RT Journal Article
SR Electronic
T1 Tumor-Specific Activation of an EGFR-Targeting Probody Enhances Therapeutic Index
JF Science Translational Medicine
FD American Association for the Advancement of Science
SP 207ra144
OP 207ra144
DO 10.1126/scitranslmed.3006682
VO 5
IS 207
A1 Desnoyers, Luc R.
A1 Vasiljeva, Olga
A1 Richardson, Jennifer H.
A1 Yang, Annie
A1 Menendez, Elizabeth E. M.
A1 Liang, Tony W.
A1 Wong, Chihunt
A1 Bessette, Paul H.
A1 Kamath, Kathy
A1 Moore, Stephen J.
A1 Sagert, Jason G.
A1 Hostetter, Daniel R.
A1 Han, Fei
A1 Gee, Jason
A1 Flandez, Jeanne
A1 Markham, Kate
A1 Nguyen, Margaret
A1 Krimm, Michael
A1 Wong, Kenneth R.
A1 Liu, Shouchun
A1 Daugherty, Patrick S.
A1 West, James W.
A1 Lowman, Henry B.
YR 2013
UL http://stm.sciencemag.org/content/5/207/207ra144.abstract
AB Target-mediated toxicity constitutes a major limitation for the development of therapeutic antibodies. To redirect the activity of antibodies recognizing widely distributed targets to the site of disease, we have applied a prodrug strategy to create an epidermal growth factor receptor (EGFR)–directed Probody therapeutic—an antibody that remains masked against antigen binding until activated locally by proteases commonly active in the tumor microenvironment. In vitro, the masked Probody showed diminished antigen binding and cell-based activities, but when activated by appropriate proteases, it regained full activity compared to the parental anti-EGFR antibody cetuximab. In vivo, the Probody was largely inert in the systemic circulation of mice, but was activated within tumor tissue and showed antitumor efficacy that was similar to that of cetuximab. The Probody demonstrated markedly improved safety and increased half-life in nonhuman primates, enabling it to be dosed safely at much higher levels than cetuximab. In addition, we found that both Probody-responsive xenograft tumors and primary tumor samples from patients were capable of activating the Probody ex vivo. Probodies may therefore improve the safety profile of therapeutic antibodies without compromising efficacy of the parental antibody and may enable the wider use of empowered antibody formats such as antibody-drug conjugates and bispecifics.