Bispecific Antibody Pretargeting of Tumor Neovasculature for Improved Systemic Radiotherapy of Solid Tumors
Purpose: Extra domain B (ED-B) fibronectin is a specific tumor matrix marker for targeting angiogenesis in solid tumors. In this study, the radiotherapeutic potential of the directly radioiodinated divalent anti-ED-B antibody fragment, L19 small immunoprotein (L19-SIP; 75,000 Da), was compared with...
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| Veröffentlicht in: | Clinical cancer research 2006-09, Vol.12 (18), p.5587-5595 |
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| creator | MOOSMAYER, Dieter BERNDORFF, Dietmar DINKELBORG, Ludger M CHANG, Chien-Hsing SHARKEY, Robert M ROTHER, Axel BORKOWSKI, Sandra ROSSI, Edmund A MCBRIDE, William J CARDILLO, Thomas M GOLDENBERG, David M |
| description | Purpose: Extra domain B (ED-B) fibronectin is a specific tumor matrix marker for targeting angiogenesis in solid tumors. In this study,
the radiotherapeutic potential of the directly radioiodinated divalent anti-ED-B antibody fragment, L19 small immunoprotein
(L19-SIP; 75,000 Da), was compared with a pretargeting approach using the bispecific antibody AP39xm679 (bsMAb; 75,000 Da).
Experimental Design: The bsMAb was prepared by coupling an anti-ED-B single-chain Fv (AP39) to the Fab′ of the murine antibody m679, which binds
to the small peptidic hapten histamine-succinyl-glycine (HSG). As an effector molecule for the pretargeting approach, the
111 In-labeled HSG-DOTA complex was injected 25 or 41 hours after the bsMAb. The kinetics of both the iodinated bsMAb and the
pretargeted 111 In-labeled HSG hapten were investigated in mice bearing human glioblastoma xenografts (U251) and compared with the kinetics
and tumor accumulation of radioiodinated L19-SIP. 111 In and 125 I were used as surrogate marker for the therapeutic radioisotopes 90 Y/ 177 Lu and 131 I, respectively.
Results: Tumor uptake of the pretargeted 111 In-labeled peptide was significantly higher than 125 I-L19-SIP over 7 days. At the calculated maximally tolerated dose for each agent (with the kidney being the dose-limiting
organ for pretargeting and the bone marrow for direct targeting), a mouse tumor dose of 146 Gy could be given by pretargeting
versus 45 Gy delivered by the direct approach.
Conclusions: These data suggest that pretargeting of ED-B with AP39xm679 and subsequent injection of the 90 Y-hapten-peptide would improve the therapeutic efficacy in solid tumors by >3-fold compared with directly radiolabeled 131 I-L19-SIP. |
| doi_str_mv | 10.1158/1078-0432.CCR-06-0210 |
| format | Article |
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the radiotherapeutic potential of the directly radioiodinated divalent anti-ED-B antibody fragment, L19 small immunoprotein
(L19-SIP; 75,000 Da), was compared with a pretargeting approach using the bispecific antibody AP39xm679 (bsMAb; 75,000 Da).
Experimental Design: The bsMAb was prepared by coupling an anti-ED-B single-chain Fv (AP39) to the Fab′ of the murine antibody m679, which binds
to the small peptidic hapten histamine-succinyl-glycine (HSG). As an effector molecule for the pretargeting approach, the
111 In-labeled HSG-DOTA complex was injected 25 or 41 hours after the bsMAb. The kinetics of both the iodinated bsMAb and the
pretargeted 111 In-labeled HSG hapten were investigated in mice bearing human glioblastoma xenografts (U251) and compared with the kinetics
and tumor accumulation of radioiodinated L19-SIP. 111 In and 125 I were used as surrogate marker for the therapeutic radioisotopes 90 Y/ 177 Lu and 131 I, respectively.
