The pharmacokinetic characteristics of glycolated humanized anti-tac Fabs are determined by their isoelectric points
To evaluate a method for preventing the nephrotoxicity caused by the high renal accumulation of radiolabeled or toxin-conjugated small immunoproteins used for cancer therapy, we conjugated humanized anti-Tac Fab fragments with various numbers of glycolate molecules [glycolated Fab fragments (glyco-F...
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| Veröffentlicht in: | Cancer research (Chicago, Ill.) Ill.), 1999-01, Vol.59 (2), p.422-430 |
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| creator | KOBAYASHI, H NHAT LE KIM, I.-S KIM, M.-K PIE, J.-E DRUMM, D PAIK, D. S WALDMANN, T. A PAIK, C. H CARRASQUILLO, J. A |
| description | To evaluate a method for preventing the nephrotoxicity caused by the high renal accumulation of radiolabeled or toxin-conjugated small immunoproteins used for cancer therapy, we conjugated humanized anti-Tac Fab fragments with various numbers of glycolate molecules [glycolated Fab fragments (glyco-Fabs)] and separated the conjugates by means of ion-exchange columns into three fractions, depending on their isoelectric points (pIs). We evaluated the biodistribution, pharmacokinetics, and catabolism in normal nude mice of nonglycolated Fab (pI > or = 9.3) and three different preparations of glyco-Fab, including strongly anionic glyco-Fab (sa-glyco-Fab: pI < or = 4.5), mildly anionic glyco-Fab (pI = 4.5-7), and mildly cationic glyco-Fab (pI = 7-9.3). In addition, the biodistributions of 125I-labeled sa-glyco-Fab and 131I-labeled nonglycolated Fab were evaluated in normal nude mice coinjected with 50 mg of L-lysine and/or 1 microg of furosemide and in a control group without coinjection. We then evaluated the serial biodistribution of 125I-labeled sa-glyco-Fab (4 microCi/1 microg) and 131I-labeled nonglycolated Fab (5 microCi/1 microg) in Tac antigen-positive (ATAC4) and -negative (A431) tumor-bearing nude mice with s.c. tumor xenografts derived from Tac antigen-positive ATAC4 cells and receptor-negative A431 cells. These animals were coinjected with 30 mg of lysine i.v. and 30 mg of lysine i.p. 15 min after the radiolabeled Fab injection. To evaluate the biodistribution data and study scintigraphic imaging, we performed serial scintigraphy on normal and tumor-bearing mice with all four 131I-labeled preparations. 125I-labeled mildly cationic glyco-Fab and 131I-labeled nonglycolated Fab had similar distributions, except in the kidney. However, both 125I-labeled anionic glyco-Fab preparations showed significantly different distributions from both cationic Fabs in the blood, liver, lung, and spleen. Renal accumulation of all four radiolabeled Fab preparations increased significantly as the pI increased (P < 0.01). In addition, the intact fraction of Fab excreted into urine increased as pI decreased. Therefore, the glomerular filtration depended on whether the charge on the Fab was positive or negative. The proportion of Fab reabsorbed by the proximal tubules increased as pI increased. 125I-labeled sa-glyco-Fab and 125I-labeled mildly anionic glyco-Fab showed a similar distribution in the blood and all organs except the kidney. Lysine led to an additional blocking |
