Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 116, Issue 14, Pages 6812-6817Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1817246116
Keywords
antibody therapeutic; Frizzled receptors; Wnt signaling; X-ray crystallography; protein engineering
Categories
Funding
- Mitacs Accelerate Grant [IT06689]
- Canada Research Chairs program
- Canada Foundation for Innovation
- Natural Sciences and Engineering Research Council of Canada
- University of Saskatchewan
- Government of Saskatchewan
- Western Economic Diversification Canada
- National Research Council Canada
- Canadian Institutes of Health Research
- National Cancer Institute [ACB-12002]
- National Institute of General Medical Sciences [AGM-12006]
- NIH-Office of Research Infrastructure Programs, High-End Instrumentation Grant [1S10OD012289-01A1]
- DOE Office of Science [DE-AC02-06CH11357]
Ask authors/readers for more resources
Aberrant activation of Wnt/beta-catenin signaling occurs frequently in cancer. However, therapeutic targeting of this pathway is complicated by the role of Wnt in stem cell maintenance and tissue homeostasis. Here, we evaluated antibodies blocking 6 of the 10 human Wnt/Frizzled (FZD) receptors as potential therapeutics. Crystal structures revealed a common binding site for these monodonal antibodies (mAbs) on FZD, blocking the interaction with the Wnt palmitoleic acid moiety. However, these mAbs displayed gastroin-testinal toxicity or poor plasma exposure in vivo. Structure-guided engineering was used to refine the binding of each mAb for FZD receptors, resulting in antibody variants with improved in vivo tolerability and developability. Importantly, the lead variant mAb significantly inhibited tumor growth in the HPAF-II pancreatic tumor xenograft model. Taken together, our data demonstrate that anti-FZD cancer therapeutic antibodies with broad specificity can be fine-tuned to navigate in vivo exposure and tolerability while driving therapeutic efficacy.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available