Immunotherapies Targeting CD123 and CD303: A New Frontier in Treating Blastic Plasmacytoid Dendritic Cell Neoplasm

Abstract

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematologic malignancy characterized by the overexpression of CD123 and CD303 surface antigens. These molecular markers play a crucial role in diagnosing diseases and developing targeted therapies. Traditional treatment options for BPDCN have demonstrated limited effectiveness, highlighting the need for new and innovative therapeutic strategies. Recent advances in immunotherapy, particularly therapeutic monoclonal antibodies, bispecific T-cell engagers, and CAR T-cell therapy, have provided promising alternatives. Tagraxofusp, the first FDA-approved CD123-targeted therapy, has significantly improved patient outcomes. Additionally, emerging CD303-targeting strategies offer the potential for further advancements. Despite these breakthroughs, challenges such as treatment resistance and toxicity remain. This review explores the latest developments in BPDCN treatment, emphasizing the potential of CD123 and CD303 as targets for precision medicine interventions. The ongoing evolution of targeted immunotherapies holds promise for improving patient survival and redefining treatment paradigms in hematologic malignancies.

Keywords: BPDCN; CD123; CD303; cancer therapy; immunotherapy; pDC.

Figure 1

(A) CD123, as the alpha subunit of the IL-3 receptor, guides hematopoietic cell maturation. When bound to IL-3, it activates the beta chain, creating a dynamic IL-3 receptor heterodimer. This receptor orchestrates crucial signaling pathways for anti-apoptotic and cell-proliferative signals. (B) CD303 (BDCA-2) is a type II C-type lectin receptor on pDCs. It signals via the FcRγ chain, which contains ITAM motifs. Ligand binding triggers ITAM phosphorylation by Src kinases (e.g., Lck, Fyn), activating Syk and downstream pathways that regulate antigen uptake, endocytosis, and type I interferon production.

Figure 2

This figure provides an overview of Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN), covering its pathophysiology (grey section), clinical features (light green section), diagnosis (blue section), and treatment options (orange section).

Figure 3

The figure depicts targeted therapies for BPDCN, focusing on CD123 and CD303 as key antigens. Anti-CD123 antibodies (SL401,IMGN632, CSL362, and BYON4413) directly target CD123 to induce cytotoxicity. Anti-CD303 antibodies (BIIB059, Ch122A2) aim at CD303-expressing cells to enhance immune clearance. BiTEs (Bispecific T-cell Engagers) (MDG006, APV0436) link T cells to BPDCN cells, promoting selective killing. CAR-T cells (UNICART123, MB-102, and UNICARo2-T) are engineered to recognize CD123 and destroy BPDCN cells. MEK inhibitors block MEK/ERK signaling, disrupting BPDCN survival and proliferation.