Silver nanoparticles (Ag NPs) have been widely used in medical and healthcare products owing to their unique antibacterial activities. However, their safety for humans and the environment has not yet been established. This study evaluated the cellular proliferation and apoptosis of Ag NPs suspended in different solvents using human liver HepG2 cells. The ionization of Ag NPs in different dispersion media [deionized water, phosphate-buffered saline (PBS), saline and cell culture] was measured using an Ag ion selective electrode. The MTT assay was used to examine the cell proliferation activities. The effects of Ag NPs on cell cycle, induction of apoptosis, production of reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) were analyzed using flow cytometry. The degree of Ag NPs ionization differed with dispersion media, with the concentrations of silver ions in deionized water being the highest in all suspensions. Ag NPs could inhibit the viability of HepG2 cells in a time-and concentration-dependent manner. Ag NPs (40, 80 and 160 μg ml À1 ) exposure could cause cell-cycle arrest in the G2/M phase, significantly increasing the apoptosis rate and ROS generation, and decreasing the MMP in HepG2 cells more sensitive to deionized water than in cell culture. These results suggested that the cellular toxicological mechanism of Ag NPs might be related to the oxidative stress of cells by the generation of ROS, leading to mitochondria injury and induction of apoptosis. It also implies that it is important to assess the physicochemical properties of NPs in the media where the biological toxicity tests are performed.

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BackgroundKN046 is a novel bispecific antibody targeting programmed death ligand 1 (PD-L1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4). This multicenter phase I trial investigated the safety, tolerability, pharmacokinetics (PK), and efficacy of KN046 in patients with advanced solid tumors.MethodsPatients who failed standard treatment were included. KN046 was administered at doses of 1, 3, and 5 mg/kg every 2 weeks (Q2W), 5 mg/kg every 3 weeks (Q3W), and 300 mg Q3W based on the modified toxicity probability interval method in the dose-escalation phase; the recommended dose was used in the expansion phase. Primary objectives were maximum tolerated dose (MTD) and recommended phase II dose (RP2D) in escalation and preliminary efficacy in expansion. Secondary objectives included PK, pharmacodynamics, safety, and tolerability of KN046. We also explored biomarkers based on PD-L1 expression, multiplex immunofluorescence (mIF) staining, and RNAseq-derived nCounter platform.ResultsTotally, 100 eligible patients were enrolled, including 59 with nasopharyngeal carcinoma (NPC), 36 with epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC), and those with other advanced solid tumors. The most common treatment-related adverse events (TRAEs) were rash (33.0%), pruritus (31.0%), and fatigue (20.0%). Grade ≥3 TRAEs were observed in 14.0% of participants. No dose-limiting toxicity occurred in the dose-escalation phase, and the MTD was not reached. The RP2D was determined as 5 mg/kg Q2W according to the pharmacokinetic–pharmacodynamic model, the preliminary exposure–response analysis, and the overall safety profile. Among 88 efficacy-evaluable participants, the objective response rate (ORR) was 12.5%, and the median duration of response was 16.6 months. In the NPC subgroup, the ORR was 15.4%, and the median overall survival (OS) was 24.7 (95% CI 16.3 to not estimable) months. In the EGFR-mutant NSCLC subgroup, the ORR was 6.3%. mIF analysis results showed patients with high CD8 expression showed longer median OS (27.1 vs 9.2 months, p=0.02); better prognosis was observed in patients with high CD8 and PD-L1 expression.ConclusionsKN046 was well tolerated and showed promising antitumor efficacy in advanced solid tumors, especially in patients with NPC. The combination of both CD8 and PD-L1 expression improved the prediction of KN046 response.Trial registration numbersNCT03733951.

