Hapten‐directed spontaneous disulfide shuffling: a universal technology for site‐directed covalent coupling of payloads to antibodies
ABSTRACT Humanized hapten‐binding IgGs were designed with an accessible cysteine close to their binding pockets, for specific covalent payload attachment. Individual analyses of known structures of digoxigenin (Dig)‐ and fluorescein (Fluo) binding antibodies and a new structure of a biotin (Biot)‐bi...
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| creator | Dengl, Stefan Hoffmann, Eike Grote, Michael Wagner, Cornelia Mundigl, Olaf Georges, Guy Thorey, Irmgard Stubenrauch, Kay‐Gunnar Bujotzek, Alexander Josel, Hans‐Peter Dziadek, Sebastian Benz, Joerg Brinkmann, Ulrich |
| description | ABSTRACT
Humanized hapten‐binding IgGs were designed with an accessible cysteine close to their binding pockets, for specific covalent payload attachment. Individual analyses of known structures of digoxigenin (Dig)‐ and fluorescein (Fluo) binding antibodies and a new structure of a biotin (Biot)‐binder, revealed a “universal” coupling position (52+2) in proximity to binding pockets but without contributing to hapten interactions. Payloads that carry a free thiol are positioned on the antibody and covalently linked to it via disulfides. Covalent coupling is achieved and driven toward complete (95‐100%) payload occupancy by spontaneous redox shuffling between antibody and payload. Attachment at the universal position works with different haptens, antibodies, and payloads. Examples are the haptens Fluo, Dig, and Biot combined with various fluorescent or peptidic payloads. Disulfide‐bonded covalent antibody‐payload complexes do not dissociate in vitro and in vivo. Coupling requires the designed cysteine and matching payload thiol because payload or antibody without the Cys/thiol are not linked ( |
| doi_str_mv | 10.1096/fj.14-263665 |
| format | Article |
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Humanized hapten‐binding IgGs were designed with an accessible cysteine close to their binding pockets, for specific covalent payload attachment. Individual analyses of known structures of digoxigenin (Dig)‐ and fluorescein (Fluo) binding antibodies and a new structure of a biotin (Biot)‐binder, revealed a “universal” coupling position (52+2) in proximity to binding pockets but without contributing to hapten interactions. Payloads that carry a free thiol are positioned on the antibody and covalently linked to it via disulfides. Covalent coupling is achieved and driven toward complete (95‐100%) payload occupancy by spontaneous redox shuffling between antibody and payload. Attachment at the universal position works with different haptens, antibodies, and payloads. Examples are the haptens Fluo, Dig, and Biot combined with various fluorescent or peptidic payloads. Disulfide‐bonded covalent antibody‐payload complexes do not dissociate in vitro and in vivo. Coupling requires the designed cysteine and matching payload thiol because payload or antibody without the Cys/thiol are not linked (<5% nonspecific coupling). Hapten‐mediated positioning is necessary as hapten‐thiol‐payload is only coupled to antibodies that bind matching haptens. Covalent complexes are more stable in vivo than noncovalent counterparts because digoxigeninylated or biotinylated fluorescent payloads without disulfide‐linkage are cleared more rapidly in mice (approximately 50% reduced 48 hour serum levels) compared with their covalently linked counterparts. The coupling technology is applicable to many haptens and hapten binding antibodies (confirmed by automated analyses of the structures of 140 additional hapten binding antibodies) and can be applied to modulate the pharma‐cokinetics of small compounds or peptides. It is also suitable to link payloads in a reduction‐releasable manner to tumor‐ or tissue‐targeting delivery vehicles.