A FZD7-specific Antibody–Drug Conjugate Induces Ovarian Tumor Regression in Preclinical Models

Abstract

Though WNT signaling is frequently dysregulated in solid tumors, drugging this pathway has been challenging due to off-tumor effects. Current clinical pan-WNT inhibitors are non-specific and lead to adverse effects, highlighting the urgent need for more specific WNT-pathway targeting strategies. We identified elevated expression of the WNT receptor Frizzled class receptor 7 (FZD7) in multiple solid cancers in The Cancer Genome Atlas, particularly in the mesenchymal and proliferative subtypes of ovarian serous cystadenocarcinoma, which correlate with poorer median patient survival. Moreover, we observed increased FZD7 protein expression in ovarian tumors compared to normal ovarian tissue, indicating that FZD7 may be a tumorspecific antigen. We therefore developed a novel antibody-drug conjugate, septuximab vedotin (F7-ADC), which is composed of a chimeric human-mouse antibody to human FZD7 conjugated to the microtubule-inhibiting drug monomethyl auristatin E (MMAE). F7-ADC selectively binds human FZD7, potently kills ovarian cancer cells in vitro, and induces regression of ovarian tumor xenografts in murine models. To evaluate F7-ADC toxicity in vivo, we generated mice harboring a modified Fzd7 gene where the resulting Fzd7 protein is reactive with the humantargeting F7-ADC. F7-ADC treatment of these mice did not induce acute toxicities, indicating a potentially favorable safety profile in patients. Overall, our data suggest that the antibody-drug conjugate approach may be a powerful strategy to combat FZD7-expressing ovarian cancers in the clinic.

Structural insights into Frizzled assembly by acylated Wnt and Frizzled Connector domain

“…Interestingly, Gumber et al, recently developed an engineered antibody (F7L6), selectively targeting the Fz7 receptor and the Lrp6 co-receptor and mimicking Wnt for the activation of signalling 57 . F7L6 antibody conjugated to the microtubule-inhibiting drug showed promising results in the regression of ovarian tumour growth 58 . More importantly, the binding epitope of the F7L6 antibody against the Fz7 receptor is located on the Connector of the Fz7 receptor 57 .…”

Wnt 2022 EMBO | the Company of Biologists workshop and Yamada conference

“…In the tenth session “Wnt signaling in stem cells and regeneration,” manipulating stem cell fate using a selective Frizzled agonist was presented by Stephane Angers (University of Toronto, Canada). Karl Willert (University of California San Diego, USA) gave a lecture on characterizing and targeting the Wnt receptor Fzd7 in cancer (Do et al, 2022). Meanwhile, Ahmad Nabhan (Genentech, South San Francisco, CA) presented targeted lung regeneration with Fzd‐specific Wnt‐mimetics.…”

Exploring the Wnt Pathway as a Therapeutic Target for Prostate Cancer

“…OMP-54F28 was well tolerated in a clinical trial for patients with advanced solid tumors, however, no further trial results have been published to date [ 245 ]. More recently, a FZD7-antibody-drug-conjugate has been developed, septuximab vedotin (F7-ADC), which elicits potent tumor regression in ovarian tumor xenografts [ 240 ].…”