Results: Tumor uptake of the pretargeted 111 In-labeled peptide was significantly higher than 125 I-L19-SIP over 7 days. At the calculated maximally tolerated dose for each agent (with the kidney being the dose-limiting
organ for pretargeting and the bone marrow for direct targeting), a mouse tumor dose of 146 Gy could be given by pretargeting
versus 45 Gy delivered by the direct approach.
Conclusions: These data suggest that pretargeting of ED-B with AP39xm679 and subsequent injection of the 90 Y-hapten-peptide would improve the therapeutic efficacy in solid tumors by >3-fold compared with directly radiolabeled 131 I-L19-SIP.</description><identifier>ISSN: 1078-0432</identifier><identifier>EISSN: 1557-3265</identifier><identifier>DOI: 10.1158/1078-0432.CCR-06-0210</identifier><identifier>PMID: 17000696</identifier><language>eng</language><publisher>Philadelphia, PA: American Association for Cancer Research</publisher><subject>angiogenesis ; Animals ; Antibodies, Bispecific - administration & dosage ; Antibodies, Bispecific - chemistry ; Antibodies, Bispecific - pharmacokinetics ; Antibodies, Bispecific - therapeutic use ; Antibodies, Neoplasm - analysis ; Antigens, Neoplasm - analysis ; Antineoplastic agents ; Biological and medical sciences ; bispecific antibody ; Drug Delivery Systems - methods ; ED-B fibronectin ; Female ; Glioblastoma - radiotherapy ; Humans ; Iodine Radioisotopes - administration & dosage ; Iodine Radioisotopes - pharmacokinetics ; Medical sciences ; Metabolic Clearance Rate - radiation effects ; Mice ; Mice, Nude ; Multiple tumors. Solid tumors. Tumors in childhood (general aspects) ; Neovascularization, Pathologic - radiotherapy ; Pharmacology. Drug treatments ; pretargeting ; Radiation Dosage ; Radioimmunotherapy - methods ; radiotherapy ; Tissue Distribution ; tumor vasculature ; Tumors ; Xenograft Model Antitumor Assays - methods</subject><ispartof>Clinical cancer research, 2006-09, Vol.12 (18), p.5587-5595</ispartof><rights>2006 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c402t-9d80ee9eb600fc05b199e00e9a61441a7abf7aa37add9a138cef1d350eef6b033</citedby><cites>FETCH-LOGICAL-c402t-9d80ee9eb600fc05b199e00e9a61441a7abf7aa37add9a138cef1d350eef6b033</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,777,781,3343,27905,27906</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=18149340$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/17000696$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>MOOSMAYER, Dieter</creatorcontrib><creatorcontrib>BERNDORFF, Dietmar</creatorcontrib><creatorcontrib>DINKELBORG, Ludger M</creatorcontrib><creatorcontrib>CHANG, Chien-Hsing</creatorcontrib><creatorcontrib>SHARKEY, Robert M</creatorcontrib><creatorcontrib>ROTHER, Axel</creatorcontrib><creatorcontrib>BORKOWSKI, Sandra</creatorcontrib><creatorcontrib>ROSSI, Edmund A</creatorcontrib><creatorcontrib>MCBRIDE, William J</creatorcontrib><creatorcontrib>CARDILLO, Thomas M</creatorcontrib><creatorcontrib>GOLDENBERG, David M</creatorcontrib><title>Bispecific Antibody Pretargeting of Tumor Neovasculature for Improved Systemic Radiotherapy of Solid Tumors</title><title>Clinical cancer research</title><addtitle>Clin Cancer Res</addtitle><description>Purpose: Extra domain B (ED-B) fibronectin is a specific tumor matrix marker for targeting angiogenesis in solid tumors. In this study,
the radiotherapeutic potential of the directly radioiodinated divalent anti-ED-B antibody fragment, L19 small immunoprotein
(L19-SIP; 75,000 Da), was compared with a pretargeting approach using the bispecific antibody AP39xm679 (bsMAb; 75,000 Da).
