A High Immune-Related Index with the Suppression of cGAS-STING Pathway is a Key Determinant to Herceptin Resistance in HER2+ Breast Cancer.

Resistance to HER2-targeted therapy is the major cause of treatment failure in patients with HER2+ breast cancer (BC). Given the key role of immune microenvironment in tumor development, there is a lack of an ideal prognostic model that fully accounts for immune infiltration. In this study, WGCNA analysis was performed to discover the relationship between immune-related signaling and prognosis of HER2+ BC. After Herceptin-resistant BC cell lines established, transcriptional profiles of resistant cell line and RNA-sequencing data from GSE76360 cohort were analyzed for candidate genes. 85 samples of HER2+ BC from TCGA database were analyzed by the Cox regression, XGBoost and Lasso algorithm to generalize a credible immune-related prognostic index (IRPI). Correlations between the IRPI signature and tumor microenvironment were further analyzed by multiple algorithms, including single-cell RNA sequencing data analysis. Patients with high IRPI had suppressive tumor immune microenvironment and worse prognosis. The suppression of type I interferon signaling indicated by the IRPI in Herceptin-resistant HER2+ BC was validated. And we elucidated that the suppression of cGAS-STING pathway is the key determinant underlying immune escape in Herceptin-resistant BC with high IRPI. A combination of STING agonist and DS-8201 could serve as a new strategy for Herceptin-resistant HER2+ BC.

Pharmacokinetics, Safety, Tolerability, and Immunogenicity of BP02 (Trastuzumab Biosimilar) Compared to EU- and US-Approved Trastuzumab in Healthy Adult Male Volunteers: A Phase 1, Randomized, Double-Blind Study.

INTRODUCTION: This study evaluated the pharmacokinetic (PK) equivalence between BP02 (a proposed trastuzumab biosimilar) and the reference trastuzumab approved in the EU (EU-trastuzumab) and the US (US-trastuzumab). METHODS: In this phase 1, double-blind, parallel-group trial, 111 healthy male volunteers were randomized 1:1:1 to receive a single 6-mg/kg intravenous infusion of BP02, EU-trastuzumab, or US-trastuzumab and were evaluated for 78 days. Serum drug concentration-time data were analyzed by non-compartmental methods. The PK similarity of BP02 to the two reference products, and between EU-trastuzumab and US-trastuzumab, was determined using the standard 80-125% bioequivalence criteria. RESULTS: Baseline demographics for the 111 subjects with evaluable pharmacokinetics were similar across all treatment groups. PK profiles were similar for the three products. The 90% confidence intervals (CIs) for the ratios of area under the serum concentration-time curve (AUC) from the time of dosing to infinity (AUC0-inf), AUC from the time of dosing until the time of the last quantifiable concentration (AUC0-t), and peak serum concentration of trastuzumab (Cmax) were within 80% to 125% for all three pairwise comparisons. Adverse events (AEs) were similar across all arms, with treatment-related AEs reported by 73.0%, 73.0%, and 89.2% of the subjects in the BP02, EU-trastuzumab, and US-trastuzumab groups, respectively. The most common AEs were headache, infusion-related reactions, and upper-respiratory-tract infections. Four subjects-three in the US-trastuzumab group and one in the BP02 group-discontinued the study due to AEs. All post-dose samples except for two tested negative for anti-drug antibodies. CONCLUSION: This study demonstrates the PK similarity among BP02, EU-trastuzumab, and US-trastuzumab. The safety and immunogenicity profiles observed for the three products in this study are consistent with previous reports for trastuzumab. TRIAL REGISTRATION: ANZCTR number: ACTRN12621000573853.

Disrupting EGFR-HER2 Transactivation by Pertuzumab in HER2-Positive Cancer: Quantitative Analysis Reveals EGFR Signal Input as Potential Predictor of Therapeutic Outcome.

