Folate receptor alpha antagonists in preclinical and early stage clinical development for the treatment of epithelial ovarian cancer

ABSTRACT

Introduction: The prognosis of patients affected by ovarian cancer has not substantially changed in the last decades and improving survival still remains a challenge. In the promising era of ‘personalized therapy’ several new biologic therapies are currently being investigated: in this setting, targeting the folate receptor (FR) has been considered a new potential strategy for biologic therapy.

Areas covered: The aim of the current review is to summarize, giving a critical overview,promising folate receptor alpha antagonists under preclinical or early clinical development for ovarian cancer.

Expert opinion: Two categories of therapeutics are included in this class: FRα targeted mAbs and FRα-binding-ADC (Antibody drug conjugates); both share the interesting possibility of selecting patients via a biomarker which is already available. In the first class, farletuzumab has reached the most advanced stage in clinical evaluation and results of a Phase II randomized trial are awaited to assess its efficacy in a specific patients’ setting. MOv18 IgE represents a novel strategy to target FRα expressing cells, which has shown encouraging results in preclinical studies: further evaluation is needed in the clinical setting. IMGN 853 is an innovative FRα-binding ADC under development, with only preliminary results of a Phase I trial available.

KEYWORDS:

• Farletuzumab
• folate receptor
• ovarian cancer
• target therapies
• folate-conjugates

Article highlights

• FRα is an ideal target for anticancer therapy since it is highly expressed in tumor cells and poorly detectable in normal cells; its expression is not affected by chemotherapy and has been found to correlate with tumor stage and grade.

• FR is a tumor cell-surface biomarker useful to target drug delivery, monitor therapy response via a specific DR-targeted imaging tool.

• Early experience with FRα targeting agents MOv18 IgE and IMGN853 has shown promising results, however strong clinical data are not yet available.

• Phase III trials with farletuzumab showed a favorable toxicity profile but controversial antitumor activity. Results from a randomized phase II trial in selected patients with low CA125 levels are awaited.

• Adoptive cell immunotherapy using FRα-specific CAR-T cells might represent an interesting strategy, even if limitations related to efficacy and toxicity should be overcome.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was not funded.