Here we expand on these findings and present the structural definition, functional characterization, and refinement of FZD antibodies that target FZD1, -2, -4, -5, -7, and -8 to potently inhibit Wnt signaling, while balancing their tolerability.
We have recently shown that antibodies specific to these six FZD receptors inhibit endothelial tube formation in vitro, whereas antibodies lacking FZD4 specificity did not ( 36). Targeting FZD4 in addition to FZD1, -2, -5, -7, and -8 may have a broader impact on the efficacy of FZD-targeting antibodies. For example, OMP-18R5 (vantictumab), a monoclonal antibody (mAb) that interacts with the CRD of FZD1, -2, -5, -7, and -8, has been shown to inhibit tumor growth in several tumor types, including breast, colon, lung, and pancreatic cancer and did not reportedly demonstrate gastrointestinal toxicity ( 31, 32). Therapeutic antibodies potentially offer advantages in that they can target specific FZD receptors rather than broadly inhibiting the Wnt pathway. Gastrointestinal toxicity has been a frequent dose-limiting toxicity observed in clinical trials, among other toxicities ( 35). However, therapeutically targeting the WNT/β-catenin pathway is challenging due to the critical involvement of the pathway in normal tissue homeostasis, and complete abrogation may have severe adverse effects. These include inhibition of Wnt palmitoleation with PORCN (a Wnt-specific acyltransferase) inhibitor LGK974, pan-Wnt neutralization with decoy receptor FZD8-Fc OMP54-28 ( 31– 33), interference in downstream signaling components such as tankyrase inhibitor XAV939, or inhibitors that disrupt β-catenin/cotranscriptional inhibitor interactions (e.g., ICG-001) ( 34). Several approaches have been taken to develop drugs capable of abrogating the Wnt pathway in cancers ( 13, 31, 32). Therefore, therapeutic modulation of the Wnt pathway is an attractive approach to treat multiple disease indications ( 13, 31).
#Finetunes meaning drivers
Mutations in FZD4 and its alternative ligand, Norrin, are primary drivers of retinal hypovascularization in familial exudative vitreoretinopathy ( 30). Signaling through FZD4 is also essential for normal angiogenesis ( 28, 29).
FZD5 expression is up-regulated in renal cell carcinoma ( 22), prostate cancer ( 23), and pancreatic tumors ( 16) aberrant FZD7 expression is observed in hepatocellular carcinoma and colorectal and triple negative breast cancer ( 14, 24, 25) FZD8 is up-regulated in acute lymphoblastic leukemia and lung cancer ( 17, 26) and FZD4 is elevated and drives epithelial-to-mesenchymal transition in TMRESS2–ERG fusion prostate cancer ( 27). These mutations have been identified in pancreatic, biliary duct, and colorectal cancers ( 19– 21). Inactivating mutations in E3 ubiquitin ligase RNF43 inhibit the down-modulation of FZD expression on the cell surface and sensitize tumor cells to Wnt-dependent growth.
#Finetunes meaning driver
Abnormal activation of the Wnt pathway is an essential driver of primary tumor formation and metastasis in multiple cancer types ( 14– 18). Wnt/FZD signaling is essential for normal cell function, but aberrations in the pathway are frequently found in cancers, fibrosis, and degenerative diseases ( 12, 13). 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. Importantly, the lead variant mAb significantly inhibited tumor growth in the HPAF-II pancreatic tumor xenograft model. 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. However, these mAbs displayed gastrointestinal toxicity or poor plasma exposure in vivo. Crystal structures revealed a common binding site for these monoclonal antibodies (mAbs) on FZD, blocking the interaction with the Wnt palmitoleic acid moiety. Here, we evaluated antibodies blocking 6 of the 10 human Wnt/Frizzled (FZD) receptors as potential therapeutics. However, therapeutic targeting of this pathway is complicated by the role of Wnt in stem cell maintenance and tissue homeostasis. Aberrant activation of Wnt/β-catenin signaling occurs frequently in cancer.
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