Rituximab in combination with chemotherapy has shown efficacy in patients with diffuse large B-cell lymphoma (DLBCL) for more than 15 years. HLX01 was developed as the rituximab biosimilar following a stepwise approach to demonstrate biosimilarity in analytical, pre-clinical, and clinical investigations to reference rituximab. With demonstrated pharmacokinetic similarity, a phase 3 multi-center, randomized, parallel, double-blind study (HLX01-NHL03) was subsequently conducted to compare efficacy and safety between HLX01 plus cyclophosphamide, doxorubicin, vincristine, and prednisone (H-CHOP) and reference rituximab plus CHOP (R-CHOP) in a total of 407 treatment-naïve, CD20-positive DLBCL patients aged 18-80 years. The primary efficacy endpoint was best overall response rate (ORR) within six cycles of treatment in the per-protocol set (PPS). Secondary endpoints included 1year efficacy outcomes, safety, and immunogenicity profile. The results showed difference in ORRs [H-CHOP 94.1%; R-CHOP 92.8%] between two treatment groups was 1.4% (95% confidence interval [CI], − 3.59 to 6.32, p = 0.608) which falls within the pre-defined equivalence margin of ± 12%. The safety profile was comparable between the treatment groups, with a similar overall incidence of treatment-emergent adverse events (H-CHOP 99.5%, R-CHOP 99.0%, p = 1.000) and serious adverse events (H-CHOP 34.0%, R-CHOP 32.5%, p = 0.752). This study established bioequivalence in efficacy and safety between HLX01 and reference rituximab. The trial was registered at http:// www.chinadrugtrials.org.cn on 26 August 2015 [#CTR20150583].

Knockout of ACTA2 promoted AngII induced progressive lumen dilation of the aortas, apoptosis, and the phenotypic modulation in VSMCs in mice.

Background In February 2019, the National Medicinal Products Administration (NMPA) approved the first China-manufactured rituximab (RTX) biosimilar, HLX01, for the treatment of non-Hodgkin's lymphoma in accordance to the development of biosimilar guidelines with stepwise approach demonstrating bioequivalence. HLX01 was also developed as a novel drug for rheumatoid arthritis (RA) since the indication has not been approved in China. Studying pharmacokinetics (PK) in healthy volunteers as the most sensitive population is not ethically acceptable due to the safety concerns associated with rituximab. The NMPA approval was based on a comprehensive data package of extensive analytical characterization, non-clinical studies, clinical trials and the population PK (PopPK) model. Here, we report the Phase 3 confirmatory study aimed to establish equivalence in safety and efficacy of HLX01 and RTX in patients with diffuse large B-cell lymphoma (DLBCL) and the PopPK model derived from the PK data of HLX01 and RTX in RA compared the PK data in DLBCL and the Caucasian RTX data in RA. Methods In this multicenter, randomized, double-blind, parallel active-controlled, Phase 3 study (NCT02787239), treatment-naïve adults aged 18-80 years with histologically confirmed CD20+ DLBCL were treated with cyclophosphamide-doxorubicin-vincristine-prednisone (CHOP) and randomly assigned at 1:1 ratio to co-administer with HLX01 (H-CHOP) or RTX (R-CHOP) every 21 days cycle treatment. The primary efficacy endpoint was the best overall response rate (ORR) for HLX01 and RTX over 6-cycle therapy. The therapeutic equivalence was concluded if 95% confidence interval (CI) of the difference in best ORRs between the two treatments fell within the pre-specified range of ±12%. Additional endpoints included long-term efficacy outcomes, safety and immunogenicity profiles and sparse PK samplings for peak and trough levels comparison. The PopPK model was developed from the randomized, double-blind PK study (NCT03355872) of HLX01 and RTX in 196 patients with moderately to severely active RA (serum sample=4289) using non-linear mixed-effect modeling (NONMEM®) and the first-order estimation with interaction (FOCEI) method. The PK and PK-pharmacodynamic relationship being characterized with various covariates were tested on forward addition (p<0·01) / backward elimination (p<0·001). After the final model being examined with Bayesian bootstrapping, visual predictive check (VPC) and 1000 simulations from the observed covariates, external validations were tested using the Phase 3 PK data in 110 patients with DLBCL and comparing the Chinese data with other races by simulations from several published PK data in Caucasian RA patients. Results The best ORRs [95% CI] within 6 cycles therapy were 94·1% [89·77%, 97·04%] in H-CHOP and 92·8% [88·19%, 96·00%] in R-CHOP with the ORR difference (1·4% [−3·59%, 6·32%], p=0·608) fell in the pre-specified equivalent margin. Long-term efficacy and safety profiles, including the incidence of treatment-emergent adverse events (p=1·000) and serious adverse events (p=0·752), were similar in two treatment groups (Table 1). The best model fit for the PopPK was a two-compartment model with first-order elimination. The estimated clearance (CL), central volume (Vc), peripheral-compartment volume and clearance-of-distribution from the central-to-peripheral-compartment were 27·32%, 16·56%, 21·61%, and 40·79%, respectively. The correlation between CL and Vc was 0.02239. The observed concentrations and simulations for the corresponding model predicted all subjects in the dataset with no significant difference in area under the curve from zero to infinity between two clinical studies of HLX01 and RTX. The PK results were also similar to the existing model in Caucasian. Conclusion HLX01 demonstrated equivalent safety and efficacy to the reference RTX with no clinically meaningful differences in CD20+ DLBCL. The PopPK model successfully proved the PK similarity between HLX01 and RTX in patients with RA or DLBCL with no racial differences. Based on the totality of evidence with the results from this Phase 3 study and PopPK modeling, China NMPA approved HLX01 as the first China RTX biosimilar with the potential to provide alternative treatment option for patients. To the best of our knowledge, we are the first reporting the establishment of biosimilarity with RTX in DLBCL patient population. Disclosures Zhao: Certara Strategic Consulting China: Employment. Hong:Shanghai Henlius Biotech, Inc.: Employment. Ma:Shanghai Henlius Biotech, Inc.: Employment. Cheng:Shanghai Henlius Biotech, Inc.: Employment. Ting:Shanghai Henlius Biotech, Inc.: Employment. Li:Shanghai Henlius Biotech, Inc.: Employment. Jiang:Shanghai Henlius Biotech, Inc.: Employment. Liu:Shanghai Henlius Biotech, Inc.: Employment. Liu:Shanghai Henlius Biotech, Inc.: Employment. Zhang:Shanghai Henlius Biotech, Inc.: Employment. Chai:Shanghai Henlius Biotech, Inc.: Employment. Yao:Shanghai Henlius Biotech, Inc.: Employment. Luk:Shanghai Henlius Biotech, Inc.: Employment.

