Table 2.
Proposed mechanisms of action of selected immune checkpoint blocking agents.
| Agent | Specificity | Mechanism |
|---|---|---|
| Ipilimumab | CTLA-4 | • Inhibits coinhibitory checkpoint molecule CTLA-4 on T cells by preventing CD80/CD86 binding on APCs • Enhances T-eff activation and T-reg inhibition |
| Pembrolizumab/nivolumab | PD-1 | • Inhibit coinhibitory checkpoint molecule PD-1 on antigen-educated T cells, preventing PD-L1-APC binding • Enhances T-eff activation • Reduces T-eff anergy |
| BMS-956559/PDR001 | PD-L1 | • Inhibits coinhibitory checkpoint molecule PD-L1 on APCs and melanoma cells preventing its binding to PD-1 and CD80/CD86 on T cells • Enhances T-eff activation • Reduces T-eff anergy |
| LAG525 | LAG-3 | • Inhibits coinhibitory checkpoint molecule LAG-2 on activated T cells preventing binding to MHC-II on DCs, pDC and melanoma cells • Enhances T-eff and myeloid cell responses (DCs, macrophages and NK cells |
| CP1-444 | A2AR | • Inhibits coinhibitory checkpoint molecule A2AR molecule on myeloid cells preventing binding to extracellular adenosine released by CD73 on T-reg and melanoma cells • Enhances myeloid cell response • Reduces T-reg cell response |
| MBG453 | TIM-3 | • Inhibits coinhibitory checkpoint molecule TIM-3 on T cells preventing to binding on galactin-9 on immune and melanoma cells and HMG-B on immune cells • Prevents T cell exhaustion • Enhances nucleic acid recognition within endosomes |
| MGA271 | B7-H3 | • Inhibits coinhibitory checkpoint molecule B7-H3 on APCs and melanoma cells preventing ligand binding on T cells • Enhances T-eff activation and T-reg inhibition |
| CA-170 | VISTA | • Inhibits coinhibitory checkpoint molecule VISTA on myeloid cells and naïve T cells preventing binding to VSIG-3 • Enhances T-eff activation and T-reg inhibition |
| Epacadostat | IDO | • Inhibits coinhibitory checkpoint molecule IDO on alternatively activated macrophages, T-regs and melanoma cells preventing the conversion of tryptophan to kynurenines on T cells • Enhances NK/ T-eff activation and T-reg inhibition |
| N/A | PKC-η | • Inhibits coinhibitory signaling molecule PKC-η on T-regs preventing its induction of anti-inflammatory cytokine transcription • Enhances T-eff activation and T-reg inhibition |