Structure-guided Design Fine-tunes Pharmacokinetics, Tolerability, and Antitumor Profile of Multispecific Frizzled Antibodies
Overview
Authors
Affiliations
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.
He A, Tian S, Kopper O, Horan D, Chen P, Bronson R PLoS Biol. 2023; 21(11):e3002353.
PMID: 37943878 PMC: 10635564. DOI: 10.1371/journal.pbio.3002353.
Park W, Kim M Cells. 2023; 12(8).
PMID: 37190019 PMC: 10136927. DOI: 10.3390/cells12081110.
Role of prostate cancer stem-like cells in the development of antiandrogen resistance.
Kushwaha P, Verma S, Kumar S, Gupta S Cancer Drug Resist. 2022; 5(2):459-471.
PMID: 35800367 PMC: 9255247. DOI: 10.20517/cdr.2022.07.
Carboxylesterase Notum Is a Druggable Target to Modulate Wnt Signaling.
Bayle E, Svensson F, Atkinson B, Steadman D, Willis N, Woodward H J Med Chem. 2021; 64(8):4289-4311.
PMID: 33783220 PMC: 8172013. DOI: 10.1021/acs.jmedchem.0c01974.
Long Non-Coding RNA Landscape in Prostate Cancer Molecular Subtypes: A Feature Selection Approach.
De Summa S, Palazzo A, Caputo M, Iacobazzi R, Pilato B, Porcelli L Int J Mol Sci. 2021; 22(4).
PMID: 33672425 PMC: 7926489. DOI: 10.3390/ijms22042227.