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S ; WALDMANN, T. A ; PAIK, C. H ; CARRASQUILLO, J. A</creator><creatorcontrib>KOBAYASHI, H ; NHAT LE ; KIM, I.-S ; KIM, M.-K ; PIE, J.-E ; DRUMM, D ; PAIK, D. S ; WALDMANN, T. A ; PAIK, C. H ; CARRASQUILLO, J. A</creatorcontrib><description>To evaluate a method for preventing the nephrotoxicity caused by the high renal accumulation of radiolabeled or toxin-conjugated small immunoproteins used for cancer therapy, we conjugated humanized anti-Tac Fab fragments with various numbers of glycolate molecules [glycolated Fab fragments (glyco-Fabs)] and separated the conjugates by means of ion-exchange columns into three fractions, depending on their isoelectric points (pIs). We evaluated the biodistribution, pharmacokinetics, and catabolism in normal nude mice of nonglycolated Fab (pI > or = 9.3) and three different preparations of glyco-Fab, including strongly anionic glyco-Fab (sa-glyco-Fab: pI < or = 4.5), mildly anionic glyco-Fab (pI = 4.5-7), and mildly cationic glyco-Fab (pI = 7-9.3). In addition, the biodistributions of 125I-labeled sa-glyco-Fab and 131I-labeled nonglycolated Fab were evaluated in normal nude mice coinjected with 50 mg of L-lysine and/or 1 microg of furosemide and in a control group without coinjection. We then evaluated the serial biodistribution of 125I-labeled sa-glyco-Fab (4 microCi/1 microg) and 131I-labeled nonglycolated Fab (5 microCi/1 microg) in Tac antigen-positive (ATAC4) and -negative (A431) tumor-bearing nude mice with s.c. tumor xenografts derived from Tac antigen-positive ATAC4 cells and receptor-negative A431 cells. These animals were coinjected with 30 mg of lysine i.v. and 30 mg of lysine i.p. 15 min after the radiolabeled Fab injection. To evaluate the biodistribution data and study scintigraphic imaging, we performed serial scintigraphy on normal and tumor-bearing mice with all four 131I-labeled preparations. 125I-labeled mildly cationic glyco-Fab and 131I-labeled nonglycolated Fab had similar distributions, except in the kidney. However, both 125I-labeled anionic glyco-Fab preparations showed significantly different distributions from both cationic Fabs in the blood, liver, lung, and spleen. Renal accumulation of all four radiolabeled Fab preparations increased significantly as the pI increased (P < 0.01). In addition, the intact fraction of Fab excreted into urine increased as pI decreased. Therefore, the glomerular filtration depended on whether the charge on the Fab was positive or negative. The proportion of Fab reabsorbed by the proximal tubules increased as pI increased. 125I-labeled sa-glyco-Fab and 125I-labeled mildly anionic glyco-Fab showed a similar distribution in the blood and all organs except the kidney. Lysine led to an additional blocking effect on proximal tubular uptake of both sa-glyco-Fab and nonglycolated Fab. Addition of furosemide yielded only a small effect when used with lysine. With lysine, the sa-glyco-Fab:nonglycolated Fab estimated integral radioactivity ratios were 4.7 and 0.7 in the ATAC4 tumor and in the kidney, respectively. The use of anionic fragments, which may be used in conjunction with lysine, represents a promising approach that may help decrease the renal toxicity of other small fragments, the molecular weights of which range from Mr 40,000 to 70,000, and, thereby, allow higher doses of radiation to the tumor.</description><identifier>ISSN: 0008-5472</identifier><identifier>EISSN: 1538-7445</identifier><identifier>PMID: 9927057</identifier><identifier>CODEN: CNREA8</identifier><language>eng</language><publisher>Philadelphia, PA: American Association for Cancer Research</publisher><subject>Animals ; Antineoplastic agents ; Biological and medical sciences ; Female ; Furosemide - pharmacology ; Glycosylation ; Immunoglobulin Fab Fragments - metabolism ; Immunotherapy ; Iodine Radioisotopes ; Isoelectric Point ; Kidney - metabolism ; Lysine - pharmacology ; Medical sciences ; Mice ; Mice, Nude ; Pharmacology. Drug treatments ; Radioimmunodetection ; Receptors, Interleukin-2 - immunology ; Tissue Distribution</subject><ispartof>Cancer research (Chicago, Ill.), 1999-01, Vol.59 (2), p.422-430</ispartof><rights>1999 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,781,785</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=1691463$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/9927057$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>KOBAYASHI, H</creatorcontrib><creatorcontrib>NHAT LE</creatorcontrib><creatorcontrib>KIM, I.