ArticleProceedings of the National Academy of Sciences of the United States of America2019
Structure-guided design fine-tunes pharmacokinetics, tolerability, and antitumor profile of multispecific frizzled antibodies.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
18 citing papers in PubMed.
- Targeting frizzled receptors (FZDs) for anti-tumor therapy: From orthosteric to allosteric inhibition.Acta pharmaceutica Sinica. B · 2026Review
- Targeting frizzleds with small-molecule compounds-back to square one or light at the end of the tunnel?The Journal of biological chemistry · 2026Review
- Tumor-targeted bispecific antibodies effectively inhibit oncogenic pathways while minimizing toxicity.Science advances · 2026Article
- A preliminary exploration of the role and mechanisms of CD93 in promoting the malignant progression of head and neck squamous cell carcinoma.Frontiers in pharmacology · 2026Article
- Targeting FZD6 creates therapeutically actionable vulnerabilities for advanced prostate cancer.Oncogene · 2025Article
- Targeted inhibition of Wnt signaling with a Clostridioides difficile toxin B fragment suppresses breast cancer tumor growth.PLoS biology · 2023Article
- A New Wave of Targeting 'Undruggable' Wnt Signaling for Cancer Therapy: Challenges and Opportunities.Cells · 2023Review
- Role of prostate cancer stem-like cells in the development of antiandrogen resistance.Cancer drug resistance (Alhambra, Calif.) · 2022Review
- An atlas of CNV maps in cattle, goat and sheep.Science China. Life sciences · 2021Article
- Carboxylesterase Notum Is a Druggable Target to Modulate Wnt Signaling.Journal of medicinal chemistry · 2021Article
- Long Non-Coding RNA Landscape in Prostate Cancer Molecular Subtypes: A Feature Selection Approach.International journal of molecular sciences · 2021Article
- Structure-Guided Molecular Engineering of a Vascular Endothelial Growth Factor Antagonist to Treat Retinal Diseases.Cellular and molecular bioengineering · 2020Article
- The structural biology of canonical Wnt signalling.Biochemical Society transactions · 2020Review
- Article
- Macromolecular crystallography beamlines at the Canadian Light Source: building on success.Acta crystallographica. Section D, Structural biology · 2020Article
- Review Article: Is Wnt Signaling an Attractive Target for the Treatment of Osteoarthritis?Rheumatology and therapy · 2020Review
- Antiepileptic Drug Carbamazepine Binds to a Novel Pocket on the Wnt Receptor Frizzled-8.Journal of medicinal chemistry · 2020Article
- Aberrant WNT/CTNNB1 Signaling as a Therapeutic Target in Human Breast Cancer: Weighing the Evidence.Frontiers in cell and developmental biology · 2020Review
Corrections and comments
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Authors and funding
20 authors.
Funding
Abstract
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.
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