ABSTRACT
The CD19-targeting bispecific T-cell engager blinatumomab has shown remarkable efficacy in patients with relapsed/refractory B-cell precursor acute lymphoblastic leukemia. However, several studies showed that blinatumomab has a short plasma half-life due to its low molecular weight, and thus its clinical use is limited. Furthermore, multiple trials have shown that approximately 30% of blinatumomab-relapsed cases are characterized by CD19 negative leukemic cells. Here, we design and characterize two novel antibodies, A-319 and A-2019. Blinatumomab and A-319 are CD3/CD19 bispecific antibodies with different molecular sizes and structures, and A-2019 is a novel CD3/CD19/CD20 trispecific antibody with an additional anti-CD20 function. Our in vitro, ex vivo, and in vivo experiments demonstrated that A-319 and A-2019 are potent antitumor agents and capable of recruiting CD3 positive T cells, enhancing T-cell function, mediating B-cell depletion, and eventually inhibiting tumor growth in Raji xenograft models. The two molecules are complementary in terms of efficacy and specificity profile. The activity of A-319 demonstrated superior to that of A-2019, whereas A-2019 has an additional capability to target CD20 in cells missing CD19, suggesting its potential function against CD19 weak or negative CD20 positive leukemic cells.
Subject(s)
Humans , Antigens, CD19/therapeutic use , Antineoplastic Agents/pharmacology , Immunotherapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , T-LymphocytesABSTRACT
Objective To evaluate the effect of therapeutic hypercapnia preconditioning on lung ischemia-reperfusion (I/R) injury in rats.Methods Forty healthy adult Sprague-Dawley rats of either sex,aged 2 months,weighing 250-300 g,were divided into 5 groups (n=8 each) using a random number table:sham operation group (group S),grouP I/R and preconditioning with therapeutic hypercapnia of different level groups (group THP1-3).Lung I/R injury was induced by clamping the left hilum of lung for 45 min followed by 120 min of reperfusion.In THP1-3 groups,the respiratory parameters were adjusted at 5 min of stability after isolating the left hilum of lung to make PETCO2 reach 55-65,65-75 and 75-85 mmHg respetively and maintained at this level for 5 min,normal ventilation was then used to make PETCO2 restore the normal level,continuously repeating for 3 circles,and then the left hilum of lung was blocked for 45 min followed by 120 min of reperfusion.The bronchoalveolar lavage fluid (BALF) was collected at the end of reperfusion for determination of the total protein (TP) concentration using Coomassie brilliant blue staining.Lung tissues were obtained at the end of reperfusion for examination of pathological changes after haematoxylin and eosin staining (under a light microscope) and for determination of wet/dry weight ratio (W/D ratio),malondialdehyde (MDA) content,superoxide dismutase (SOD) activity,interleukin-8 (IL-8) and IL-10 contents (by enzyme-linked immunosorbent assay),tumor necrosis factor-alpha (TNF-α) expression (by immunohistochemistry) and expression of TNF-α mRNA (by real-time polymerase chain reaction).Results Compared with group S,the TP concentration in BALF,W/D ratio and contents of MDA,IL-8 and IL-10 in lung tissues were significantly increased,the SOD activity was decreased,the expression of TNF-α mRNA was up-regulated (P＜0.05),strong positive expression of TNF-α was found,and the pathological changes of lung tissues were aggravated in group I/R.Compared with group I/R,the TP concentration in BALF,W/D ratio and contents of MDA and IL-8 in lung tissues were significantly decreased,the SOD activity was increased,the expression of TNF-α mRNA was down-regulated (P＜0.05),no significant change was found in IL-10 content (P＞0.05),the staining range and intensity of TNF-α were decreased,and the pathological changes of lung tissues were significantly attenuated in THP1-3 groups.Conclusion Therapeutic hypercapnia preconditioning can reduce lung I/R injury in rats,and the mechanism is related to inhibiting inflammatory responses and oxidative stress responses.
ABSTRACT
Objective To investigate the effect of different forbidden drink schemes on anesthesia induction and postoperative nausea and vomiting during pediatric interventional heart surgery.Methods One hundred and twenty pediatric patients underwent cardiac interventional procedures under general anesthesia were randomized into group A,B and C,with 40 patients in each group.Patients in cach group were fasted for 8 h preoperatively.Water was prohibited for patients in group A for 6 h preoperatively.Patients in groups B and C orally took 10％ glucose solution and a multivitamin drink (Outfast) at 2 h preoperatively,respectively.Nausea and vomiting after anesthesia induction were recorded for 24 h postoperatively.Results The sedation and mask acceptance scores were significantly higher in group B and C than those in group A,and were significantly higher in group C than those in group B (P ＜ 0.05,resoectively).Following anesthesia induction,MAP was significantly higher in group B and C than that in group A (P ＜ 0.05,resoectively).Both the severity and incidence of postoperative nausea and vomiting were higher in group B and C than those in group A,and was lower in group C than that in group B (P ＜ 0.05,resoectively).Conclusions Taking clear water orally 2 hours before surgery can decrease the restlessness of pediatric interventional heart surgery during anesthesia induction period,with stable smooth hemodynamics,reducing the degree of PONV.