Engineered Antibody Fc Variants with Enhanced Effector Function
Antibody-dependent cell-mediated cytotoxicity, a key effector function for the clinical efficacy of monoclonal antibodies, is mediated primarily through a set of closely related Fcγ receptors with both activating and inhibitory activities. By using computational design algorithms and high-throughput...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2006-03, Vol.103 (11), p.4005-4010 |
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| container_title | Proceedings of the National Academy of Sciences - PNAS |
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| creator | Lazar, Greg A. Dang, Wei Karki, Sher Vafa, Omid Peng, Judy S. Hyun, Linus Chan, Cheryl Chung, Helen S. Eivazi, Araz Yoder, Sean C. Vielmetter, Jost Carmichael, David F. Hayes, Robert J. Dahiyat, Bassil I. |
| description | Antibody-dependent cell-mediated cytotoxicity, a key effector function for the clinical efficacy of monoclonal antibodies, is mediated primarily through a set of closely related Fcγ receptors with both activating and inhibitory activities. By using computational design algorithms and high-throughput screening, we have engineered a series of Fc variants with optimized Fcγ receptor affinity and specificity. The designed variants display >2 orders of magnitude enhancement of in vitro effector function, enable efficacy against cells expressing low levels of target antigen, and result in increased cytotoxicity in an in vivo preclinical model. Our engineered Fc regions offer a means for improving the next generation of therapeutic antibodies and have the potential to broaden the diversity of antigens that can be targeted for antibody-based tumor therapy. |
| doi_str_mv | 10.1073/pnas.0508123103 |
| format | Article |
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By using computational design algorithms and high-throughput screening, we have engineered a series of Fc variants with optimized Fcγ receptor affinity and specificity. The designed variants display >2 orders of magnitude enhancement of in vitro effector function, enable efficacy against cells expressing low levels of target antigen, and result in increased cytotoxicity in an in vivo preclinical model. Our engineered Fc regions offer a means for improving the next generation of therapeutic antibodies and have the potential to broaden the diversity of antigens that can be targeted for antibody-based tumor therapy.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.0508123103</identifier><identifier>PMID: 16537476</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Alemtuzumab ; Animals ; Antibodies, Monoclonal - genetics ; Antibodies, Monoclonal - metabolism ; Antibodies, Monoclonal, Humanized ; Antibodies, Neoplasm - genetics ; Antibodies, Neoplasm - metabolism ; Antibody Affinity ; Antibody Specificity ; Antibody-Dependent Cell Cytotoxicity ; Antigens ; Antineoplastic Agents - metabolism ; B lymphocytes ; B-Lymphocytes - immunology ; Biological Sciences ; Biotechnology ; Cancer ; Cell lines ; Complement System Proteins - metabolism ; Cytotoxicity ; Cytotoxicity, Immunologic ; Genetic Variation ; Humans ; Immunoglobulin Fc Fragments - genetics ; Immunoglobulin Fc Fragments - metabolism ; In Vitro Techniques ; Lymphocyte Depletion ; Macaca fascicularis ; Macrophages ; Natural killer cells ; Protein Engineering ; Proteins ; Receptors ; Receptors, IgG - metabolism ; T lymphocytes ; Trastuzumab ; Tumors</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2006-03, Vol.103 (11), p.4005-4010</ispartof><rights>Copyright 2006 National Academy of Sciences of the United States of America</rights><rights>Copyright National Academy of Sciences Mar 14, 2006</rights><rights>2006 by The National Academy of Sciences of the USA 2006</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c528t-461cd7ddd3b81d6a7eb472b23a8f7e124e64f0ef421fbb0e86838b7215f4fc653</citedby><cites>FETCH-LOGICAL-c528t-461cd7ddd3b81d6a7eb472b23a8f7e124e64f0ef421fbb0e86838b7215f4fc653</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/103/11.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/30048873$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/30048873$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,723,776,780,799,881,27903,27904,53770,53772,57996,58229</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16537476$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lazar, Greg A.</creatorcontrib><creatorcontrib>Dang, Wei</creatorcontrib><creatorcontrib>Karki, Sher</creatorcontrib><creatorcontrib>Vafa, Omid</creatorcontrib><creatorcontrib>Peng, Judy S.</creatorcontrib><creatorcontrib>Hyun, Linus</creatorcontrib><creatorcontrib>Chan, Cheryl</creatorcontrib><creatorcontrib>Chung, Helen S.</creatorcontrib><creatorcontrib>Eivazi, Araz</creatorcontrib><creatorcontrib>Yoder, Sean C.</creatorcontrib><creatorcontrib>Vielmetter, Jost</creatorcontrib><creatorcontrib>Carmichael, David F.</creatorcontrib><creatorcontrib>Hayes, Robert J.</creatorcontrib><creatorcontrib>Dahiyat, Bassil I.