Binding characteristics and tumor targeting of a covalently linked divalent CC49 single‐chain antibody
Multivalency is a recognized means of increasing the functional affinity of single‐chain Fvs (scFvs) for optimizing tumor uptake. A unique divalent single‐chain Fv protein [sc(Fv)2], based on the variable regions of the monoclonal antibody (MAb) CC49, has been generated that differs from other dimer...
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| Veröffentlicht in: | International journal of cancer 1999-06, Vol.81 (6), p.911-917 |
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| container_title | International journal of cancer |
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| creator | Beresford, Guy W. Pavlinkova, Gabriela Booth, Barbara J.M. Batra, Surinder K. Colcher, David |
| description | Multivalency is a recognized means of increasing the functional affinity of single‐chain Fvs (scFvs) for optimizing tumor uptake. A unique divalent single‐chain Fv protein [sc(Fv)2], based on the variable regions of the monoclonal antibody (MAb) CC49, has been generated that differs from other dimeric single‐chain constructs in that a linker sequence (L) is encoded between the repeated VL and VH domains (VL‐L‐VH‐L‐VL‐L‐VH). This construct was expressed in soluble form in Escherichia coli and purified by ion‐exchange and gel‐filtration chromatography. Purity and immunoreactivity were determined by SDS‐PAGE, HPLC and competitive RIA. sc(Fv)2 exhibited a relative KA (3.34 × 107 M−1) similar to that of the native IgG (1.14 × 108 M−1) as determined by BIAcore analysis. Pharmacokinetic studies showed rapid blood clearance for sc(Fv)2, with a T1/2 less than 40 min. Whole‐body clearance analysis also revealed rapid clearance, suggesting no significant retention in the extravascular space or normal tissues. Biodistribution studies of radiolabeled sc(Fv)2 showed tumor uptake greater than 6% ID/g after 30 min, which remained at this level for 6 hr. High tumor uptake and retention of sc(Fv)2 coupled with rapid blood and whole‐body clearance makes this dimeric scFv of MAb CC49 a strong candidate for imaging and therapeutic applications. Int. J. Cancer 81:911–917, 1999. © 1999 Wiley‐Liss, Inc. |
| doi_str_mv | 10.1002/(SICI)1097-0215(19990611)81:6<911::AID-IJC12>3.0.CO;2-O |
| format | Article |
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A unique divalent single‐chain Fv protein [sc(Fv)2], based on the variable regions of the monoclonal antibody (MAb) CC49, has been generated that differs from other dimeric single‐chain constructs in that a linker sequence (L) is encoded between the repeated VL and VH domains (VL‐L‐VH‐L‐VL‐L‐VH). This construct was expressed in soluble form in Escherichia coli and purified by ion‐exchange and gel‐filtration chromatography. Purity and immunoreactivity were determined by SDS‐PAGE, HPLC and competitive RIA. sc(Fv)2 exhibited a relative KA (3.34 × 107 M−1) similar to that of the native IgG (1.14 × 108 M−1) as determined by BIAcore analysis. Pharmacokinetic studies showed rapid blood clearance for sc(Fv)2, with a T1/2 less than 40 min. Whole‐body clearance analysis also revealed rapid clearance, suggesting no significant retention in the extravascular space or normal tissues. Biodistribution studies of radiolabeled sc(Fv)2 showed tumor uptake greater than 6% ID/g after 30 min, which remained at this level for 6 hr. High tumor uptake and retention of sc(Fv)2 coupled with rapid blood and whole‐body clearance makes this dimeric scFv of MAb CC49 a strong candidate for imaging and therapeutic applications. Int. J. Cancer 81:911–917, 1999. © 1999 Wiley‐Liss, Inc.</description><identifier>ISSN: 0020-7136</identifier><identifier>EISSN: 1097-0215</identifier><identifier>DOI: 10.1002/(SICI)1097-0215(19990611)81:6<911::AID-IJC12>3.0.CO;2-O</identifier><identifier>PMID: 10362138</identifier><identifier>CODEN: IJCNAW</identifier><language>eng</language><publisher>New York: John Wiley & Sons, Inc</publisher><subject>Animals ; Antibodies, Monoclonal - biosynthesis ; Antibodies, Monoclonal - isolation & purification ; Antibodies, Monoclonal - pharmacokinetics ; Antibodies, Neoplasm - biosynthesis ; Antibodies, Neoplasm - isolation & purification ; Antibodies, Neoplasm - metabolism ; Biological and medical sciences ; Colonic Neoplasms - metabolism ; Escherichia coli ; Female ; Humans ; Immunoglobulin G - metabolism ; Immunoglobulin Heavy Chains ; Immunoglobulin Light Chains ; Immunoglobulin Variable Region ; Iodine Radioisotopes - pharmacokinetics ; Medical sciences ; Metabolic Clearance Rate ; Mice ; Mice, Nude ; Other treatments ; Recombinant Proteins - biosynthesis ; Recombinant Proteins - isolation & purification ; Recombinant Proteins - pharmacokinetics ; Tissue Distribution ; Transplantation, Heterologous ; Treatment. 