Background: Despite recent FDA approval of immune checkpoint inhibitor pembrolizumab and drug-antibody conjugate in the treatment of mTNBC, the overall survival benefit of these patients remains modest. We conducted a phase 2 study to assess the efficacy and safety of anti-PD-L1/CTLA-4 bispecific antibody KN046 in combination with nab-paclitaxel in mTNBC patients (pts) regardless of PD-L1 status. Preliminary results have been delivered in 2021 AACR[1], here we reported the final results of the progression-free survival (PFS) and overall survival (OS) analysis. Methods: This study enrolled pts with treatment-naïve locally advanced inoperable or metastatic TNBC. Eligible pts received nab-paclitaxel plus KN046 at two dose levels (DL1: KN046 3 mg/kg Q2W or DL2: KN046 5 mg/kg Q2W). Tumor response was evaluated Q8W per RECIST 1.1. The primary endpoint included objective response (ORR) and duration of response (DoR), secondary included disease control rate (DCR), clinical benefit rate (CBR), PFS, 1-year/2-year OS rate and safety/tolerability. Results: As of May 9, 2022 (cut-off date), 27 pts were enrolled into DL1 (n=16) and DL2 (n=11). Median patient age in the study was 50 years (range, 33-70 years). At baseline, 52% and 48% of patients had ECOG PS of 0 and 1, respectively. By the cut-off date, there are 1 pts under treatment and 16pts alive. The median study follow-up time was 26.3 months (95% CI, 20.7 - 29.8). Based on the intent-to-treatment (ITT) population, the confirmed ORR was 33.3% (95% CI, 16.5% - 54.0%), DCR was 88.9% (95% CI, 70.8% - 97.7%), and CBR was 48.1% (95% CI, 28.7% - 68.1%), which remained stable compared with last reported in 2021 [1]. The DoR was 11.9 (95% CI, 5.6 - NR) months. The median PFS was 7.3 (95% CI, 3.7 - 13.7) months. The median OS is immature, the preliminary result is 27.7 (95% CI, 14.8 - NR) months, and the 2-year OS rate was 60.1% (95%CI, 37.2% - 76.9%). Among the 11 pts with PD-L1 positive (≥1% IC), confirmed ORR was 45.5% (95%CI, 16.7% - 76.6%) and mPFS was 8.61 (95%CI, 1.6 - 13.8) months. Both PD-L1 positive and negative pts derived OS benefit from the combination treatment, with the 2-year OS rate of 57.14% (95%CI, 25.4% - 79.6%) and 62.5% (95%CI, 22.9% - 86.1%) respectively. Patients tolerated well to combination therapy in this trial. The most common reported treatment related adverse event (TRAEs) were ALT elevation (13 pts, 48%), AST elevation (12 pts, 44%), pyrexia (9 pts, 33%), neutropenia (8 pts, 30%), and anemia (7 pts, 26%). Grade ≥3 TRAEs (≥10%) were neutropenia (7 pts, 26%), leukopenia (6 pts, 22%) and AST elevation (5 pts, 15%). 13 pts (48%) experienced immune related adverse events (irAEs), and only 3 irAEs (11%) were grade 3. The incidence of SAE was 33%, with no TRAE leading to death. Conclusions: The combination therapy of KN046 plus nab-paclitaxel has shown favorable clinical efficacy in mTNBC, especially in PD-L1 positive patients. By the cut-off date, the mOS is not mature and there is still more than half of pts alive, which demonstrated an encouraging 2-year OS rate. Pts in this trial tolerated well to the combination therapy and safety profile was manageable. Clinical trial information: NCT03872791 Reference 1. Cancer Res (2021) 81 (13_Supplement): 1660. Citation Format: Qiao Li, Qingyuan Zhang, Yue Zhang, Quchang Ouyang, Qiang Liu, Tao Sun, Feng Ye, Baochun Zhang, Ting Xu, Summer Xia, Karl Zhang, Bangyong Zhang, Binghe Xu. PD11-10 Efficacy, Safety, and Tolerability of KN046 (an anti-PD-L1/CTLA-4 Bispecific Antibody) in combination with Nab-paclitaxel in Metastatic Triple-negative Breast Cancer (mTNBC):Final results of the Phase II trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD11-10.