Experimental Design: The bsMAb was prepared by coupling an anti-ED-B single-chain Fv (AP39) to the Fab′ of the murine antibody m679, which binds
to the small peptidic hapten histamine-succinyl-glycine (HSG). As an effector molecule for the pretargeting approach, the
111 In-labeled HSG-DOTA complex was injected 25 or 41 hours after the bsMAb. The kinetics of both the iodinated bsMAb and the
pretargeted 111 In-labeled HSG hapten were investigated in mice bearing human glioblastoma xenografts (U251) and compared with the kinetics
and tumor accumulation of radioiodinated L19-SIP. 111 In and 125 I were used as surrogate marker for the therapeutic radioisotopes 90 Y/ 177 Lu and 131 I, respectively.
Results: Tumor uptake of the pretargeted 111 In-labeled peptide was significantly higher than 125 I-L19-SIP over 7 days. At the calculated maximally tolerated dose for each agent (with the kidney being the dose-limiting
organ for pretargeting and the bone marrow for direct targeting), a mouse tumor dose of 146 Gy could be given by pretargeting
versus 45 Gy delivered by the direct approach.
Conclusions: These data suggest that pretargeting of ED-B with AP39xm679 and subsequent injection of the 90 Y-hapten-peptide would improve the therapeutic efficacy in solid tumors by >3-fold compared with directly radiolabeled 131 I-L19-SIP.</description><subject>angiogenesis</subject><subject>Animals</subject><subject>Antibodies, Bispecific - administration & dosage</subject><subject>Antibodies, Bispecific - chemistry</subject><subject>Antibodies, Bispecific - pharmacokinetics</subject><subject>Antibodies, Bispecific - therapeutic use</subject><subject>Antibodies, Neoplasm - analysis</subject><subject>Antigens, Neoplasm - analysis</subject><subject>Antineoplastic agents</subject><subject>Biological and medical sciences</subject><subject>bispecific antibody</subject><subject>Drug Delivery Systems - methods</subject><subject>ED-B fibronectin</subject><subject>Female</subject><subject>Glioblastoma - radiotherapy</subject><subject>Humans</subject><subject>Iodine Radioisotopes - administration & dosage</subject><subject>Iodine Radioisotopes - pharmacokinetics</subject><subject>Medical sciences</subject><subject>Metabolic Clearance Rate - radiation effects</subject><subject>Mice</subject><subject>Mice, Nude</subject><subject>Multiple tumors. Solid tumors. Tumors in childhood (general aspects)</subject><subject>Neovascularization, Pathologic - radiotherapy</subject><subject>Pharmacology. Drug treatments</subject><subject>pretargeting</subject><subject>Radiation Dosage</subject><subject>Radioimmunotherapy - methods</subject><subject>radiotherapy</subject><subject>Tissue Distribution</subject><subject>tumor vasculature</subject><subject>Tumors</subject><subject>Xenograft Model Antitumor Assays - methods</subject><issn>1078-0432</issn><issn>1557-3265</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkE1v1DAQhi1ERUvhJ4ByoRKHlHH8kfhYVgUqVYDacrYce7xrSNaLnbTaf4-jXdSTR9bzvjN6CHlH4ZJS0X2i0HY1cNZcrlZ3NcgaGgovyBkVoq1ZI8XLMv9nTsnrnH8DUE6BvyKntAUAqeQZ-fM55B3a4IOtrrZT6KPbVz8TTiatcQrbdRV99TCPMVXfMT6abOfBTHPCypevm3GX4iO66n6fJxxLx51xIU4bTGa3X6L3cQjuUJDfkBNvhoxvj-85-fXl-mH1rb798fVmdXVbWw7NVCvXAaLCXgJ4C6KnSiEAKiMp59S0pvetMaw1zilDWWfRU8dECXnZA2Pn5OLQW477O2Oe9BiyxWEwW4xz1lRxyRshCigOoE0x54Re71IYTdprCnqxrBeDejGoi2UNUi-WS-79ccHcj-ieU0etBfhwBIowM_hktjbkZ66jXDG-FH08cJuw3jyFhNoWElPCjCbZjaZNgbUQXcv-AX7JlcI</recordid><startdate>20060915</startdate><enddate>20060915</enddate><creator>MOOSMAYER, Dieter</creator><creator>BERNDORFF, Dietmar</creator><creator>DINKELBORG, Ludger M</creator><creator>CHANG, Chien-Hsing</creator><creator>SHARKEY, Robert M</creator><creator>ROTHER, Axel</creator><creator>BORKOWSKI, Sandra</creator><creator>ROSSI, Edmund A</creator><creator>MCBRIDE, William J</creator><creator>CARDILLO, Thomas M</creator><creator>GOLDENBERG, David