The canonical Wnt signaling pathway is an evolutionary conserved signaling cascade imperative for normal growth and development, and is required throughout the life of an organism. The pathway is activated by Wnt ligands binding to cell surface Frizzled receptors. Aberrant activation of the pathway, however, has been associated with several types of cancers. Owing to its ubiquitous nature and involvement in tissue homeostasis, therapeutic targeting of the Wnt pathway has been challenging. The Julien laboratory and collaborators used structure-based antibody engineering to fine-tune the developability of therapeutic antibodies that target the extracellular domain of Frizzled receptors to block the Wnt-Frizzled interaction. Antibody-antigen structures solved from data collected at GM/CA@APS were used to guide the modification of antibody paratope residues to obtain a spectrum of binding affinities to different Frizzled receptors. One particular antibody variant showed the desired combination of in vitro potency, was well tolerated in vivo and significantly inhibited tumor growth in a pancreatic tumor xenograft model. Together, this study demonstrates that cancer therapeutic antibodies can be fine-tuned using structure-guided principles to precisely navigate tolerability and therapeutic efficacy.
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Figure: Crystal structure of the extracellular domain of Frizzled 5 (pink) in complex with the Fab fragment of mAb F2.I. The antibody heavy and light chains are colored blue and purple, respectively. The inset shows critical interacting residues at the center of modifications made to enhance the developability profile of the antibody. |
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, SS, Magram, J, Sinclair, AM, Fransson, J, Julien, JP., Structure-guided design fine-tunes pharmacokinetics, tolerability, and antitumor profile of multispecific frizzled antibodies, Proc.Nat.Acad.Sci. USA 116, 6812-6817 (2019). DOI: 10.1073/pnas.1817246116
GM/CA @ APS
