CD64: An Attractive Immunotherapeutic Target for M1-type Macrophage Mediated Chronic Inflammatory Diseases

Abstract

To date, no curative therapy is available for the treatment of most chronic inflammatory diseases such as atopic dermatitis, rheumatoid arthritis, or autoimmune disorders. Current treatments require a lifetime supply for patients to alleviate clinical symptoms and are unable to stop the course of disease. In contrast, a new series of immunotherapeutic agents targeting the Fc γ receptor I (CD64) have emerged and demonstrated significant clinical potential to actually resolving chronic inflammation driven by M1-type dysregulated macrophages. This subpopulation plays a key role in the initiation and maintenance of a series of chronic diseases. The novel recombinant M1-specific immunotherapeutics offer the prospect of highly effective treatment strategies as they have been shown to selectively eliminate the disease-causing macrophage subpopulations. In this review, we provide a detailed summary of the data generated, together with the advantages and the clinical potential of CD64-based targeted therapies for the treatment of chronic inflammatory diseases.

Keywords: CD64; chronic inflammatory disease; dysregulated macrophage; human cytolytic fusion protein; immunotherapy; immunotoxins.

Figure 1

Cellular interplay during the initiation and amplification cycle of inflammation. During the early phase of inflammation, tissue-resident macrophages sense damage and become activated, herewith releasing signals that induce rapid recruitment of other immune effector cells. The stimulation and presentation of antigen to TH1 cells result a complex process which amplifies the phagocytic and destructive ability of macrophages.

Figure 2

Diagrammatic representation of the human Fc receptors. There are five activating FcγRs: FcγRI, FcγRIIa, FcγRIIc, FcγRIIIa, FcγRIIIb, and one inhibitory Fc receptor; FcγRIIb. They all consist of an immunoglobulin-binding polypeptide chain with two Ig-like extracellular domains with the exception of FcγRI (CD64) which has three. An activating signalling cascade is mostly generated by the cross-linking of activating FcγRs by immune complexes which results in the phosphorylation of ITAMs on FcγRIIa and FcγRIIc. The FcR-γchain common to the Fc receptors is the only inhibitory FcγR. FcγRIIb also binds immune-complexed IgG and contain an ITIM in its cytoplasmic domain. ITAM: immunoreceptor tyrosine-based activation motif; γ₂: dimer of FcRγ subunits; ITIM: immunoreceptor tyrosine-based inhibitory motif; GPI: glycosyl-phosphatidylinositol; NK cells: Natural Killer cells; +: indicates expression; (-): No expression; (#): only on activated Neutrophils; (§): Low; (‡): conflicting reports: (ψ): expressed only in 30% of humans [32,36].

Figure 3

Binding, internalization and routing of CD64 directed bacteria immunotoxins (ETA’) and human cytolytic fusion protein (Granzyme B). H22 based fusion proteins bind CD64 and are internalize by receptor mediated endocytosis after which they are processed in the endosomal compartment. As mentioned earlier, the targeted killing of M1 macrophages by these fusion proteins is due to the differential post-internalization kinetics of these fusion proteins in M1 macrophages versus endosomal degradation in the M2-type macrophages. Once, internalized, a furin cleavage site separates the ligand from the effector molecules (1–3). ETA’ (Panel A) naturally contains a translocation domain by which it leaves the endosome and traffics through the endoplasmic reticulum into the cytosol (4–6) Here it enzymatically inactivates protein synthesis by ADP-ribosylation of EF-2,which subsequently leads to cell death (13). On the other hand, granzyme B based fusion proteins (Panel B) are often engineered to contain an adapter domain that allows their translocation into the cytosol (7) where they initiate apoptosis by cleaving; caspase dependent substrates (8), caspase independent substrates (9), BH3-only pro-apoptotic protein (Bid) (11) with subsequent cytochrome C release (12). Note (10): Some other intracellular apoptosis inducing pathway not yet identified.