FOLR1 expression

A significant proportion of LGSC express high FOLR1 levels supporting the development of clinical trials to investigate ADCs targeting FOLR1 as novel agents for treating this disease. In LGSC, high FOLR1 expression was associated with fewer MAPK pathway alterations, low PR expression, and p16 loss.

MIRV confers meaningful PFS benefit for a subset of individuals with HGSOC. Resistance may be associated with decreased FOLR1 target expression or payload resistance. FOLR1-targeted ADCs with a different payload should be evaluated for patients who progress on MIRV but retain high tumor FOLR1 expression.

Furthermore, MIRV's therapeutic versatility extends to other FRα-positive tumors, such as endometrial and breast cancers, broadening its clinical relevance. Despite challenges such as accessibility and cost, MIRV represents a significant advancement in precision medicine, with potential to redefine prevention and treatment strategies for hereditary and sporadic cancers.

These data highlight the need for caution in antibody selection when developing immunohistochemistry-based assays, as some antibodies failed to cleanly and specifically identify FRα expression. We identified 2 antibodies appropriate for further investigation; however, as developed, these antibodies may overselect patients for treatment with FRα-targeted therapies.

This case report highlights an Aisan patient with ovarian cancer, who exhibited tolerance, recurrence, and progression after several prior lines of treatment. The application of Mirvetuximab Soravtansine, facilitated by positive FRα expression identified through IHC analysis, notably reduced tumor lesions and CA125 levels, achieving a complete response and maintaining low CA125 levels during treatment, underscoring its efficacy in treating platinum-resistant recurrent ovarian cancer.

Urticarial skin reactions following MOv18 IgE treatment were unlikely to result from allergic mechanisms or skin antigen recognition. The clinical presentation is consistent with infusion-related reactions commonly observed with monoclonal antibody treatments.

FOLR1 is a stemness-associated biomarker for HCC, with serum levels serving as a diagnostic marker for HCC and a prognostic indicator for early-stage disease.

P1, N=86, Completed, Shattuck Labs, Inc. | Active, not recruiting --> Completed | Trial completion date: Nov 2024 --> Feb 2025 | Trial primary completion date: Nov 2024 --> Feb 2025

P2, N=125, Active, not recruiting, AbbVie | Trial completion date: Dec 2026 --> May 2026 | Trial primary completion date: Jun 2025 --> May 2026

We revealed that FOLR1 orchestrates the malignant advancement of GBM by stimulating the SRC/ERK1/2 signaling axis, underscoring its pivotal role in the pathogenesis of GBM.

P1/2, N=404, Recruiting, Genmab | Trial completion date: Apr 2026 --> Oct 2026 | Trial primary completion date: Oct 2025 --> Apr 2026

Furthermore, NSD2 or FOLR1 silencing decreased the expression of key glycolytic genes (HK2, TIGAR, and G6PD) by suppressing their promoter activity and weakening the interaction between FOLR1/H3K36me2 and these gene promoters. Our findings suggest that NSD2-mediated H3K36me2 recruits FOLR1 to promote PAH, and FOLR1 acts as a transcriptional factor to upregulate glycolytic gene expression in PAECs.

P2, N=79, Completed, AbbVie | Active, not recruiting --> Completed

P1, N=50, Recruiting, Telix Pharmaceuticals (Innovations) Pty Ltd | Not yet recruiting --> Recruiting | Initiation date: Aug 2024 --> Oct 2024 | Trial primary completion date: Dec 2025 --> Mar 2026

Our results highlight a need for standardized protocols for FRα testing to ensure accurate biomarker evaluation across varied clinical settings. The heterogeneity in FRα expression, influenced by tumor histology and anatomical origin, warrant further investigation to optimize therapeutic outcomes.

We identified a gene expression signature correlated to high FRα expression and OC prognosis, which may be used to refine therapeutic strategies targeting FRα in OC. These findings warrant validation in larger cohorts.

