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Selective targeting of WNT receptor FZD7 in human pluripotent stem cells and ovarian cancer


WNT signaling is a highly conserved pathway with dual roles in development and disease. In human pluripotent stem (hPS) cells, an in vitro model of mammalian development, low-level WNT signaling maintains the self-renewal state, but carefully timed increases in WNT can induce terminal differentiation. While the WNT receptor Frizzled-7 (FZD7) is an established regulator of pluripotency in hPS cells, it is unclear if FZD7 or additional FZD receptors mediate the WNT signal that promotes stem cell differentiation. To address whether FZD7 is required for this process, my co-authors and I engineered bispecific antibody F7L6, which acts as a WNT signaling agonist by selectively heterodimerizing FZD7 and its coreceptor, LRP6. F7L6 treatment of hPS cells elicited a transcriptional response similar to that observed for Wnt3a treatment, thus establishing that FZD7 signaling is sufficient to promote mesendodermal differentiation. Though WNT signaling is required for normal embryonic development, it can be dysregulated in diseases such as cancer. Targeting WNT signaling in solid tumors has been historically challenging due to the WNT requirement for bone homeostasis. Clinical pan-WNT inhibitors frequently induce bone-related adverse events, creating a need for more specific WNT-pathway targeting strategies. We identified elevated RNA expression of FZD7 in aggressive subtypes of ovarian serous cystadenocarcinoma (OV) in The Cancer Genome Atlas and confirmed high FZD7 protein expression in OV, but low FZD7 in normal ovary tissues, indicating that FZD7 is a tumor-specific antigen. We developed novel antibody-drug conjugate (F7-ADC), septuximab vedotin, a chimeric human-mouse IgG1 antibody to human FZD7 conjugated to antimitotic payload drug MMAE. The F7-ADC specifically binds FZD7, potently kills ovarian cancer cells in vitro, and induces regression of ovarian tumor xenografts in nude mouse models. To evaluate F7-ADC toxicity in vivo, we engineered immunocompetent Fzd7hF7/hF7 mice to express Fzd7P188L receptors reactive with our human-targeting F7-ADC. F7-ADC treatment did not induce adverse effects on Fzd7hF7/hF7 mouse health or histopathological changes at the tissue level. Overall, our data suggest that the F7-ADC approach may be a powerful strategy to combat FZD7-expressing ovarian cancers in the clinic.

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