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

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• WNT signaling pathway dysregulation is common in solid tumors, but targeting it clinically is challenging due to non-specific inhibitors and off-tumor effects.
• Frizzled class receptor 7 (FZD7) is overexpressed in solid cancers, particularly in aggressive ovarian cancer subtypes, correlating with reduced patient survival.
• FZD7 protein expression is elevated in ovarian tumors versus normal tissue, suggesting it as a potential tumor-specific antigen.

Purpose of the Study:

• To develop and evaluate a novel antibody-drug conjugate (ADC) targeting FZD7 for ovarian cancer treatment.
• To assess the efficacy and safety of the FZD7-targeting ADC in preclinical ovarian cancer models.

Main Methods:

• Identified FZD7 overexpression in The Cancer Genome Atlas and ovarian tumor samples.
• Developed septuximab vedotin (F7-ADC), an ADC comprising an anti-FZD7 antibody and monomethyl auristatin E (MMAE).
• Evaluated F7-ADC's in vitro cytotoxicity against ovarian cancer cells and in vivo tumor regression in xenograft models.
• Assessed F7-ADC's in vivo toxicity using genetically engineered mice expressing human-reactive Fzd7.

Main Results:

• F7-ADC selectively binds FZD7 and potently kills ovarian cancer cells in vitro.
• F7-ADC treatment induced regression of ovarian tumor xenografts in murine models.
• F7-ADC demonstrated no acute toxicities in mice engineered to mimic human FZD7 expression, suggesting a favorable safety profile.

Conclusions:

• The antibody-drug conjugate approach is a promising strategy for targeting FZD7-expressing ovarian cancers.
• Septuximab vedotin (F7-ADC) exhibits potent anti-tumor activity and a potentially favorable safety profile.
• Targeting FZD7 represents a viable therapeutic strategy for overcoming challenges in WNT pathway-driven cancers.