FOLR1 (FRα) is becoming an increasingly important focus in tumor therapy research, with multiple ADCs advancing rapidly in clinical development worldwide. Since October, Eli Lilly has registered the Phase III trial of LY4170156 (FRAmework‑01) for the treatment of platinum-resistant or platinum-sensitive ovarian cancer, while AstraZeneca has registered the Phase III trial of AZD5335 (TREVI‑OC‑01) targeting platinum-resistant ovarian cancer. In addition, several innovative FRα-targeted therapies developed by other companies, including Bio Thera and ProTarget Bio, are also progressing swiftly. These developments reflect the growing global clinical and R&D momentum for FRα as a tumor target, attracting significant attention from pharmaceutical companies worldwide. 

Overview of Folate Receptor Alpha (FRα)

The folate receptor (FR) family is a group of membrane proteins associated with folate metabolism, primarily responsible for the high-affinity binding and internalization of folate. This family comprises four members—FRα, FRβ, FRγ, and FRδ—encoded by the FOLR1, FOLR2, FOLR3, and FOLR4 genes, respectively. FR family members display tissue-specific distribution in normal tissues, while they are often aberrantly overexpressed in tumor tissues, making them potential targets for cancer therapy and diagnostics.

Among them, FRα (encoded by FOLR1) is a GPI-anchored membrane protein, primarily localized at the apical surface of polarized epithelial cells in normal tissues such as the kidney, pancreas, lung, and ovarian epithelium. Its main function is to bind folate and its derivatives with high affinity and mediate their internalization, supporting DNA synthesis and cell proliferation.

Expression of FRα

Compared with normal tissues, FRα is aberrantly overexpressed in various epithelial-derived cancers, including ovarian cancer, non-small cell lung cancer (NSCLC), breast cancer, and colorectal cancer, making it an ideal candidate target for drug delivery, immunotherapy, and diagnostics.

In ovarian cancer, 76–89% of epithelial ovarian tumors exhibit high FRα expression, which is closely associated with high-grade and advanced-stage disease. In NSCLC, 14–74% of cases show FRα overexpression, with membranous expression significantly higher in adenocarcinomas than in squamous cell carcinomas. In breast cancer, FRα is expressed in 35–68% of triple-negative breast cancers, while normal breast tissue shows minimal expression.

Physiological Functions of FRα

FRα functions primarily as a folate transporter, binding folate derivatives and mediating folate uptake and transport. It can also act as a transcription factor and plays a critical role in embryonic development, potentially mediating neural tube formation and maternal-fetal folate transport. Deficiency of FRα can lead to abnormal embryonic development and impaired organ function.

Beyond folate transport, FRα may influence tumor biology by activating downstream signaling pathways such as STAT3 and ERK1/2, thereby regulating tumor cell proliferation, migration, and the immune microenvironment, ultimately affecting tumor progression and therapy resistance. Some studies have also shown that high FRα expression is closely associated with clinical features such as tumor stage, invasiveness, and prognosis.

FRα-Targeted Therapeutics

Clinically, the high expression of FRα in malignant tumors makes it a potential target for anti-cancer drug development. Various strategies are currently being explored, including monoclonal antibodies, antibody-drug conjugates (ADCs), FRα-specific CAR-T cell therapies, vaccines, small-molecule drugs, and folate-drug conjugates.

Antibody–Drug Conjugates (ADCs)

Among these strategies, ADCs have progressed the fastest. The first FRα-targeted ADC, Elahere, received accelerated approval from the FDA in 2022. Based on Phase III clinical data, it has demonstrated differentiated efficacy compared with chemotherapy in the PROC (platinum-resistant ovarian cancer) indication. As shown in the trial, the median progression-free survival (mPFS, INV) for the treatment group was 5.62 months, compared with 3.98 months in the chemotherapy control group. Overall survival (OS) was 16.46 months in the treatment group versus 12.75 months in the control group.

Huadong Medicine holds the rights to this marketed drug in China and also obtained NMPA approval in 2024.

In addition to the approved Elahere®, multiple FRα-targeted ADCs are advancing rapidly in development. Among them, BAT8006, PRO1184, LY4170156, and AZD5335 have entered Phase III clinical trials, reflecting a closely competitive development landscape following Elahere.

Monoclonal Antibodies

Monoclonal antibody drugs targeting FOLR1 include Farletuzumab, KHK2805, MOv19, MOv18-IgG1, and MOv18-IgE, among others.

FRα-Specific CAR-T Cell Therapy

CAR-T cell therapies targeting FRα are also under investigation. A Phase I clinical trial involved engineering autologous T cells to express a chimeric antigen receptor (CAR) recognizing FRα, for the treatment of relapsed ovarian cancer. The CAR construct included a 4-1BB costimulatory domain. Although preliminary safety was confirmed, in vivo persistence and expansion of the T cells remained limited, and no significant tumor burden reduction was observed. Current research efforts are focused on improving T-cell durability, minimizing human anti-mouse antibody (HAMA) responses triggered by murine scFv domains, and optimizing strategies to enhance in vivo expansion.

Vaccine Therapy

Vaccine therapies targeting FRα are currently under development, including multi-epitope FRα peptide vaccines and dendritic cell (DC)–based vaccines. For example, a Phase II study is evaluating the efficacy of an FRα peptide vaccine combined with GM-CSF versus GM-CSF alone in patients with triple-negative breast cancer. Another Phase II study (FAROUT trial, NCT06639074) is investigating an FRα fusion–loaded DC vaccine in patients with stage III/IV ovarian, fallopian tube, or primary peritoneal cancer. Although still in early stages, these studies indicate that FRα-targeted vaccines have the potential to induce specific T-cell responses.

Small Molecules / Folate–Drug Conjugates (FDCs)

Among other FRα-related therapeutic strategies, folate-conjugated small molecules or folate–drug conjugates (FDCs) have also been extensively studied. For example, Vintafolide is an early folate–drug conjugate designed to deliver cytotoxic agents directly to tumor cells via FRα-mediated uptake; however, it did not meet its primary endpoint in Phase III clinical trials. On the other hand, small-molecule inhibitors such as BGC945 (also known as ONX0801) enter cells through FRα-mediated transport and inhibit thymidylate synthase, with partial clinical benefit observed in some ovarian cancer patients during Phase I studies. These approaches highlight the potential of exploiting FRα as a selective drug delivery pathway.

Conclusion

Overall, FRα (FOLR1) has emerged as a prominent target in the field of precision oncology, transitioning from early validation to multi-platform and multi-mechanism clinical translation. With the successful market approval of Elahere® and several follow-up ADC candidates entering pivotal studies, the clinical value of FRα-targeted therapies is being progressively validated. Looking ahead, the integration of diverse strategies—including ADCs, bispecific antibodies, CAR-T cells, and small-molecule conjugates—positions FRα as a promising breakthrough target for epithelial-derived tumors such as ovarian cancer, paving the way for more personalized approaches in cancer treatment.

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