M</creator><general>American Association for Cancer Research</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></search><sort><creationdate>20060915</creationdate><title>Bispecific Antibody Pretargeting of Tumor Neovasculature for Improved Systemic Radiotherapy of Solid Tumors</title><author>MOOSMAYER, Dieter ; BERNDORFF, Dietmar ; DINKELBORG, Ludger M ; CHANG, Chien-Hsing ; SHARKEY, Robert M ; ROTHER, Axel ; BORKOWSKI, Sandra ; ROSSI, Edmund A ; MCBRIDE, William J ; CARDILLO, Thomas M ; GOLDENBERG, David M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c402t-9d80ee9eb600fc05b199e00e9a61441a7abf7aa37add9a138cef1d350eef6b033</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2006</creationdate><topic>angiogenesis</topic><topic>Animals</topic><topic>Antibodies, Bispecific - administration & dosage</topic><topic>Antibodies, Bispecific - chemistry</topic><topic>Antibodies, Bispecific - pharmacokinetics</topic><topic>Antibodies, Bispecific - therapeutic use</topic><topic>Antibodies, Neoplasm - analysis</topic><topic>Antigens, Neoplasm - analysis</topic><topic>Antineoplastic agents</topic><topic>Biological and medical sciences</topic><topic>bispecific antibody</topic><topic>Drug Delivery Systems - methods</topic><topic>ED-B fibronectin</topic><topic>Female</topic><topic>Glioblastoma - radiotherapy</topic><topic>Humans</topic><topic>Iodine Radioisotopes - administration & dosage</topic><topic>Iodine Radioisotopes - pharmacokinetics</topic><topic>Medical sciences</topic><topic>Metabolic Clearance Rate - radiation effects</topic><topic>Mice</topic><topic>Mice, Nude</topic><topic>Multiple tumors. Solid tumors. Tumors in childhood (general aspects)</topic><topic>Neovascularization, Pathologic - radiotherapy</topic><topic>Pharmacology. Drug treatments</topic><topic>pretargeting</topic><topic>Radiation Dosage</topic><topic>Radioimmunotherapy - methods</topic><topic>radiotherapy</topic><topic>Tissue Distribution</topic><topic>tumor vasculature</topic><topic>Tumors</topic><topic>Xenograft Model Antitumor Assays - methods</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>MOOSMAYER, Dieter</creatorcontrib><creatorcontrib>BERNDORFF, Dietmar</creatorcontrib><creatorcontrib>DINKELBORG, Ludger M</creatorcontrib><creatorcontrib>CHANG, Chien-Hsing</creatorcontrib><creatorcontrib>SHARKEY, Robert M</creatorcontrib><creatorcontrib>ROTHER, Axel</creatorcontrib><creatorcontrib>BORKOWSKI, Sandra</creatorcontrib><creatorcontrib>ROSSI, Edmund A</creatorcontrib><creatorcontrib>MCBRIDE, William J</creatorcontrib><creatorcontrib>CARDILLO, Thomas M</creatorcontrib><creatorcontrib>GOLDENBERG, David M</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><jtitle>Clinical cancer research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>MOOSMAYER, Dieter</au><au>BERNDORFF, Dietmar</au><au>DINKELBORG, Ludger M</au><au>CHANG, Chien-Hsing</au><au>SHARKEY, Robert M</au><au>ROTHER, Axel</au><au>BORKOWSKI, Sandra</au><au>ROSSI, Edmund A</au><au>MCBRIDE, William J</au><au>CARDILLO, Thomas M</au><au>GOLDENBERG, David M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Bispecific Antibody Pretargeting of Tumor Neovasculature for Improved Systemic Radiotherapy of Solid Tumors</atitle><jtitle>Clinical cancer research</jtitle><addtitle>Clin Cancer Res</addtitle><date>2006-09-15</date><risdate>2006</risdate><volume>12</volume><issue>18</issue><spage>5587</spage><epage>5595</epage><pages>5587-5595</pages><issn>1078-0432</issn><eissn>1557-3265</eissn><abstract>Purpose: Extra domain B (ED-B) fibronectin is a specific tumor matrix marker for targeting angiogenesis in solid tumors. In this study,
the radiotherapeutic potential of the directly radioiodinated divalent anti-ED-B antibody fragment, L19 small immunoprotein
(L19-SIP; 75,000 Da), was compared with a pretargeting approach using the bispecific antibody AP39xm679 (bsMAb; 75,000 Da).
