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Purpose
This article reviews the mechanism of action of trastuzumab emtansine (T-DM1), existing clinical data relating to its use for human growth factor receptor 2 (HER2)-positive breast cancer, potential pathways of resistance, and ongoing studies evaluating this novel agent.
Background
The development of HER2-targeted therapies has dramatically...
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Background:
Human epidermal growth factor receptor 2 (HER2)-positive breast cancer is a particularly aggressive form of the disease, and ultimately progresses in patients with metastases on standard therapies. Anthracyclines, such as doxorubicin, are an effective treatment for HER2-positive breast cancer, particularly when administered in combinat...
Rationale:
Pyrotinib is a novel dual pan-ErbB receptor tyrosine kinase inhibitor, approved for the treatment of human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC). However, there was still limited information regarding specific effect of pyrotinib on HER2-positive MBC patients with phosphoinositol-3 kinase muta...
Human epidermal growth factor receptor 2 (HER2) is overexpressed in approximately 20% of all breast cancers. Before the development of HER2‐directed monoclonal antibodies, HER2–positive breast cancer was associated with a rather poor prognosis. With the advent of monoclonal HER2–targeting antibodies (trastuzumab and pertuzumab) and antibody‐drug co...
Purpose
Lapatinib (L) is approved in combination with capecitabine or letrozole for patients with trastuzumab-resistant HER2-positive metastatic breast cancer (MBC). However, there is no efficacy data of L in patients who received prior pertuzumab (P) and ado-trastuzumab emtansine (T-DM1), now included as standard first- and second-line therapies,...
Background: This study aimed to investigate the impact of early adverse events (AE) following the initiation of lapatinib plus capecitabine on the progression-free survival (PFS) and overall survival (OS) outcomes of human epidermal growth factor receptor 2 (HER2) positive advanced breast cancer (ABC) patients.
Methods: A secondary analysis of part...
Citations
... The produced anti-CD22 Nanobody DM1 binds to CD22 at the surface of target cells and after internalization by endocytosis process, DM1 is released from SMCC by lysosomal proteolysis. In the cytoplasm, released DM1 inhibits tubulin dynamics and induces apoptosis [43]. ...
Antibody drug conjugates (ADCs) with twelve FDA approved drugs, known as a novel category of anti-neoplastic treatment created to merge the monoclonal antibody specificity with cytotoxicity effect of chemotherapy. However, despite many undeniable advantages, ADCs face certain problems, including insufficient internalization after binding, complex structures and large size of full antibodies especially in targeting of solid tumors. Camelid single domain antibody fragments (Nanobody®) offer solutions to this challenge by providing nanoscale size, high solubility and excellent stability, recombinant expression in bacteria, in vivo enhanced tissue penetration, and conjugation advantages. Here, an anti-human CD22 Nanobody was expressed in E.coli cells and conjugated to Mertansine (DM1) as a cytotoxic payload. The anti-CD22 Nanobody was expressed and purified by Ni–NTA resin. DM1 conjugated anti-CD22 Nanobody was generated by conjugation of SMCC-DM1 to Nanobody lysine groups. The conjugates were characterized using SDS-PAGE and Capillary electrophoresis (CE-SDS), RP-HPLC, and MALDI-TOF mass spectrometry. Additionally, flow cytometry analysis and a competition ELISA were carried out for binding evaluation. Finally, cytotoxicity of conjugates on Raji and Jurkat cell lines was assessed. The drug-to-antibody ratio (DAR) of conjugates was calculated 2.04 using UV spectrometry. SDS-PAGE, CE-SDS, HPLC, and mass spectrometry confirmed conjugation of DM1 to the Nanobody. The obtained results showed the anti-CD22 Nanobody cytotoxicity was enhanced almost 80% by conjugation with DM1. The binding of conjugates was similar to the non-conjugated anti-CD22 Nanobody in flow cytometry experiments. Concludingly, this study successfully suggest that the DM1 conjugated anti-CD22 Nanobody can be used as a novel tumor specific drug delivery system.
... It is a receptor tyrosine kinase erbB-2 (HER2) antibody covalently linked to DM1 that binds the epidermal growth factor receptor family of transmembrane receptors. The antibody binds to the linker at lysine residues [ Fig. 14.3] [24,25]. ...
