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.
Highlights
Cancer treatment has involved various combinations of surgery, radiation, and chemotherapy
FRα has been a well-studied target of immunotherapies for over two decades and continues to be optimized with FRα targeted chimeric antigen receptor (CAR) T cells [5,6], an FRα-specific antibody (Farletuzumab) [7,8,9,10,11,12], and FRα-specific drug conjugated antibodies [13,14,15] all being evaluated in clinical trials
While FRα is primarily expressed on epithelial tissues, making it a target in some solid tumors, FRβ is expressed on myeloid lineage hematopoietic cells [16] and has been shown to be expressed in up to 70% of cases of acute myeloid leukemia [17] making it a potential therapeutic target
Summary
Cancer treatment has involved various combinations of surgery, radiation, and chemotherapy. M909 is an FRβ-specific human monoclonal antibody that was shown to recognize activated macrophages from rheumatoid patients and to mediate antibody-dependent cell-mediated cytotoxicity (ADCC) [27]. An antibody against FRβ could be used to improve the treatment of solid tumors such as ovarian cancer by eliminating immunosuppressive, pro-tumorigenic M2 macrophages in the microenvironment. M909 Detects FRβ Expression and Can Mediate ADCC of AML Cell Lines. 2021,in22,s5p5e7c2ific cytotoxicity for all cell lines correlated with increasing surface expression of FRβ (Figure 1e). Ie%Anslalosmcpveeeelcrldailfiilonlcnecocserydl,ltteohmteooxinniccsitrtreyaatsewedainas specific cytotoxicity for all cell lines correlated with increasing surface expression of FRβ (Figure 1e). We first assessed whether the presence of the antibody in the absence of effector cells affected the growth of FRβ-expressing cells in culture. In this study, the majority of samples expressed at least moderate levels of FRβ with an average of 21.9% expression and a range of 2.0–60.1% among the 12 samples
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
