We clarified the molecular mechanism of GA protection against UVB-induced inflammation by modulating NF-κB signaling pathways and determined the optimal concentration of GA in mice skin exposed to UVB irradiation.
Epithelial cell adhesion molecule (EpCAM) is known to be overexpressed in epithelial cancers associated with enhanced malignant potential, particularly colorectal carcinoma (CRC) and head and neck squamous cell carcinoma (HNSCC). However, it is unknown whether progression of malignance can be directly inhibited by targeting EpCAM. Here, we have generated five novel monoclonal antibodies (mAbs) against EpCAM. One of these anti-EpCAM mAbs, EpAb2-6, was found to induce cancer cell apoptosis in vitro, inhibit tumor growth, and prolong the overall survival of both a pancreatic cancer metastatic mouse model and mice with human colon carcinoma xenografts. EpAb2-6 also increases the therapeutic efficacy of irinotecan, fluorouracil, and leucovorin (IFL) therapy in a colon cancer animal model and gemcitabine therapy in a pancreatic cancer animal model. Furthermore, EpAb2-6, which binds to positions Y95 and D96 of the EGF-II/TY domain of EpCAM, inhibits production of EpICD, thereby decreasing its translocation and subsequent signal activation. Collectively, our results indicate that the novel anti-EpCAM mAb can potentially be used for cancer-targeted therapy.
A new SELEX protocol for the development of DNA aptamers has been demonstrated, referred to as magnetic-assisted rapid aptamer selection (MARAS). This method uses magnetic beads and an externally applied rotating magnetic field to provide the competitive mechanism for the selection aptamers with different affinities to the molecular target. The MARAS protocol efficiently generated aptamers with high affinity and specificity for C-reactive protein, a common cardiovascular disease indicator. The binding affinities of the selected aptamers could be varied by changing the frequency of the externally applied rotating magnetic field and optimal cases bound with low-nanomolar dissociation constants.
Antibody-drug conjugate (ADC) targeting antigens expressed on the surface of tumor cells are an effective approach for delivering drugs into the cells via antigen-mediated endocytosis. One of the well-known tumor antigens, the CD20 of B-lymphocyte, has long been suggested to be noninternalizing epitope, and is thus not considered a desirable target for ADCs. Here, sortase A (srtA)-mediated transpeptidation is used to specifically conjugate triple glycine-modified monomethyl auristatin E (MMAE), a highly toxic antimitotic agent, to anti-CD20 ofatumumab (OFA) equipped with a short C-terminal LPETG (5 amino acids) tag at heavy chain (HL), which generates ADCs that show extremely strong potency in killing CD20 positive cancer cells. One of the srtA-generated ADCs with a cleavable dipeptide linker (valine-citrulline, vc), OFA-HL-vcMMAE, shows IC50 values ranging from 5 pg mL to 4.1 ng mL against CD20+ lymphoma cells. Confocal laser scanning microscopy confirms that OFA-HL-vcMMAE internalization by Ramos cells is significantly improved compared to OFA alone, consistent with the high antitumor activity of the new ADC. OFA-HL-vcMMAE, at 5 mg kg dose, is able to eliminate tumors with mean volume ≈400 mm while no obvious drug-related toxicity is observed. The results show that srtA-generated OFA-MMAE conjugate system provides a viable strategy for targeting CD20+ B lineage lymphomas.
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