P3, N=453, Completed, ImmunoGen, Inc. | Active, not recruiting --> Completed

We also report a parallel expression of Shh and MBP in oligodendroglial cells during early post-natal myelination of the mouse brain. Thus, we identify a crucial Shh signal involved in oligodendroglial cell differentiation and remyelination, with potential interest in the design of better-targeted remyelinating therapeutic strategies.

FRα-targeting ADCs, including MIRV, demonstrated definite efficacy and good safety as novel choices for second-line and beyond treatment of advanced or recurrent ovarian cancer. Patients with high FRα expression showed ORR and PFS benefits similar to those in the overall cohort.

As demonstrated among 682 participants, the safety profile of MIRV is well tolerated and consists primarily of low-grade gastrointestinal, fatigue, headache, peripheral neuropathy, and resolvable ocular adverse events.

Though less than in high-grade disease, a notable portion of low-grade tumors were FOLR1+, suggesting FOLR1 expression in LGSOC could be a viable target for this rare histology, particularly in the recurrent setting.

Introduction Mirvetuximab soravtansine-gynx (MIRV) is an antibody-drug conjugate that binds to folate receptor alpha and delivers a microtubule inhibitor payload...Median PFS did not significantly differ based on number of prior treatment lines (for 1-3 versus >3 lines, P = 0.3) or prior PARP inhibitor ( P = 0.9) or bevacizumab ( P = 0.4) use...Conclusion/Implications MIRV confers meaningful PFS benefit for a subset of individuals. Biomarkers of response and resistance are urgently needed to optimize patient selection for treatment.

97.5% had prior taxanes, 81% prior poly (ADP-ribose) polymerase inhibitors (PARPi) [74.7% of whom progressed while on PARPi], 64.6% prior bevacizumab, 98.8% had 2+ prior lines of therapy, and BRCA status was 27.8% positive, 72.2% negative. MIRV demonstrated notable efficacy in this heavily pretreated PSOC population, including among those who may have PARPi resistance. MIRV continues to demonstrate a differentiated safety profile consisting primarily of low-grade neurosensory, GI, and resolvable ocular AEs. These data position MIRV to become a novel treatment option for patients in ≥3L PSOC with FRα positive expression.

P1, N=86, Active, not recruiting, Shattuck Labs, Inc. | Trial completion date: Apr 2025 --> Nov 2024

Our data highlight the need for caution in antibody selection when developing immunohistochemical-based assays, as some FRα antibodies failed to cleanly and specifically identify FRα expression. We identified two antibodies appropriate for further investigation; however, as developed, both stain more intensely than the FDAapproved test and may, therefore, over-select patients for treatment with FRα-targeted therapies intended for use with the FDA-approved companion diagnostic. From these data, we advise the use of the FDAapproved assay for patient selection.

FOLR1 expression was upregulated by VPA, apicidin, and trichostatin A, but downregulated by MS-275 after 24 h treatment. By contrast, HDAC inhibitors exert different regulatory effects on folate carriers. Moreover, HDAC1/2 inhibition may be a potential mechanism involved in altering FOLR1 and SLC46A1 levels.

Here, we report updated nonanalytical results based on a median follow-up of 16.7 months. 453 PROC pts with high FRα expression (VENTANA FOLR1 [FOLR1-2.1] RxDx Assay) with 1-3 prior therapies were randomized 1:1 to MIRV 6 mg/kg, adjusted ideal body weight, Day 1 of a 21-day cycle or ICC: paclitaxel (PAC), pegylated liposomal doxorubicin (PLD), or topotecan (Topo). With a median follow-up of 16.7 months, MIRV demonstrated improved efficacy vs ICC in pts with PROC. The efficacy data, along with the well-characterized safety profile, supports MIRV as the standard of care for pts with FRα positive PROC. Clinical Trial Information: NCT04209855.