ADCs are empowered monoclonal antibodies that are designed to harness their targeting ability by linking them to cell-killing agents. They are made up of three main components, the antibody, linker and the cytotoxic drug. The specificity of the antibody with the antigen on the tumor cell surface helps with its internalization into the cell after which the active drug is released causing cell death. The investigation of ADCs can be done using a variety of MS methods. Here, we talk about the bottom-up approach, the top-down approaches such as ECD and ETD, the ESI/MS method and IM-MS. Further, we also focus on the applications of MALDI/MS such as UV-MALDI, IR-MALDI and IMS-MALDI and provide examples of the mass spectra that provide tremendous amount of information on ADC structures.
... High-grade differentiated PDAC tumors are often associated with the expression of human epidermal growth factor receptor 2 (HER2, ErbB2) which stimulates proliferation of tumor cells (Harder et al., 2012). Since anti-HER2 therapies are successful for the treatment of HER2-expressing tumors, HER2 is often selected as a tumor target antigen (Loibl & Gianni, 2017;Sadeghi, Olevsky, & Hurvitz, 2014). A bispecific antibody which targets effector cells to HER2-expressing PDAC cells was applied in several assays of this study. ...
The enhancement of immune responses against tumor cells is a main focus of cancer immunotherapy. Immunotherapeutic approaches comprise a broad range of clinical applications including adjuvant therapies, check point inhibitors, cellular therapies, oncolytic viruses or targeted biologics such as bispecific antibodies. The usage of bispecific antibodies is one promising approach to enhance cytotoxicity and to selectively target effector cells to tumor-associated antigens. Here, we discuss the real-time cell analysis system as a suitable in vitro method to determine the interaction of tumor cell with effector cells alone or within a heterogeneous mixture of immune cells in peripheral blood or within tumor-infiltrating cells. The determination of cytotoxic effector cell activity using the real-time cell analyzer is highly useful to monitor the dynamic cellular interplay over extended periods of time.
... 1 Among breast cancer subtypes, the Her2+ ones were once associated with dismal prognostics until the approval in the early 2000's of trastuzumab (Herceptin ® ), an anti-Her2 monoclonal antibody. 2,3 Combined with taxanes (ie, docetaxel or paclitaxel) it has been approved as first-line treatment for Her2+ patients. 4 Indeed, for metastatic diseases, trastuzumab plus docetaxel largely improved the overall response Dovepress Dovepress 6678 rodallec et al rate (ie, 61% vs 34%, P=0.0002) and overall survival (ie, 31.2 vs 22.7 months, P=0.0325) when compared to docetaxel alone. ...
Purpose
Nanoparticles are of rising interest in cancer research, but in vitro canonical cell monolayer models are not suitable to evaluate their efficacy when prototyping candidates. Here, we developed three-dimensional (3D) spheroid models to test the efficacy of trastuzumab-docetaxel immunoliposomes in breast cancer prior to further testing them in vivo.
Materials and methods
Immunoliposomes were synthesized using the standard thin film method and maleimide linker. Two human breast cancer cell lines varying in Her2 expression were tested: Her2+ cells derived from metastatic site: mammary breast MDA-MB-453 and triple-negative MDA-MB-231 cells. 3D spheroids were developed and tested with fluorescence detection to evaluate viability. In vivo efficacy and biodistribution studies were performed on xenograft bearing nude mice using fluorescent and bioluminescent imaging.
Results
In vitro, antiproliferative efficacy was dependent upon cell type, size of the spheroids, and treatment scheduling, resulting in subsequent changes between tested conditions and in vivo results. Immunoliposomes performed better than free docetaxel + free trastuzumab and ado-trastuzumab emtansine (T-DM1). On MDA-MB-453 and MDA-MB-231 cell growth was reduced by 76% and 25%, when compared to free docetaxel + free trastuzumab and by 85% and 70% when compared to T-DM1, respectively. In vivo studies showed tumor accumulation ranging from 3% up to 15% of the total administered dose in MDA-MB-453 and MDA-MB-231 bearing mice. When compared to free docetaxel + free trastuzumab, tumor growth was reduced by 89% (MDA-MB-453) and 25% (MDA-MB-231) and reduced by 66% (MDA-MB-453) and 29% (MDA-MB-231) when compared to T-DM1, an observation in line with data collected from 3D spheroids experiments.
Conclusion
We demonstrated the predictivity of 3D in vitro models when developing and testing nanoparticles in experimental oncology. In vitro and in vivo data showed efficient drug delivery with higher efficacy and prolonged survival with immunoliposomes when compared to current anti-Her2 breast cancer strategies.
