Preclinical toxicity evaluation of a novel immunotoxin, D2C7-(scdsFv)-PE38KDEL, administered via intracerebral convection-enhanced delivery in rats
Summary D2C7-(scdsFv)-PE38KDEL (D2C7-IT) is a novel immunotoxin that reacts with wild-type epidermal growth factor receptor (EGFRwt) and mutant EGFRvIII proteins overexpressed in glioblastomas. This study assessed the toxicity of intracerebral administration of D2C7-IT to support an initial Food and...
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| Veröffentlicht in: | Investigational new drugs 2016-04, Vol.34 (2), p.149-158 |
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| creator | Bao, Xuhui Chandramohan, Vidyalakshmi Reynolds, Randall P. Norton, John N. Wetsel, William C. Rodriguiz, Ramona M. Aryal, Dipendra K. McLendon, Roger E. Levin, Edward D. Petry, Neil A. Zalutsky, Michael R. Burnett, Bruce K. Kuan, Chien-Tsun Pastan, Ira H. Bigner, Darell D. |
| description | Summary
D2C7-(scdsFv)-PE38KDEL (D2C7-IT) is a novel immunotoxin that reacts with wild-type epidermal growth factor receptor (EGFRwt) and mutant EGFRvIII proteins overexpressed in glioblastomas. This study assessed the toxicity of intracerebral administration of D2C7-IT to support an initial Food and Drug Administration Investigational New Drug application. After the optimization of the formulation and administration, two cohorts (an acute and chronic cohort necropsied on study days 5 and 34) of Sprague–Dawley (SD) rats (four groups of 5 males and 5 females) were infused with the D2C7-IT formulation at total doses of 0, 0.05, 0.1, 0.4 μg (the acute cohort) and 0, 0.05, 0.1, 0.35 μg (the chronic cohort) for approximately 72 h by intracerebral convection-enhanced delivery using osmotic pumps. Mortality was observed in the 0.40 μg (5/10 rats) and 0.35 μg (4/10 rats) high-dose groups of each cohort. Body weight loss and abnormal behavior were only revealed in the rats treated with high doses of D2C7-IT. No dose-related effects were observed in clinical laboratory tests in either cohort. A gross pathologic examination of systemic tissues from the high-dose and control groups in both cohorts exhibited no dose-related or drug-related pathologic findings. Brain histopathology revealed the frequent occurrence of dose-related encephalomalacia, edema, and demyelination in the high-dose groups of both cohorts. In this study, the maximum tolerated dose of D2C7-IT was determined to be between 0.10 and 0.35 μg, and the no-observed-adverse-effect-level was 0.05 μg in SD rats. Both parameters were utilized to design the Phase I/II D2C7-IT clinical trial. |
| doi_str_mv | 10.1007/s10637-015-0318-3 |
| format | Article |
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D2C7-(scdsFv)-PE38KDEL (D2C7-IT) is a novel immunotoxin that reacts with wild-type epidermal growth factor receptor (EGFRwt) and mutant EGFRvIII proteins overexpressed in glioblastomas. This study assessed the toxicity of intracerebral administration of D2C7-IT to support an initial Food and Drug Administration Investigational New Drug application. After the optimization of the formulation and administration, two cohorts (an acute and chronic cohort necropsied on study days 5 and 34) of Sprague–Dawley (SD) rats (four groups of 5 males and 5 females) were infused with the D2C7-IT formulation at total doses of 0, 0.05, 0.1, 0.4 μg (the acute cohort) and 0, 0.05, 0.1, 0.35 μg (the chronic cohort) for approximately 72 h by intracerebral convection-enhanced delivery using osmotic pumps. Mortality was observed in the 0.40 μg (5/10 rats) and 0.35 μg (4/10 rats) high-dose groups of each cohort. Body weight loss and abnormal behavior were only revealed in the rats treated with high doses of D2C7-IT. No dose-related effects were observed in clinical laboratory tests in either cohort. A gross pathologic examination of systemic tissues from the high-dose and control groups in both cohorts exhibited no dose-related or drug-related pathologic findings. Brain histopathology revealed the frequent occurrence of dose-related encephalomalacia, edema, and demyelination in the high-dose groups of both cohorts. In this study, the maximum tolerated dose of D2C7-IT was determined to be between 0.10 and 0.35 μg, and the no-observed-adverse-effect-level was 0.05 μg in SD rats. Both parameters were utilized to design the Phase I/II D2C7-IT clinical trial.