Antibody drug conjugates beyond cytotoxic payloads.

For many years, antibody drug conjugates (ADC) have teased with the promise of targeted payload delivery to diseased cells, embracing the targeting of the antibody to which a cytotoxic payload is conjugated. During the past decade this promise has started to be realised with the approval of more than a dozen ADCs for the treatment of various cancers. Of these ADCs, brentuximab vedotin really laid the foundations of a template for a successful ADC with lysosomal payload release from a cleavable dipeptide linker, measured DAR by conjugation to the Cys-Cys interchain bonds of the antibody and a cytotoxic payload. Using this ADC design model oncology has now expanded their repertoire of payloads to include non-cytotoxic compounds. These new payload classes have their origins in prior medicinal chemistry programmes aiming to design selective oral small molecule drugs. While this may not have been achieved, the resulting compounds provide excellent starting points for ADC programmes with some compounds amenable to immediate linker attachment while for others extensive SAR and structural information offer invaluable design insights. Many of these new oncology payload classes are of interest to other therapeutic areas facilitating rapid access to drug-linkers for exploration as non-oncology ADCs. Other therapeutic areas have also pursued unique payload classes with glucocorticoid receptor modulators (GRM) being the most clinically advanced in immunology. Here, ADC payloads come full circle, as oncology is now investigating GRM payloads for the treatment of cancer. This chapter aims to cover all these new ADC approaches while describing the medicinal chemistry origins of the new non-cytotoxic payloads.

Role of visfatin-intracellular Nampt axis in the progression of epithelial ovarian cancer / 西安交通大学学报(医学版)

【Objective】 To explore the role of visfatin-nicotinamide phosphoribosyl transferase （Nampt） axis in the progression of epithelial ovarian cancer （EOC） and its effect on the patients’ prognosis. 【Methods】 Immunohistochemical analysis was used to detect the expression of Nampt protein in tissues from epithelial ovarian cancer and normal ovary； ELISA was used to determine the level of visfatin in serum. Then the two were further analyzed to estimate their effects on clinicopathological characteristics and the EOC patients’ overall survival. 【Results】 The mean level of serum visfatin in these EOC patients was significantly elevated compared with that of the patients with benign ovarian tumors and normal population. ROC curve analysis showed that the area under curve （AUC） of serum visfatin for diagnosis of EOC was 0.744， with a cut-off value of 5.95 ng/mL. Serum visfatin of the EOC patients was related to T， N and FIGO stage （P<0.05）， and was positively correlated with CA125 （rs=0.389， P=0.001）. The rate of Nampt positive expression in tissues from EOC was significantly increased and correlated with FIGO stage and serum visfatin （P<0.05）. Nampt protein expression in EOC was positively correlated with serum visfatin level （rs=0.55， P<0.001）. The 1-year， 3-year and 5-year survival rate of these patients with EOC was 98.6%， 74.3% and 34.3%， respectively. Survival analysis demonstrated that the overall survival of these patients was related to T， N， FIGO stage， serum visfatin and Nampt expression in EOC， and both FIGO stage and Nampt expression were independent prognostic factors （P<0.05）. 【Conclusion】 The overall survival of these EOC patients was related to T， N， FIGO stage， serum visfatin and Nampt expression， and FIGO stage and Nampt expression are independent factors predicting the outcome. This highlights that visfatin-Nampt axis promotes the progression of epithelial ovarian cancer and affects the prognosis of EOC patients.

Nicotinamide phosphoribosyl transferase regulates cell growth via the Sirt1/P53 signaling pathway and is a prognosis marker in colorectal cancer.

Colorectal cancer (CRC) is the third most common malignancy, and the metabolic properties of CRC cells include enhanced aerobic glycolysis (the Warburg effect). Nicotinamide phosphoribosyl transferase (NAMPT) is one of the crucial enzymes that regulate the activity of nicotinamide adenine dinucleodinucleotide dependent enzymes. Targeting NAMPT is a potential method of CRC therapy. Nevertheless, the underlying clinical implications and regulatory mechanisms of NAMPT in CRC remain unclear. In this study, we showed that NAMPT protein expression was increased in subjects with rectal localization compared with those with colon localization, and NAMPT was a poor prognostic marker for the overall survival rate in patients with CRC. In addition, the NAMPT inhibitor FK866 or lentivirus-mediated silencing induced CRC cell growth inhibition. Mechanistically, NAMPT regulated Sirt1 and P53 expression and induced G0/G1 cell cycle arrest, along with the upregulation of downstream p21 and downregulation of cyclin D1, cyclin E1, and cyclin E2 expression. FK866 administration or knockdown of NAMPT induced CRC cell apoptosis via upregulation of caspase-3. In conclusion, NAMPT regulated Sirt1/P53 signaling during CRC cell growth and warrants further investigation for clinical administration in CRC.