Pd-1

The PD-1 protein (PD-1 = acronym for "Programmed Death-1") is a membrane receptor (PD-1 receptor) consisting of 268 amino acids. Like CTL-4, PD-1 is a member of the extended CD28 / CTLA-4 family. Its molecular structure comprises an extracellular IgV domain, followed by a transmembrane region and an intracellular domain.

Tumor cells often camouflage themselves before their elimination, e.g. by expressing the programmed death ligands PD-L1 and PD-L2 on their surface. An encounter of the PD-1 receptor protein with its ligand on activated T cells leads to a suppression of the antitumor immune response. The CD28 / CTLA-4 protein family thus acts as T-cell regulators and slows down T-cell activation after antigen stimulation. Compared to CTL-4, the PD-1 receptor has a higher and broader selectivity for immunosuppressive signals that are triggered directly by tumor cells or the cells of the tumor stroma. It was therefore to be expected that modulation or antagonization of this regulatory mechanism (see PD-1 antibodies below) would have a higher antitumour efficiency than antagonization of the CTL-4 receptor protein (see ipilimumab below). Substances that pursue this approach are also referred to as"checkpoint modifiers" or "checkpoint inhibitors".

A humanized monoclonal antibody against the surface protein PD-1 is pembrolizumab, which is currently being used successfully in the KEYNOTE-002 study in ipilimumab-resistant metastatic malignant melanoma.

1. Topalian SL et al (2012) Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366: 2443-2454
2. Blank C et al (2004) PD-L1 / B7H-1 inhibits the effector phase of tumor rejection by T-cell receptor (TCR) transgenic CD8 + T-cells. Cancer Res 64: 1140-1145
3. Ribas A et al(2015) Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractorymelanoma
   (KEYNOTE-002): a randomised, controlled, phase 2 trial.Lancet Oncol.16:908-918.