Monoclonal Antibody Development Targeting CD70-CD27 for Autoimmune Diseases

Introduction to CD70-CD27

The cluster of differentiation 27 (CD27) is a receptor that is constitutively expressed on the majority of T lymphocytes, B lymphocytes, natural killer (NK) cells. As a costimulatory molecule, CD27 is an important member of the tumor necrosis factor (TNF) receptor superfamily, which plays a fundamental role in the generation and long-term maintenance of T cell immunity. Structurally, CD27 is a type I transmembrane homodimeric phosphoglycoprotein with 260 amino acids and three extracellular cysteine-rich domains. The identified ligand of CD27, CD70 (also known as CD27L or TNFSF7), is a trimeric type II transmembrane TNF protein that mainly presents restricted to activated T cells, mature dendritic cells (DCs), and activated B cells.

The binding of CD70 ligand to CD27 receptor plays a key role in multiple immune bioprocesses, including activation, proliferation, and differentiation of T cells and B cells, antibody secretion, and cytokine production, through the activation of NF-κB and JNK signaling pathways. The CD70-CD27 interactions have been demonstrated to be closely associated with a variety of immune-related diseases, especially in autoimmune diseases and cancers.

Fig.1 Structures of CD70, CD27, and CD70-CD27 complex. (Wajant, 2016)

The Role of CD70-CD27 in Autoimmune Diseases

Upon activated by an antigen, the naïve CD4+ and CD8+ T cells increase the expression of CD27. Meanwhile, the stimulation of antigens induces the transiently exclusive CD70 expression by activated B cells and DCs. Thus, the elevated circulating CD27 and CD70 can serve as diagnostic markers of the early stages of immunity activation. The CD70 interacting with CD27 on the surface T cells results in the signaling pathways activation, thereby the increased transcriptions of transcription factors and the production of effector proteins. CD27-CD70 mediated signaling pathways play an important role in a variety of autoimmune diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), multiple sclerosis, and so forth.

• CD27-CD70 in SLE

Patients suffering from SLE had been detected with an increased level of CD27-high-expressed plasma cells in peripheral blood and correlated with SLE disease activity index. And CD70 was overexpressed by circulating CD4 T lymphocytes in SLE patients. IgG production was stimulated when the CD70 overexpressed CD4 T cells co-cultured with B cell, while, was inhibited when adding CD70-blocking antibodies.

• CD27-CD70 in RA

Compared with normal individuals, the expression of CD70 on both naive and memory CD4 T lymphocytes in RA patients was up-regulated remarkably. And this increased expression of CD70 associates with increased IFN-γ and IL-17 production after T lymphocyte activation.

• CD27-CD70 in neuro-immunological diseases

CD27-CD70 interactions play an important role in neurological immune response and homeostatic mechanisms. It has been shown that soluble CD27 was significantly elevated in the cerebrospinal fluid of patients with progressive multiple sclerosis as well as other neurological immune diseases. While anti-CD70 monoclonal antibody treatment markedly prevented experimental autoimmune encephalomyelitis in mice model.

Fig.2 CD27–CD70 pathway in immune regulation. (Han, 2016)

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References

1. Wajant, H. Therapeutic targeting of CD70 and CD27. Expert Opinion on Therapeutic Targets. 2016, 20(8): 959-973.
2. Han, A.K.; et al. The CD27-CD70 pathway and pathogenesis of autoimmune disease. Seminars in Arthritis and Rheumatism. 2016, 45(4): 496-501.

For Research Use Only | Not For Clinical Use