Background and Purpose: PD-1 and PD-L1 antibodies have brought extraordinary clinical beneficial for cancer patients and their indications are expanding incessantly. Currently, most PD-1/PD-L1 products are delivered intravenously which may be inconvenient for some cancer patients. Here, we developed a novel oral delivered small molecular, YPD-29B, which targeted human PD-L1 specifically. Experimental Approach: HTRF and SPR assay were used to detect the binding affinity of YPD-29B and PD-L1. The PD-L1 dimerization were proved by native page and HTRF. PD-L1 cell based assay and PBMC cell activation assay were conducted to detect the T cell activation by YPD-29B in vitro. And human PD-1 humanized mice were used to test the antitumor activity and tolerance of YPD-29B in vivo. Key Results:: Our data suggested that YPD-29B could potently and selectively block the interaction between PD-L1 and PD-1, but did not inhibit any other immune checkpoints. Mechanistically, YPD-29B induced human PD-L1 dimerization and internalization, which subsequently activated T lymphocytes and therefore overcomes immunity tolerance in vitro. Moreover, YPD-29B exhibited great antitumor activity and was well tolerated in vivo. Conclusion and Implications: Our results indicated that YPD-29B serves as a promising therapeutic anti-human PD-L1 candidate for cancer immunotherapy.

Background and Purpose：As important components of lung tissue, endothelial cells (ECs) are associated with many lung diseases. The role of ECs dysfunction in idiopathic pulmonary fibrosis (IPF) and how to improve alveolar capillary barrier (ACB) to treat IPF is incompletely understood. Therefore we investigated the involvment of endothelial Sphingosine-1-phosphate receptor 1 (S1pr1) in PF and therapeutic effect of selective S1pr1 agonist IMMH002. Experimental approach：Databases of IPF patients and individuals without fibrosis were mined by Seurat. We generated an endothelial-conditional S1pr1 knockout (S1pr1+/−) mice and we also examined a bleomycin-induced model of pulmonary fibrosis (PF). We performed qRT-PCR,Western blot, Immunofluorescence staining and EC permeability experiments. Key results：Expression of S1pr1 in ECs was reduced markedly in IPF patients. Mice with endothelial-specific S1pr1 deficiency exhibited severer inflammation and fibrosis upon challenge with bleomycin. Significant accumulation of alpha-smooth muscle actin (α-SMA) was observed near vessels after S1pr1 deficiency, which indicated a potential connection between ACB injury and fibrosis. S1pr1 activation by a selective agonist IMMH002 could ameliorate PF by improving tight junctions in ECs and protects the ACB. Conclusion and Implications: Our results suggest that S1pr1 plays a significant role in ACB and it could be a potential target for IPF. Activation of S1pr1 with IMMH002 elicits a potent therapeutic effect in bleomycin-induced fibrosis by increasing tight junctions in endothelial cells and protecting the integrity of ACB therefore improve survial rate and lung function.