... In an attempt to optimize anti-HER2 therapies, the initial monotherapy with humanized anti-HER2 mAb trastuzumab (Herceptin ® , Genentech, South San Francisco, CA, USA) against metastatic gastric or breast cancer was gradually replaced by combination therapies with cytostatic agents (e.g., docetaxel, capecitabine, paclitaxel) and/or other anti-HER2 mAb (e.g., pertuzumab), and/or tyrosine kinase inhibitors (e.g., lapatinib) (2,3,(6)(7)(8)(9)(10)(11)(12). Alternatively, the antibody-drug conjugate (ADC) trastuzumab emtansine (T-DM-1) consisting of the anti-HER2 mAb trastuzumab linked to the cytotoxic agent emtansine (DM-1), which enters and destroys the HER2-overexpressing cells by binding to tubulin, was successful in patients with advanced breast cancer (13,14). Trastuzumab and pertuzumab induce antibody-dependent cell-mediated cytotoxicity (ADCC) and/or cell death of tumor cells by inhibition of HER2 signaling (15)(16)(17). ...
... An attempt to combat trastuzumab resistance was the development of the ADC trastuzumab emtansine (T-DM-1). The cytotoxic agent emtansine (DM-1), which destroys tumor cells by binding to tubulin, has been conjugated to trastuzumab which inhibits the PI3K signaling (13,49). An improvement of progression-free and overall survival in heavily pretreated patients with advanced HER2 + breast cancer and an acceptable toxicity profile has been demonstrated in phase III clinical trials (66,67). ...
An enhanced expression of human epidermal growth factor receptor 2 (HER2, ErbB2) often occurs in an advanced stage of breast, ovarian, gastric or esophageal cancer, and pancreatic ductal adenocarcinoma (PDAC). Commonly, HER2 expression is associated with poor clinical outcome or chemoresistance in ovarian and breast cancer patients. Treatment with humanized anti-HER2 monoclonal antibodies, such as trastuzumab or pertuzumab, has improved the outcome of patients with HER2-positive metastatic gastric or breast cancer, but not all patients benefit. In this study, the bispecific antibody [(HER2)2xCD16] in the tribody format was employed to re-direct CD16-expressing γδ T lymphocytes as well as natural killer (NK) cells to the tumor-associated cell surface antigen HER2 to enhance their cytotoxic anti-tumor activity. Tribody [(HER2)2xCD16] comprises two HER2-specific single chain fragment variable fused to a fragment antigen binding directed to the CD16 (FcγRIII) antigen expressed on γδ T cells and NK cells. Our results revealed the superiority of tribody [(HER2)2xCD16] compared to trastuzumab in triggering γδ T cell and NK cell-mediated lysis of HER2-expressing tumor cells, such as PDAC, breast cancer, and autologous primary ovarian tumors. The increased efficacy of [(HER2)2xCD16] can be explained by an enhanced degranulation of immune cells. Although CD16 expression was decreased on γδ T cells in several PDAC patients and the number of tumor-infiltrating NK cells and γδ T cells was impaired in ovarian cancer patients, [(HER2)2xCD16] selectively enhanced cytotoxicity of cells from these patients. Here, unique anti-tumor properties of tribody [(HER2)2xCD16] are identified which beyond addressing HER2 overexpressing solid tumors may allow to treat with similar immunoconstructs combined with the adoptive transfer of γδ T cells and NK cells refractory hematological malignancies. A major advantage of γδ T cells and NK cells in the transplant situation of refractory hematological malignancies is given by their HLA-independent killing and a reduced graft-versus-host disease.
... Conjugation of TTZ to the surface of CPT-PCL NRs significantly inhibited the growth of BT-474 breast cancer cells. Overexpression of HER-2 increases breast cancer cell proliferation in part by transactivation of enhanced growth factor receptor signaling [37,49,64]. Blocking of HER-2 by TTZ binding proved to suppress the cells growth. ...
