Folate Receptor Beta as a Direct and Indirect Target for Antibody-Based Cancer Immunotherapy

Abstract

Folate receptor beta (FRβ) is a folate binding receptor expressed on myeloid lineage hematopoietic cells. FRβ is commonly expressed at high levels on malignant blasts in patients with acute myeloid leukemia (AML), as well as on M2 polarized tumor-associated macrophages (TAMs) in the tumor microenvironment of many solid tumors. Therefore, FRβ is a potential target for both direct and indirect cancer therapy. We demonstrate that FRβ is expressed in both AML cell lines and patient-derived AML samples and that a high-affinity monoclonal antibody against FRβ (m909) has the ability to cause dose- and expression-dependent ADCC against these cells in vitro. Importantly, we find that administration of m909 has a significant impact on tumor growth in a humanized mouse model of AML. Surprisingly, m909 functions in vivo with and without the infusion of human NK cells as mediators of ADCC, suggesting potential involvement of mouse macrophages as effector cells. We also found that TAMs from primary ovarian ascites samples expressed appreciable levels of FRβ and that m909 has the ability to cause ADCC in these samples. These results indicate that the targeting of FRβ using m909 has the potential to limit the outgrowth of AML in vitro and in vivo. Additionally, m909 causes cytotoxicity to TAMs in the tumor microenvironment of ovarian cancer warranting further investigation of m909 and its derivatives as therapeutic agents in patients with FRβ-expressing cancers.

Folate Receptor Beta for Macrophage Imaging in Rheumatoid Arthritis

“…Macrophage FRb is a valid target for folate-based imaging (Figure 1B), along with other FRb targeting approaches (Figure 1C) by (drug-conjugated) monoclonal antibodies, folate-conjugated drugs, CAR T cells and folate antagonists (25,31,34,50,51). FRb contains a binding pocket for folic acid where binding of folic acid is facilitated by a conformational change in two regions of the receptor, in particular the region connecting beta strand 1 and 2 and the region of alpha helix 1 (52).…”

Redox-Sensitive and Folate-Receptor-Mediated Targeting of Cervical Cancer Cells for Photodynamic Therapy Using Nanophotosensitizers Composed of Chlorin e6-Conjugated β-Cyclodextrin via Diselenide Linkage

“…Among them, folate receptors are normally overexpressed in various types of cancer [ 58 ]. For example, folate receptor β, which is expressed on myeloid lineage hematopoietic cells, is highly expressed on malignant blasts in patients having myeloid leukemia and tumor-associated macrophages in the tumor microenvironment [ 59 ]. These properties of folate receptor enable nanocarriers to target cancer cells specifically and allow for application of nanocarriers in direct/indirect therapy of cancer.…”

Defining and targeting macrophage heterogeneity in the mammary gland and breast cancer

“…Also expressed on LYVE‐1+ macrophages, FOLR2 may be a druggable target for the inhibition of LYVE‐1+ macrophages, as FOLR2 expression is more restricted to macrophages 169–171 . Notably, targeting FOLR2 with a monoclonal antibody reduced tumor growth in a humanized mouse model of acute myeloid leukemia, coupled with NK cell transfer 172 . Further studies are needed to determine whether FOLR2 may be a druggable target for breast cancer patients.…”