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A unique divalent single‐chain Fv protein [sc(Fv)2], based on the variable regions of the monoclonal antibody (MAb) CC49, has been generated that differs from other dimeric single‐chain constructs in that a linker sequence (L) is encoded between the repeated VL and VH domains (VL‐L‐VH‐L‐VL‐L‐VH). This construct was expressed in soluble form in Escherichia coli and purified by ion‐exchange and gel‐filtration chromatography. Purity and immunoreactivity were determined by SDS‐PAGE, HPLC and competitive RIA. sc(Fv)2 exhibited a relative KA (3.34 × 107 M−1) similar to that of the native IgG (1.14 × 108 M−1) as determined by BIAcore analysis. Pharmacokinetic studies showed rapid blood clearance for sc(Fv)2, with a T1/2 less than 40 min. Whole‐body clearance analysis also revealed rapid clearance, suggesting no significant retention in the extravascular space or normal tissues. Biodistribution studies of radiolabeled sc(Fv)2 showed tumor uptake greater than 6% ID/g after 30 min, which remained at this level for 6 hr. High tumor uptake and retention of sc(Fv)2 coupled with rapid blood and whole‐body clearance makes this dimeric scFv of MAb CC49 a strong candidate for imaging and therapeutic applications. Int. J. Cancer 81:911–917, 1999. © 1999 Wiley‐Liss, Inc.</description><subject>Animals</subject><subject>Antibodies, Monoclonal - biosynthesis</subject><subject>Antibodies, Monoclonal - isolation & purification</subject><subject>Antibodies, Monoclonal - pharmacokinetics</subject><subject>Antibodies, Neoplasm - biosynthesis</subject><subject>Antibodies, Neoplasm - isolation & purification</subject><subject>Antibodies, Neoplasm - metabolism</subject><subject>Biological and medical sciences</subject><subject>Colonic Neoplasms - metabolism</subject><subject>Escherichia coli</subject><subject>Female</subject><subject>Humans</subject><subject>Immunoglobulin G - metabolism</subject><subject>Immunoglobulin Heavy Chains</subject><subject>Immunoglobulin Light Chains</subject><subject>Immunoglobulin Variable Region</subject><subject>Iodine Radioisotopes - pharmacokinetics</subject><subject>Medical sciences</subject><subject>Metabolic Clearance Rate</subject><subject>Mice</subject><subject>Mice, Nude</subject><subject>Other treatments</subject><subject>Recombinant Proteins - biosynthesis</subject><subject>Recombinant Proteins - isolation & purification</subject><subject>Recombinant Proteins - pharmacokinetics</subject><subject>Tissue Distribution</subject><subject>Transplantation, Heterologous</subject><subject>Treatment. General aspects</subject><subject>Tumors</subject><issn>0020-7136</issn><issn>1097-0215</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1999</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkdtu1DAQhiMEokvhFVAuEGovsszYiRMvCFTCKahSLgDB3cjrOK1pNil2FrR3PALPyJPgkOUggdQrS6Nvfv2eL4qeICwRgD04elOV1TGCzBNgmB2hlBIE4nGBK_FIIq5WJ9WzpHpdInvMl7As64csqa9Fi98716NFSIIkRy4OolvefwRAzCC9GR0gcMGQF4vo_KntG9ufxfpcOaVH46wfrfax6pt43G4GF4_KnZlxYoY2VrEePqvO9GO3izvbX5gmbuw8icsylbEPZGe-f_0WEm0fcka7Hprd7ehGqzpv7uzfw-jdi-dvy1fJaf2yKk9OE52CZIlZ84y3AgstULFUN1KzNDdZq8P300xkWQ4SWwVrhaoVRYqN0phrQJZinrX8MLo_51664dPW-JE21mvTdao3w9aTkMWEyitBzDlkkEMA38-gdoP3zrR06exGuR0h0GSLaLJF0-Vpujz9skUFkqBgiyjYop-2iBNQWROjOiTf3VfYrjem-St31hOAe3tAea261qleW_-Hy6VAOTX8MGNfbGd2_9S7st3_ys0D_gPut700</recordid><startdate>19990611</startdate><enddate>19990611</enddate><creator>Beresford, Guy W.</creator><creator>Pavlinkova, Gabriela</creator><creator>Booth, Barbara J.M.</creator><creator>Batra, Surinder K.</creator><creator>Colcher, David</creator><general>John Wiley & Sons, Inc</general><general>Wiley-Liss</general><scope>IQODW</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>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>7X8</scope></search><sort><creationdate>19990611</creationdate><title>Binding characteristics and tumor targeting of a covalently linked divalent CC49 single‐chain antibody</title><author>Beresford, Guy W. ; Pavlinkova, Gabriela ; Booth, Barbara J.M. ; Batra, Surinder K. ; Colcher, David</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4092-eb353f618c61a24cd9c247e5fc061456557091fa0ba1af6841dac17c0124175f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1999</creationdate><topic>Animals</topic><topic>Antibodies, Monoclonal - biosynthesis</topic><topic>Antibodies, Monoclonal - isolation & purification</topic><topic>Antibodies, Monoclonal - pharmacokinetics</topic><topic>Antibodies, Neoplasm - biosynthesis</topic><topic>Antibodies, Neoplasm - isolation & purification</topic><topic>Antibodies, Neoplasm - metabolism</topic><topic>Biological and medical sciences</topic><topic>Colonic Neoplasms - metabolism</topic><topic>Escherichia coli</topic><topic>Female</topic><topic>Humans</topic><topic>Immunoglobulin G - metabolism</topic><topic>Immunoglobulin Heavy Chains</topic><topic>Immunoglobulin Light Chains</topic><topic>Immunoglobulin Variable Region</topic><topic>Iodine Radioisotopes - pharmacokinetics</topic><topic>Medical sciences</topic><topic>Metabolic Clearance Rate</topic><topic>Mice</topic><topic>Mice, Nude</topic><topic>Other treatments</topic><topic>Recombinant Proteins - biosynthesis</topic><topic>Recombinant Proteins - isolation & purification</topic><topic>Recombinant Proteins - pharmacokinetics</topic><topic>Tissue Distribution</topic><topic>Transplantation, Heterologous</topic><topic>Treatment. General aspects</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Beresford, Guy W.</creatorcontrib><creatorcontrib>Pavlinkova, Gabriela</creatorcontrib><creatorcontrib>Booth, Barbara J.M.</creatorcontrib><creatorcontrib>Batra, Surinder K.</creatorcontrib><creatorcontrib>Colcher, David</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>International journal of cancer</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Beresford, Guy W.</au><au>Pavlinkova, Gabriela</au><au>Booth, Barbara J.M.</au><au>Batra, Surinder K.</au><au>Colcher, David</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Binding characteristics and tumor targeting of a covalently linked divalent CC49 single‐chain antibody</atitle><jtitle>International journal of cancer</jtitle><addtitle>Int J Cancer</addtitle><date>1999-06-11</date><risdate>1999</risdate><volume>81</volume><issue>6</issue><spage>911</spage><epage>917</epage><pages>911-917</pages><issn>0020-7136</issn><eissn>1097-0215</eissn><coden>IJCNAW</coden><abstract>Multivalency is a recognized means of increasing the functional affinity of single‐chain Fvs (scFvs) for optimizing tumor uptake. A unique divalent single‐chain Fv protein [sc(Fv)2], based on the variable regions of the monoclonal antibody (MAb) CC49, has been generated that differs from other dimeric single‐chain constructs in that a linker sequence (L) is encoded between the repeated VL and VH domains (VL‐L‐VH‐L‐VL‐L‐VH). This construct was expressed in soluble form in Escherichia coli and purified by ion‐exchange and gel‐filtration chromatography. Purity and immunoreactivity were determined by SDS‐PAGE, HPLC and competitive RIA. sc(Fv)2 exhibited a relative KA (3.34 × 107 M−1) similar to that of the native IgG (1.14 × 108 M−1) as determined by BIAcore analysis. Pharmacokinetic studies showed rapid blood clearance for sc(Fv)2, with a T1/2 less than 40 min. Whole‐body clearance analysis also revealed rapid clearance, suggesting no significant retention in the extravascular space or normal tissues. Biodistribution studies of radiolabeled sc(Fv)2 showed tumor uptake greater than 6% ID/g after 30 min, which remained at this level for 6 hr. High tumor uptake and retention of sc(Fv)2 coupled with rapid blood and whole‐body clearance makes this dimeric scFv of MAb CC49 a strong candidate for imaging and therapeutic applications. Int. J. Cancer 81:911–917, 1999. © 1999 Wiley‐Liss, Inc.</abstract><cop>New York</cop><pub>John Wiley & Sons, Inc</pub><pmid>10362138</pmid><doi>10.1002/(SICI)1097-0215(19990611)81:6<911::AID-IJC12>3.0.CO;2-O</doi><tpages>7</tpages></addata></record> |
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| ispartof | International journal of cancer, 1999-06, Vol.81 (6), p.911-917 |
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| source | MEDLINE; Access via Wiley Online Library; EZB-FREE-00999 freely available EZB journals |
| subjects | Animals Antibodies, Monoclonal - biosynthesis Antibodies, Monoclonal - isolation & purification Antibodies, Monoclonal - pharmacokinetics Antibodies, Neoplasm - biosynthesis Antibodies, Neoplasm - isolation & purification Antibodies, Neoplasm - metabolism Biological and medical sciences Colonic Neoplasms - metabolism Escherichia coli Female Humans Immunoglobulin G - metabolism Immunoglobulin Heavy Chains Immunoglobulin Light Chains Immunoglobulin Variable Region Iodine Radioisotopes - pharmacokinetics Medical sciences Metabolic Clearance Rate Mice Mice, Nude Other treatments Recombinant Proteins - biosynthesis Recombinant Proteins - isolation & purification Recombinant Proteins - pharmacokinetics Tissue Distribution Transplantation, Heterologous Treatment. General aspects Tumors |
| title | Binding characteristics and tumor targeting of a covalently linked divalent CC49 single‐chain antibody |
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