Pertuzumab (Perjeta®), a humanized antibody binding to the dimerization arm of HER2 (Human epidermal growth factor receptor-2), has failed as a monotherapy agent in HER2 overexpressing malignancies. Since the molecular interaction of HER2 with ligand-bound EGFR (epidermal growth factor receptor) has been implied in mitogenic signaling and malignant proliferation, we hypothesized that this interaction, rather than HER2 expression and oligomerization alone, could be a potential molecular target and predictor of the efficacy of pertuzumab treatment. Therefore, we investigated static and dynamic interactions between HER2 and EGFR molecules upon EGF stimulus in the presence and absence of pertuzumab in HER2+ EGFR+ SK-BR-3 breast tumor cells using Förster resonance energy transfer (FRET) microscopy and fluorescence correlation and cross-correlation spectroscopy (FCS/FCCS). The consequential activation of signaling and changes in cell proliferation were measured by Western blotting and MTT assay. The autocorrelation functions of HER2 diffusion were best fitted by a three-component model corrected for triplet formation, and among these components the slowly diffusing membrane component revealed aggregation induced by EGFR ligand binding, as evidenced by photon-counting histograms and co-diffusing fractions. This aggregation has efficiently been prevented by pertuzumab treatment, which also inhibited the post-stimulus interaction of EGFR and HER2, as monitored by changes in FRET efficiency. Overall, the data demonstrated that pertuzumab, by hindering post-stimulus interaction between EGFR and HER2, inhibits EGFR-evoked HER2 aggregation and phosphorylation and leads to a dose-dependent decrease in cell proliferation, particularly when higher amounts of EGF are present. Consequently, we propose that EGFR expression on HER2-positive tumors could be taken into consideration as a potential biomarker when predicting the outcome of pertuzumab treatment.

DNA Methylation-Regulated HOXC8's Role in HER2-Positive Breast Cancer Function and its Contribution to Herceptin Resistance.

BACKGROUND: The epidermal growth factor receptor 2 (HER2) is overexpressed in 30% of breast cancers, and this overexpression is strongly correlated with a poor prognosis. Herceptin is a common treatment for HER2-positive breast cancer; however, cancer cells tend to adapt gradually to the drug, rendering it ineffective. The study revealed an association between the methylation status of the Homeobox C8 (HOXC8) gene and tumor development. Therefore, it is of paramount importance to delve into the interaction between HOXC8 and HER2-positive breast cancer, along with its molecular mechanisms. This exploration holds significant implications for a deeper understanding of the pathophysiological processes underlying HER2-positive breast cancer. METHOD: Tumor tissue and pathological data from patients with HER2-positive breast cancer were systematically collected. Additionally, the human HER2-positive breast cancer cell line, SKBR3, was cultured in vitro to assess both the expression level of HOXC8 and the degree of DNA methylation. The study aimed to explore the relationship between the relative expression of HOXC8 and the clinical characteristics of breast cancer patients. The expression level of HOXC8 and the promoter methylation of HOXC8 were verified by methylation treatment of SKBR3 breast cancer cells. The regulation of HOXC8 was meticulously carried out, leading to the division of the cells into distinct groups. The study further analyzed the expression levels and biological capabilities within each group. Finally, the in vitro and in vivo sensitivity of the cells to Herceptin, a common treatment for HER2-positive breast cancer, was measured to assess the efficacy of the drug. RESULT: In HER2-positive breast cancer cases characterized by poor methylation, there was an up-regulation of HOXC8. Its expression was found to be correlated with key clinical factors such as tumor size, lymph node status, clinical tumor, node, metastasis (cTNM) staging, and Herceptin resistance (p < 0.05). Upon methylation of breast cancer cells, there was a significant decrease in HOXC8 expression (p < 0.05). The study revealed that overexpression of HOXC8 resulted in increased proliferation, cloning, and metastasis of HER2-positive breast cancer cells, along with a reduced apoptosis rate (p < 0.05). Conversely, interference with HOXC8 expression reversed this scenario (p < 0.05). A Herceptin-resistant substrain, POOL2, was established using SKBR3 cells. Animal studies demonstrated that overexpressing HOXC8 accelerated tumor development and enhanced POOL2 cells' resistance to Herceptin (p < 0.05). However, following interference with HOXC8, POOL2 cells exhibited increased responsiveness to Herceptin, leading to a gradual reduction in tumor size (p < 0.05). CONCLUSIONS: In HER2-positive breast cancer, the expression of HOXC8 is elevated in a manner dependent on DNA methylation, and this elevated expression is closely linked to the pathology of the patient. Interfering with HOXC8 expression demonstrates the potential to partially inhibit the development and spread of breast cancer, as well as to alleviate resistance to Herceptin.

