Folate Receptor-Targeted Diagnostics and Therapeutics for Inflammatory Diseases

Abstract

Inflammation, an innate immune response mediated by macrophages, forms the first line of defence to protect our body from the invasion of various pathogens. Although inflammation is a defensive response, chronic inflammation has been regarded as the major cause of many types of human diseases such as inflammatory/autoimmune diseases, cancers, neurological diseases, and cardiovascular diseases. Folate receptor (FR) is a cell surface glycosylphosphatidylinositol (GPI)-anchored glycoprotein, and its three isoforms, FR-α, FR-β, and FR-γ, are found in humans. Interestingly, FRs are highly expressed on a variety of cells, including cancer cells and activated macrophages, whereas their expression on normal cells is undetectable, indicating that FR-targeting could be a good selective strategy for the diagnosis and therapeutic treatment of cancers and activated macrophage-mediated inflammatory diseases. Previous studies successfully showed FR-targeted imaging of many types of cancers in animal models as well as human patients. Recently, a number of emerging studies have found that activated macrophages, which are critical players for a variety of inflammatory diseases, highly express FRs, and selective targeting of these FR-positive activated macrophages is a good approach to diagnose and treat inflammatory diseases. In this review, we describe the characteristics and structure of FRs, and further discuss FR-targeted diagnostics and therapeutics of human diseases, in particular, activated macrophage-mediated inflammatory diseases.

Keywords: Diagnostics; Folate receptor; Inflammatory diseases; Macrophage; Therapeutics.

Figure 1. (A) Structure of a folate conjugate. Folate conjugates consist of three major parts: folic acid, which binds with the folate receptor (FR) on target cells, a linker, which connects folate and the imaging/drug agent, and the imaging/drug agent that is necessary for diagnosis and therapy of folate receptor-positive cells in human diseases. (B) FR-mediated endocytosis of folate conjugate. Folate conjugates bind with FRs expressed on various types of cancer cells and activated macrophages, and enter the cells by receptor-mediated endocytosis. Endocytosed folate conjugates in endosomes are then fused with lysosomes inside the cells, and the conjugated agent is released from folate into the cells. After releasing folic acid and the conjugated agent, folate receptors are transported to the cell membrane and recycled to bind with further folate conjugate. (C) Structure of ^99mTc-EC20. ^99mTc-EC20 consists of two parts: an FR binding moiety (folic acid) and a chelating moiety that forms a pocket to chelate ^99mTc.

Figure 2. (A) Folate receptor (FR)-targeted immunotherapy by antibody-dependent cellular cytotoxicity (ADCC) by NK cells and macrophages. A folate-hapten conjugate binds with the FR on target cells, and antibodies specific for the hapten directly bind with the hapten on the conjugate. Macrophages and NK cells then recognize the antibody through their Fc receptors and kill the target cells by ADCC. (B) FR-targeted immunotherapy by complement-dependent cellular cytotoxicity (CDC). A folate-hapten conjugate binds with the FR on target cells and antibodies specific for the hapten bind directly to it. Complement components then bind to the antibody, and this binding activates complement cascades, followed by the formation of a membrane attack complex (MAC) at the surface of the target cells, which leads to cell death.