-S</creatorcontrib><creatorcontrib>KIM, M.-K</creatorcontrib><creatorcontrib>PIE, J.-E</creatorcontrib><creatorcontrib>DRUMM, D</creatorcontrib><creatorcontrib>PAIK, D. S</creatorcontrib><creatorcontrib>WALDMANN, T. A</creatorcontrib><creatorcontrib>PAIK, C. H</creatorcontrib><creatorcontrib>CARRASQUILLO, J. A</creatorcontrib><title>The pharmacokinetic characteristics of glycolated humanized anti-tac Fabs are determined by their isoelectric points</title><title>Cancer research (Chicago, Ill.)</title><addtitle>Cancer Res</addtitle><description>To evaluate a method for preventing the nephrotoxicity caused by the high renal accumulation of radiolabeled or toxin-conjugated small immunoproteins used for cancer therapy, we conjugated humanized anti-Tac Fab fragments with various numbers of glycolate molecules [glycolated Fab fragments (glyco-Fabs)] and separated the conjugates by means of ion-exchange columns into three fractions, depending on their isoelectric points (pIs). We evaluated the biodistribution, pharmacokinetics, and catabolism in normal nude mice of nonglycolated Fab (pI > or = 9.3) and three different preparations of glyco-Fab, including strongly anionic glyco-Fab (sa-glyco-Fab: pI < or = 4.5), mildly anionic glyco-Fab (pI = 4.5-7), and mildly cationic glyco-Fab (pI = 7-9.3). In addition, the biodistributions of 125I-labeled sa-glyco-Fab and 131I-labeled nonglycolated Fab were evaluated in normal nude mice coinjected with 50 mg of L-lysine and/or 1 microg of furosemide and in a control group without coinjection. We then evaluated the serial biodistribution of 125I-labeled sa-glyco-Fab (4 microCi/1 microg) and 131I-labeled nonglycolated Fab (5 microCi/1 microg) in Tac antigen-positive (ATAC4) and -negative (A431) tumor-bearing nude mice with s.c. tumor xenografts derived from Tac antigen-positive ATAC4 cells and receptor-negative A431 cells. These animals were coinjected with 30 mg of lysine i.v. and 30 mg of lysine i.p. 15 min after the radiolabeled Fab injection. To evaluate the biodistribution data and study scintigraphic imaging, we performed serial scintigraphy on normal and tumor-bearing mice with all four 131I-labeled preparations. 125I-labeled mildly cationic glyco-Fab and 131I-labeled nonglycolated Fab had similar distributions, except in the kidney. However, both 125I-labeled anionic glyco-Fab preparations showed significantly different distributions from both cationic Fabs in the blood, liver, lung, and spleen. Renal accumulation of all four radiolabeled Fab preparations increased significantly as the pI increased (P < 0.01). In addition, the intact fraction of Fab excreted into urine increased as pI decreased. Therefore, the glomerular filtration depended on whether the charge on the Fab was positive or negative. The proportion of Fab reabsorbed by the proximal tubules increased as pI increased. 125I-labeled sa-glyco-Fab and 125I-labeled mildly anionic glyco-Fab showed a similar distribution in the blood and all organs except the kidney. Lysine led to an additional blocking effect on proximal tubular uptake of both sa-glyco-Fab and nonglycolated Fab. Addition of furosemide yielded only a small effect when used with lysine. With lysine, the sa-glyco-Fab:nonglycolated Fab estimated integral radioactivity ratios were 4.7 and 0.7 in the ATAC4 tumor and in the kidney, respectively. The use of anionic fragments, which may be used in conjunction with lysine, represents a promising approach that may help decrease the renal toxicity of other small fragments, the molecular weights of which range from Mr 40,000 to 70,000, and, thereby, allow higher doses of radiation to the tumor.