Immunoprofiles and Oncologic Outcomes of 15 Patients with Androgen Receptor-Positive Salivary Duct Carcinoma.

BACKGROUND: Salivary duct carcinomas (SDC) are a rare and aggressive subtype of salivary gland neoplasm. They can present with distinct immunoprofiles, such as androgen receptor (AR) and HER-2/Neu-positivity. To date, no consensus exists on how to best manage this entity. METHODS: All patients diagnosed with nonmetastatic AR+ SDC of the parotid from 2013 to 2019 treated with curative intent were included. Immunologic tumor profiling was conducted using 24 distinct markers. Kaplan-Meier analyses were used to estimate locoregional recurrence (LRR), distant control, and overall survival (OS). RESULTS: Fifteen patients were included. Nine (60%) patients presented with T4 disease and eight (53%) had positive ipsilateral cervical lymphadenopathy. Ten (67%) patients underwent trimodality therapy, including surgery followed by adjuvant radiation and concurrent systemic therapy. The median follow-up was 5.5 years (interquartile range, 4.8-6.1). The estimated 5-year rates of LRR, distant progression, and OS were 6%, 13%, and 87%, respectively. CONCLUSION: Despite only including AR+ SDC of the parotid, immunoprofiles, such as expression of HER-2, were highly variable, highlighting the potential to tailor systemic regimens based on individual histologic profiles in the future. Studies with larger patient numbers using tumor-specific molecular profiling and tumor heterogeneity analyses are justified to better understand the biology of these tumors. Molecularly informed treatment approaches, including the potential use of AR- and HER-2/Neu-directed therapies upfront in the definitive setting, may hold future promise to further improve outcomes for these patients.

Comparative analysis of Herceptin N-Linked glycosylation by HILIC-FLD and LC-MS/MS methods.

Monoclonal antibodies like Herceptin play a pivotal role in modern therapeutics, with their glycosylation patterns significantly influencing their bioactivity. To characterize the N-glycan profile and their relative abundance in Herceptin, we employed two analytical methods: hydrophilic interaction chromatography with fluorescence detection (HILIC-FLD) for released glycans and liquid chromatography tandem mass spectrometry (LC-MS/MS) for glycopeptides. Our analysis included 21 European Union (EU)-Herceptin lots and 14 United States (US)-Herceptin lots. HILIC-FLD detected 25 glycan species, including positional isomers, revealing comparable chromatographic profiles for both EU and US lots. On the other hand, LC-MS/MS identified 26 glycoforms within the glycopeptide EEQYNSTYR. Both methods showed that a subset of glycans dominated the total abundance. Notably, EU-Herceptin lots with an expiration date of October 2022 exhibited increased levels of afucosylated and high mannose N-glycans. Our statistical comparisons showed that the difference in quantitative results between HILIC-FLD and LC-MS/MS is significant, indicating that the absolute quantitative values depend on the choice of the analytical method. However, despite these differences, both methods demonstrated a strong correlation in relative glycan proportions. This study contributes to the comprehensive analysis of Herceptin's glycosylation, offering insights into the influence of analytical methods on glycan quantification and providing valuable information for the biopharmaceutical industry.

Hypofunction of macrophage chemotaxis contributes to defective efficacy of herceptin in HER2-positive breast cancer patients.