Background The prognosis of pancreatic cancer (PC) is relatively dismal due to the lack of effective therapy. In this study, we explored the specific functions and molecular mechanisms of miR-107 to uncover effective therapeutic targets for PC. Method The miR-107 expression in PC cell lines was assessed via quantitative real-time polymerase chain reaction (qRT-PCR). Besides, online bioinformatics analysis was adopted to predict the underlying targets of miR-107. Meanwhile, TCGA database was employed to explore the prognosis of PC patients. In addition, MTT and transwell assays were conducted to explore the PC cells’ biological functions. Result MiR-107 was remarkably increased in PC cells which could promote the proliferation, invasion and migration of PC cells. In addition, miR-107 could directly down-regulate TGFBR3 expression through binding to TGFBR3 3’UTR. Survival analysis from TCGA suggested that PC patients with higher miR-107 expression was significantly involved in poorer prognosis. Conclusion We concluded that miR-107 promoted proliferation, invasion and migration of PC cells via targeting TGFBR3, which may provide novel underlying therapeutic targets.

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The aim of this paper was to identify DNA methylation based biomarkers for predicting overall survival (OS) of stage I–II lung adenocarcinoma (LUAD) patients. Methylation profile data of patients with stage I–II LUAD from The Cancer Genome Atlas (TCGA) database was used to determine methylation sites-based hallmark for stage I–II LUAD patients’ OS. The patients were separated into training and validation datasets by using median risk score as cutoff. Univariate Cox, least absolute shrinkage and selection operator (LASSO) and multivariate Cox analyses were employed to develop a DNA methylation signature for OS of patients with stage I–II LUAD. As a result, an 11-DNA methylation signature was determined to be critically associated with the OS of patients with stage I–II LUAD. Analysis of receiver operating characteristics (ROC) suggested a high prognostic effectiveness of the 11-DNA methylation signature in patients with stage I–II LUAD (AUC at 1, 3, 5 years in training set were (0.849, 0.879, 0.831, respectively), validation set (0.742, 0.807, 0.904, respectively), entire TCGA dataset (0.747, 0.818, 0.870, respectively). Kaplan–Meier survival analyses exhibited that survival was significantly longer in the low-risk cohort compared to the high-risk cohort in the training dataset (P = 7e − 07), in the validation dataset (P = 1e − 08), and in the all-cohort dataset (P = 6e − 14). In addition, a nomogram was developed based on molecular factor (methylation risk score) as well as clinical factors (age and cancer status) (AUC at 1, 3, 5 years entire TCGA dataset were 0.770, 0.849, 0.979, respectively). The result verified that our methylomics-associated nomogram had a strong robustness for predicting stage I–II LUAD patients’ OS. Furthermore, the nomogram combined clinical and molecular factors to determine an individualized probability of recurrence for patients with stage I–II LUAD, which stood for a major advance in the field of personalized medicine for pulmonary oncology. Collectively, we successfully identified a DNA methylation biomarker and a DNA methylation-based nomogram to predict the OS of patients with stage I–II LUAD.

Background and Aim: Some studies have verified that miR-133a played an inhibitory role in several cancers. Whereas, the effect of miRNA-133a in colorectal cancer (CRC) has not been fully elucidated. Our study aims to confirm UBA2 as a direct target gene of miRNA-133a and explore the upstream modulatory molecules of miR-133a. In addition, their impacts on the biological characteristics of CRC cells were assessed. Methods: QRT-PCR analyzed miR-133a expression levels in colorectal cells including HCT116, SW48 cells and human normal colorectal cell line NCM460. A serial biological experiment assessed miR-133a effects on cell proliferation, migration, invasion and apoptosis capacities in HCT116 and SW48 cells. MiRNA targeting gene prediction and a dual luciferase assay were employed to confirm miR-133a-targeted UBA2. Transcription factors (TFs) FOXD3 was identified as an upstream regulator of miR-133a via JASPAR. The influence of miR-133a and FOXD3 on UBA2 expression was analyzed by qRT-PCR or western blot. Results: miR-133a was lowly expressed in CRC cells. High miRNA-133a expression suppressed the proliferation, migration, invasion and enhanced apoptosis capacities of CRC cells. MiR-133a targeted the UBA2 mRNA 3ʹUTR area and reduced UBA2 protein expression. We also unveiled that FOXD3 high-expression significantly raised miR-133a expression and diminished UBA2 expression. We also discovered that high miR-133a expression augmented the effects of elevated FOXD3 expression on CRC cell proliferation, migration and invasion, whereas, low miR-133a expression generated the opposite outcomes. Conclusion: FOXD3 induced miRNA-133a directly targeting UBA2 could affect the progression and growth of CRC.

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