6O39
Crystal structure of Frizzled 5 CRD in complex with F2.I Fab
Summary for 6O39
Entry DOI | 10.2210/pdb6o39/pdb |
Descriptor | Antibody F2.I Fab, Light chain, Antibody F2.I Fab, Heavy chain, Frizzled-5, ... (7 entities in total) |
Functional Keywords | receptor, wnt, frizzled, crd, antibody, signaling protein |
Biological source | Homo sapiens More |
Total number of polymer chains | 3 |
Total formula weight | 61757.36 |
Authors | Raman, S.,Beilschmidt, M.,Fransson, J.,Julien, J.P. (deposition date: 2019-02-26, release date: 2019-04-03, Last modification date: 2024-11-20) |
Primary citation | Raman, 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: 30894493DOI: 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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