FCRH5, also known as Fc receptor-like protein 5 or FcRL5, is a protein found on the surface of certain immune cells. It belongs to the Fc receptor-like (FCRL) family. FCRH5 regulates immune responses, particularly those involving B cells. Its function provides insights into healthy immune system operation and its role in various diseases.
Understanding FCRH5
FCRH5 is a type I transmembrane protein, spanning the cell membrane. Its extracellular part contains nine immunoglobulin-like domains, which are protein segments resembling antibodies. These domains allow FCRH5 to interact with other molecules outside the cell. The intracellular cytoplasmic domain contains signaling motifs: immunotyrosine activation motifs (ITAMs) and immunotyrosine inhibitory motifs (ITIMs). These motifs transmit signals within the cell, influencing cell behavior.
FCRH5 is primarily located on the surface of B lymphocytes, a type of white blood cell in the adaptive immune system. It is also found on plasma cells, which are mature B cells that produce antibodies. The gene encoding FCRH5 is clustered with other FCRL genes on the long arm of chromosome 1. This protein binds to intact immunoglobulin G (IgG) molecules, suggesting a role in how B cells recognize and respond to antibodies.
FCRH5 in Healthy Immune Function
FCRH5 contributes to immune system function by modulating B cell activity. It influences B cell response to antigens, acting as either a negative or positive co-receptor depending on the cellular context. For instance, FCRH5 can inhibit B-cell receptor (BCR) signaling when certain co-stimulatory signals are absent. This inhibitory action involves recruiting signaling molecules like SHP-1 to its intracellular ITIMs, which then reduce calcium mobilization and protein tyrosine phosphorylation within the B cell.
When FCRH5 engages alongside CD21, another B cell protein, it promotes calcium signaling and B-cell activation. FCRH5 forms a receptor complex with CD21, and its interaction with IgG-containing immune complexes leads to strong B cell activation. FCRH5 is also involved in the development and differentiation of B cells in lymphoid organs and serves as a marker for different stages of B cell maturation. It also has an immunoregulatory role in marginal zone B-cells, a type of innate-like B cell.
FCRH5 and Human Disease
Dysregulation or altered expression of FCRH5 links to several human diseases, particularly certain cancers and autoimmune conditions. FCRH5 is highly expressed on malignant plasma cells in multiple myeloma (MM), a type of blood cancer. Its expression in myeloma samples shows high prevalence. This makes FCRH5 a promising target for therapies aimed at eliminating cancerous B cells.
Beyond multiple myeloma, FCRH5 associates with other B cell malignancies, such as chronic lymphocytic leukemia and mantle cell lymphoma, where soluble forms can be elevated in the blood. In autoimmune diseases, FCRH5’s involvement relates to its ability to modulate B cell activation. For example, FCRH5 upregulation in B cells can disrupt B cell anergy, a state of unresponsiveness that normally prevents autoreactive B cells from causing harm. This disruption leads to systemic autoimmunity and worsens conditions similar to systemic lupus erythematosus in animal models. Genetic variations in the FCRL5 gene also associate with susceptibility to multiple sclerosis, supporting its role in autoimmune processes.
Targeting FCRH5 for Treatment
The selective expression of FCRH5 on cancerous B cells and plasma cells, particularly its high prevalence in multiple myeloma, makes it a promising therapeutic target. One approach uses antibody-drug conjugates (ADCs) that specifically target FCRH5-expressing cells. These ADCs consist of an antibody designed to bind to FCRH5, linked to a potent anti-cancer drug. When the antibody binds to FCRH5 on a cell, the ADC is internalized, and the drug is released inside, leading to cell death.
DFRF4539A is an anti-FCRH5 ADC that uses monomethyl auristatin E (MMAE), a drug inhibiting cell division, to kill myeloma cells. An initial phase I study of DFRF4539A showed limited anti-tumor activity, but FCRH5 was confirmed as a valid target. Another strategy involves bispecific antibodies, like cevostamab, designed to engage both FCRH5 on myeloma cells and CD3 on T cells, redirecting T cells to kill cancer cells. Preclinical studies show FCRH5-targeted CAR T cells effectively kill myeloma cells, even those resistant to other therapies.