In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. 2486-2486
Kurzfassung:
Conjugation of small molecule drugs to specific sites on the antibody molecule has been increasingly used for the generation of relatively homogenous preparations of antibody-drug conjugates (ADCs) with physicochemical properties similar or identical to those of the naked antibody. We previously developed a method for conjugation of small molecules to glycoproteins through existing glycans by using an engineered glycotransferase and a chemically reactive sugar as a handle to conjugate a small molecule. Here, for the first time, we report the use of this method with some modifications to generate an ADC from a monoclonal antibody, m860, which we identified from a human naïve phage display Fab library by panning against the extracellular domain of human HER2. M860 bound to cell surface-associated HER2 with affinity comparable to that of trastuzumab (Herceptin®), but to a different epitope. The ADC m860 was generated by enzymatically adding a reactive keto-galactose to galactose-free m860 using an engineered glycotransferase and conjugating the reactive m860 to aminooxy auristatin F with a non-cleavable linker. It exhibited exceptional serum stability and potent and specific cell-killing activity against HER2 positive cancer cells, including trastuzumab-resistant breast cancer cells. This unique ADC may have utility as a potential therapeutic for HER2 positive cancers alone or in combination with other drugs. Our results also validate the keto-galactose/engineered glycotransferase method for generation of functional ADCs, which could potentially also be used for preparation of ADCs targeting other disease markers. This project was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, and by federal funds from the National Cancer Institute, NIH, under contract N01-CO-12400, HHSN261200800001E as well as by the SU2C-St.Baldrick's Foundation. Citation Format: Zhongyu Zhu, Ramakrishnan Boopathy, Jinyu Li, Ponraj Prabakaran, Simona Colantonio, Yang Feng, Yanping Wang, Marzena A. Dyba, Dimiter S. Dimitrov. Site-specific antibody-drug conjugation through an engineered glycotransferase and a chemically reactive sugar. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2486. doi:10.1158/1538-7445.AM2015-2486
Materialart:
Online-Ressource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2015-2486
Sprache:
Englisch
Verlag:
American Association for Cancer Research (AACR)
Publikationsdatum:
2015
ZDB Id:
2036785-5
ZDB Id:
1432-1
ZDB Id:
410466-3