</description><subject>Animals</subject><subject>Antineoplastic agents</subject><subject>Biological and medical sciences</subject><subject>Female</subject><subject>Furosemide - pharmacology</subject><subject>Glycosylation</subject><subject>Immunoglobulin Fab Fragments - metabolism</subject><subject>Immunotherapy</subject><subject>Iodine Radioisotopes</subject><subject>Isoelectric Point</subject><subject>Kidney - metabolism</subject><subject>Lysine - pharmacology</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Nude</subject><subject>Pharmacology. Drug treatments</subject><subject>Radioimmunodetection</subject><subject>Receptors, Interleukin-2 - immunology</subject><subject>Tissue Distribution</subject><issn>0008-5472</issn><issn>1538-7445</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1999</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kE1LxDAQhoMo67r6E4QcxFshSZOmPcriFyx4Wc9lkk5ttF8m6WH99QYsnmZe3mdeZuaMbLnKy0xLqc7JljFWZkpqcUmuQvhMUnGmNmRTVUIzpbckHjukcwd-ADt9uRGjs9QmDTaidyHJQKeWfvQnO_UQsaHdMsDoflIHY3RZBEufwAQKHmmDaWpIMQ01Jxo7dJ66MGGPNvqUPE9ujOGaXLTQB7xZ6468Pz0e9y_Z4e35df9wyDpRlTFDjnkDpUxLK9MyAUyjqLgxSmhrDReFkg3LdYtCiQJKJYwFbSEdXQpVyXxH7v9yZz99LxhiPbhgse9hxGkJNddCyEQn8HYFFzNgU8_eDeBP9fqm5N-tPgQLfethtC78Y7youCzy_Bc9iHMi</recordid><startdate>19990115</startdate><enddate>19990115</enddate><creator>KOBAYASHI, H</creator><creator>NHAT LE</creator><creator>KIM, I.-S</creator><creator>KIM, M.-K</creator><creator>PIE, J.-E</creator><creator>DRUMM, D</creator><creator>PAIK, D. S</creator><creator>WALDMANN, T. A</creator><creator>PAIK, C. H</creator><creator>CARRASQUILLO, J. A</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>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope></search><sort><creationdate>19990115</creationdate><title>The pharmacokinetic characteristics of glycolated humanized anti-tac Fabs are determined by their isoelectric points</title><author>KOBAYASHI, H ; NHAT LE ; KIM, I.-S ; KIM, M.-K ; PIE, J.-E ; DRUMM, D ; PAIK, D. S ; WALDMANN, T. A ; PAIK, C. H ; CARRASQUILLO, J. 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Drug treatments</topic><topic>Radioimmunodetection</topic><topic>Receptors, Interleukin-2 - immunology</topic><topic>Tissue Distribution</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>KOBAYASHI, H</creatorcontrib><creatorcontrib>NHAT LE</creatorcontrib><creatorcontrib>KIM, I.-S</creatorcontrib><creatorcontrib>KIM, M.-K</creatorcontrib><creatorcontrib>PIE, J.-E</creatorcontrib><creatorcontrib>DRUMM, D</creatorcontrib><creatorcontrib>PAIK, D. S</creatorcontrib><creatorcontrib>WALDMANN, T. A</creatorcontrib><creatorcontrib>PAIK, C. H</creatorcontrib><creatorcontrib>CARRASQUILLO, J. A</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>Biotechnology Research Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><jtitle>Cancer research (Chicago, Ill.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>KOBAYASHI, H</au><au>NHAT LE</au><au>KIM, I.-S</au><au>KIM, M.-K</au><au>PIE, J.-E</au><au>DRUMM, D</au><au>PAIK, D. S</au><au>WALDMANN, T. A</au><au>PAIK, C. H</au><au>CARRASQUILLO, J. A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The pharmacokinetic characteristics of glycolated humanized anti-tac Fabs are determined by their isoelectric points</atitle><jtitle>Cancer research (Chicago, Ill.)