Browsing by Subject "HER2"

Now showing 1 - 2 of 2

Open Access
A cellular device to target cancer cells
(2021-10) Ostaku, Julian
Cancer is the second leading cause of death globally, affecting one out of three people during their lifetime. Due to its severity and high incidence, numerous treatment methods have been implemented, with the Chimeric Antigen Receptor T-Cell (CAR-T) therapy remaining the most promising one. Other therapy options such as surgery, chemotherapy and radiation therapy remain the backbone of cancer treatment, however these therapies are not effective enough as they do not discriminate among the healthy and cancerous tissues. Therefore, there is an imperative need in developing novel cancer treatment therapies that offer precise localization and on target therapeutics release. In this study, we aim to develop an engineered bacterial device, that can sense Jimt1 breast cancer cells, which are characterized by overexpression of human epidermal growth factor receptor 2 (HER2). 2Rs15d, a nanobody that binds to HER2 receptor, is expressed on the surface of Escherichia coli BL21 (DE3) via Ag43 autotransporter protein. Upon localization in the tumor site, a therapeutic agent will be released on the outer surface. By creating this platform, we aim to target the main problems of the existing cancer therapies.
Open Access
Novel anti-HER2 monoclonal antibodies: synergy and antagonism with tumor necrosis factor-α
(BioMed Central, 2012) Ceran, Ceyhan; Çokol, M.; Cingöz, S.; Taşan, İpek; Öztürk, Mehmet; Yağcı, Tamer
Background: One-third of breast cancers display amplifications of the ERBB2 gene encoding the HER2 kinase receptor. Trastuzumab, a humanized antibody directed against an epitope on subdomain IV of the extracellular domain of HER2 is used for therapy of HER2-overexpressing mammary tumors. However, many tumors are either natively resistant or acquire resistance against Trastuzumab. Antibodies directed to different epitopes on the extracellular domain of HER2 are promising candidates for replacement or combinatorial therapy. For example, Pertuzumab that binds to subdomain II of HER2 extracellular domain and inhibits receptor dimerization is under clinical trial. Alternative antibodies directed to novel HER2 epitopes may serve as additional tools for breast cancer therapy. Our aim was to generate novel anti-HER2 monoclonal antibodies inhibiting the growth of breast cancer cells, either alone or in combination with tumor necrosis factor-α (TNF-α). Methods: Mice were immunized against SK-BR-3 cells and recombinant HER2 extracellular domain protein to produce monoclonal antibodies. Anti-HER2 antibodies were characterized with breast cancer cell lines using immunofluorescence, flow cytometry, immunoprecipitation, western blot techniques. Antibody epitopes were localized using plasmids encoding recombinant HER2 protein variants. Antibodies, either alone or in combination with TNF-α, were tested for their effects on breast cancer cell proliferation. Results: We produced five new anti-HER2 monoclonal antibodies, all directed against conformational epitope or epitopes restricted to the native form of the extracellular domain. When tested alone, some antibodies inhibited modestly but significantly the growth of SK-BR-3, BT-474 and MDA-MB-361 cells displaying ERBB2 amplification. They had no detectable effect on MCF-7 and T47D cells lacking ERBB2 amplification. When tested in combination with TNF-α, antibodies acted synergistically on SK-BR-3 cells, but antagonistically on BT-474 cells. A representative anti-HER2 antibody inhibited Akt and ERK1/2 phosphorylation leading to cyclin D1 accumulation and growth arrest in SK-BR-3 cells, independently from TNF-α. Conclusions: Novel antibodies against extracellular domain of HER2 may serve as potent anti-cancer bioactive molecules. Cell-dependent synergy and antagonism between anti-HER2 antibodies and TNF-α provide evidence for a complex interplay between HER2 and TNF-α signaling pathways. Such complexity may drastically affect the outcome of HER2-directed therapeutic interventions.