TARGETING HUMAN CD27 WITH AN AGONIST ANTIBODY STIMULATES T-CELL ACTIVATION AND ANTITUMOR IMMUNITY

When it comes to controlling immunity and tolerance, CD27 is known to play a vital role. Recently, there has been wide adoption of the Abs immunoregulatory molecules to treat certain diseases like cancers and other related conditions. The CD27 belongs to the superfamily of the tumor necrosis factor receptor. Due to the benefits derived from CD27, immunologists are currently interested in CD27 as a co-stimulatory immune checkpoint. While there are other means employed for targeting drugs to fight cancer in different clinical research, the CD27 remains a major target. 

https://www.researchgate.net/figure/CD70-CD27-based-agonists-for-cancer-therapy-CD70-is-highly-expressed-on-malignant-cells_fig6_248386132

What is CD27?

As said earlier, CD27 belongs to the superfamily of the tumor necrosis factor receptor. However, the protein encoded by the gene belongs to the superfamily Tnf-receptor as a member. To generate and maintain T cell immunity, there is a need for this receptor in the long run. They are useful for binding to ligand CD70. They, however, carry out important functions when it comes to the regulation of activation of B-cell, including immunoglobulin synthesis. CD27, also known as T14, LPFS2, or S152, covert the signals that result in activating NF-KappaB and MAPK8/JNK. 

When it comes to diverse immunological processes, this receptor plays an important part. Also, the receptor has a role to play in the T cells effector, activation and survival, proliferation, and cytotoxic natural killer activities (NK) cells. CD27 receptor has unique characteristics, and that is, it can constitutively express itself even at a significant level of most T cells. They also have the same feature when it comes to naïve T cells. To translate these research work into applications for clinical use in the future, researchers established a fully composed of human antibodies specific for the CD27 by mice immunization. It was a genetic modification for the expression of human immunoglobulins with the extracellular human CD27 domain.

https://bpsbioscience.com/anti-cd27-agonist-antibody-100111

The monoclonal antibodies panel passed through screening by different binding and functional assays. This, however, resulted in choosing a lead IgG1 antibody, known as clone 1F5. There is a high exhibition of affinity from this antibody for CD27 variants for both human and macaque, binding to the expression of this TNFRSF member on the cell surface. This, however, blocks the binding of CD70, which may be indicating that 1F5 may also bind to (or even closer to) CD27’s ligand-binding site. 

For Vivo studies performance based on the 1F5 antibody, researchers generated transgenic mice with human CD27 (hCD27-Tg) expression. This was done through a bacterial artificial chromosome (BAC) with the whole CD27-coding gene, including the promoter of presumed upstream. There was backcrossing of the hCD27-Tg mice to various strains, and expression of the transgene was characterized largely. 

Throughout the world, the pattern of human CD27 transgenic mice, whether they are in steady-state conditions or the state of immune responses, provides a kind of suggestion. They suggest that the hCD27-Tg transgene mice have an expression and regulation in a way that has consistency with the CD27 biology. The mouse affinity CD70 for human CD27 relates to the human CD70. This, however, indicates that interaction can of natural CD70-CD27 take place in hCD27-Tg mice.

Agonist Antibody

The demonstration of the agonistic activity of the 1F5 antibody took place in vitro with the use of either hCD27-Tg or human T-cells derived from mice. Particularly, 1F5 showed that it increases the proliferation and cytokine expression of CD4+ and CD8+ cells exposed to suboptimal amounts of anti-CD3 antibodies. However, this was observed only when there was a crosslink of the 1F5 with antihuman IgGs or bound to the microtiter plate. The provision of 1F5 in the solution or crosslinking 1F5 with no T-cell receptor (TCR) stimulation led to no activation of T-cell. However, 1F5 seems to lack the power to trigger a likely dangerous Polyclonal T-cell activation as co-stimulatory superagonists do, such as Cd28-specific antibodies. 

The CD27 pathway

Having explained earlier that CD27 is a member of the subgroup of T-cell co-stimulatory TRAFs, they communicate the receptors of TNFSF. Also, they are responsible for the activation of the signaling pathway that leads to the activation of transcription factors of the NFκB family and MAP kinases. When these pathways are activated, these receptors will help to improve cellular proliferation, including the apoptotic protein expression. The activation of CD27 during this process will employ the TNF receptor connected to factor-2 (TRAF2) and maybe, TRAF5 and/or NFκB inducing kinase (NIK) to CD27. 

https://jlb.onlinelibrary.wiley.com/doi/10.1189/jlb.0610351

There has been a development of monoclonal antibody which functions as anti CD27, 1F5 that has shown to activate the hCD27-Tg mouse T cells in the TCR stimulation context. However, 1F5 can be very effective being a part of combinatorial Immuno(chemo) therapeutic regimens. According to the data from CD27-deficient mice, there were indications that there may be enhancement of the immunosuppressive activity of regulatory T-cell by stimulation. Hence, there will be a promotion of tumor growth. 

Conclusion

Suggestions and evidence have currently revealed that animal models and the human disease pathway of CD27-CD70 are great contributors to the pathophysiology of autoimmunity. Although many questions about this remain unanswered, the available research and findings point out that a target on the components of this pathway can be helpful when it comes to providing useful and therapeutic needs. 

One thought on “TARGETING HUMAN CD27 WITH AN AGONIST ANTIBODY STIMULATES T-CELL ACTIVATION AND ANTITUMOR IMMUNITY”

  1. How about using the vitamin D metabolite calcifediol to treat autoimmune diseases? It’s safer than calcitriol (also used to regulate calcium and phosphate levels) and faster acting than cholecalcifediol (D3). Calcitriol can be manufactured locally from calcifediol by immune cells (if calcifiediol levels are adequate between 50-60 ng/ml) and used to reduce inflammation when infection has been cleared locally.

    Calcitriol is called the “active” form of vitamin D. However, even though the metabolite calcifediol may only have 10% of the activity of calcitriol, calcifediol may be present at 1000x the level of calcitriol and may actually dominate activation of VDRs.

    https://link.springer.com/article/10.1007/s00223-019-00577-2

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