</jtitle><addtitle>Cancer Res</addtitle><date>1999-01-15</date><risdate>1999</risdate><volume>59</volume><issue>2</issue><spage>422</spage><epage>430</epage><pages>422-430</pages><issn>0008-5472</issn><eissn>1538-7445</eissn><coden>CNREA8</coden><abstract>To evaluate a method for preventing the nephrotoxicity caused by the high renal accumulation of radiolabeled or toxin-conjugated small immunoproteins used for cancer therapy, we conjugated humanized anti-Tac Fab fragments with various numbers of glycolate molecules [glycolated Fab fragments (glyco-Fabs)] and separated the conjugates by means of ion-exchange columns into three fractions, depending on their isoelectric points (pIs). We evaluated the biodistribution, pharmacokinetics, and catabolism in normal nude mice of nonglycolated Fab (pI > or = 9.3) and three different preparations of glyco-Fab, including strongly anionic glyco-Fab (sa-glyco-Fab: pI < or = 4.5), mildly anionic glyco-Fab (pI = 4.5-7), and mildly cationic glyco-Fab (pI = 7-9.3). In addition, the biodistributions of 125I-labeled sa-glyco-Fab and 131I-labeled nonglycolated Fab were evaluated in normal nude mice coinjected with 50 mg of L-lysine and/or 1 microg of furosemide and in a control group without coinjection. We then evaluated the serial biodistribution of 125I-labeled sa-glyco-Fab (4 microCi/1 microg) and 131I-labeled nonglycolated Fab (5 microCi/1 microg) in Tac antigen-positive (ATAC4) and -negative (A431) tumor-bearing nude mice with s.c. tumor xenografts derived from Tac antigen-positive ATAC4 cells and receptor-negative A431 cells. These animals were coinjected with 30 mg of lysine i.v. and 30 mg of lysine i.p. 15 min after the radiolabeled Fab injection. To evaluate the biodistribution data and study scintigraphic imaging, we performed serial scintigraphy on normal and tumor-bearing mice with all four 131I-labeled preparations. 125I-labeled mildly cationic glyco-Fab and 131I-labeled nonglycolated Fab had similar distributions, except in the kidney. However, both 125I-labeled anionic glyco-Fab preparations showed significantly different distributions from both cationic Fabs in the blood, liver, lung, and spleen. Renal accumulation of all four radiolabeled Fab preparations increased significantly as the pI increased (P < 0.01). In addition, the intact fraction of Fab excreted into urine increased as pI decreased. Therefore, the glomerular filtration depended on whether the charge on the Fab was positive or negative. The proportion of Fab reabsorbed by the proximal tubules increased as pI increased. 125I-labeled sa-glyco-Fab and 125I-labeled mildly anionic glyco-Fab showed a similar distribution in the blood and all organs except the kidney. Lysine led to an additional blocking effect on proximal tubular uptake of both sa-glyco-Fab and nonglycolated Fab. Addition of furosemide yielded only a small effect when used with lysine. With lysine, the sa-glyco-Fab:nonglycolated Fab estimated integral radioactivity ratios were 4.7 and 0.7 in the ATAC4 tumor and in the kidney, respectively. The use of anionic fragments, which may be used in conjunction with lysine, represents a promising approach that may help decrease the renal toxicity of other small fragments, the molecular weights of which range from Mr 40,000 to 70,000, and, thereby, allow higher doses of radiation to the tumor.</abstract><cop>Philadelphia, PA</cop><pub>American Association for Cancer Research</pub><pmid>9927057</pmid><tpages>9</tpages></addata></record> |
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| ispartof | Cancer research (Chicago, Ill.), 1999-01, Vol.59 (2), p.422-430 |
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| source | MEDLINE; American Association for Cancer Research; EZB-FREE-00999 freely available EZB journals |
| subjects | Animals Antineoplastic agents Biological and medical sciences Female Furosemide - pharmacology Glycosylation Immunoglobulin Fab Fragments - metabolism Immunotherapy Iodine Radioisotopes Isoelectric Point Kidney - metabolism Lysine - pharmacology Medical sciences Mice Mice, Nude Pharmacology. Drug treatments Radioimmunodetection Receptors, Interleukin-2 - immunology Tissue Distribution |
| title | The pharmacokinetic characteristics of glycolated humanized anti-tac Fabs are determined by their isoelectric points |
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