Anti-TNFR-SF Agonistic Antibody Introduction

It is generally accepted that co-stimulatory receptors are as important as checkpoint inhibitors in the treatment of disease and that, together, they complement each other in promoting immune anti-tumor activity. The tumor necrosis factor receptor superfamily (TNFRSF) has an important role in cell biology. Almost all members have pro-inflammatory activity, activated in part by the transcription factor NF-kB. Some members exhibit proliferative activity in hematopoietic cells through the activation of various mitogen-activated kinases, and some molecules play a role in apoptosis. Many TNFRSF members have now been identified as co-stimulatory receptors in anti-tumor immunity. They also play an important role in the field of cancer therapy. Based on our rich field experience and advanced research platform, Creative Biolabs provides comprehensive services to support custom agonistic antibodies and checkpoint agonistic antibodies.

Fig 1. TRAF and TNF receptor-associated protein (TTRAP)

Anti-TNFR-SF Agonistic Antibody

The tumor necrosis factor superfamily (TNFSF) and its receptor superfamily (TNFRSF) consist of 19 ligands and 29 receptors in inflammation, apoptosis, proliferation, and morphogenesis, respectively. Many TNFRSF members have been evaluated as potential novel immunotherapeutic targets because of their roles in activation, clonal expansion, and survival of immune cells, including cytotoxic T cells, in the same populations as those regulated by PD-1. Today, there are dozens, if not hundreds, of TNFRSF agonist candidates in monoclonal or multispecific antibody form being tested in clinical trials. They are being studied or developed as monotherapies or in combination with standard treatments such as immune checkpoint inhibitors (e.g., anti-CTLA4 or anti-PD-1/PD-L1 antibodies) or chemotherapy.

Current studies have found that the mechanism of action of TNFRSF agonist antibodies has several main aspects. One is that TNFSF ligands are naturally present in the cell membrane as trimers or dimers, which in turn can promote the formation of TNFRSF trimers and secondary aggregation of oligomers, leading to receptor activation. Second, Fc-FcγRIIB interaction is the dominant factor in the therapeutic agonistic activity of TNFRSF antibodies. Binding to cell surface TNFSF ligands via cell-to-cell interactions induces physiological TNFRSF receptor activation, leading to receptor-ligand trimer cross-linking and oligomerization. Receptor aggregation leads to the productive docking of intracellular adapter molecules and the assembly of signaling mechanisms. Antibodies can activate TNFRSF because of their ability to crosslink receptor dimers or trimers at the cell surface, but their activity varies widely due to a combination of factors, including various Fab, hinge, and Fc sequences. Each structural feature of an antibody contributes to agonistic activity and can be assessed individually in experiments. However, overall agonistic activity is an integration of all interactions in the tissue microenvironment.

TNFRSF signaling stimulates the activation and proliferation of various immune cells, including myeloid cells and T cells, providing potential targets for cancer agonistic antibody therapy. However, TNFRSF agonist antibodies have shown limited clinical success, which may be due to limited receptor aggregation-mediated signaling or the associated dose-limiting toxicity of these early products. Studies investigating the mechanism and function of various TNFRSF agonist antibodies have identified an important role for FcγRIIB, which has been shown to mediate TNFRSF clustering bridged by TNFRSF antibodies. The agonistic activity of the antibody may be influenced by the Fab, hinge, or Fc region, but the Fc-FcγRIIB interaction has been identified as a major determinant of the overall agonistic outcome (efficacy and toxicity). Strongly agonistic antibodies without Fc cross-linking can be identified in vitro that exhibit agonism upon target binding, and when Fc-FcγR cross-linking is available, these antibodies become super agonists. In the absence of Fc cross-linking, TNFRSF antibodies with weak or no detectable agonistic activity can exhibit strong agonism when Fc-FcγRIIB is engaged.

Creative Biolabs has a wealth of knowledge and experience in antibody discovery. We would be happy to share with you our knowledge and experience in custom agonistic antibodies and anti-TNFR-SF agonistic antibodies.

All listed services and products are For Research Use Only. Do Not use in any diagnostic or therapeutic applications.

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