Experimental Design: The bsMAb was prepared by coupling an anti-ED-B single-chain Fv (AP39) to the Fab′ of the murine antibody m679, which binds
to the small peptidic hapten histamine-succinyl-glycine (HSG). As an effector molecule for the pretargeting approach, the
111 In-labeled HSG-DOTA complex was injected 25 or 41 hours after the bsMAb. The kinetics of both the iodinated bsMAb and the
pretargeted 111 In-labeled HSG hapten were investigated in mice bearing human glioblastoma xenografts (U251) and compared with the kinetics
and tumor accumulation of radioiodinated L19-SIP. 111 In and 125 I were used as surrogate marker for the therapeutic radioisotopes 90 Y/ 177 Lu and 131 I, respectively.
Results: Tumor uptake of the pretargeted 111 In-labeled peptide was significantly higher than 125 I-L19-SIP over 7 days. At the calculated maximally tolerated dose for each agent (with the kidney being the dose-limiting
organ for pretargeting and the bone marrow for direct targeting), a mouse tumor dose of 146 Gy could be given by pretargeting
versus 45 Gy delivered by the direct approach.
Conclusions: These data suggest that pretargeting of ED-B with AP39xm679 and subsequent injection of the 90 Y-hapten-peptide would improve the therapeutic efficacy in solid tumors by >3-fold compared with directly radiolabeled 131 I-L19-SIP.</abstract><cop>Philadelphia, PA</cop><pub>American Association for Cancer Research</pub><pmid>17000696</pmid><doi>10.1158/1078-0432.CCR-06-0210</doi><tpages>9</tpages></addata></record> |
| fulltext | fulltext |
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| ispartof | Clinical cancer research, 2006-09, Vol.12 (18), p.5587-5595 |
| issn | 1078-0432 1557-3265 |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; American Association for Cancer Research; Alma/SFX Local Collection |
| subjects | angiogenesis Animals Antibodies, Bispecific - administration & dosage Antibodies, Bispecific - chemistry Antibodies, Bispecific - pharmacokinetics Antibodies, Bispecific - therapeutic use Antibodies, Neoplasm - analysis Antigens, Neoplasm - analysis Antineoplastic agents Biological and medical sciences bispecific antibody Drug Delivery Systems - methods ED-B fibronectin Female Glioblastoma - radiotherapy Humans Iodine Radioisotopes - administration & dosage Iodine Radioisotopes - pharmacokinetics Medical sciences Metabolic Clearance Rate - radiation effects Mice Mice, Nude Multiple tumors. Solid tumors. Tumors in childhood (general aspects) Neovascularization, Pathologic - radiotherapy Pharmacology. Drug treatments pretargeting Radiation Dosage Radioimmunotherapy - methods radiotherapy Tissue Distribution tumor vasculature Tumors Xenograft Model Antitumor Assays - methods |
| title | Bispecific Antibody Pretargeting of Tumor Neovasculature for Improved Systemic Radiotherapy of Solid Tumors |
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