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MPDL3280A is a human monoclonal antibody that targets programmed cell death-1 ligand 1 (PD-L1), and exerts anti-tumor activity mainly by blocking PD-L1 interaction with programmed cell death-1 (PD-1) and B7.1. It is being investigated as a potential therapy for locally advanced or metastatic malignancies. The purpose of the study reported here was to characterize the pharmacokinetics, pharmacodynamics, tissue distribution and tumor penetration of MPDL3280A and/or a chimeric anti-PD-L1 antibody PRO304397 to help further clinical development.The pharmacokinetics of MPDL3280A in monkeys at 0.5, 5 and 20 mg¢kg ¡1 and the pharmacokinetics / pharmacodynamics of PRO304397 in mice at 1, 3 10 mg¢kg ¡1 were determined after a single intravenous dose. Tissue distribution and tumor penetration for radiolabeled PRO304397 in tumor-bearing mouse models were determined.The pharmacokinetics of MPDL3280A and PRO304397 were nonlinear in monkeys and mice, respectively. Complete saturation of PD-L1 in blood in mice was achieved at serum concentrations of PRO304397 above »0.5 mg¢mL ¡1 . Tissue distribution and tumor penetration studies of PRO304397 in tumor-bearing mice indicated that the minimum tumor interstitial to plasma radioactivity ratio was »0.3; saturation of target-mediated uptake in non-tumor tissues and desirable exposure in tumors were achieved at higher serum concentrations, and the distribution into tumors was dose-and time-dependent.The biodistribution data indicated that the efficacious dose is mostly likely higher than that estimated based on simple pharmacokinetics/pharmacodynamics in blood. These data also allowed for estimation of the target clinical dose for further development of MPDL3280A.

Background Coronavirus disease 2019 (COVID-19) is a public health emergency of international concern and has caused traumatic experience for nurses worldwide. However, the prevalence of depression and anxiety symptoms in nurses, and how psychosocial factors influence nurses in this public crisis are unknown. Objectives To determine the effect of COVID-19 on the mental health of nurses and the prevalence of anxiety and depression symptoms among nurses in China during the outbreak. Design A cross-sectional study. Settings and participants A total of 3,228 nurses in Sichuan Province and Wuhan City were selected by convenience sampling. All participants were invited to complete the questionnaire through WeChat from January 27 to February 3, 2020. Methods A self-reported questionnaire combining depression and anxiety scale was used to collect data anonymously. Binary and multivariate logistic regression was applied to measure the odds of psychosocial factors of anxiety and depression and perceived health, respectively. Results The total incidence of depression (34.3%) and anxiety (18.1%) during the COVID-19 outbreak was lower than that during the SARS outbreak; however, the rate of depression in our study (47.1%) was high and similar in a recent study (50.4%) about the health care workers exposed to COVID-19 in China. The results indicated that COVID-19-related stress, relationship quality with family, and demographic characteristics were associated with depression, anxiety, and perceived health status. Furthermore, the prevalence of depression was similar between nurses working in low-risk COVID-19 wards was as high as working in high-risk COVID-19 wards (OR, 1.078; 95% CI, 0.784–1.481). Conclusions Our study revealed the high prevalence of depression and anxiety among nurses during the outbreak of COVID-19. COVID-19 factors and psychosocial factors were associated with mental health of nurses. The results suggest that hospitals should implement effective mental health promotion programs focused on occupational safety and family support to improve the well-being of nurses.

ABSTRACT:The neonatal Fc receptor (FcRn) plays a critical role in maintaining homeostasis of IgG antibodies. Recent studies have shown that the FcRn-IgG interaction can be modulated to alter the pharmacokinetics of the antibody. This has been achieved by altering amino acid residues in the FcRn-binding domain of the antibody, resulting in a change in the pH-dependent binding affinity of the antibody to FcRn. The purpose of this study was to examine the impact of the pH-dependent FcRn binding affinity on the pharmacokinetics of the antibody with changes in the Asn434 residue. Two anti-tumor necrosis factor-␣ monoclonal antibody (mAb) FcRn variants (N434A and N434H) were engineered, and pharmacokinetic studies of the two FcRn variants together with the wild type (WT) were conducted in mice and cynomolgus monkeys. N434A, which had binding properties to murine FcRn similar to those of the WT, had the same pharmacokinetic profile as the WT in mice. N434H, with the highest binding affinity to murine FcRn at pH 7.4, had a faster clearance (16.1 ml/day/kg) and a lower bioavailability (61.3%) compared with the WT (5.07 ml/day/kg, 73.2%) and N434A (5.90 ml/day/ kg, 72.4%) in mice. N434A and N434H, which had higher binding affinity at pH 6.0 to monkey FcRn with comparable affinity at pH 7.4, had significantly higher areas under the serum concentrationtime curve from time 0 to day 7 than the WT (749 ؎ 71.9 and 819 ؎ 81.5 versus 592 ؎ 56.8 g/ml ⅐ day) in monkeys. Thus, increasing the binding affinity of mAbs to FcRn at pH 6.0 while keeping a low binding affinity at pH 7.4 improves the pharmacokinetics of these molecules.