Folate receptor beta (FR-beta) (FR-beta)

Folate receptor beta (FR-beta), encoded by the FOLR2 gene, is a glycosylphosphatidylinositol (GPI)-anchored cell surface protein that binds folic acid and its derivatives with high affinity [1, 4, 10]. Unlike the more widely studied alpha isoform (FR-alpha), FR-beta is primarily expressed on cells of the myeloid lineage, including monocytes, activated macrophages, and malignant blasts in acute myeloid leukemia (AML) [8, 10, 16, 18]. In healthy individuals, its expression is largely restricted to the placenta and a subset of hematopoietic cells, but it is significantly upregulated in inflammatory environments and the tumor microenvironment [4, 6, 14]. In these contexts, FR-beta-expressing macrophages (often M2-polarized) contribute to immunosuppression and disease progression in conditions like rheumatoid arthritis and various solid tumors [2, 6, 18]. Therapeutically, FR-beta is exploited as a molecular address for the targeted delivery of imaging agents and potent drugs, such as folate-conjugated toxins, TLR7 agonists, or radioisotopes [6, 7, 11, 12]. By utilizing receptor-mediated endocytosis, these conjugates can selectively enter and eliminate or reprogram pathogenic macrophages and leukemia cells while sparing healthy tissues [3, 10, 11]. Current research also explores FR-beta as a target for antibody-based therapies and CAR-T cells, aiming to disrupt the immunosuppressive niche of tumors and enhance the efficacy of existing immunotherapies [14, 18].

Other names

Folate receptor 2FOLR2Folate-binding protein 2Placental folate-binding proteinFBPFolate receptor, fetal/placental

Drugs targeting Folate receptor beta typically utilize receptor-mediated endocytosis to deliver conjugated therapeutic payloads (such as toxins, TLR7 agonists, or chemotherapeutics) directly into the cytoplasm of FR-beta-expressing cells [3, 10, 11]. Monoclonal antibodies like m909 target the receptor to induce antibody-dependent cellular cytotoxicity (ADCC) against malignant blasts or immunosuppressive macrophages [8, 18]. Additionally, folate-targeted agonists can be used to reprogram M2-polarized tumor-associated macrophages into a pro-inflammatory M1 phenotype to stimulate an anti-tumor immune response [6, 7].