Dual targeting non-overlapping epitopes in HER2 domain IV substantially enhanced HER2/HER2 homodimers and HER2/EGFR heterodimers internalization leading to potent antitumor activity in HER2-positive human gastric cancer.

BACKGROUND: Trastuzumab and pertuzumab combination has been approved for the treatment of patients with HER2-positive metastatic breast cancer. However, trastuzumab and pertuzumab combination did not show improvement in overall survival in patients with HER2-positive metastatic gastric cancer. METHODS: We developed a new HER2-targeted monoclonal antibody, HLX22, targeting HER2 subdomain IV as trastuzumab but with non-overlapping epitopes. We examined the antitumor effects of this novel HER2-antibody in gastric cell lines and cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models. RESULTS: HLX22 in combination with HLX02 (trastuzumab biosimilar) induced enhancement of HER2/HER2 homodimers and HER2/EGFR heterodimers internalization, which ultimately led to the reduction in signal transductions involving STAT3, P70 S6, and AKT; gene expressions of FGF-FGFR-PI3K-MTOR, EGF-EGFR-RAS, TGF-ß-SMAD, PLCG and cell cycle progression related pathways that favor tumor development, proliferation, progression, migration and survival in gastric cancer cell line NCI-N87 were also reduced. These differing but complementary actions contributed to the synergistic antitumor efficacy of the HLX22 and HLX02 combination in gastric cancer cell lines, CDX and PDX. In addition, HLX22 in combination with HLX02 demonstrated stronger antitumor efficacy than HLX02 and HLX11 (a potential pertuzumab biosimilar) combination treatment both in vitro and in vivo. CONCLUSIONS: These results suggested that the application of non-competing antibodies HLX22 and HLX02 targeting HER2 subdomain IV together may be of substantial benefit to gastric cancer patients who currently respond suboptimal to trastuzumab therapy.

A randomized phase 2 study of HLX22 plus trastuzumab biosimilar HLX02 and XELOX as first-line therapy for HER2-positive advanced gastric cancer.

BACKGROUND: Gastric cancer is the fifth most common cancer and the fourth most common cause of cancer death worldwide, yet the prognosis of advanced disease remains poor. METHODS: This was a randomized, double-blinded, phase 2 trial (ClinicalTrials.gov: NCT04908813). Patients with locally advanced/metastatic HER2-positive gastric/gastroesophageal junction cancer and no prior systemic antitumor therapy were randomized 1:1:1 to 25 mg/kg HLX22 (a novel anti-HER2 antibody) + HLX02 (trastuzumab biosimilar) + oxaliplatin and capecitabine (XELOX) (group A), 15 mg/kg HLX22 + HLX02 + XELOX (group B), or placebo + HLX02 + XELOX (group C) in 3-week cycles. Primary endpoints were progression-free survival (PFS) and objective response rate (ORR) assessed by independent radiological review committee (IRRC). FINDINGS: Between November 29, 2021, and June 6, 2022, 82 patients were screened; 53 were randomized to group A (n = 18), B (n = 17), and C (n = 18). With 14.3 months of median follow-up, IRRC-assessed median PFS was prolonged with the addition of HLX22 (A vs. C, 15.1 vs. 8.2 months, hazard ratio [HR] 0.5 [95% confidence interval (CI) 0.17-1.27]; B vs. C, not reached vs. 8.2 months, HR 0.1 [95% CI 0.04-0.52]). Confirmed ORR was comparable among groups (A vs. B vs. C, 77.8% vs. 82.4% vs. 88.9%). Treatment-related adverse events (TRAEs) were observed in 18 (100%), 16 (94.1%), and 17 (94.4%) patients, respectively. One (5.6%) patient in group C reported a grade 5 TRAE. CONCLUSIONS: Adding HLX22 to HLX02 and XELOX prolonged PFS and enhanced antitumor response in the first-line treatment of HER2-positive gastric cancer, with manageable safety. FUNDING: Shanghai Henlius Biotech, Inc.

Matrix metalloproteinases are regulated by MicroRNA 320 in macrophages and are associated with aortic dissection.