</description><identifier>ISSN: 0167-6997</identifier><identifier>EISSN: 1573-0646</identifier><identifier>DOI: 10.1007/s10637-015-0318-3</identifier><identifier>PMID: 26728879</identifier><identifier>CODEN: INNDDK</identifier><language>eng</language><publisher>New York: Springer US</publisher><subject>Animals ; Brain - drug effects ; Brain - pathology ; Brain cancer ; Brain research ; Cancer therapies ; Clinical trials ; Convection ; Cytotoxicity ; Drug Delivery Systems ; Drug dosages ; Drug Evaluation, Preclinical ; Epidermal growth factor ; Female ; Gene amplification ; Glioma ; Immunoconjugates - administration & dosage ; Immunoconjugates - toxicity ; Immunotoxins - administration & dosage ; Immunotoxins - toxicity ; Inhibitory Concentration 50 ; Injections, Intraventricular ; Laboratory animals ; Male ; Males ; Medical research ; Medicine ; Medicine & Public Health ; Neurosciences ; Oncology ; Pharmacology/Toxicology ; Preclinical Studies ; Proteins ; Rats, Sprague-Dawley ; Single-Chain Antibodies - administration & dosage ; Single-Chain Antibodies - toxicity ; Studies ; Toxicity ; Tumors</subject><ispartof>Investigational new drugs, 2016-04, Vol.34 (2), p.149-158</ispartof><rights>Springer Science+Business Media New York 2016</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c573t-cd09b961750a2c29509f0335f932cb12d020390dd2d7b72a32f8f6a3baf992f63</citedby><cites>FETCH-LOGICAL-c573t-cd09b961750a2c29509f0335f932cb12d020390dd2d7b72a32f8f6a3baf992f63</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s10637-015-0318-3$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s10637-015-0318-3$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>230,314,780,784,885,27924,27925,41488,42557,51319</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26728879$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Bao, Xuhui</creatorcontrib><creatorcontrib>Chandramohan, Vidyalakshmi</creatorcontrib><creatorcontrib>Reynolds, Randall P.</creatorcontrib><creatorcontrib>Norton, John N.</creatorcontrib><creatorcontrib>Wetsel, William C.</creatorcontrib><creatorcontrib>Rodriguiz, Ramona M.</creatorcontrib><creatorcontrib>Aryal, Dipendra K.</creatorcontrib><creatorcontrib>McLendon, Roger E.</creatorcontrib><creatorcontrib>Levin, Edward D.</creatorcontrib><creatorcontrib>Petry, Neil A.</creatorcontrib><creatorcontrib>Zalutsky, Michael R.</creatorcontrib><creatorcontrib>Burnett, Bruce K.</creatorcontrib><creatorcontrib>Kuan, Chien-Tsun</creatorcontrib><creatorcontrib>Pastan, Ira H.</creatorcontrib><creatorcontrib>Bigner, Darell D.</creatorcontrib><title>Preclinical toxicity evaluation of a novel immunotoxin, D2C7-(scdsFv)-PE38KDEL, administered via intracerebral convection-enhanced delivery in rats</title><title>Investigational new drugs</title><addtitle>Invest New Drugs</addtitle><addtitle>Invest New Drugs</addtitle><description>Summary
D2C7-(scdsFv)-PE38KDEL (D2C7-IT) is a novel immunotoxin that reacts with wild-type epidermal growth factor receptor (EGFRwt) and mutant EGFRvIII proteins overexpressed in glioblastomas. This study assessed the toxicity of intracerebral administration of D2C7-IT to support an initial Food and Drug Administration Investigational New Drug application. After the optimization of the formulation and administration, two cohorts (an acute and chronic cohort necropsied on study days 5 and 34) of Sprague–Dawley (SD) rats (four groups of 5 males and 5 females) were infused with the D2C7-IT formulation at total doses of 0, 0.05, 0.1, 0.4 μg (the acute cohort) and 0, 0.05, 0.1, 0.35 μg (the chronic cohort) for approximately 72 h by intracerebral convection-enhanced delivery using osmotic pumps. Mortality was observed in the 0.40 μg (5/10 rats) and 0.35 μg (4/10 rats) high-dose groups of each cohort. Body weight loss and abnormal behavior were only revealed in the rats treated with high doses of D2C7-IT. No dose-related effects were observed in clinical laboratory tests in either cohort. A gross pathologic examination of systemic tissues from the high-dose and control groups in both cohorts exhibited no dose-related or drug-related pathologic findings. Brain histopathology revealed the frequent occurrence of dose-related encephalomalacia, edema, and demyelination in the high-dose groups of both cohorts. In this study, the maximum tolerated dose of D2C7-IT was determined to be between 0.10 and 0.35 μg, and the no-observed-adverse-effect-level was 0.05 μg in SD rats. Both parameters were utilized to design the Phase I/II D2C7-IT clinical trial.