</creatorcontrib><title>Engineered Antibody Fc Variants with Enhanced Effector Function</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Antibody-dependent cell-mediated cytotoxicity, a key effector function for the clinical efficacy of monoclonal antibodies, is mediated primarily through a set of closely related Fcγ receptors with both activating and inhibitory activities. 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Our engineered Fc regions offer a means for improving the next generation of therapeutic antibodies and have the potential to broaden the diversity of antigens that can be targeted for antibody-based tumor therapy.</description><subject>Alemtuzumab</subject><subject>Animals</subject><subject>Antibodies, Monoclonal - genetics</subject><subject>Antibodies, Monoclonal - metabolism</subject><subject>Antibodies, Monoclonal, Humanized</subject><subject>Antibodies, Neoplasm - genetics</subject><subject>Antibodies, Neoplasm - metabolism</subject><subject>Antibody Affinity</subject><subject>Antibody Specificity</subject><subject>Antibody-Dependent Cell Cytotoxicity</subject><subject>Antigens</subject><subject>Antineoplastic Agents - metabolism</subject><subject>B lymphocytes</subject><subject>B-Lymphocytes - immunology</subject><subject>Biological Sciences</subject><subject>Biotechnology</subject><subject>Cancer</subject><subject>Cell lines</subject><subject>Complement System Proteins - metabolism</subject><subject>Cytotoxicity</subject><subject>Cytotoxicity, Immunologic</subject><subject>Genetic Variation</subject><subject>Humans</subject><subject>Immunoglobulin Fc Fragments - genetics</subject><subject>Immunoglobulin Fc Fragments - metabolism</subject><subject>In Vitro Techniques</subject><subject>Lymphocyte Depletion</subject><subject>Macaca fascicularis</subject><subject>Macrophages</subject><subject>Natural killer cells</subject><subject>Protein Engineering</subject><subject>Proteins</subject><subject>Receptors</subject><subject>Receptors, IgG - metabolism</subject><subject>T lymphocytes</subject><subject>Trastuzumab</subject><subject>Tumors</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqF0T1vFDEQBmALgcgRqKmAVQpEs8n4Y9feBhRFd4AUiQZoLa_Xzvm0Zx-2F5J_j5c75YACKhd-ZjQzL0LPMZxj4PRi51U6hwYEJhQDfYAWGDpct6yDh2gBQHgtGGEn6ElKGwDoGgGP0QluG8oZbxfo3dLfOG9MNEN16bPrw3BXrXT1VUWnfE7VD5fX1dKvldeFLK01OodYrSavswv-KXpk1ZjMs8N7ir6slp-vPtTXn95_vLq8rnVDRK5Zi_XAh2GgvcBDq7jpGSc9oUpYbjBhpmUWjGUE274HI1pBRc8Jbiyzukx7it7u--6mfmsGbXyOapS76LYq3smgnPzzx7u1vAnfJaai4zA3eH1oEMO3yaQsty5pM47KmzAl2XI-34T-F2IOoqHACjz7C27CFH25giSAKQgBXUEXe6RjSCkaez8yBjlHKOcI5THCUvHy902P_pBZAa8OYK48tqMSY8ng165v_i2kncYxm9tc6Is93aQS672lAEwITulP4z-43A</recordid><startdate>20060314</startdate><enddate>20060314</enddate><creator>Lazar, Greg A.</creator><creator>Dang, Wei</creator><creator>Karki, Sher</creator><creator>Vafa, Omid</creator><creator>Peng, Judy S.</creator><creator>Hyun, Linus</creator><creator>Chan, Cheryl</creator><creator>Chung, Helen S.</creator><creator>Eivazi, Araz</creator><creator>Yoder, Sean C.</creator><creator>Vielmetter, Jost</creator><creator>Carmichael, David F.</creator><creator>Hayes, Robert J.</creator><creator>Dahiyat, Bassil I.</creator><general>National Academy of Sciences</general><general>National Acad Sciences</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>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7QO</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20060314</creationdate><title>Engineered Antibody Fc Variants with Enhanced Effector Function</title><author>Lazar, Greg A. ; Dang, Wei ; Karki, Sher ; Vafa, Omid ; Peng, Judy S. ; Hyun, Linus ; Chan, Cheryl ; Chung, Helen S. ; Eivazi, Araz ; Yoder, Sean C. ; Vielmetter, Jost ; Carmichael, David F. ; Hayes, Robert J. ; Dahiyat, Bassil I.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c528t-461cd7ddd3b81d6a7eb472b23a8f7e124e64f0ef421fbb0e86838b7215f4fc653</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2006</creationdate><topic>Alemtuzumab</topic><topic>Animals</topic><topic>Antibodies, Monoclonal - 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| subjects | Alemtuzumab Animals Antibodies, Monoclonal - genetics Antibodies, Monoclonal - metabolism Antibodies, Monoclonal, Humanized Antibodies, Neoplasm - genetics Antibodies, Neoplasm - metabolism Antibody Affinity Antibody Specificity Antibody-Dependent Cell Cytotoxicity Antigens Antineoplastic Agents - metabolism B lymphocytes B-Lymphocytes - immunology Biological Sciences Biotechnology Cancer Cell lines Complement System Proteins - metabolism Cytotoxicity Cytotoxicity, Immunologic Genetic Variation Humans Immunoglobulin Fc Fragments - genetics Immunoglobulin Fc Fragments - metabolism In Vitro Techniques Lymphocyte Depletion Macaca fascicularis Macrophages Natural killer cells Protein Engineering Proteins Receptors Receptors, IgG - metabolism T lymphocytes Trastuzumab Tumors |
| title | Engineered Antibody Fc Variants with Enhanced Effector Function |
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