Breast cancer was considered as a kind of prone breast tumors with the complicated pathological mechanisms and diverse clinical classifications. In the clinical treatments of HER2-positive tumor patients, HER2 monoclonal antibodies, such as Herceptin, have shown well-defined therapeutic effects. Nevertheless, due to the heterogeneity of breast cancers, drug resistance inevitably appeared during the application of Herceptin. In order to fully understand the immune tolerance status of the tumor microenvironment in the population of sensitive and insensitive patients, this study carried out a series of studies through Luminex cytokines assay, clinicopathological analysis, immunofluorescence, and PCR. The results confirmed that in clinical samples sensitive to Herceptin, there were a large number of macrophages, and the protein expression levels and in situ expression of macrophage-related chemokines and inflammatory mediators are significantly higher than drug-resistant tumor samples. Further studies found that T cell function has a low correlation with tumor growth, and there are obvious obstacles in the process of peripheral blood immune cells entering the tumor microenvironment. In summary, this study provided clues for understanding the clinical drug resistance of HER2 monoclonal antibody and the clinical rational use of drugs and combination drugs.

Based on whole-exome sequencing to explore the rule of Herceptin and TKI resistance in breast cancer patients.

BACKGROUND: Breast cancer is the second leading cause of cancer-related death in women, and drug resistance during treatment is a major challenge. However, the mechanisms underlying drug resistance are not fully understood. Here we applied whole-exome sequencing (WES) to clarify resistant rules to Herceptin and tyrosine kinase inhibitors (TKIs). METHODS: There are 12 HER2+ breast cancer patients who were done WES. Samples from tumor and surrounding tissues underwent DNA sequencing and analysis. Various experimental and bioinformatics techniques were employed, including genomic capture, mutation analysis (Genome Analysis Toolkit (GATK), etc.), bioinformatics assessments, and drug-gene interaction investigations. Ultimately, the study explored the association of APOB gene expression with breast cancer recurrence rates, immune cell infiltration, and drug response. RESULTS: The C > T mutation frequency was highest in the Herceptin-insensitive (HI) and verification groups, codenamed YI, contrasting with the Herceptin-sensitive (HE) group. No microsatellite instability (MSI)-H patients were in the HE group, but both HI and YI groups had 1 each. Significant differences in transition-transversion (TiTv) were observed in the HI and YI groups rather than the HE group. In the TKI- insensitive (TI) group, C > T mutations were highest, differing from the TKI-sensitive (TE) group. TE group included 2 MSI-H patients. Significant differences in TiTv were found in the TI group rather than the TE group. Mutated APOB may resist Herceptin and TKI, increasing immune infiltration. We identified potential drugs targeting it. CONCLUSIONS: Our study suggested that a higher percentage of C > T mutations, significant differences in TiTv, and MSI-H status may indicate Herceptin resistance, while a higher percentage of C > T mutations, significant differences in TiTv, and the absence of MSI-H may indicate TKI resistance in breast cancer patients. For patients resistant to both Herceptin and TKI, mutated APOB may play a crucial role in resistance.

Case Report of Graves' Disease in a 45-Year-Old Woman Secondary to Herceptin Treatment for Breast Cancer.

Graves' disease is the most common cause of thyrotoxicosis and is characterized by ophthalmopathy with proptosis, chemosis, or conjunctival injection; pretibial myxedema; and thyroid acropachy. It is an autoimmune disease that can be genetic or influenced by coexisting environmental factors such as exposure to anticancer drugs, including immune checkpoint inhibitors. The incidence rate of breast cancer is increasing due to rising awareness of risk factors and screening for breast cancer, and the mortality rate is decreasing due to recent advances in cancer treatment. However, there are side effects that are attributed to these treatment modalities, manifesting in various forms in breast cancer survivors, which are reflected in the patient in this case study.

Enzyme - Switch sensors for therapeutic drug monitoring of immunotherapies.

