Background Dengue disease is a mosquito-borne infection caused by four dengue virus serotypes (DENV1-4). Secondary infections can produce flavivirus cross-reactive antibodies at sub-neutralizing levels. This phenomenon can significantly increase the severity of secondary infections via antibody-dependent enhancement (ADE). ADE activity is associated with a high risk of viral infection in immune effector cells, triggering cytokine cascade and activating the complement system, which lead to severe symptoms. Despite extensive studies, therapeutic antibodies, particularly fully human monoclonal antibodies, which can be an option for immune passive therapy, have not yet been discovered. Methodology/Principal Findings This study generated LALA-mutated human monoclonal antibody clone B3B9 (LALA-B3B9 HuMAb) that can neutralize all four DENV serotypes without enhancing viral activity. The number of infected cells obtained with the ADE assay was compared among wild-type antibody (B3B9), and modified Fc, LALA-B3B9 HuMAb, and N297Q (N297Q-B3B9), with or without complement proteins. Moreover, the therapeutic efficacy of these HuMAbs against ADE infection by competing with natural antibodies in patients with acute dengue was determined using the in vitro suppression-of-enhancement assay in K562 cells. The novel Fc-modified antibody LALA-B3B9 (Leu234Ala/Leu235Ala mutations) could have a therapeutic effect. Further, it exhibited neutralization properties against all dengue virus serotypes without triggering ADE activity at any antibody concentration. This outcome was similar to that of the previous Fc-modified N297Q-B3B9 antibody (N297Q mutation). Moreover, the effect of complement protein on enhancing and neutralizing activities was evaluated to assess unwanted inflammatory responses to these therapeutic antibodies. Results showed that the elimination of complement activity could reduce the severity of dengue. The activities of LALA-B3B9 and N297Q-B3B9 HuMAbs were complement-independent in all dengue virus serotypes. Conclusions LALA-B3B9 and N297Q-B3B9 HuMAbs can prevent the suppression-of-enhancement activity in K562 cells caused by human DENV2. Hence, they are promising candidates for dengue treatment.
Neuroblastoma (NB) is the most common extracranial solid tumor in pediatric population with a high degree of heterogeneity in clinical outcomes, ranging from spontaneous remission to rapid progression and death. Upregulation of a tumor suppressor miR-204 in patient-derived neuroblastoma tumors was associated with good prognosis independent of known risk factors. While miR-204 is recognized as a therapeutic candidate, its delivery was unavailable. This study aimed to develop red blood cell-derived extracellular vesicles (RBC-EVs) as the miR-204 carrier and evaluate the inhibitory activity against neuroblastoma cell lines and spheroids. MiR-204 mimics were loaded into RBC-EVs (RBC-EVmiR-204) by electroporation with the optimized parameters of 250 V, 20 ms, 10 pulsing times. RBC-EVmiR-204, but not the native RBC-EVs, could inhibit cell viability, migration and spheroid formation and growth of MYCN-amp and MYCN non-amplification (MYCN-NA) NB cells, even though the suppressive effects were more preferable in MYCN-amp NB. For the mechanistic insight, SWATH-proteomics suggested that RBC-EVmiR-204induced dysregulation of ribosomal proteins and alterations in RNA metabolism, leading to inhibiting neuroblastoma progression. This study developed RBC-EVmiR-204as an alternative/adjunct therapy of pediatric neuroblastoma. The therapeutic efficacy of RBC-EVmiR-204should be further investigated in preclinical models and clinical studies.
Human leukaemia cells have an often unique ability to either undergo apoptotic cell death mechanisms or, at other times, undergo proliferative expansion, sometimes to the same stimulus such as the pluripotent cytokine TNFα (tumour necrosis factor α). This potential for life/death switching helps us to understand the molecular signalling machinery that underlies these cellular processes. Furthermore, looking at the involvement of these switching signalling pathways that may be aberrant in leukaemia informs us of their importance in cancer tumorigenesis and how they may be targeted pharmacologically to treat various types of human leukaemias. Furthermore, these important pathways may play a crucial role in acquired chemotherapy resistance and should be studied further to overcome in the clinic many drug-resistant forms of blood cancers. In the present article, we uncover the relationship that exists in human leukaemia life/death switching between the anti-apoptotic pro-inflammatory transcription factor NF-κB (nuclear factor κB) and the cytoprotective antioxidant-responsive transcription factor Nrf2 (nuclear factor-erythroid 2-related factor 2). We also discuss recent findings that reveal a major role for Btk (Bruton's tyrosine kinase) in both lymphocytic and myeloid forms of human leukaemias and lymphomas.
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