The PD-1 / PD-L1 Pathway
Introduction The immune system fights off pathogens, but this defensive force can be pathogenic itself when hyperactive, resulting in autoimmune diseases such as lupus and multiple sclerosis. Consequently, the body has developed multiple mechanisms to suppress the immune system when necessary. One method of immunosuppression is the PD-1 pathway. This pathway is activated in response to the mobilization of the immune system. The receptor PD-1 is expressed on the surface of activated lymphocytes. Similarly, its ligand, PD-L1, is expressed by antigen-presenting cells in response to cytokine signaling. When PD-L1 is bound to PD-1, downstream signaling undoes the phosphorylation events associated with activation, thereby reverting lymphocytes to an inactive state [1, 2]. Antibody Cat no. Type Applications PD-1/CD279 Antibody 18106-1-AP Rabbit Poly ELISA, WB, FC, IHC Immunotherapy: A Promising Treatment for Cancer Tumor cells take advantage of the PD-1 pathway to evade the immune system [3]. Consequently, many pharmaceutical companies have been developing drugs to inhibit PD-1 and PD-L1. In clinical trials, many patients have shown strong responses to these therapies [4-10]. For these drugs to be most effective, a high number of CD8+ T cells must already be at the tumor site, ready to be mobilized after inhibition of the PD-1 pathway [11].Recent investigations have uncovered promising methods of increasing the efficacy of PD1 inhibitors. One method is combining PD1 inhibitors with other drugs, such as HDAC inhibitors [12] and anti-CTLA4 antibodies [9]. Another method is using biomarkers to predict response to therapy [13,14]. Recent work has also suggested that GSK3 inhibitors can enhance effects of immunotherapy [15].Though these results have been encouraging, several challenges remain, including the mitigation of autoimmune effects and how to overcome drug resistance. Current Antibody Drug Development Drug Company PD-1 SHR-1210 Incyte Nivolumab Bristol-Myers Squibb Pembrolizumab Merck Pidilizumab CureTech BMS 936559 Bristol-Myers Squibb PD-L1 Atezolizumab Roche Durvalumab AstraZeneca Avelumab Pfizer/Merck MDX-1105 Bristol-Myers Squibb CTLA-4 Ipilimumab Bristol-Myers Squibb Tremelimumab Pfizer/AstraZeneca Antibody Cat no. Type Applications PD-L1/CD274 Antibody 17952-1-AP Rabbit Poly ELISA, IF, IHC, IP, WB KD/KO Validated, 9 Publications Related Products Antibody Cat no. Type Applications PD-L1/CD274 66248-1-Ig Mouse mono ELISA, WB, IHC, IF, FC CD86/CTLA 4 13395-1-AP Rabbit poly ELISA, WB, FC CD3 epsilon 17617-1-AP Rabbit poly ELISA, WB, IHC, IP, FC GSK3B 22104-1-AP Rabbit poly ELISA, WB, IHC, IF, IP BRAF 20899-1-AP Rabbit poly ELISA, IHC, IF References 1. Ohegbulam et al. (2015) Human cancer immunotherapy with antibodies to the PD-1 and PD-L1 pathway. Trends Mol Med. 21:24-33. 2. Haanen, J. (2013) Immunotherapy of Melanoma. EJC Suppl 11:97-105. 3. Yao et al. (2013) Advances in targeting cell surface signaling molecules for immune modulation. Nat Rev Drug Discov. 12:130-146. 4. Topalian, S. et al. (2012) Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 366:2443-2454. 5. Hamid, O. et al. (2013) Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N. Engl. J. Med. 369:134-144. 6. Topalian, S. L. et al. (2012) Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 366:2443–2454 7. Brahmer, J. R. et al. (2012) Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med. 366:2455–2465 8. Hamid, O. et al. (2013) Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N. Engl. J. Med. 369:134–144 9. Wolchok, J. D. et al. (2013) Nivolumab plus ipilimumab in advanced melanoma. N. Engl. J. Med. 369:122–133 10. Topalian, S. L. et al. (2014) Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J. Clin. Oncol. 32:1020–1030 11. Tumeh, P. et al. (2014) PD-1 blockade induces responses by inhibiting adaptive immune response. Nature. 515:568-71. 12. Woods, D. et al. (2015) HDAC inhibition upregulates PD-1 ligands in melanoma and augments immunotherapy with PD-1 blockade. Cancer Immunol Res 12:1375-85. 13. Chakravarti, N., & Prieto, V. G. (2015). Predictive factors of activity of anti-programmed death-1/programmed death ligand-1 drugs: immunohistochemistry analysis. Translational Lung Cancer Research, 4:743–751. 14. Barak, V. et al. (2015) Assessing response to new treatments and prognosis in melanoma patients, by the biomarker S-100B. Anticancer Res. 35:6755-60. 15. Taylor, A. et al. (2014) Glycogen synthase kinase 3 inactivation drives T-bet-mediated downregulation of co-receptor PD-1 to enhance CD8+ cytolytic T cell responses. Immunity 44:274-86.