—Dengl, S., Hoffmann, E., Grote, M., Wagner, C., Mundigl, O., Georges, G., Thorey, I., Stubenrauch, K.‐G., Bujotzek, A., Josel, H.‐P., Dziadek, S., Benz, J., Brinkmann, U. Hapten‐directed spontaneous disulfide shuffling: a universal technology for site‐directed covalent coupling of payloads to antibodies. FASEB J. 29, 1763‐1779 (2015). www.fasebj.org</description><identifier>ISSN: 0892-6638</identifier><identifier>EISSN: 1530-6860</identifier><identifier>DOI: 10.1096/fj.14-263665</identifier><identifier>PMID: 25670234</identifier><language>eng</language><publisher>United States: Federation of American Societies for Experimental Biology</publisher><subject>Animals ; Antibodies - chemistry ; Antibodies - immunology ; Antibodies - metabolism ; biotin ; Disulfides - chemistry ; Disulfides - immunology ; Disulfides - metabolism ; Haptens - chemistry ; Haptens - immunology ; Haptens - metabolism ; Mice ; Peptide Fragments - chemistry ; Peptide Fragments - immunology ; Peptide Fragments - metabolism ; pharmacokinetics ; Protein Binding ; protein engineering ; Research Communication ; Sulfhydryl Compounds - chemistry ; Sulfhydryl Compounds - immunology ; Sulfhydryl Compounds - metabolism ; targeted delivery ; X‐ray structure</subject><ispartof>The FASEB journal, 2015-05, Vol.29 (5), p.1763-1779</ispartof><rights>FASEB</rights><rights>The Author(s).</rights><rights>The Author(s) 2015 FASEB</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4665-329fea0c630ecfe4c7150a798ab4b0eb52fd89624cd7eaeb9ad24c8884b631e83</citedby><cites>FETCH-LOGICAL-c4665-329fea0c630ecfe4c7150a798ab4b0eb52fd89624cd7eaeb9ad24c8884b631e83</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1096%2Ffj.14-263665$$EPDF$$P50$$Gwiley$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1096%2Ffj.14-263665$$EHTML$$P50$$Gwiley$$Hfree_for_read</linktohtml><link.rule.ids>230,314,776,780,881,1411,27901,27902,45550,45551</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25670234$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Dengl, Stefan</creatorcontrib><creatorcontrib>Hoffmann, Eike</creatorcontrib><creatorcontrib>Grote, Michael</creatorcontrib><creatorcontrib>Wagner, Cornelia</creatorcontrib><creatorcontrib>Mundigl, Olaf</creatorcontrib><creatorcontrib>Georges, Guy</creatorcontrib><creatorcontrib>Thorey, Irmgard</creatorcontrib><creatorcontrib>Stubenrauch, Kay‐Gunnar</creatorcontrib><creatorcontrib>Bujotzek, Alexander</creatorcontrib><creatorcontrib>Josel, Hans‐Peter</creatorcontrib><creatorcontrib>Dziadek, Sebastian</creatorcontrib><creatorcontrib>Benz, Joerg</creatorcontrib><creatorcontrib>Brinkmann, Ulrich</creatorcontrib><title>Hapten‐directed spontaneous disulfide shuffling: a universal technology for site‐directed covalent coupling of payloads to antibodies</title><title>The FASEB journal</title><addtitle>FASEB J</addtitle><description>ABSTRACT
Humanized hapten‐binding IgGs were designed with an accessible cysteine close to their binding pockets, for specific covalent payload attachment. Individual analyses of known structures of digoxigenin (Dig)‐ and fluorescein (Fluo) binding antibodies and a new structure of a biotin (Biot)‐binder, revealed a “universal” coupling position (52+2) in proximity to binding pockets but without contributing to hapten interactions. Payloads that carry a free thiol are positioned on the antibody and covalently linked to it via disulfides. Covalent coupling is achieved and driven toward complete (95‐100%) payload occupancy by spontaneous redox shuffling between antibody and payload. Attachment