RESUMO
Therapeutic antibodies (Abs) which act on a broader range of epitopes may provide more durable protection against the genetic drift of a target, typical of viruses or tumors. When these Abs exist concurrently on the targeted antigen, several mechanisms of action (MoAs) can be engaged, boosting therapeutic potency. This study selected combinations of four and five Abs with non- or partially overlapping epitopes to the SARS-CoV-2 spike glycoprotein, on or outside the crucial receptor binding domain (RBD), to offer resilience to emerging variants and trigger multiple MoAs. The combinations were derived from a pool of unique-sequence scFv Ab fragments retrieved from two SARS-CoV-2-naïve human phage display libraries. Following recombinant expression to full-length human IgG1 candidates, a biolayer interferometric analysis mapped epitopes to bins and confirmed that up to four Abs from across the bins can exist simultaneously on the spike glycoprotein trimer. Not all the bins of Abs interfered with the spike protein binding to angiotensin converting enzyme 2 (ACE2) in competitive binding assays, nor neutralized the pseudovirus or authentic virus in vitro, but when combined in vivo, their inclusion resulted in a much stronger viral clearance in the lungs of intranasally challenged hamsters, compared to that of those treated with mono ACE2 blockers. In addition, the Ab mixtures activated in vitro reporter cells expressing Fc-gamma receptors (FcγRs) involved in antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP). The best four-Ab combination neutralized seventeen variants of concern from Wuhan-Hu1 to Omicron BA.4/BA.5 in vitro.
RESUMO
BACKGROUND: Intentional self-inflicted injuries present unique challenges in treatment and prevention. We hypothesized intentional self-inflicted injuries would have higher in-hospital and postdischarge mortality than nonintentional self-inflicted injuries trauma. METHODS: Adult patients evaluated 2008 to 2012 were identified in our trauma registry and matched with mortality data from the National Death Index. Intentional self-inflicted injuries were identified using E-Codes. Readmissions were identified and analyzed. Intentional self-inflicted injuries patients who died in-hospital were compared with those surviving to discharge. Univariate analysis was performed using nonparametric tests. Kaplan-Meier curves were plotted to compare mortality ≤5 years postdischarge between intentional self-inflicted injuries and non-intentional self-inflicted injuries patients. RESULTS: In the study, 8,716 patient records were evaluated with 245 (2.8%) classified as intentional self-inflicted injuries. Eighteen (7.8%) patients with intentional self-inflicted injuries had multiple admissions, compared with 352 (4.4%) patients with nonintentional self-inflicted injuries with readmissions (P = .0210). In-hospital mortality was higher for intentional self-inflicted injuries compared with patients with non-intentional self-inflicted injuries (18.7% vs 4.9%, P < .0001). Survival analysis demonstrated that patients with intentional self-inflicted injuries had significantly lower postdischarge mortality at multiple time points. CONCLUSION: Patients with intentional self-inflicted injuries trauma have high in-hospital mortality, but low postdischarge mortality. We attribute this to high lethality mechanisms but appropriate psychiatric treatment and rehabilitation. However, the high intentional self-inflicted injuries readmission rate indicates further study of intentional self-inflicted injuries follow-up is warranted. Better prevention strategies are needed to identify and intervene in patients at-risk for intentional self-inflicted injuries.