97.5% had prior taxanes, 81% prior poly (ADP-ribose) polymerase inhibitors (PARPi) [74.7% of whom progressed while on PARPi], 64.6% prior bevacizumab, 98.8% had 2+ prior lines of therapy, and BRCA status was 27.8% positive, 72.2% negative. MIRV demonstrated clinically meaningful antitumor activity and favorable tolerability in patients with FRα-high PSOC. The efficacy and safety data support the use of MIRV in PSOC patients with ≥ 2 prior platinum-containing regimens or platinum allergy. Clinical Trial: NCT05041257.

Mirvetuximab soravtansine (MIRV), an FRα-targeting antibody-drug conjugate, is active in high-grade serous epithelial ovarian cancer (HGSOC)... FRα was highest in HGSOC and was associated with advanced stage and BRCA status. Sample age, anatomical site, and PFI did not affect FRα expression, suggesting that any sample is suitable for determining FRα status. Variability was observed in cores from the same specimen, which appeared to be driven by tumour heterogeneity versus biological changes.

However, identified gaps, including limited diversity in patient populations, sparse quality of life data, and the need for long-term safety information, indicate areas for future research. Exploration of additional biomarkers predicting mirvetuximab soravtansine responsiveness is essential for personalized treatment.

P1/2, N=374, Recruiting, ProfoundBio US Co. | N=134 --> 374 | Trial completion date: Sep 2025 --> Apr 2026 | Trial primary completion date: Jan 2025 --> Oct 2025

P2, N=114, Active, not recruiting, ImmunoGen, Inc. | Recruiting --> Active, not recruiting | Trial primary completion date: Jun 2024 --> Jun 2025

P2/3, N=600, Recruiting, Sutro Biopharma, Inc. | Phase classification: P2 --> P2/3 | N=140 --> 600

Mesenchymal deletion of Alms1 recapitulates metabolic features of AS, including fatty liver. This confirms a key role for Alms1 in the adipose lineage, where its loss is sufficient to cause systemic metabolic effects and damage to remote organs. Hyperphagia in females may depend on Alms1 deficiency in oligodendrocyte precursor cells rather than neurones. AS should be regarded as a forme fruste of lipodystrophy.

At the current price, MIRV for PROC with high-FRα expression is not the cost-effective strategy in the US. However, its treatment has higher health benefits in bevacizumab-naïve patients, which is likely to be an alternative.

This triplet regimen (MIRV+carboplatin+bevacizumab) was highly active, with a tolerable AE profile in participants with recurrent, platinum-sensitive, FRα-expressing ovarian cancer. Thrombocytopenia was the primary cause of dose modifications. These outcomes compare favorably to historical data reported for platinum-based chemotherapy plus bevacizumab regimens in similar patient populations.

Recently, the FDA approved mirvetuximab soravtansine for platinum-resistant ovarian carcinoma with FOLR1 overexpression, typically high-grade serous carcinoma... To our knowledge, this is the largest study to date of FOLR1 expression in USC. Nearly 1 in 5 USC patients are FOLR1+, independent of HER2 status. Further research testing the efficacy of FOLR1-targeted therapy in USC is needed, as approval could potentially double the proportion of patients with available targeted therapies.

Together, these data showed that the assay is highly reliable, consistently producing evaluable results in the clinical setting. The VENTANA FOLR1 Assay is a robust and reproducible assay for detecting FRα expression and identifying a patient population that derived clinically meaningful benefit from MIRV in the SORAYA study.

MIRV and gemcitabine demonstrate promising activity in platinum resistant EOC at RP2D, but frequent hematologic toxicities.

Finally, we performed additional in vitro assays recapitulating immune suppressive mechanisms present in solid tumors and developed a process for the automated manufacturing of our CAR T cell candidate. These findings demonstrate the feasibility of anti-FOLR1 CAR T cells for ovarian cancer and potentially other FOLR1-expressing tumors.

Folate transporters are present throughout the terminal ileum and colon; there is little evidence that a low dose folic acid supplementation affects colonic absorption.

P3, N=418, Recruiting, ImmunoGen, Inc.