at the universal position works with different haptens, antibodies, and payloads. Examples are the haptens Fluo, Dig, and Biot combined with various fluorescent or peptidic payloads. Disulfide‐bonded covalent antibody‐payload complexes do not dissociate in vitro and in vivo. Coupling requires the designed cysteine and matching payload thiol because payload or antibody without the Cys/thiol are not linked (<5% nonspecific coupling). Hapten‐mediated positioning is necessary as hapten‐thiol‐payload is only coupled to antibodies that bind matching haptens. Covalent complexes are more stable in vivo than noncovalent counterparts because digoxigeninylated or biotinylated fluorescent payloads without disulfide‐linkage are cleared more rapidly in mice (approximately 50% reduced 48 hour serum levels) compared with their covalently linked counterparts. The coupling technology is applicable to many haptens and hapten binding antibodies (confirmed by automated analyses of the structures of 140 additional hapten binding antibodies) and can be applied to modulate the pharma‐cokinetics of small compounds or peptides. It is also suitable to link payloads in a reduction‐releasable manner to tumor‐ or tissue‐targeting delivery vehicles.—Dengl, S., Hoffmann, E., Grote, M., Wagner, C., Mundigl, O., Georges, G., Thorey, I., Stubenrauch, K.‐G., Bujotzek, A., Josel, H.‐P., Dziadek, S., Benz, J., Brinkmann, U. Hapten‐directed spontaneous disulfide shuffling: a universal technology for site‐directed covalent coupling of payloads to antibodies. FASEB J. 29, 1763‐1779 (2015). www.fasebj.org</description><subject>Animals</subject><subject>Antibodies - chemistry</subject><subject>Antibodies - immunology</subject><subject>Antibodies - metabolism</subject><subject>biotin</subject><subject>Disulfides - chemistry</subject><subject>Disulfides - immunology</subject><subject>Disulfides - metabolism</subject><subject>Haptens - chemistry</subject><subject>Haptens - immunology</subject><subject>Haptens - metabolism</subject><subject>Mice</subject><subject>Peptide Fragments - chemistry</subject><subject>Peptide Fragments - immunology</subject><subject>Peptide Fragments - metabolism</subject><subject>pharmacokinetics</subject><subject>Protein Binding</subject><subject>protein engineering</subject><subject>Research Communication</subject><subject>Sulfhydryl Compounds - chemistry</subject><subject>Sulfhydryl Compounds - immunology</subject><subject>Sulfhydryl Compounds - metabolism</subject><subject>targeted delivery</subject><subject>X‐ray structure</subject><issn>0892-6638</issn><issn>1530-6860</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>EIF</sourceid><recordid>eNqFkTFv1DAUxy0EokdhY0YeGUhrO47jMCCVqkeLKjEAs-XYz3c--eIQJ4duY-3GZ-ST4CpH1S5l8pP888_vvT9Cryk5oaQRp25zQnnBRClE9QQtaFWSQkhBnqIFkQ0rhCjlEXqR0oYQQgkVz9ERq0RNWMkX6OZS9yN0f379tn4AM4LFqY_dqDuIU8LWpyk4bwGn9eRc8N3qPdZ46vwOhqQDHsGsuxjiao9dHHDyI9x3mbjTAboxF1N_-xpHh3u9D1HbhMeIdTf6NloP6SV65nRI8OpwHqPvy4tv55fF9ZdPV-dn14XhecKiZI0DTYwoCRgH3NS0IrpupG55S6CtmLOyEYwbW4OGttE211JK3oqSgiyP0YfZ20_tFqzJ3Q06qH7wWz3sVdRePbzp_Fqt4k5xnn9iPAveHgRD_DFBGtXWJwMhzDtTVBIpWF41-z8q6lpKKkuS0XczaoaY0gDuriNK1G3Qym0U5WoOOuNv7k9xB_9LNgNyBn76APtHZWr59SNbfqb84P4L6RO7Rg</recordid><startdate>201505</startdate><enddate>201505</enddate><creator>Dengl, Stefan</creator><creator>Hoffmann, Eike</creator><creator>Grote, Michael</creator><creator>Wagner, Cornelia</creator><creator>Mundigl, Olaf</creator><creator>Georges, Guy</creator><creator>Thorey, Irmgard</creator><creator>Stubenrauch, Kay‐Gunnar</creator><creator>Bujotzek, Alexander</creator><creator>Josel, Hans‐Peter</creator><creator>Dziadek, Sebastian</creator><creator>Benz, Joerg</creator><creator>Brinkmann, Ulrich</creator><general>Federation