FR-specific CAR-T == Preclinical investigations have indicated that FR-specific chimeric antigen receptor (CAR) T cell therapy has promising antitumor effects (103,104). MIRV, Elahere, antibody-drug conjugate, ADC == 1. Introduction == Epithelial ovarian malignancy (EOC) accounts for approximately 95% of ovarian malignancy incidence, and is a leading cause of gynecologic malignancy mortality worldwide (1,2). Current standard-of-care treatment for newly diagnosed patients is usually cytoreductive debulking surgery plus neoadjuvant or post-operative platinum-based chemotherapy. Most patients in the beginning respond to chemotherapy, but unfortunately up to 80% will eventually relapse leading to individual demise (3). Thus, platinum resistance presents a major clinical challenge. Angiogenesis inhibitor (bevacizumab) and the poly (ADP-ribose) polymerase inhibitors (olaparib, rucaparib and niraparib) provide some benefits for any subset of patients, but can only delay the relapse of platinum-resistant EOC (4,5). Notably, recent large-scale clinical trials using immune-checkpoint inhibitors (anti-PD1/L1 monoclonal antibodies) failed to provide clinical benefit in EOC. In the past decades, the 5-12 months relative survival rates of ovarian malignancy have only been moderately improved, from 43% in 1995 to 50% in 2018 in the USA (6,7). Thus, treatment options for platinum-resistant EOC patients are limited, and present a major unmet clinical need. Folate receptor alpha (FR), encoded by the FOLR1 gene, has attracted considerable interest due to its high expression in several malignancy types including those of lung and breast. FR shows restricted tissue expression around the plasma membrane (R)-Pantetheine of epithelial cells in kidney, lung, ovary, fallopian tube, uterus, cervix, epididymis and placenta, and is highly expressed in approximately 80% of EOC. Additionally, the ability of FR to internalize relatively large molecules renders it suitable for developing targeted therapies (8,9). Despite their anti-tumor effects in preclinical models, folate-cytotoxic drug conjugates and no conjugated humanized antibody have yet Rabbit Polyclonal to NPM to demonstrate clinical efficacies (10). In contrast, mirvetuximab soravtansine (MIRV), or Elahere (ImmunoGen), the first FR-targeting antibody-drug conjugate (ADC), has recently been approved by the US FDA to treat platinum-resistant ovarian malignancy (11). Here, we summarize the biology of folate receptors, review different strategies to target FR, and discuss potential mechanisms of ocular adverse events associated with MIRV. The approval of MIRV has renewed interest to develop other FR-targeting therapeutics for treatment beyond EOC. == 2. Folate transporter proteins == Humans cannot synthesize folate, an essential vitamin for eukaryotic cell proliferation and differentiation, and must obtain folate from dietary sources (12). The uptake of extracellular folate is usually achieved mainly through three forms of folate transporters, including the reduced folate carrier, RFC (encoded by the SLC19A1 gene), the (R)-Pantetheine proton-coupled folate transporter, PCFT(encoded by the SLC46A1 gene), and folate receptors (FRs) (13). Ubiquitously expressed RFC serves as the major route of folate transport into systemic tissues (12), whereas PCFT is a proton-coupled transporter responsible for dietary folate absorption in the small intestine (14). Both RFC and PCFT are low-affinity, high-throughput transporters. In contrast, FRs are high affinity, low-throughput transporters that transfer folate through endocytosis in selected tissues (Physique 1). == Physique 1. == The three forms of folate transporters. The uptake of extracellular folate is usually achieved mainly through three forms of folate transporters. (1) RFC, an anion antiporter that uses a gradient of higher organic phosphate in the cell to transport folate into the cell while transporting organic phosphate out of the cell, (2) PCFT, a proton-coupled transporter, (3) folate receptor family (only FR is shown). They transfer folate through endocytosis in selected tissues. Folate trafficking via FR is considered to proceed via potocytosis, a lipid raft-mediated endocytosis mechanism (15). Folate binds specifically to FR, forming a receptor-ligand complex, and subsequently intracellular vesicles are generated by invagination and budding off. Once internalized, the vesicles join together to from early endosomes, which acidify and fuse with lysosomes to release folates for the one-carbon metabolic reaction (16,17). There are four (R)-Pantetheine users in FRs family, including FR (257aa, 30kDa), FR (255aa, 29kDa), FR (245aa, 28kDa) and (R)-Pantetheine FR (250aa, 28.6kDa), encoded by FOLR1 (Gene ID: 2348), FOLR2 (Gene ID: 2350), FOLR3 (Gene ID: 2352) and FOLR4 (Gene ID: 390243), respectively. FRs, also known as the folate binding proteins (FBPs), bind folic acid (FA) and 5-mTHF as well as folate-conjugated compounds with high affinity, and transport them inside cells by receptor-mediated endocytosis. FR, FR and FR are all glycophosphatidylinositol (GPI) anchored cell-membrane proteins, whereas FR is a secreted protein lack of a GPI anchored region (18). FR is the most analyzed family member, and is the focus of this Review. FR is mainly expressed in placental and myeloid leukocytes, including activated macrophages, tumor-infiltrating macrophages.