Abstract:
:Antibody-drug conjugates (ADC) represent a promising therapeutic modality for the clinical management of cancer. We sought to develop a novel ADC that targets 5T4, an oncofetal antigen expressed on tumor-initiating cells (TIC), which comprise the most aggressive cell population in the tumor. We optimized an anti-5T4 ADC (A1mcMMAF) by sulfydryl-based conjugation of the humanized A1 antibody to the tubulin inhibitor monomethylauristatin F (MMAF) via a maleimidocaproyl linker. A1mcMMAF exhibited potent in vivo antitumor activity in a variety of tumor models and induced long-term regressions for up to 100 days after the last dose. Strikingly, animals showed pathologic complete response in each model with doses as low as 3 mg antibody/kg dosed every 4 days. In a non-small cell lung cancer patient-derived xenograft model, in which 5T4 is preferentially expressed on the less differentiated tumor cells, A1mcMMAF treatment resulted in sustained tumor regressions and reduced TIC frequency. These results highlight the potential of ADCs that target the most aggressive cell populations within tumors, such as TICs. In exploratory safety studies, A1mcMMAF exhibited no overt toxicities when administered to cynomolgus monkeys at doses up to 10 mg antibody/kg/cycle × 2 and displayed a half-life of 5 days. The preclinical efficacy and safety data established a promising therapeutic index that supports clinical testing of A1mcMMAF.
journal_name
Mol Cancer Therjournal_title
Molecular cancer therapeuticsauthors
Sapra P,Damelin M,Dijoseph J,Marquette K,Geles KG,Golas J,Dougher M,Narayanan B,Giannakou A,Khandke K,Dushin R,Ernstoff E,Lucas J,Leal M,Hu G,O'Donnell CJ,Tchistiakova L,Abraham RT,Gerber HPdoi
10.1158/1535-7163.MCT-12-0603subject
Has Abstractpub_date
2013-01-01 00:00:00pages
38-47issue
1eissn
1535-7163issn
1538-8514pii
1535-7163.MCT-12-0603journal_volume
12pub_type
杂志文章abstract::Our previous studies and those of others have indicated that X-linked inhibitor of apoptosis protein (XIAP) holds promise as a target gene in colon cancer gene therapy. In this study, we constructed an adenoviral vector to deliver small hairpin RNA (shRNA) against XIAP (XIAP-shRNA) into colon cancer cells and tested i...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-13-0395
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journal_title:Molecular cancer therapeutics
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journal_title:Molecular cancer therapeutics
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
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pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-11-0303
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pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-08-0183
更新日期:2008-06-01 00:00:00
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journal_title:Molecular cancer therapeutics
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pub_type: 杂志文章
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pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-17-1240
更新日期:2018-09-01 00:00:00
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pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-04-0290
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pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-14-0209
更新日期:2014-10-01 00:00:00
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-15-0598
更新日期:2016-04-01 00:00:00
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pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-07-0444
更新日期:2007-12-01 00:00:00
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-06-0073
更新日期:2006-06-01 00:00:00
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-16-0683
更新日期:2017-04-01 00:00:00
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pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-09-0906
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-09-1036
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:
更新日期:2002-06-01 00:00:00
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
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更新日期:2004-12-01 00:00:00
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pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-18-0212
更新日期:2018-10-01 00:00:00
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-10-1117
更新日期:2011-08-01 00:00:00
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-12-1218
更新日期:2013-10-01 00:00:00
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-09-0493
更新日期:2009-11-01 00:00:00
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
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更新日期:2015-11-01 00:00:00