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6O39

Crystal structure of Frizzled 5 CRD in complex with F2.I Fab

Summary for 6O39
Entry DOI10.2210/pdb6o39/pdb
DescriptorAntibody F2.I Fab, Light chain, Antibody F2.I Fab, Heavy chain, Frizzled-5, ... (7 entities in total)
Functional Keywordsreceptor, wnt, frizzled, crd, antibody, signaling protein
Biological sourceHomo sapiens
More
Total number of polymer chains3
Total formula weight61757.36
Authors
Raman, S.,Beilschmidt, M.,Fransson, J.,Julien, J.P. (deposition date: 2019-02-26, release date: 2019-04-03, Last modification date: 2023-10-11)
Primary citationRaman, S.,Beilschmidt, M.,To, M.,Lin, K.,Lui, F.,Jmeian, Y.,Ng, M.,Fernandez, M.,Fu, Y.,Mascall, K.,Duque, A.,Wang, X.,Pan, G.,Angers, S.,Moffat, J.,Sidhu, S.S.,Magram, J.,Sinclair, A.M.,Fransson, J.,Julien, J.P.
Structure-guided design fine-tunes pharmacokinetics, tolerability, and antitumor profile of multispecific frizzled antibodies.
Proc. Natl. Acad. Sci. U.S.A., 116:6812-6817, 2019
Cited by
PubMed 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.
PubMed: 30894493
DOI: 10.1073/pnas.1817246116
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (1.8 Å)
Structure validation

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