6O3A

Crystal structure of Frizzled 7 CRD in complex with F7.B Fab

Summary for 6O3A

• Entry DOI: 10.2210/pdb6o3a/pdb
• Descriptor: Antibody F7.B Fab, Light chain, Antibody F7.B Fab, Heavy chain, Frizzled-7, ... (8 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: 62730.00

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 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

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

Experimental method

X-RAY DIFFRACTION (2.1 Å)