Therapeutic monoclonal antibodies (TmAb) have emerged as effective treatments for a number of cancers and autoimmune diseases. However, large interpatient disparities in the pharmacokinetics of TmAb treatment requires close therapeutic drug monitoring (TDM) to optimise dosage for individual patients. Here we demonstrate an approach for achieving rapid, sensitive quantification of two monoclonal antibody therapies using a previously described enzyme switch sensor platform. The enzyme switch sensor consists of a ß-lactamase - ß-lactamase inhibitor protein (BLA-BLIP) complex with two anti-idiotype binding proteins (Affimer proteins) as recognition elements. The BLA-BLIP sensor was engineered to detect two TmAbs (trastuzumab and ipilimumab) by developing constructs incorporating novel synthetic binding reagents to each of these mAbs. Trastuzumab and ipilimumab were successfully monitored with sub nM sensitivity in up to 1% serum, thus covering the relevant therapeutic range. Despite the modular design, the BLA-BLIP sensor was unsuccessful in detecting two further TmAbs (rituximab and adalimumab), an explanation for which was explored. In conclusion, the BLA-BLIP sensors provide a rapid biosensor for TDM of trastuzumab and ipilimumab with the potential to improve therapy. The sensitivity of this platform alongside its rapid action would be suitable for bedside monitoring in a point-of-care (PoC) setting.

Long Terms Follow-Up of the Randomized MetaspHER Study Comparing Intravenous Versus Subcutaneous Trastuzumab in Patients' With HER2-Positive Metastatic Breast Cancer.

INTRODUCTION: The subcutaneous (H-SC) formulation of trastuzumab was demonstrated to be as effective and safe as intravenous (H-IV) and highly preferred by patients in early breast cancer. The present randomized MetaspHER trial (NCT01810393) has been the first study assessing patient's preference in metastatic setting and we report the final analysis with long term follow-up. METHODS: Patients with HER2-positive metastatic breast cancer who completed a first line chemotherapy with trastuzumab and achieved a long terms response lasting more than 3 years were randomized to receive 3 cycles of 600 mg fixed-dose H-SC, followed by 3 cycles of standard H-IV, or the reverse sequence. The primary endpoint was overall preference for H-SC or H-IV at cycle 6 and was previously reported. Secondary endpoints included safety over 1 year of treatment and with 4 additional years follow up. Overall survival (OS) and progression free survival (PFS) were assessed in this final analysis. RESULTS: A total of 113 patients were randomized and treated and the median follow-up duration was 45.4 months (range: 0.8-48.8). After the cross over period all patients excepted 2 pursued the H-SC. During the 18 cycles overall treatment period, at least 1 adverse event (AE), 1 AE of grade ≥3, and 1 serious adverse events (SAE) were respectively reported among 104 patients (92.0%), 23 patients (20.4%), and 16 patients (14.2%), respectively. Also, 10 patients (8.9%) experienced at least 1 cardiac event, including 4 patients (3.5%) with ejection fraction decreased. Beyond cycle 18 no significant additional safety concern emerged. PFS and OS rates at months 42 were 74.8% (64.7%-82.4%) and 94.9% (88.2%-97.9%), respectively. No factor appeared related to the survival outcome excepted the complete response status at baseline. CONCLUSION: The safety was consistent with the known H-IV and H-SC profiles without any safety concern raised over a prolonged exposure to H-SC.

Influence of Carboxyl Group Ratios on the Design of Breast Cancer Targeting Bimodal MR/NIR-II Imaging Probe from PLGA@Gd-DOTA@PEG Micelles Conjugating Herceptin.

We developed a small MRI/NIR-II probe to target HER2 (tetanucleotide) breast cancer cells. The probe is composed of PLGA-b-PEG micelles encapsulated NIR-II, and Gd-DOTA is conjugated at the border of PLGA/PEG. Herceptin was then conjugated to carboxyl residues of PLGA-b-PEG chains. We examined the influence of carboxyl group ratios on the probe property stability and Herceptin concentration and the binding affinity to HER2(+) cells corresponding to the -COOH ratios. The binding assays demonstrated that the optimal surface ratio of -COOH is 5%, which is less affected by fluorescence reduction and which exhibited the highest antigen-capturing activity.

The use of neoadjuvant systemic therapies in breast cancer in Australia and New Zealand: Breast Surgeons of Australia and New Zealand quality audit.

