Structure-guided design fine-tunes pharmacokinetics, tolerability, and antitumor profile of multispecific frizzled antibodies.
Frizzled receptors
Wnt signaling
X-ray crystallography
antibody therapeutic
protein engineering
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
02 04 2019
02 04 2019
Historique:
pubmed:
22
3
2019
medline:
22
5
2019
entrez:
22
3
2019
Statut:
ppublish
Résumé
Aberrant activation of Wnt/β-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 monoclonal antibodies (mAbs) on FZD, blocking the interaction with the Wnt palmitoleic acid moiety. However, these mAbs displayed gastrointestinal 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.
Identifiants
pubmed: 30894493
pii: 1817246116
doi: 10.1073/pnas.1817246116
pmc: PMC6452705
doi:
Substances chimiques
Antineoplastic Agents, Immunological
0
FZD10 protein, human
0
FZD6 protein, human
0
Frizzled Receptors
0
Banques de données
PDB
['6O39', '6O3A', '6O3B']
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
6812-6817Subventions
Organisme : NIH HHS
ID : S10 OD012289
Pays : United States
Organisme : Canadian Institutes of Health Research
Pays : International
Déclaration de conflit d'intérêts
Conflict of interest statement: The authors have filed a patent application for the antibodies described in this work.
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