib>Chamberlain, Aaron K</creatorcontrib><creatorcontrib>Horton, Holly M</creatorcontrib><creatorcontrib>Karki, Sher</creatorcontrib><creatorcontrib>Leung, Irene W L</creatorcontrib><creatorcontrib>Sproule, Thomas J</creatorcontrib><creatorcontrib>Lazar, Greg A</creatorcontrib><creatorcontrib>Roopenian, Derry C</creatorcontrib><creatorcontrib>Desjarlais, John R</creatorcontrib><title>Enhanced antibody half-life improves in vivo activity</title><title>Nature biotechnology</title><addtitle>Nat Biotechnol</addtitle><addtitle>Nat Biotechnol</addtitle><description>A correlation between drug exposure and efficacy has never been demonstrated for therapeutic antibodies. Zalevsky
et al
. use a humanized mouse model to show that a reduction in antibody clearance engineered through increased antibody affinity for the neonatal Fc receptor enhances antitumor activity.
Improved affinity for the neonatal Fc receptor (FcRn) is known to extend antibody half-life
in vivo
. However, this has never been linked with enhanced therapeutic efficacy. We tested whether antibodies with half-lives extended up to fivefold in human (h)FcRn transgenic mice and threefold in cynomolgus monkeys retain efficacy at longer dosing intervals. We observed that prolonged exposure due to FcRn-mediated enhancement of half-life improved antitumor activity of Fc-engineered antibodies in an hFcRn/Rag1
−/−
mouse model. This bridges the demand for dosing convenience with the clinical necessity of maintaining efficacy.</description><subject>631/154/436/1729</subject><subject>631/553/1886</subject><subject>631/61/51/1568</subject><subject>Agriculture</subject><subject>Animals</subject><subject>Antibodies</subject><subject>Antibodies, Monoclonal - immunology</subject><subject>Antibodies, Monoclonal - therapeutic use</subject><subject>Bioinformatics</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedical Engineering/Biotechnology</subject><subject>Biomedicine</subject><subject>Biotechnology</subject><subject>brief-communication</subject><subject>Cynomolgus</subject><subject>Fc receptors</subject><subject>Half-Life</subject><subject>Life Sciences</subject><subject>Macaca fascicularis</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Transgenic</subject><subject>Monkeys & apes</subject><subject>Monoclonal antibodies</subject><subject>Physiological aspects</subject><subject>Rodents</subject><subject>Structure</subject><subject>Transgenic animals</subject><subject>Viral antibodies</subject><issn>1087-0156</issn><issn>1546-1696</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>N95</sourceid><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNqNkm1r1TAUx4sobk7BTyBFwQew1yRN0vSNMMbUwWDg09uQJie9GW1y17TF--3N5c5tVRETOAk5v_PnkPPPsqcYrTAqxTvfjCvMEb6XHWJGeYF5ze-nOxJVgTDjB9mjGC8RQpxy_jA7IAgJLHh1mLFTv1Zeg8mVH10TzDZfq84WnbOQu34zhBli7nw-uznkSo9uduP2cfbAqi7Ck-vzKPv24fTryafi_OLj2cnxeaErhMcUa9owZXRjUVUjYwzDzJjKALVgLUGqBsRJBY0WUBJNtRZUM4pKRTBnuDzK3u91N1PTg9Hgx0F1cjO4Xg1bGZSTy4x3a9mGWRLBGK1JEnh1LTCEqwniKHsXNXSd8hCmKKuyFDWrCUvky3-SBJeYlEIk8Plv4GWYBp--QZK0Sk74rvEXe6hVHUjnbUjt6Z2iPCa4xpQIyhO1-guVtoHe6eDBuvS-KHizKEjMCD_GVk0xyrMvn_-fvfi-ZN_eYZspOg8xheja9Rj3JQv89R7XQ4hxAHszEYzkzpAyGVLuDJnQZ3cneAP-cuBtmzGlfAvD7Xf-IfYT8dblzA</recordid><startdate>20100201</startdate><enddate>20100201</enddate><creator>Zalevsky, Jonathan</creator><creator>Chamberlain, Aaron K</creator><creator>Horton, Holly M</creator><creator>Karki, Sher</creator><creator>Leung, Irene W L</creator><creator>Sproule, Thomas J</creator><creator>Lazar, Greg A</creator><creator>Roopenian, Derry C</creator><creator>Desjarlais, John R</creator><general>Nature Publishing Group US</general><general>Nature Publishing Group</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>N95</scope><scope>XI7</scope><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QO</scope><scope>7QP</scope><scope>7QR</scope><scope>7T7</scope><scope>7TK</scope><scope>7TM</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>88I</scope><scope>8AO</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>M2P</scope><scope>M7P</scope><scope>M7S</scope><scope>MBDVC</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PTHSS</scope><scope>Q9U</scope><scope>RC3</scope><scope>7T5</scope><scope>H94</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20100201</creationdate><title>Enhanced antibody half-life improves in vivo activity</title><author>Zalevsky, Jonathan ; Chamberlain, Aaron K ; Horton, Holly M ; Karki, Sher ; Leung, Irene W L ; Sproule, Thomas J ; Lazar, Greg A ; Roopenian, Derry C ; Desjarlais, John