</description><subject>Animals</subject><subject>Brain - drug effects</subject><subject>Brain - pathology</subject><subject>Brain cancer</subject><subject>Brain research</subject><subject>Cancer therapies</subject><subject>Clinical trials</subject><subject>Convection</subject><subject>Cytotoxicity</subject><subject>Drug Delivery Systems</subject><subject>Drug dosages</subject><subject>Drug Evaluation, Preclinical</subject><subject>Epidermal growth factor</subject><subject>Female</subject><subject>Gene amplification</subject><subject>Glioma</subject><subject>Immunoconjugates - administration & dosage</subject><subject>Immunoconjugates - toxicity</subject><subject>Immunotoxins - administration & dosage</subject><subject>Immunotoxins - toxicity</subject><subject>Inhibitory Concentration 50</subject><subject>Injections, Intraventricular</subject><subject>Laboratory animals</subject><subject>Male</subject><subject>Males</subject><subject>Medical research</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Neurosciences</subject><subject>Oncology</subject><subject>Pharmacology/Toxicology</subject><subject>Preclinical Studies</subject><subject>Proteins</subject><subject>Rats, Sprague-Dawley</subject><subject>Single-Chain Antibodies - administration & dosage</subject><subject>Single-Chain Antibodies - toxicity</subject><subject>Studies</subject><subject>Toxicity</subject><subject>Tumors</subject><issn>0167-6997</issn><issn>1573-0646</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><recordid>eNp1kVFrFDEUhYModlv9Ab5IwJcWGr1JdiaTF0G2WxUX7IM-h0ySaVNmkprMDO7v8A-bYWupgk8h3O-eew4HoVcU3lIA8S5TqLkgQCsCnDaEP0ErWglOoF7XT9EKaC1ILaU4Qsc53wIAl2L9HB2xWrCmEXKFfl0lZ3ofvNE9HuNPb_y4x27W_aRHHwOOHdY4xNn12A_DFOIChXN8wTaCnGZj8-V8Rq62vPlysd2dY22HopZHl5zFs9fYhzFpU75tKidMDLMzizJx4UYHUyjrej-7tC8oTnrML9CzTvfZvbx_T9D3y-23zSey-_rx8-bDjpiScSTGgmxlTUUFmhkmK5AdcF51kjPTUmaBlbxgLbOiFUxz1jVdrXmrOylZV_MT9P6geze1g7PGLU57dZf8oNNeRe3V35Pgb9R1nNVaNE1VQRE4vRdI8cfk8qgGn43rex1cnLKioqkYZ4It6Jt_0Ns4pVDiFaoAVTErCkUPlEkx5-S6BzMU1FK5OlSuSuVqqVzxsvP6cYqHjT8dF4AdgFxG4dqlR6f_q_obAHO4dg</recordid><startdate>20160401</startdate><enddate>20160401</enddate><creator>Bao, 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toxicity evaluation of a novel immunotoxin, D2C7-(scdsFv)-PE38KDEL, administered via intracerebral convection-enhanced delivery in rats</title><author>Bao, Xuhui ; Chandramohan, Vidyalakshmi ; Reynolds, Randall P. ; Norton, John N. ; Wetsel, William C. ; Rodriguiz, Ramona M. ; Aryal, Dipendra K. ; McLendon, Roger E. ; Levin, Edward D. ; Petry, Neil A. ; Zalutsky, Michael R. ; Burnett, Bruce K. ; Kuan, Chien-Tsun ; Pastan, Ira H. ; Bigner, Darell D.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c573t-cd09b961750a2c29509f0335f932cb12d020390dd2d7b72a32f8f6a3baf992f63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Animals</topic><topic>Brain - drug effects</topic><topic>Brain - pathology</topic><topic>Brain cancer</topic><topic>Brain research</topic><topic>Cancer therapies</topic><topic>Clinical trials</topic><topic>Convection</topic><topic>Cytotoxicity</topic><topic>Drug Delivery Systems</topic><topic>Drug dosages</topic><topic>Drug Evaluation, Preclinical</topic><topic>Epidermal growth factor</topic><topic>Female</topic><topic>Gene amplification</topic><topic>Glioma</topic><topic>Immunoconjugates - administration & dosage</topic><topic>Immunoconjugates - toxicity</topic><topic>Immunotoxins - administration & dosage</topic><topic>Immunotoxins - toxicity</topic><topic>Inhibitory Concentration 50</topic><topic>Injections, Intraventricular</topic><topic>Laboratory animals</topic><topic>Male</topic><topic>Males</topic><topic>Medical research</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Neurosciences</topic><topic>Oncology</topic><topic>Pharmacology/Toxicology</topic><topic>Preclinical Studies</topic><topic>Proteins</topic><topic>Rats, Sprague-Dawley</topic><topic>Single-Chain Antibodies - administration & dosage</topic><topic>Single-Chain Antibodies - 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Drugs</addtitle><date>2016-04-01</date><risdate>2016</risdate><volume>34</volume><issue>2</issue><spage>149</spage><epage>158</epage><pages>149-158</pages><issn>0167-6997</issn><eissn>1573-0646</eissn><coden>INNDDK</coden><abstract>Summary
