The principle of PD1 / PDCD1 / CD279 blockade in clinical trials is developing humanized antibodies or human IgG to bind either PD-1, thereby blocking the ligation of PD-1 and PD-L1 and the downstream inhibitory signaling events. So far, several anti-PD-1 monoclonal antibodies have been developed by various pharmaceutical companies. Some of the blockade agents have been in different stages of clinical trials against various types of tumor. The clinical outcomes differ between antibodies, which could be because of the discrepancies in antibody sources, antibody isotypes (IgG, IgG1, or IgG4), and antibody affinities. CT-011 (pidilizumab), a human-ized IgG1, is the first biological inhibitor of PD-1 in clinical trials.The objective response rates (ORR) of CT-011 to follicular lymphoma and advanced melanoma are 66% and 5.9%, respectively, indicating that different mechanisms might be involved in hematologic malignancies and solid tumors. The treatment-associated severe adverse event (SAE) in melanoma is 4%, showing a good tolerance. MK-3475 (pembrolizumab), a humanized IgG4, is the first FDA approved anti-PD-1 mAb to treat metastatic melanoma. The ORR of MK-3475 to advanced melanoma and NSCLC are 38% and 21%, respectively. The drug-related SAEs are acceptable (13% in melanoma). BMS-936558 (nivolumab) is a human IgG4 mAb against PD-1 developed by Bristol-Myers Squibb and currently in phase III clinical trials in various tumors. The use of nivolumab has achieved an improved outcome in metastatic melanoma and NSCLS. A study reported that compared to dacarbazine (a drug used in chemotherapy), the ORR could be increased from 13.9% to 40% in the nivolumab arm. Similarly, the overall survival (OS) was increased from 42.1% to 72.9%. Moreover, the drug-related SAEs were decreased in the nivolumab arm (11.7% vs 17.6%). In NSCLC, the OS was significantly better in the nivolumab arm when compared to docetaxel (9.2 vs 6 months). The efficacy of AMP-224, a PD-L2 IgG2a fusion protein, has also been evaluated in clinical trials. As opposed to the direct blocking PD-1/PD-L1 interaction, PD-L2 promotes the apoptosis of lymphocytes with high PD-1 expression.
Peilin Zheng et al. Human Cancer Immunotherapy with PD-1/PD-L1 Blockade. iomark Cancer. 2015; 7(Suppl 2): 15–18.
Huang Z et al. Clinical Research Progress of Anti PD-1/PD-L1 Monoclonal Antibody in the Treatment of Lung Cancer. Zhongguo fei ai za zhi= Chinese journal of lung cancer, 2015, 18(11): 706.