CD123 is a protein found on the surface of certain cells in the body, where it functions as a receptor for specific signaling molecules. It plays a role in both normal biological processes and the development of certain diseases, particularly blood cancers. This makes CD123 a focus of medical research and new treatment development.
What is CD123 and Its Normal Function?
CD123 is formally known as the alpha chain of the interleukin-3 (IL-3) receptor. Cytokines are small proteins that act as messengers between cells, influencing cell behavior. When IL-3 binds to CD123, it triggers events inside the cell, promoting cell growth, differentiation, and survival.
This receptor is involved in hematopoiesis, the process by which all blood cellular components are formed. CD123 is expressed on the surface of various healthy blood cells, including hematopoietic stem cells, myeloid progenitor cells, monocytes, basophils, and plasmacytoid dendritic cells. The binding of IL-3 to CD123, often in conjunction with a common beta subunit (CD131), activates signaling pathways like the JAK/STAT pathway, which regulates cell proliferation and differentiation.
CD123’s Connection to Disease
CD123 expression can become dysregulated, particularly its overexpression in various blood cancers. This is observed in conditions like acute myeloid leukemia (AML) and blastic plasmacytoid dendritic cell neoplasm (BPDCN). Normal hematopoietic stem cells have low CD123 expression, but leukemic stem cells and blasts in AML show higher levels.
The increased presence of CD123 on malignant cells contributes to uncontrolled cell proliferation and survival. In AML, high CD123 expression is associated with an increased proliferative response to IL-3, even at low concentrations, and can lead to increased viability of cancer cells. This makes CD123 a distinct marker for these cancerous cells, including leukemic stem cells that are often responsible for disease relapse. CD123 overexpression is a consistent feature in nearly all BPDCN cases, making it a reliable diagnostic indicator for this aggressive malignancy.
CD123 as a Diagnostic and Therapeutic Target
The distinct expression of CD123 makes it a valuable diagnostic biomarker for identifying specific cancers. CD123 immunohistochemistry is used in skin biopsies to diagnose BPDCN, as nearly all cases show universal CD123 expression. In AML, flow cytometry measures CD123 expression levels on blasts, aiding diagnosis and correlating with treatment response and patient outcomes.
Beyond diagnosis, CD123 is a therapeutic target, leading to the development of several treatment approaches.
Antibody-Drug Conjugates (ADCs)
ADCs combine an antibody that specifically binds to CD123 with a potent chemotherapy drug. IMGN632 is an example, designed to target CD123-positive AML cells while minimizing harm to healthy bone marrow cells.
Bispecific Antibodies
This strategy utilizes bispecific antibodies, engineered to bind simultaneously to CD123 on cancer cells and CD3 on T cells. This effectively redirects the patient’s own T cells to recognize and eliminate malignant cells.
CAR-T Cell Therapies and Targeted Toxins
CAR-T cell therapies are also being developed to target CD123. This involves genetically modifying a patient’s T cells to express a chimeric antigen receptor (CAR) that specifically recognizes CD123 on cancer cells. Once infused, these CAR-T cells identify and destroy CD123-expressing leukemic cells. Tagraxofusp, a recombinant human IL-3 fused to a diphtheria toxin, is an approved therapy for BPDCN. It demonstrates the effectiveness of CD123-targeted approaches by binding to the receptor and delivering a toxic payload to the cells.