R</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c701t-c794b5adcbf0790ddd515dd7de4feff20a9e0627ebc8e32c4cc84c5403a216513</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>631/154/436/1729</topic><topic>631/553/1886</topic><topic>631/61/51/1568</topic><topic>Agriculture</topic><topic>Animals</topic><topic>Antibodies</topic><topic>Antibodies, Monoclonal - immunology</topic><topic>Antibodies, Monoclonal - therapeutic use</topic><topic>Bioinformatics</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedical Engineering/Biotechnology</topic><topic>Biomedicine</topic><topic>Biotechnology</topic><topic>brief-communication</topic><topic>Cynomolgus</topic><topic>Fc receptors</topic><topic>Half-Life</topic><topic>Life Sciences</topic><topic>Macaca fascicularis</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Transgenic</topic><topic>Monkeys & apes</topic><topic>Monoclonal antibodies</topic><topic>Physiological aspects</topic><topic>Rodents</topic><topic>Structure</topic><topic>Transgenic animals</topic><topic>Viral antibodies</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zalevsky, Jonathan</creatorcontrib><creatorcontrib>Chamberlain, Aaron K</creatorcontrib><creatorcontrib>Horton, Holly M</creatorcontrib><creatorcontrib>Karki, Sher</creatorcontrib><creatorcontrib>Leung, Irene W L</creatorcontrib><creatorcontrib>Sproule, Thomas J</creatorcontrib><creatorcontrib>Lazar, Greg A</creatorcontrib><creatorcontrib>Roopenian, Derry C</creatorcontrib><creatorcontrib>Desjarlais, John R</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale Business: Insights</collection><collection>Business Insights: Essentials</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Biotechnology Research Abstracts</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Research Library</collection><collection>Science Database</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Research Library (Corporate)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>Engineering Collection</collection><collection>ProQuest Central Basic</collection><collection>Genetics Abstracts</collection><collection>Immunology Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Nature biotechnology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zalevsky, Jonathan</au><au>Chamberlain, Aaron K</au><au>Horton, Holly M</au><au>Karki, Sher</au><au>Leung, Irene W L</au><au>Sproule, Thomas J</au><au>Lazar, Greg A</au><au>Roopenian, Derry C</au><au>Desjarlais, John R</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Enhanced antibody half-life improves in vivo activity</atitle><jtitle>Nature biotechnology</jtitle><stitle>Nat Biotechnol</stitle><addtitle>Nat Biotechnol</addtitle><date>2010-02-01</date><risdate>2010</risdate><volume>28</volume><issue>2</issue><spage>157</spage><epage>159</epage><pages>157-159</pages><issn>1087-0156</issn><eissn>1546-1696</eissn><abstract>A correlation between drug exposure and efficacy has never been demonstrated for therapeutic antibodies. Zalevsky
et al
. use a humanized mouse model to show that a reduction in antibody clearance engineered through increased antibody affinity for the neonatal Fc receptor enhances antitumor activity.
Improved affinity for the neonatal Fc receptor (FcRn) is known to extend antibody half-life
in vivo
. However, this has never been linked with enhanced therapeutic efficacy. We tested whether antibodies with half-lives extended up to fivefold in human (h)FcRn transgenic mice and threefold in cynomolgus monkeys retain efficacy at longer dosing intervals. We observed that prolonged exposure due to FcRn-mediated enhancement of half-life improved antitumor activity of Fc-engineered antibodies in an hFcRn/Rag1
−/−
mouse model. This bridges the demand for dosing convenience with the clinical necessity of maintaining efficacy.</abstract><cop>New York</cop><pub>Nature Publishing Group US</pub><pmid>20081867</pmid><doi>10.1038/nbt.1601</doi><tpages>3</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Nature biotechnology, 2010-02, Vol.28 (2), p.157-159 |
| issn | 1087-0156 1546-1696 |
| language | eng |
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| source | MEDLINE; Springer Nature - Complete Springer Journals; Nature Journals Online |
| subjects | 631/154/436/1729 631/553/1886 631/61/51/1568 Agriculture Animals Antibodies Antibodies, Monoclonal - immunology Antibodies, Monoclonal - therapeutic use Bioinformatics Biomedical and Life Sciences Biomedical Engineering/Biotechnology Biomedicine Biotechnology brief-communication Cynomolgus Fc receptors Half-Life Life Sciences Macaca fascicularis Mice Mice, Inbred C57BL Mice, Transgenic Monkeys & apes Monoclonal antibodies Physiological aspects Rodents Structure Transgenic animals Viral antibodies |
| title | Enhanced antibody half-life improves in vivo activity |
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