The depth and versatility of siRNA technologies enable their use in disease targets that are undruggable by small molecules or that seek to achieve a refined turn-off of the genes for any therapeutic area. Major extracellular barriers are enzymatic degradation of siRNAs by serum endonucleases and RNAases, renal clearance of the siRNA delivery system, the impermeability of biological membranes for siRNA, activation of the immune system, plasma protein sequestration, and capillary endothelium crossing. To overcome the intrinsic difficulties of the use of siRNA molecules, therapeutic applications require nanometric delivery carriers aiming to protect double-strands and deliver molecules to target cells. This review discusses the history of siRNAs, siRNA design, and delivery strategies, with a focus on progress made regarding siRNA molecules in clinical trials and how siRNA has become a valuable asset for biopharmaceutical companies.
Infections caused by SARS-CoV-2 induce a severe acute respiratory syndrome called COVID-19 and have led to more than six million deaths worldwide. Vaccination is the most effective preventative measure, and cellular and humoral immunity is crucial to developing individual protection. Here, we aim to investigate hybrid immunity against SARS-CoV-2 triggered by the ChAadOx1 nCoV-19 vaccine in a Brazilian cohort. We investigated the immune response from ChAadOx1 nCoV-19 vaccination in naïve (noCOVID-19) and previously infected individuals (COVID-19) by analyzing levels of D-dimers, total IgG, neutralizing antibodies (Nabs), IFN-γ (interferon-γ) secretion, and immunophenotyping of memory lymphocytes. No significant differences in D-dimer levels were observed 7 or 15 days after vaccination (DAV). All vaccinated individuals presented higher levels of total IgG or Nabs with a positive correlation (R = 0.88). Individuals in the COVID-19 group showed higher levels of antibody and memory B cells, with a faster antibody response starting at 7 DAV compared to noCOVID-19 at 15 DAV. Further, ChAadOx1 nCoV-19 vaccination led to enhanced IFN-γ production (15 DAV) and an increase in activated T CD4+ naïve cells in noCOVID-19 individuals in contrast with COVID-19 individuals. Hence, our data support that hybrid immunity triggered by ChAadOx1 nCoV-19 vaccination is associated with enhanced humoral response, together with a balanced cellular response.
This work aims to evaluate the biosimilar and biobetters of rituximab developed in Bio-Manguinhos regarding their ability to bind to the CD20 antigen and the in vitro biological activity. Methodology: Through flow cytometry assays it was possible to analyze the binding properties of the constructs to the CD20 antigen on the surface of leukemia cells (K562 CD20+) and the presence of NKG2DL in the constructs. Potential ADCC and CDC were evaluated using the CytoTox96 kit, a non-radioactive cytotoxicity colorimetric assay capable of measuring the lactate dehydrogenase in the medium, and NK cells expanded in vitro as effector cells. Results: Flow cytometry assays have demonstrated that the constructs produced in Bio-Manguinhos are capable of binding to CD20+ cells and that NKG2DLs are present in the biobetters constructs. ADCC and CDC assays demonstrated that the presence of NKG2DLs in the constructs improved the in vitro biological activity of the mAb, evidencing a higher percentage of cell lysis of the biobetter when compared to the biosimilar and rituximab (MabThera) antibodies. Conclusion: The conclusion is that the antibodies developed are capable of binding to CD20 expressing cells and the biobetters presented improved biological activity in vitro when compared to the biosimilar and reference rituximab, suggesting that the addition of the NK-cell ligand to the anti-CD20 mAb may enhance the therapeutic efficacy of rituximab and other therapeutic antibodies. To reinforce this hypothesis, we have established an in vivo model consisting in xenografts of CD20+ the human lymphoma cell line (RAJI) in immunodeficient mice. The immunodeficient animals will be treated with primary human NK cells and/or the mAbs of interest to evaluate the in vivo enhancing function of the new conformations of the anti CD20 mAbs.
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