Ineffective drug release at the target site is among the top challenges for cancer treatment. This reflects the facts that interaction with the physiological condition can denature active ingredients of drugs, and low delivery to the disease microenvironment leads to poor therapeutic outcomes. We hypothesize that depositing a thin layer of bioresponsive polymer on the surface of drug nanoparticles would not only protect drugs from degradation but also allow the release of drugs at the target site. Here, we report a one-step process to prepare bioresponsive polymer coated drug nanorods (NRs) from liquid precursors using the solvent diffusion method. A thin layer (10.3 ± 1.4 nm) of poly(ε-caprolactone) (PCL) polymer coating was deposited on the surface of camptothecin (CPT) anti-cancer drug NRs. The mean size of PCL-coated CPT NRs was 500.9 ± 91.3 nm length × 122.7 ± 10.1 nm width. The PCL polymer coating was biodegradable at acidic pH 6 as determined by Fourier transform infrared spectroscopy. CPT drugs were released up to 51.5% when PCL coating dissolved into non-toxic carboxyl and hydroxyl groups. Trastuzumab (TTZ), a humanized IgG monoclonal antibody, was conjugated to the NR surface for breast cancer cell targeting. Combination treatments using CPT and TTZ decreased the HER-2 positive BT-474 breast cancer cell growth by 66.9 ± 5.3% in vitro. These results suggest effective combination treatments of breast cancer cells using bioresponsive polymer coated drug delivery.
... Ado-trastuzumab emtansine is composed of the anti-HER2 antibody trastuzumab connected via a stable thioether linker to the potent antimicrotubule 156699_2_art_file_3450457_h5mfx3.docx agent derivative of maytansine 1, an inhibitor of microtubule dimerization (11,12). It was approved in the US and Europe in 2013 for patients with advanced or metastatic HER2-positive breast cancer (13,14). ...
Purpose:
To assess the safety, tolerability, and preliminary antitumor activity of the investigational anti-GCC antibody-drug conjugate TAK-264 (formerly MLN0264) in adult patients with advanced gastrointestinal malignancies.
Experimental design:
Adult patients with GCC-expressing gastrointestinal malignancies (H-score {greater than or equal to}10) were eligible for inclusion. TAK-264 was administered as a 30-minute IV infusion once every 3 weeks for up to 17 cycles. Dose escalation proceeded using a Bayesian continual reassessment method. At the maximum tolerated dose (MTD), 25 patients with metastatic colorectal cancer (mCRC) were enrolled in a prespecified dose-expansion cohort.
Results:
41 patients were enrolled, including 35 (85%) with mCRC. During dose escalation (0.3-2.4 mg/kg), 4 of 19 patients experienced dose-limiting toxicities of grade 4 neutropenia; the MTD was determined as 1.8 mg/kg. Patients received a median of 2 cycles of TAK-264 (range 1-12); 9 received {greater than or equal to}4 cycles. Common drug-related adverse events (AEs) included nausea and decreased appetite (each 41%), fatigue (32%), diarrhea, anemia, alopecia, and neutropenia (each 27%); grade {greater than or equal to}3 AEs included neutropenia (22%), hypokalemia, and febrile neutropenia (each 7%). Peripheral neuropathy was reported in 4 (10%) patients. Pharmacokinetic data showed approximately dose-proportional systemic exposure and a mean plasma half-life of around 4 days, supporting the dosing schedule. Overall, 39 patients were response-evaluable; 3 experienced durable stable disease and 1 with gastric adenocarcinoma had a partial response. GCC expression did not appear to correlate with treatment duration.
Conclusions:
These findings suggest that TAK-264 has a manageable safety profile, with preliminary evidence of potential antitumor activity in specific gastrointestinal malignancies. Further investigation is underway.
... In addition, treatments for targets other than ErbB1 are not yet available for CRC. ErbB2 is targeted by the monoclonal antibody trastuzumab (Herceptin™) in breast cancer (12,13), and therapeutic agents targeting ErbB3, including MM-121, AMG 888, TK-A3, and TK-A4 are available, however, they are not used clinically (14). A detailed evaluation, describing the synchronous modulation of expression between EGFR family receptors and their ligands, in terms of K-ras mutations in CRC tissues, has not been reported. ...