D2C7-(scdsFv)-PE38KDEL (D2C7-IT) is a novel immunotoxin that reacts with wild-type epidermal growth factor receptor (EGFRwt) and mutant EGFRvIII proteins overexpressed in glioblastomas. This study assessed the toxicity of intracerebral administration of D2C7-IT to support an initial Food and Drug Administration Investigational New Drug application. After the optimization of the formulation and administration, two cohorts (an acute and chronic cohort necropsied on study days 5 and 34) of Sprague–Dawley (SD) rats (four groups of 5 males and 5 females) were infused with the D2C7-IT formulation at total doses of 0, 0.05, 0.1, 0.4 μg (the acute cohort) and 0, 0.05, 0.1, 0.35 μg (the chronic cohort) for approximately 72 h by intracerebral convection-enhanced delivery using osmotic pumps. Mortality was observed in the 0.40 μg (5/10 rats) and 0.35 μg (4/10 rats) high-dose groups of each cohort. Body weight loss and abnormal behavior were only revealed in the rats treated with high doses of D2C7-IT. No dose-related effects were observed in clinical laboratory tests in either cohort. A gross pathologic examination of systemic tissues from the high-dose and control groups in both cohorts exhibited no dose-related or drug-related pathologic findings. Brain histopathology revealed the frequent occurrence of dose-related encephalomalacia, edema, and demyelination in the high-dose groups of both cohorts. In this study, the maximum tolerated dose of D2C7-IT was determined to be between 0.10 and 0.35 μg, and the no-observed-adverse-effect-level was 0.05 μg in SD rats. Both parameters were utilized to design the Phase I/II D2C7-IT clinical trial.</abstract><cop>New York</cop><pub>Springer US</pub><pmid>26728879</pmid><doi>10.1007/s10637-015-0318-3</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Investigational new drugs, 2016-04, Vol.34 (2), p.149-158 |
| issn | 0167-6997 1573-0646 |
| language | eng |
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| source | MEDLINE; SpringerLink Journals - AutoHoldings |
| subjects | Animals Brain - drug effects Brain - pathology Brain cancer Brain research Cancer therapies Clinical trials Convection Cytotoxicity Drug Delivery Systems Drug dosages Drug Evaluation, Preclinical Epidermal growth factor Female Gene amplification Glioma Immunoconjugates - administration & dosage Immunoconjugates - toxicity Immunotoxins - administration & dosage Immunotoxins - toxicity Inhibitory Concentration 50 Injections, Intraventricular Laboratory animals Male Males Medical research Medicine Medicine & Public Health Neurosciences Oncology Pharmacology/Toxicology Preclinical Studies Proteins Rats, Sprague-Dawley Single-Chain Antibodies - administration & dosage Single-Chain Antibodies - toxicity Studies Toxicity Tumors |
| title | Preclinical toxicity evaluation of a novel immunotoxin, D2C7-(scdsFv)-PE38KDEL, administered via intracerebral convection-enhanced delivery in rats |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-07T08%3A07%3A21IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Preclinical%20toxicity%20evaluation%20of%20a%20novel%20immunotoxin,%20D2C7-(scdsFv)-PE38KDEL,%20administered%20via%20intracerebral%20convection-enhanced%20delivery%20in%20rats&rft.jtitle=Investigational%20new%20drugs&rft.au=Bao,%20Xuhui&rft.date=2016-04-01&rft.volume=34&rft.issue=2&rft.spage=149&rft.epage=158&rft.pages=149-158&rft.issn=0167-6997&rft.eissn=1573-0646&rft.coden=INNDDK&rft_id=info:doi/10.1007/s10637-015-0318-3&rft_dat=%3Cproquest_pubme%3E1785232720%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1772050207&rft_id=info:pmid/26728879&rfr_iscdi=true |