Dose escalation and expansion (phase Ia/Ib) study of GLS-010, a recombinant fully human antiprogrammed death-1 monoclonal antibody for advanced solid tumors or lymphoma.

BACKGROUND: GLS-010, a novel engineered fully human immunoglobin G4 monoclonal antibody, can specially block the PD-1/PD-L1/2 axis and reactivate the antitumor immunity. AIM: This phase Ia/Ib study was carried out to evaluate the safety, recommended phase II dose (R2PD), and primary antitumor effects of GLS-010 in patients with advanced, refractory lymphoma and solid tumors. METHODS: In phase Ia study, patients with refractory solid tumors and lymphoma enrolled and received GLS-010 at a dose of 1, 4, or 10 mg/kg Q2W; 240 mg Q3W or Q2W. The primary objective was to assess the dose-limiting toxicity (DLT). In phase Ib study, doses were expanded in 9 specific tumors to ensure the R2PD and explore the efficacy. Tumor mutation burden level and PD-L1 expression were also assessed with whole-exome sequencing and immunohistochemistry (SP263), respectively. RESULTS: Up to April 18, 2020, a total of 289 patients (n = 24, phase Ia; n = 265, phase Ib) were enrolled. DLT was not observed in phase Ia part. The T1/2, CLss, and Vd were similar among all dose groups and different tumors. The most common treatment-emergent adverse events (TEAEs) were anemia, leukopenia, elevated alanine aminotransaminase/asparate aminotransferase (ALT/AST), and elevated bilirubin. And hypothyroidism was the most common immune-related adverse event (irAE). The incidence of grade ≥3 TEAE was 39.8%, while grade ≥3 irAE was only 4.5%. Based on safety studies, pharmacokinetics/pharmacodynamics, and preclinical data, 240-mg Q2W was recommended as the expansion dose. The overall objective response rate was 23.6%, with 10 patients achieving complete response. Patients with a high PD-L1 expression level (31.3% Versus. 13.7%, p = 0.012) or t-issue tumor mutation burden level (31.3% Versus. 5.6%, p = 0.009) showed a significantly better response. CONCLUSION: GLS-010 showed acceptable safety profile and favorable clinical response. The dose of 240 mg Q2W was an optimal recommended dose as monotherapy.

[Bioequivalence of tiopronin enteric capsules in healthy volunteers].

OBJECTIVE: To evaluate the bioequivalence of tiopronin enteric capsules (testing preparation, T) versus tablets (reference preparation, R). METHODS: A single oral dose of tiopronin enteric capsules or tablets at 200 mg was administered in 2 groups of Chinese healthy volunteers (n=9) in a randomized crossover design at the interval of 2 weeks. The plasma concentrations of tiopronin were measured by HPLC-MS/MS, and the pharmacokinetic parameters were calculated by DAS 2.0 program. The bioequivalence between the two preparations was evaluated. RESULTS: The main pharmacokinetic parameters were as follows: C(max)(microg.ml(-1)) 3.612-/+1.2393 (R), 3.644-/+1.540 (T); t(max) 4.333-/+1.0853 (R), 3.611-/+1.420 (T); t((1/2))(h) 18.245-/+11.270 (R), 23.403-/+10.500 (T); AUC0-t (microg.h.ml(-1)) 18.732-/+6.92318 (R), 18.713-/+6.585 (T); AUC0-infinity (microg.h.ml(-1)) 21.900-/+7.31220 (R), 20.780-/+7.965 (T). The relative bioavailability of tiopronin enteric capsule was 103.712-/+23.956%, with 90% confidential intervals of ln(AUC0-->72), ln(AUC0-infinity) and ln(C(max)) of 91.1%-111.8%, 96.8%-118.3%, and 85.1%-113.0%, respectively. CONCLUSION: The tiopronin enteric capsules were bioequivalent to the tablets.

[Transfection with human adenovirus type 5 early-region 1A protects the primary human fibroblasts from ras-induced premature senescence in vitro].

OBJECTIVE: To investigate the role of human adenovirus type 5 (Ad5) early-region 1A (E1A) in premature senescence of human fibroblasts induced by Ras activation. METHODS: Human fibroblasts were cotransduced with E1A, E1A1-143, or their vector (BP) and Ha-RasV12 or its vector (WH). The growth curves and percentages of the apoptotic cells were determined. RESULTS: Expression of E1A or Ha-RasV12 in human fibroblasts significantly inhibited the cell growth. Transduction of Ha-RasV12 along with E1A or E1A 1-143 into human fibroblast cells resulted in active and rapid cell proliferation. CONCLUSION: E1A can rescue human fibroblasts from Ras-induced premature senescence, and the senescence bypassing activity of E1A resides in its NH2 terminus.