The present study investigated the expression profiles of the epidermal growth factor receptor (EGFR) family, which consists of four transmembrane tyrosine kinase receptors and their eight ligands, in 122 patients with colorectal cancer (CRC) using reverse transcription-quantitative polymerase chain reaction analysis. On comparison of the CRC primary tumor and matched adjacent normal mucosa (ANM) tissue samples, the mRNA expression levels of ErbB3, but not ErbB1, were significantly increased in CRC tissue samples, compared with those in the ANM tissues. The expression levels of the ligands exhibited opposing trends to their corresponding receptors, including EGF, BTC, AREG, EREG and HB‑EGF, which were increased in the CRC tissues, whereas NRG1 and NGR2 were decreased in thee CRC tissues, compared with those in the AMN tissues. Subsequently, the present study investigated the frequency of K-ras mutations in the patients with CRC. The K‑ras mutations were found to be present in 36.8% (45/122) of the cases, however, no correlation was observed between K‑ras mutations and clinicopathological characteristics. In the CRC tissues, the expression levels of the EGFR family receptors and their ligands were determined in wild-type and mutant K-ras CRC cases. The expression levels of ErbB1, ErbB2, ErbB3, BTC, AREG, EREG, NRG1 and NRG2 were significantly decreased in the mutant K‑ras cases, compared with those in the wild‑type K‑ras cases. These results suggested that the tumorigenesis of CRC with wild‑type K‑ras was mediated through, not only ErbB1, but also through the ErbB2 and ErbB3 pathways. Notably, although ErbB2 does not bind any ErbB ligands, ErbB2 may activate tumorigenesis via a heterodimer, rather than a homodimer. Therefore, the results of the present study suggest that the most effective strategy to target not only ErbB1, but also ErbB2 and ErbB3, is the use of monoclonal antibody treatment.
... In the treatment of several kinds of cancer, including lung cancer, potential therapeutic targets such as epidermal growth factor receptor (EGFR), 7 Kirsten rat sarcoma viral oncogene, 8 and human EGFR-2, 9 have been the focus of recent attention. Yet, the development of drugs aimed at these targets has been hampered by drug resistance and a high mutation rate of the relevant genes. ...
Background
The association between the expression of programmed cell death-ligand 1 (PD-L1) and survival in patients with non-small-cell lung cancer (NSCLC) is controversial. Thus, we conducted a meta-analysis of all available studies to evaluate the prognostic role of PD-L1 expression in NSCLC.
Materials and methods
PubMed, Embase, and Chinese (China National Knowledge Infrastructure and Wanfang) databases were searched to identify all eligible studies evaluating PD-L1 expression and the survival of NSCLC patients. Hazard ratios (HRs) and 95% confidence interval (CI) used to assess overall survival were extracted and pooled. Subgroup, sensitivity, and publication-bias analyses were also performed.
Results
Eleven articles reporting 12 studies that included a total of 1,653 patients met the inclusion criteria and were included in the meta-analysis. Higher PD-L1 expression did not correlate with prognosis in terms of overall survival in patients with NSCLC (HR =1.21, 95% CI: 0.85–1.71, P=0.29). However, a subgroup analysis showed a significant association between PD-L1 expression and poor prognosis in Chinese patients with NSCLC (HR =1.55, 95% CI: 1.04–2.29, P=0.03). The sensitivity analysis showed that the pooled results were not affected by the removal of any single study. There was also no significant publication bias.
Conclusion
Our meta-analysis indicated no statistically significant difference between PD-L1 expression and prognosis for patients with NSCLC. Additional, high-quality studies with larger sample sizes are needed to determine the prognostic value of PD-L1 expression in NSCLC.
... The search for novel agents in the class has therefore been intensive 19,20 and whereas the more recent approvals, such as vinflunine, 21 eribulin, 22−24 ixabepilone, 25,26 and the antibody− drug conjugate trastuzumab emtansine, 27 have proven beneficial for a limited number of indications, not all clinical studies have demonstrated improved efficacy, and classical MTA-associated adverse reactions, 28−30 including PN, 31−33 are still encountered with these newer agents. It is worth noting that eribulin in particular has shown evidence of an improved safety profile and promise for wider application 34 although drug resistance has also been encountered with this agent. ...
A number of indole-3-glyoxylamides have previously been reported as tubulin polymerization inhibitors, though none has yet been successfully developed clinically. We report here a new series of related compounds-modified according to a strategy of reducing aromatic ring count and introducing a greater degree of saturation-which retain potent tubulin polymerization activity but with a distinct SAR from previously documented libraries. A subset of active compounds from the reported series is shown to interact with tubulin at the colchicine binding site, disrupt the cellular microtubule network, and exert a cytotoxic effect against multiple cancer cell lines. Two compounds demonstrated significant tumor growth inhibition in a mouse xenograft model of head and neck cancer, a type of the disease which often proves resistant to chemotherapy, supporting further development of the current series as potential new therapeutics.