BACKGROUND: Breast surgeons must maintain contemporary knowledge regarding appropriate referral for neoadjuvant chemotherapy (NACT) in breast cancer (BC) patients. To date, the greatest benefit is seen in stage II-III HER2-enriched and triple negative breast cancers (TNBC). This study is the first audit of use of NACT in Australia and New Zealand to stratify data by BC biological subtype. METHODS: Prospective data from 116,745 patients between 2010 and 2019 was provided by the Breast Surgeons of Australia and New Zealand (BreastSurgANZ) Quality Audit (BQA) of Breast Cancer Care. Annual rates of NACT use were determined and change across time analysed with fractional regression. Data from 2018 to 2019 were combined and stratified by biological subtype (LumA, LumB HER2-neg, LumB HER2-pos, HER2 enriched, TNBC, Other basal-like), and age (<50, 51-74, and ≥75 years) and compared using negative binomial regression. RESULTS: The use of NACT increased annually (OR 1.26, P < 0.001), and the use of additional adjuvant chemotherapy (ACT) decreased (OR 0.78, P < 0.001). A significantly greater use of NACT was noted in patients with TNBC and HER2+ BC, and in all patients aged <50 years compared with older ages (P < 0.001), regardless of biological subtype. CONCLUSION: Increased uptake of NACT and decreased use of additional ACT is in keeping with progressive change in practice in response to contemporary evidence. Expansion of BQA data fields related to use of NACT, and detailed audit of NACT rates in Stage II-III TNBC and HER2 enriched BC will allow accurate determination of quality of practice in ANZ.

Stability of trastuzumab during nanomedicine formulation using SEC-HPLC coupled with polyacrylamide gel electrophoresis.

The anti-HER2 antibody trastuzumab has been proven to be an effective targeting ligand for drug delivery. This study investigates the structural integrity of trastuzumab under different stress factors in formulation development and its long-term stability. A validated size exclusion high performance liquid chromatographic (SEC-HPLC) method was first developed. The stability of trastuzumab (0.21-21 mg/ml) under stress conditions (mechanical, freeze-and-thaw, pH and temperature) and long-term storage in the presence of formulation excipients were monitored for up to 12 months, using both the SEC-HPLC method and sodium-dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE). The anti-proliferation activity of the reconstituted antibody stored at 4 °C against HER2+ BT-474 breast cells was also monitored over 12 months. The developed SEC-HPLC method was sensitive and accurate. Solutions of trastuzumab were resistant to mechanical stress and repeated freeze-and-thaw; but were unstable under acidic (pH 2.0 and 4.0) and alkaline (pH 10.0 and 12.0) environments. The samples degraded over 5 days at 60 °C, and within 24 h at 75 °C. Low temperature (-80 °C or 4 °C) and low concentration (0.21 mg/ml) favoured the long-term stability. The anti-proliferation activity was conserved at 4 °C for at least 12 months. This study provided valuable stability information in developing trastuzumab involved nano-formulation as well as in clinical settings.

A Review and Meta-analysis on Trastuzumab Resistance in Patients with HER2+ Breast Cancer.

BACKGROUND: Trastuzumab is a monoclonal antibody that revolutionized the treatment of HER2+ breast cancer. However, about 30% of patients demonstrate resistance to this drug. OBJECTIVE: The purpose of this study is to identify the mechanisms involved in resistance to treatment. with trastuzumab in women undergoing HER2+ breast cancer treatment. METHODS: A wide review and meta-analysis were performed in the PubMed and Scielo databases up to January 2022. All articles that analyzed the efficacy of the drug in HER2+ human patients treated with trastuzumab were selected, except reviews, meta-analyses, and reports. Egger's test was applied to verify publication bias. Forest plot and PRISMA flowchart were employed. RESULTS: 60 articles were selected for the review and 15 included in the meta-analysis. A total of 102 resistance mechanisms were identified, 73 of which are different from each other. The mechanisms have been classified into 5 different categories. The main resistance mechanisms found are in the PI3K/Akt/mTOR pathway or related to low HER2, often resulting from failure to assess HER2 status. Both groups presented statistical significance. The two groups were not significantly different from each other. CONCLUSION: Drug resistance is the main challenge of trastuzumab-based treatment. To overcome this challenge, it is important to continue efforts to understand the mechanisms of cancer drug resistance, identify therapies that can treat refractory cancer to current therapies, and possibly create a panel of genes that predict resistance, avoiding symptomatic and economic costs. The main limitation of this study was the selection and population bias.

