Antibody-directed fibrinolysis: a bispecific (Fab')2 that binds to fibrin and tissue plasminogen activator
A bispecific (Fab')2 molecule was constructed by linking the monovalent Fab' from an anti-fibrin monoclonal antibody to the Fab' from an anti tissue plasminogen activator (tPA, single chain) monoclonal antibody by means of inter-heavy-chain disulfide bonds. An immunochemical complex c...
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| Veröffentlicht in: | Bioconjugate chemistry 1990-07, Vol.1 (4), p.274-277 |
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| container_title | Bioconjugate chemistry |
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| creator | Runge, Marschall S Bode, Christoph Savard, Christopher E Matsueda, Gary R Haber, Edgar |
| description | A bispecific (Fab')2 molecule was constructed by linking the monovalent Fab' from an anti-fibrin monoclonal antibody to the Fab' from an anti tissue plasminogen activator (tPA, single chain) monoclonal antibody by means of inter-heavy-chain disulfide bonds. An immunochemical complex composed of the bispecific (Fab')2 molecule bound to tPA [tPA-bispecific (Fab')2 complex] was then generated and purified. Its molecular weight was 170 kDa [less than half the molecular weight of a previously described tPA-bispecific antibody complex containing the entire anti-fibrin and anti-tPA immunoglobulin molecules; Runge, M. S., et al. (1987) Trans. Assoc. Am. Phys. 100, 250-255]. The tPA-bispecific (Fab')2 complex was 8.6-fold more efficient in fibrinolysis than tPA alone and 94-fold more potent than urokinase. This enhancement in the fibrinolytic potency of tPA compares favorably with that observed for the bispecific whole-antibody complex. These results suggest that this smaller, less immunogenic molecule is capable of binding both fibrin and tPA with high affinity and of enhancing the thrombolytic efficiency of exogenous and, perhaps, endogenous tPA. |
| doi_str_mv | 10.1021/bc00004a008 |
| format | Article |
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An immunochemical complex composed of the bispecific (Fab')2 molecule bound to tPA [tPA-bispecific (Fab')2 complex] was then generated and purified. Its molecular weight was 170 kDa [less than half the molecular weight of a previously described tPA-bispecific antibody complex containing the entire anti-fibrin and anti-tPA immunoglobulin molecules; Runge, M. S., et al. (1987) Trans. Assoc. Am. Phys. 100, 250-255]. The tPA-bispecific (Fab')2 complex was 8.6-fold more efficient in fibrinolysis than tPA alone and 94-fold more potent than urokinase. This enhancement in the fibrinolytic potency of tPA compares favorably with that observed for the bispecific whole-antibody complex. These results suggest that this smaller, less immunogenic molecule is capable of binding both fibrin and tPA with high affinity and of enhancing the thrombolytic efficiency of exogenous and, perhaps, endogenous tPA.</description><identifier>ISSN: 1043-1802</identifier><identifier>EISSN: 1520-4812</identifier><identifier>DOI: 10.1021/bc00004a008</identifier><identifier>PMID: 2129015</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Antibodies, Monoclonal - pharmacology ; Cross-Linking Reagents ; Electrophoresis, Polyacrylamide Gel - methods ; Fibrin - immunology ; Fibrin - metabolism ; Fibrinolysis ; Immunoglobulin Fab Fragments - metabolism ; Immunoglobulin Fragments - metabolism ; Tissue Plasminogen Activator - immunology ; Tissue Plasminogen Activator - metabolism</subject><ispartof>Bioconjugate chemistry, 1990-07, Vol.1 (4), p.274-277</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a378t-edc8e01cd0707d8056c25020c545ff497118f32b3379732dd7e65d9aa9123e323</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/bc00004a008$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/bc00004a008$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>315,782,786,2769,27085,27933,27934,56747,56797</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/2129015$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Runge, Marschall S</creatorcontrib><creatorcontrib>Bode, Christoph</creatorcontrib><creatorcontrib>Savard, Christopher E</creatorcontrib><creatorcontrib>Matsueda, Gary R</creatorcontrib><creatorcontrib>Haber, Edgar</creatorcontrib><title>Antibody-directed fibrinolysis: a bispecific (Fab')2 that binds to fibrin and tissue plasminogen activator</title><title>Bioconjugate chemistry</title><addtitle>Bioconjugate Chem</addtitle><description>A bispecific (Fab')2 molecule was constructed by linking the monovalent Fab' from an anti-fibrin monoclonal antibody to the Fab' from an anti tissue plasminogen activator (tPA, single chain) monoclonal antibody by means of inter-heavy-chain disulfide bonds. An immunochemical complex composed of the bispecific (Fab')2 molecule bound to tPA [tPA-bispecific (Fab')2 complex] was then generated and purified. Its molecular weight was 170 kDa [less than half the molecular weight of a previously described tPA-bispecific antibody complex containing the entire anti-fibrin and anti-tPA immunoglobulin molecules; Runge, M. S., et al. (1987) Trans. Assoc. Am. Phys. 100, 250-255]. The tPA-bispecific (Fab')2 complex was 8.6-fold more efficient in fibrinolysis than tPA alone and 94-fold more potent than urokinase. This enhancement in the fibrinolytic potency of tPA compares favorably with that observed for the bispecific whole-antibody complex. These results suggest that this smaller, less immunogenic molecule is capable of binding both fibrin and tPA with high affinity and of enhancing the thrombolytic efficiency of exogenous and, perhaps, endogenous tPA.</description><subject>Antibodies, Monoclonal - pharmacology</subject><subject>Cross-Linking Reagents</subject><subject>Electrophoresis, Polyacrylamide Gel - methods</subject><subject>Fibrin - immunology</subject><subject>Fibrin - metabolism</subject><subject>Fibrinolysis</subject><subject>Immunoglobulin Fab Fragments - metabolism</subject><subject>Immunoglobulin Fragments - metabolism</subject><subject>Tissue Plasminogen Activator - immunology</subject><subject>Tissue Plasminogen Activator - metabolism</subject><issn>1043-1802</issn><issn>1520-4812</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1990</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkM1P3DAQxS3UigLlxLmST6VVFTq249jpjaLyISFaqcDVcmyn9TabbD0OYv_7Gu0K9cBcZjTvN2-kR8gRgxMGnH3uHJSqLYDeIXtMcqhqzfirMkMtKqaBvyH7iItCtUzzXbLLGW-ByT2yOB1z7Ca_rnxMweXgaR-7FMdpWGPEL9TSLuIquNhHRz-c2-74I6f5t81lP3qkedoeUDt6miPiHOhqsLgsHr9CWbscH2ye0lvyurcDhsNtPyB3599uzy6r6-8XV2en15UVSucqeKcDMOdBgfIaZOO4BA5O1rLv61YxpnvBOyFUqwT3XoVG-tbalnERBBcH5P3Gd5Wmv3PAbJYRXRgGO4ZpRqNB1E3dyAJ-2oAuTYgp9GaV4tKmtWFgnpI1_yVb6Hdb27lbBv_MbqMserXRI-bw-Czb9Mc0Sihpbn_8NI24uYd7-GpY4Y83vHVoFtOcxhLKi5__ATX2jf8</recordid><startdate>19900701</startdate><enddate>19900701</enddate><creator>Runge, Marschall S</creator><creator>Bode, Christoph</creator><creator>Savard, Christopher E</creator><creator>Matsueda, Gary R</creator><creator>Haber, Edgar</creator><general>American Chemical Society</general><scope>BSCLL</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></search><sort><creationdate>19900701</creationdate><title>Antibody-directed fibrinolysis: a bispecific (Fab')2 that binds to fibrin and tissue plasminogen activator</title><author>Runge, Marschall S ; Bode, Christoph ; Savard, Christopher E ; Matsueda, Gary R ; Haber, Edgar</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a378t-edc8e01cd0707d8056c25020c545ff497118f32b3379732dd7e65d9aa9123e323</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1990</creationdate><topic>Antibodies, Monoclonal - pharmacology</topic><topic>Cross-Linking Reagents</topic><topic>Electrophoresis, Polyacrylamide Gel - methods</topic><topic>Fibrin - immunology</topic><topic>Fibrin - metabolism</topic><topic>Fibrinolysis</topic><topic>Immunoglobulin Fab Fragments - metabolism</topic><topic>Immunoglobulin Fragments - metabolism</topic><topic>Tissue Plasminogen Activator - immunology</topic><topic>Tissue Plasminogen Activator - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Runge, Marschall S</creatorcontrib><creatorcontrib>Bode, Christoph</creatorcontrib><creatorcontrib>Savard, Christopher E</creatorcontrib><creatorcontrib>Matsueda, Gary R</creatorcontrib><creatorcontrib>Haber, Edgar</creatorcontrib><collection>Istex</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Bioconjugate chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Runge, Marschall S</au><au>Bode, Christoph</au><au>Savard, Christopher E</au><au>Matsueda, Gary R</au><au>Haber, Edgar</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Antibody-directed fibrinolysis: a bispecific (Fab')2 that binds to fibrin and tissue plasminogen activator</atitle><jtitle>Bioconjugate chemistry</jtitle><addtitle>Bioconjugate Chem</addtitle><date>1990-07-01</date><risdate>1990</risdate><volume>1</volume><issue>4</issue><spage>274</spage><epage>277</epage><pages>274-277</pages><issn>1043-1802</issn><eissn>1520-4812</eissn><abstract>A bispecific (Fab')2 molecule was constructed by linking the monovalent Fab' from an anti-fibrin monoclonal antibody to the Fab' from an anti tissue plasminogen activator (tPA, single chain) monoclonal antibody by means of inter-heavy-chain disulfide bonds. An immunochemical complex composed of the bispecific (Fab')2 molecule bound to tPA [tPA-bispecific (Fab')2 complex] was then generated and purified. Its molecular weight was 170 kDa [less than half the molecular weight of a previously described tPA-bispecific antibody complex containing the entire anti-fibrin and anti-tPA immunoglobulin molecules; Runge, M. S., et al. (1987) Trans. Assoc. Am. Phys. 100, 250-255]. The tPA-bispecific (Fab')2 complex was 8.6-fold more efficient in fibrinolysis than tPA alone and 94-fold more potent than urokinase. This enhancement in the fibrinolytic potency of tPA compares favorably with that observed for the bispecific whole-antibody complex. These results suggest that this smaller, less immunogenic molecule is capable of binding both fibrin and tPA with high affinity and of enhancing the thrombolytic efficiency of exogenous and, perhaps, endogenous tPA.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>2129015</pmid><doi>10.1021/bc00004a008</doi><tpages>4</tpages></addata></record> |
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| identifier | ISSN: 1043-1802 |
| ispartof | Bioconjugate chemistry, 1990-07, Vol.1 (4), p.274-277 |
| issn | 1043-1802 1520-4812 |
| language | eng |
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| source | MEDLINE; ACS Publications |
| subjects | Antibodies, Monoclonal - pharmacology Cross-Linking Reagents Electrophoresis, Polyacrylamide Gel - methods Fibrin - immunology Fibrin - metabolism Fibrinolysis Immunoglobulin Fab Fragments - metabolism Immunoglobulin Fragments - metabolism Tissue Plasminogen Activator - immunology Tissue Plasminogen Activator - metabolism |
| title | Antibody-directed fibrinolysis: a bispecific (Fab')2 that binds to fibrin and tissue plasminogen activator |
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