HER2, a ligand-free tyrosine kinase receptor of the HER family, is frequently overexpressed in breast cancer. The anti-HER2 antibody trastuzumab has shown significant clinical benefits in metastatic breast cancer; however, resistance to trastuzumab is common. The development of monoclonal antibodies that have complementary mechanisms of action results in a more comprehensive blockade of ErbB2 signaling, especially HER2/HER3 signaling. Use of such antibodies may have clinical benefits if these antibodies can become widely accepted. Here, we describe a novel anti-HER2 antibody, hHERmAb-F0178C1, which was isolated from a screen of a phage display library. A step-by-step optimization method was employed to maximize the inhibitory effect of this anti-HER2 antibody. Crystallographic analysis was used to determine the three-dimensional structure to 3.5 Å resolution, confirming that the epitope of this antibody is in domain III of HER2. Moreover, this novel anti-HER2 antibody exhibits superior efficacy in blocking HER2/HER3 heterodimerization and signaling, and its use in combination with pertuzumab has a synergistic effect. Characterization of this antibody revealed the important role of a ligand binding site within domain III of HER2. The results of this study clearly indicate the unique potential of hHERmAb-F0178C1, and its complementary inhibition effect on HER2/HER3 signaling warrants its consideration as a promising clinical treatment.

BackgroundLong non-coding RNA SPRY4 intronic transcript 1 (lncRNA SPRY4-IT1) has been reported to be associated with the progression of several cancers, but its expression level in colorectal cancer (CRC) has rarely been reported. The purpose of this study was to estimate the clinical significance of SPRY4-IT1 in CRC.Material/MethodsThe relative expression levels of SPRY4-IT1 were detected by quantitative real-time polymerase chain reaction (qRT-PCR) in diseased tissues and the adjacent normal tissues of 106 CRC patients. Chi-square method was used to evaluate the association between SPRY4-IT1 expression and the clinical features. Additionally, we assessed the overall survival at different expression levels of SPRY4-IT1 using Kaplan-Meier method. The prognostic significance of SPRY4-IT1 was estimated by Cox regression analysis.ResultsUp-regulated level of SPRY4-IT1 was detected in pathologic tissues of CRC patients compared with adjacent normal tissues (P=0.000). The relative expression of SPRY4-IT1 was associated with the tumor size, the depth of invasion, lymph node invasion, distant invasion, and tumor stage (P<0.05). Patients with high expression of SPRY4-IT1 had poor overall survival compared with those with high level (39.3 vs. 49.3 months, log-rank test, P=0.016). Cox regression analysis showed that SPRY4-IT1 could act as an independent prognostic factor in CRC (HR=2.341, 95% CI=1.136–4.826, P=0.021).ConclusionsSPRY4-IT1 might be associated with tumorigenesis and progression of CRC, and it may be a promising biomarker for prognosis in patients with CRC.

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Although promising progress has been made with dual HER2 blockade in patients with HER2-positive breast cancer, whether the strategy of combined HER2 blockade increases the risk of severe diarrhea remains inclusive. In the present study, we investigated the overall incidence and risk of severe diarrhea when patients were treated with a combination of anti-HER2 therapies compared to anti-HER2 monotherapy. Studies that evaluated the administration of an anti-HER2 monotherapy (lapatinib or trastuzumab or pertuzumab) versus anti-HER2 combination therapy (pertuzumab plus trastuzumab or trastuzumab plus lapatinib) in breast cancer were identified from the PubMed database (1966-2013), the Cochrane library, abstracts presented at the American Society of Clinical Oncology annual conference (2004-2013), and the Web of Science database (1998-2013). Eligible studies were those in which the only systematic difference between the study arms was the type of anti-HER2 therapy used. Incidence, relative risk (RR), and 95% confidence intervals (CIs) were calculated using random effects or fixed-effects models based on the heterogeneity of the included studies. Seven trials were considered eligible. The overall incidence results for severe diarrhea in the combined anti-HER2 therapy and the anti-HER2 monotherapy were 3.48% (95% CI: 11.60-15.37%) and 8.68% (9 % CI: 7.33-10.03%), respectively. The odds ratio (OR) of severe diarrhea between anti-HER2 combination therapy and monotherapy was 1.67 (95% CI: 1.38 -5.57, p = 0.00001). This meta-analysis provides evidence that the incidence rates of severe diarrhea are comparable between anti-HER2 combination therapy and anti-HER2 monotherapy.