Aortic dissection (AD) is the circumferential or transversal tear of the aorta wall that allows blood to infiltrate the layers. MicroRNA (miR) analyses have demonstrated a correlation between miR-320 family and AD. The underlying mechanism is yet unclear. The matrix metalloproteinases (MMPs) are a group of proteolytic enzymes that could catalyze the degeneration of the extracellular matrix and the destruction of the vasculature. In this study, we investigated whether miR-320 presented a role in regulating the production of MMPs in aortic dissection. In a cohort of 30 CE patients and 30 healthy controls, the transcription and secretion of MMP-1, MMP-2, MMP-3, MMP-8, MMP-9, and MMP-12 by monocytes were investigated. The monocyte from AD patients presented significantly elevated capacity of MMP expression than those from healthy controls. In contrast, the monocyte/macrophage expression of miR-320 was significantly lower in AD patients than in controls. In both AD patients and healthy controls, LPS-activation of macrophages resulted in MMP upregulation and miR-320 downregulation, in which the MMP expression was significantly higher while the miR-320 expression was significantly lower in AD patients than in healthy controls. Transfection of miR-320 mimic did not affect MMP gene transcription but significantly reduced the protein production in some MMPs, demonstrated that miR-320 were involved in the post-transcriptional regulation of MMPs. Together, these results demonstrated that miR-320 could regulate the expression of MMPs by macrophages, through which miR-320 may interfere with AD development.

Rapamycin: A Bacteria-Derived Immunosuppressant That Has Anti-atherosclerotic Effects and Its Clinical Application.

Atherosclerosis (AS) is the leading cause of stroke and death worldwide. Although many lipid-lowering or antiplatelet medicines have been used to prevent the devastating outcomes caused by AS, the serious side effects of these medicines cannot be ignored. Moreover, these medicines are aimed at preventing end-point events rather than addressing the formation and progression of the lesion. Rapamycin (sirolimus), a fermentation product derived from soil samples, has immunosuppressive and anti-proliferation effects. It is an inhibitor of mammalian targets of rapamycin, thereby stimulating autophagy pathways. Several lines of evidence have demonstrated that rapamycin possess multiple protective effects against AS through various molecular mechanisms. Moreover, it has been used successfully as an anti-proliferation agent to prevent in-stent restenosis or vascular graft stenosis in patients with coronary artery disease. A thorough understanding of the biomedical regulatory mechanism of rapamycin in AS might reveal pathways for retarding AS. This review summarizes the current knowledge of biomedical mechanisms by which rapamycin retards AS through action on various cells (endothelial cells, macrophages, vascular smooth muscle cells, and T-cells) in early and advanced AS and describes clinical and potential clinical applications of the agent.

Correlation between expression of epidermal growth factor receptor and adverse reactions after chemotherapy of advanced non-small-cell lung cancer.

OBJECTIVE: To analyze the correlation between expression of epidermal growth factor receptor (EGFR) and adverse reactions after chemotherapy of advanced non-small-cell lung cancer (NSCLC). METHODS: A total of 120 NSCLC patients who were treated in our hospital from August 2009 to September 2011 were selected as an observation group, and another 120 healthy subjects were selected as a control group. EGFR expressions in both groups were detected. The observation group was subjected to combination chemotherapy, and their shorter- and long-term prognostic outcomes, adverse reactions and mortality were recorded. Meanwhile, correlation analysis was performed. RESULTS: The observation group had significantly higher percentage and positive rate in EGFR expression than those of the control group (P<0.05). With increasing stage and lymphatic metastasis, the positive expression rate of EGFR rose significantly (P<0.05). In the observation group, the response rate of treatment was 62.5%, and the incidence rate of adverse reactions after chemotherapy was 28.3% (34/120). The 1-, 2- and 3-year survival rates were 38.3%, 15.0% and 10.0% respectively. Multiple Logistic regression analysis showed that TNM stage, lymphatic metastasis and positive EGFR expression were the main independent risk factors for post-chemotherapy adverse reactions (P<0.05). CONCLUSION: Advanced NSCLC was commonly accompanied by high EGFR expression. Although chemotherapy was able to improve the prognosis and survival rate, adverse reactions were also induced, being associated with the pathological characteristics and EGFR expressions of patients.