کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
10914527 | 1088791 | 2016 | 11 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Dual Constant Domain-Fab: A novel strategy to improve half-life and potency of a Met therapeutic antibody
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کلمات کلیدی
EGFRHGFRCancer targeted therapyHGFmAbMonoclonal antibody - آنتی بادی مونوکلونالstandard error of the mean - خطای استاندارد میانگینNSCLC - سرطان ریوی غیر سلول کوچکNon-small cell lung cancer - سرطان غیر سلول کوچک ریهHepatocyte growth factor - عامل رشد هپاتوسیتFab - فابSEM - مدل معادلات ساختاری / میکروسکوپ الکترونی روبشیMET - ملاقات کردProtein engineering - مهندسی پروتئینHalf-life - نیمه عمرAntibody - پادتَن یا آنتیبادیPoly ethylene glycol - پلی اتیلن گلیکولPEG - پلیاتیلن گلیکول CRC - کد افزونگی دورهای hepatocyte growth factor receptor - گیرنده عامل فاکتور رشد هپاتوسیتEpidermal growth factor receptor - گیرنده فاکتور رشد اپیدرمال
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
تحقیقات سرطان
پیش نمایش صفحه اول مقاله
![عکس صفحه اول مقاله: Dual Constant Domain-Fab: A novel strategy to improve half-life and potency of a Met therapeutic antibody Dual Constant Domain-Fab: A novel strategy to improve half-life and potency of a Met therapeutic antibody](/preview/png/10914527.png)
چکیده انگلیسی
The kinase receptor encoded by the Met oncogene is a sensible target for cancer therapy. The chimeric monovalent Fab fragment of the DN30 monoclonal antibody (MvDN30) has an odd mechanism of action, based on cell surface removal of Met via activation of specific plasma membrane proteases. However, the short half-life of the Fab, due to its low molecular weight, is a severe limitation for the deployment in therapy. This issue was addressed by increasing the Fab molecular weight above the glomerular filtration threshold through the duplication of the constant domains, in tandem (DCD-1) or reciprocally swapped (DCD-2). The two newly engineered molecules showed biochemical properties comparable to the original MvDN30 in vitro, acting as full Met antagonists, impairing Met phosphorylation and activation of downstream signaling pathways. As a consequence, Met-mediated biological responses were inhibited, including anchorage-dependent and -independent cell growth. In vivo DCD-1 and DCD-2 showed a pharmacokinetic profile significantly improved over the original MvDN30, doubling the circulating half-life and reducing the clearance. In pre-clinical models of cancer, generated by injection of tumor cells or implant of patient-derived samples, systemic administration of the engineered molecules inhibited the growth of Met-addicted tumors.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Molecular Oncology - Volume 10, Issue 6, June 2016, Pages 938-948
Journal: Molecular Oncology - Volume 10, Issue 6, June 2016, Pages 938-948
نویسندگان
Simona Cignetto, Chiara Modica, Cristina Chiriaco, Lara Fontani, Paola Milla, Paolo Michieli, Paolo M. Comoglio, Elisa Vigna,