Preclinical Pharmacokinetics and Pharmacology Study of RC98: A Programmed Cell Death Ligand 1 Monoclonal Antibody in Cynomolgus Monkeys.

INTRODUCTION: RC98 is the monoclonal antibody against Programmed Cell Death Ligand 1 (PD-L1). Relevant reports have confirmed that the influence of PD-L1 expressed by tumor cells on antitumor CD8+ T cell responses is well characterized, but the impact of PD-L1 expressed by immune cells has not been well defined. OBJECTIVE: This study aimed to design a Pharmacokinetics/Pharmacology (PK/PD) study of RC98 in normal cynomolgus monkeys to research the effect on the immune system. METHODS: RC98 and vehicle were administered to cynomolgus monkeys at 15 mg/kg via intravenous infusion once a week for 4 weeks to evaluate the relationship between PK and PD. The pharmacodynamic activity was measured by the PD-L1 receptor occupancy (RO) in CD3+ T cells, A T-cell-dependent antibody response (TDAR), and the concentration of soluble PD-L1. RESULTS: The pharmacokinetic result showed that the exposure from the last administration was lower than that of the first administration, probably due to immunogenicity production. There was a strong correlation between systemic exposure and RO in CD3+ T cells but decreased RO levels after the last dose, which indirectly reflected the activation of T cells. The keyhole limpet hemocyanin (KLH)-induced TDAR in the RC98 group was higher than in the vehicle group. The concentration of soluble PD-L1 had increased feedback with RC98, and the concentration of soluble PD-L1 was maintained at a higher level after multiple doses than before dosing. CONCLUSION: These data indicate that the immune system was clearly activated. In addition, the non-clinical data could provide a basis for its efficacy evaluation in clinical trials.

Development and validation of bioanalytical methods to support clinical study of disitamab vedotin.

Disitamab vedotin (RC48), a humanized anti-HER2 antibody conjugated with monomethyl auristatin E (MMAE), is the first antibody-drug conjugate in China with an approved biological license application. A bioanalytical method was established for three analytes (total antibody, conjugate antibody and free payload) to help characterize their pharmacokinetic behavior in clinical settings. The bioanalytical methods were validated according to M10 guidance. Electrochemiluminescence assay methods were used for the quantitative measurement of total antibody and conjugated antibody in human serum. A LC-MS/MS method was used to quantify the concentration of MMAE in human serum. The method had high specificity and sensitivity with a quantitative range of 19.531-1250.000 ng/ml (total antibody), 39.063-5000.000 ng/ml (conjugated antibody) and 0.04-10.0 ng/ml (MMAE), respectively.

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Translation of the efficacy of antibody-drug conjugates from preclinical to clinical using a semimechanistic PK/PD model: A case study with RC88.

Three semimechanistic pharmacokinetic/pharmacodynamic (PK/PD) models, Simeoni, Jumbe, and Hybrid, were used for the efficacy translation of RC88 from preclinical to clinical. RC88 is a mesothelin-targeting antibody-drug conjugate for malignant solid tumor. In the preclinical study, the relationship between PKs and PDs was determined using the xenograft mouse model derived from ovarian cancer and lung cancer cell lines. A secondary parameter representing the efficacy index of the drug, termed as tumor static concentration (TSC), was calculated using the three semimechanistic PK/PD models. A mechanism-based target-mediated drug disposition model was used to predict the human PKs. TSC from mice and predicted human PK were integrated to predict human efficacy dose. Results showed that 2 cell lines were sensitive to drugs, and the predicted efficacy dose was between 0.82 and 1.96 mg/kg q1w.

A High-Sensitivity Vacuum Diode Temperature Sensor Based on Barrier-Lowering Effect.

A new kind of temperature sensor based on a vacuum diode was proposed and numerically studied in this paper. This device operated under different electron emission mechanisms according to the electron density in the vacuum channel. The temperature determination ability of this device was only empowered when working in the electric-field-assisted thermionic emission regime (barrier-lowering effect). The simulated results indicated that the temperature-sensing range of this device was around 273 K-325 K with a supply current of 1 µA. To obtain a linear dependency of voltage on temperature, we designed a proportional-to-absolute-temperature (PTAT) circuit. The mathematic derivation of the PTAT voltage is presented in this study. The temperature-sensing sensitivity was calculated as 7.6 mV/K according to the measured I-U (current versus voltage) characteristic. The structure and principle of the device presented in this paper might provide an alternative method for the study of temperature sensors.

Nanoscale Vacuum Diode Based on Thermionic Emission for High Temperature Operation.

Vacuum diodes, based on field emission mechanisms, demonstrate a superior performance in high-temperature operations compared to solid-state devices. However, when considering low operating voltage and continuous miniaturization, the cathode is usually made into a tip structure and the gap between cathode and anode is reduced to a nanoscale. This greatly increases the difficulty of preparation and makes it difficult to ensure fabrication consistency. Here, a metal-insulator-semiconductor (MIS) structural nanoscale vacuum diode, based on thermionic emission, was numerically studied. The results indicate that this device can operate at a stable level in a wide range of temperatures, at around 600 degrees Kelvin above 260 K at 0.2 V voltage bias. Moreover, unlike the conventional vacuum diodes working in field emission regime where the emission current is extremely sensitive to the gap-width between the cathode and the anode, the emission current of the proposed diode shows a weak correlation to the gap-width. These features make this diode a promising alternative to vacuum electronics for large-scale production and harsh environmental applications.

Apoptosis in response to heat stress is positively associated with heat-shock protein 90 expression in chicken myocardial cells in vitro.

To determine heat-shock protein (Hsp)90 expression is connected with cellular apoptotic response to heat stress and its mechanism, chicken (Gallus gallus) primary myocardial cells were treated with the Hsp90 promoter, aspirin, and its inhibitor, geldanamycin (GA), before heat stress. Cellular viability, heat-stressed apoptosis and reactive oxygen species level under different treatments were measured, and the expression of key proteins of the signaling pathway related to Hsp90 and their colocalization with Hsp90 were detected. The results showed that aspirin treatment increased the expression of protein kinase B (Akt), the signal transducer and activator of transcription (STAT)-3 and p-IKKα/ß and the colocalization of Akt and STAT-3 with Hsp90 during heat stress, which was accompanied by improved viability and low apoptosis. GA significantly inhibited Akt expression and p-IKKα/ß level, but not STAT-3 quantity, while the colocalization of Akt and STAT-3 with Hsp90 was weakened, followed by lower cell viability and higher apoptosis. Aspirin after GA treatment partially improved the stress response and apoptosis rate of tested cells caused by the recovery of Akt expression and colocalization, rather than the level of STAT-3 (including its co-localization with Hsp90) and p-IKKα/ß. Therefore, Hsp90 expression has a positive effect on cellular capacity to resist heat-stressed injury and apoptosis. Moreover, inhibition of Hsp90 before stress partially attenuated its positive effects.