An innovative immunotherapeutic strategy for rheumatoid arthritis: Selectively suppressing angiogenesis and osteoclast differentiation by fully human antibody targeting thymocyte antigen-1.

Thymocyte antigen-1 (THY-1)is a potential target for rheumatoid arthritis (RA) treatment, and THY-1 positive fibroblast-like synoviocytes (FLS) are enriched in the synovium of RA patients and participate in angiogenesis to accelerate RA progression. In this study, we screened an antibody targeting THY-1 (THY-1 Ab) and explored its mechanism in alleviating RA progression. THY-1 Ab was screened from ScFv phage antibody library by phage display technology (PDT). THY-1 Ab-treated collagen induced arthritis (CIA) mice had lower degree of arthritis scores. We explore the mechanism of THY-1 Ab in alleviating RA progression. THY-1 Ab can remarkably inhibit the secretion of pro-inflammatory factors and promote the secretion of anti-inflammatory factors. Further experiments showed that THY1 Ab downregulated the expression of JUNB by the hsa_circ_0094342/miRNA-155-5P/SPI1 axis, inhibited RA angiogenesis and osteoclast differentiation, and relieved RA progression. These findings support that THY-1 Ab is a promising therapeutic antibody for RA treatment.

Discovery of 4-methoxy-N-(1-naphthyl)benzenesulfonamide derivatives as small molecule dual-target inhibitors of tubulin and signal transducer and activator of transcription 3 (STAT3) based on ABT-751.

Overexpressed tubulin and continuously activated STAT3 play important roles in the development of many cancers and are potential therapeutic targets. A series of 4-methoxy-N -(1-naphthalene) benzenesulfonamide derivatives were designed and optimized based on ß-tubulin inhibitor ABT-751 to verify whether STAT3 and tubulin dual target inhibitors have better antitumor effects. Compound DL14 showed strong inhibitory activity against A549, MDA-MB-231 and HCT-116 cells in vitro with IC50 values of 1.35 µM, 2.85 µM and 3.04 µM, respectively. Further experiments showed that DL14 not only competitively bound to colchicine binding site to inhibit tubulin polymerization with IC50 values 0.83 µM, but also directly bound to STAT3 protein to inhibit STAT3 phosphorylation with IC50 value of 6.84 µM. Three other compounds (TG03, DL15, and DL16) also inhibit this phosphorylation. In terms of single target inhibition, DL14 is slightly inferior to positive drugs, but it shows a good anti-tumor effect in vivo, and can inhibit >80% of xenograft tumor growth. This study describes a novel 4-methoxy-N-(1-naphthyl) benzenesulfonamide skeleton as an effective double-targeted anticancer agent targeting STAT3 and tubulin.