A CD19-Anti-ErbB2 scFv Engager Protein Enables CD19-Specific CAR T Cells to Eradicate ErbB2+ Solid Cancer.

The efficacy of CD19-specific CAR T cells in the treatment of leukemia/lymphoma relies, at least in part, on the unique properties of the particular CAR and the presence of healthy B cells that enhance the target cell lysis and cytokine secretion through repetitive stimulation. Here, we report to apply the same CAR to target solid tumors, such as ErbB2+ carcinoma. CD19 CAR T cells are redirected towards the ErbB2+ cells by a fusion protein that is composed of the herceptin-derived anti-ErbB2 scFv 4D5 linked to the CD19 exodomain. The CD19-4D5scFv engager enabled CD19 CAR T cells to recognize the ErbB2+ cancer cells and to suppress the ErbB2+ tumor growth. The primary killing capacity by the ErbB2-redirected CD19 CAR T cells was as efficient as by the ErbB2 CAR T cells, however, adding CD19+ B cells furthermore reinforced the activation of the CD19 CAR T cells, thereby improving the anti-tumor activities. The ErbB2-redirected CD19 CAR T cells, moreover, showed a 100-fold superior selectivity in targeting cancer cells versus healthy fibroblasts, which was not the case for the ErbB2 CAR T cells. The data demonstrate that the CD19 CAR T cells can be high-jacked by a CD19-scFv engager protein to attack specifically solid cancer, thereby expanding their application beyond the B cell malignancies.

Systemic investigation of inetetamab in combination with small molecules to treat HER2-overexpressing breast and gastric cancers.

Most patients with metastatic breast cancer or gastric cancer who are treated with trastuzumab, an anti-HER2 monoclonal antibody, become refractory to the drug within a year after the initiation of treatment. Although the combination of trastuzumab with pertuzumab produced synergetic effects in the treatment of HER2-overexpressing cancers, not all patients with HER2 overexpression benefited from the trastuzumab plus pertuzumab combination. To improve the clinical benefits of trastuzumab, we systemically investigated the combination of inetetamab (Cipterbin), an analog of trastuzumab, with a variety of small molecules, including tyrosine kinase inhibitors (TKIs) and chemotherapeutic agents in vivo. We showed that pan-TKIs-induced synergistic antitumor effects with inetetamab in the treatment of these two types of cancers and that adding chemotherapeutic agents to the existing TKI plus anti-HER2 monoclonal antibody combination strategies induced additional inhibitory effects, suggesting that such combination strategies may be choices for the treatment of these two tumors. Thus, combination therapies targeting distinct and broad pathways that are essential for tumor growth and survival can be effective for treating metastatic breast cancers and gastric cancers.

A Randomized, Single-dose, Phase I Clinical Comparison of a Trastuzumab Biosimilar With a Reference Trastuzumab Formulation in Healthy Chinese Male Volunteers.

The test drug, a recombinant humanized monoclonal antibody, is a biosimilar candidate for the reference drug. The purpose of this study was to evaluate the bioequivalence of these two drugs. The study was divided into two parts, a pre-study and a formal trial. The pre-study included two subjects who were each given a single intravenous infusion of 6 mg/kg test drug. The formal trial was designed to be a randomized, double-blind, parallel controlled trial in which 70 subjects were randomly assigned 1:1 to receive either test or reference drug as a single 6 mg/kg intravenous infusion. In the pre-study, the immunogenicity was negative in both subjects and the safety of the test drug was considered to be good. The two groups in the formal trial had similar demographic characteristics. The 90% confidence interval of geometric mean ratios of area under the serum concentration-time curve from the time 0 to the time of last quantifiable concentration, area under the serum concentration-curve from time 0 to infinity, and maximum observed serum concentration between the test group and the reference group fell between 80% and 125% and the bioequivalence was recognized. There was no significant difference in the positive rate of antidrug antibodies. The treatment-emergent adverse events in the test group were similar to those in the reference group. This study showed that the test drug has similar pharmacokinetics, immunogenicity, and safety to the reference drug in healthy male subjects.