of American Societies for Experimental Biology</general><scope>24P</scope><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>7X8</scope><scope>7T5</scope><scope>H94</scope><scope>5PM</scope></search><sort><creationdate>201505</creationdate><title>Hapten‐directed spontaneous disulfide shuffling: a universal technology for site‐directed covalent coupling of payloads to antibodies</title><author>Dengl, Stefan ; 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Humanized hapten‐binding IgGs were designed with an accessible cysteine close to their binding pockets, for specific covalent payload attachment. Individual analyses of known structures of digoxigenin (Dig)‐ and fluorescein (Fluo) binding antibodies and a new structure of a biotin (Biot)‐binder, revealed a “universal” coupling position (52+2) in proximity to binding pockets but without contributing to hapten interactions. Payloads that carry a free thiol are positioned on the antibody and covalently linked to it via disulfides. Covalent coupling is achieved and driven toward complete (95‐100%) payload occupancy by spontaneous redox shuffling between antibody and payload. Attachment at the universal position works with different haptens, antibodies, and payloads. Examples are the haptens Fluo, Dig, and Biot combined with various fluorescent or peptidic payloads. Disulfide‐bonded covalent antibody‐payload complexes do not dissociate in vitro and in vivo. Coupling requires the designed cysteine and matching payload thiol because payload or antibody without the Cys/thiol are not linked (<5% nonspecific coupling). Hapten‐mediated positioning is necessary as hapten‐thiol‐payload is only coupled to antibodies that bind matching haptens. Covalent complexes are more stable in vivo than noncovalent counterparts because digoxigeninylated or biotinylated fluorescent payloads without disulfide‐linkage are cleared more rapidly in mice (approximately 50% reduced 48 hour serum levels) compared with their covalently linked counterparts. The coupling technology is applicable to many haptens and hapten binding antibodies (confirmed by automated analyses of the structures of 140 additional hapten binding antibodies) and can be applied to modulate the pharma‐cokinetics of small compounds or peptides. It is also suitable to link payloads in a reduction‐releasable manner to tumor‐ or tissue‐targeting delivery vehicles.—Dengl, S., Hoffmann, E., Grote, M., Wagner, C., Mundigl, O., Georges, G., Thorey, I., Stubenrauch, K.‐G., Bujotzek, A., Josel, H.‐P., Dziadek, S., Benz, J., Brinkmann, U. Hapten‐directed spontaneous disulfide shuffling: a universal technology for site‐directed covalent coupling of payloads to antibodies. FASEB J. 29, 1763‐1779 (2015). www.fasebj.org</abstract><cop>United States</cop><pub>Federation of American Societies for Experimental Biology</pub><pmid>25670234</pmid><doi>10.1096/fj.14-263665</doi><tpages>17</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Antibodies - chemistry Antibodies - immunology Antibodies - metabolism biotin Disulfides - chemistry Disulfides - immunology Disulfides - metabolism Haptens - chemistry Haptens - immunology Haptens - metabolism Mice Peptide Fragments - chemistry Peptide Fragments - immunology Peptide Fragments - metabolism pharmacokinetics Protein Binding protein engineering Research Communication Sulfhydryl Compounds - chemistry Sulfhydryl Compounds - immunology Sulfhydryl Compounds - metabolism targeted delivery X‐ray structure |
| title | Hapten‐directed spontaneous disulfide shuffling: a universal technology for site‐directed covalent coupling of payloads to antibodies |
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