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

Folate receptor beta (FR beta) is a folate binding receptor expressed on myeloid lineage hematopoietic cells. FR beta 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, FR beta is a potential target for both direct and indirect cancer therapy. We demonstrate that FR beta is expressed in both AML cell lines and patient-derived AML samples and that a high-affinity monoclonal antibody against FR beta (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 FR beta and that m909 has the ability to cause ADCC in these samples. These results indicate that the targeting of FR beta 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 FR beta-expressing cancers.

Automated summary

FR beta is a potential target for cancer therapy, as demonstrated by high expression levels on malignant blasts in AML and M2 polarized TAMs in solid tumors. The monoclonal antibody m909 is effective in causing ADCC against FR beta-expressing cells, leading to tumor growth inhibition in AML mouse models and cytotoxicity to TAMs in ovarian cancer microenvironment. Further investigation of m909 and its derivatives as therapeutic agents for FR beta-expressing cancers is warranted.