Antibody-drug conjugates: Recent advances in payloads

Antibody‒drug conjugates (ADCs), which combine the advantages of monoclonal antibodies with precise targeting and payloads with efficient killing, show great clinical therapeutic value. The ADCs' payloads play a key role in determining the efficacy of ADC drugs and thus have attracted great attention in the field. An ideal ADC payload should possess sufficient toxicity, low immunogenicity, high stability, and modifiable functional groups. Common ADC payloads include tubulin inhibitors and DNA damaging agents, with tubulin inhibitors accounting for more than half of the ADC drugs in clinical development. However, due to clinical limitations of traditional ADC payloads, such as inadequate efficacy and the development of acquired drug resistance, novel highly efficient payloads with diverse targets and reduced side effects are being developed. This perspective summarizes the recent research advances of traditional and novel ADC payloads with main focuses on the structure-activity relationship studies, co-crystal structures, and designing strategies, and further discusses the future research directions of ADC payloads. This review also aims to provide valuable references and future directions for the development of novel ADC payloads that will have high efficacy, low toxicity, adequate stability, and abilities to overcome drug resistance.

Effect of neurokinin 1 receptor antagonist on airway inflammation and hyperresponsiveness in asthmatic mice / 中国小儿急救医学

Objective@#To investigate the effects of neurokinin-1 receptor antagonist WIN 62, 577 on airway inflammation and airway hyperresponsiveness in asthmatic mice.@*Methods@#Thirty-two BALB/c mice(Specific-pathogen-free grade) were randomly divided into 4 groups: control group, asthmatic group, WIN 62, 577 intervention group and dexamethasone group.The asthmatic group, the WIN 62, 577 intervention group, and the dexamethasone group were given intraperitoneal injection of 0.2 ml of OVA sensitization solution at 0 d, 7 d, and 14 d, respectively.Then the asthmatic group, WIN 62, 577 group and dexamethasone group were given OVA challenge solution(4% OVA solution) by inhalation once a day for 30 min from 21 d to 28 d for 7 consecutive days.The WIN 62, 577 intervention group was given WIN 62, 577 300 μg intraperitoneal injection 1 h before each challenge; the dexamethasone group was given intraperitoneal injection of dexamethasone 2 mg/kg 1 h before each challenge.The airway responsiveness of each group of mice was detected by non-invasive pulmonary function test.The bronchoalveolar lavage fluid(BALF) was obtained for inflammatory count.The HE staining of lung tissue was used to observe airway inflammation in mice.@*Results@#Compared with the asthmatic group, the mice in the WIN 62, 577 intervention group showed less restlessness, standing upright, crouching back, scratching the ears and scratching the cheeks, shortness of breath and cyanosis of the lips.After inhaling different concentrations of acetylcholine, the Penh value of mice in the WIN 62, 577 intervention group and the dexamethasone group was significantly lower than that in the asthmatic group(P<0.05). Compared with the asthmatic group, the number of WBC and EOS in BALF decreased significantly in the WIN 62, 577 intervention group and the dexamethasone group(P<0.01). HE staining showed that the inflammatory changes in the lung tissue of mice in the WIN 62, 577 intervention group were significantly reduced, the bronchial epithelium did not fall off significantly, the mucosal edema was not obvious, the smooth muscle proliferation was reduced, and the inflammatory cell infiltration was reduced, similar to the airway changes in the dexamethasone group.@*Conclusion@#Neurokinin-1 receptor antagonist WIN 62, 577 can reduce airway inflammation and airway hyperresponsiveness in asthmatic mice.

Protective effect of neurokinin 1 receptor antagonist on interleukin-13 induced oxidative stress injury of bronchial epithelial cells / 中国小儿急救医学

Objective:To investigate whether WIN 62, 577 which is an antagonist of neurokinin 1 receptor(NK-1R) has protective effects on interleukin(IL)-13-induced bronchial epithelial cell oxidative stress injury.Methods:Human bronchial epithelial cells (16HBE) were cultured and divided into 4 groups: control group, IL-13 group, IL-13+ SP group[IL-13+ sensory neuropeptide substance P(SP)] and IL-13+ WIN 62, 577 group.16HBE cells were treated with IL-13 (25 ng/ml) for 48 hours.After 48 hours, the IL-13 + SP group was treated with sensory neuropeptide SP(10 nmol/L) for 1 hour, and the IL-13+ WIN 62, 577 group was treated with WIN 62, 577 (10 nmol/L) for 1 hour, respectively.The proliferation ability, reactive oxygen species (ROS)level, malondialdehyde (MDA)content and total superoxide dismutase (SOD) activity in each group were detected by corresponding kits.Results:Compared with the control group, cell proliferation ability reduced ( P<0.001), ROS level increased ( P=0.001), MDA content increased( P<0.001), and SOD activity reduced ( P<0.001) in the IL-13 group.Compared with the IL-13 group, the cell proliferation ability reduced ( P=0.016), the ROS level increased ( P=0.031), the MDA content increased( P<0.001), and the SOD activity decreased ( P=0.011)after sensory neuropeptide SP stimulation.However, the intervention of WIN 62, 577 could inhibit the decrease of cell proliferation ( P=0.018), the increase of ROS level ( P=0.018), the increase of MDA content ( P<0.001), and the decrease of SOD activity ( P=0.001) in human bronchial epithelial cells induced by IL-13. Conclusion:Sensory neuropeptide SP could aggravate oxidative stress induced by IL-13 in human bronchial epithelial cells, while the sensory neuropeptide SP receptor NK-1R antagonist WIN 62, 577 could alleviate oxidative stress induced by IL-13 in human bronchial epithelial cells.

Effect of neurokinin 1 receptor antagonist on airway inflammation and hyperresponsiveness in asthmatic mice / 中国小儿急救医学

Objective:To investigate the effects of neurokinin-1 receptor antagonist WIN 62, 577 on airway inflammation and airway hyperresponsiveness in asthmatic mice.Methods:Thirty-two BALB/c mice(Specific-pathogen-free grade) were randomly divided into 4 groups: control group, asthmatic group, WIN 62, 577 intervention group and dexamethasone group.The asthmatic group, the WIN 62, 577 intervention group, and the dexamethasone group were given intraperitoneal injection of 0.2 ml of OVA sensitization solution at 0 d, 7 d, and 14 d, respectively.Then the asthmatic group, WIN 62, 577 group and dexamethasone group were given OVA challenge solution(4% OVA solution) by inhalation once a day for 30 min from 21 d to 28 d for 7 consecutive days.The WIN 62, 577 intervention group was given WIN 62, 577 300 μg intraperitoneal injection 1 h before each challenge; the dexamethasone group was given intraperitoneal injection of dexamethasone 2 mg/kg 1 h before each challenge.The airway responsiveness of each group of mice was detected by non-invasive pulmonary function test.The bronchoalveolar lavage fluid(BALF) was obtained for inflammatory count.The HE staining of lung tissue was used to observe airway inflammation in mice.Results:Compared with the asthmatic group, the mice in the WIN 62, 577 intervention group showed less restlessness, standing upright, crouching back, scratching the ears and scratching the cheeks, shortness of breath and cyanosis of the lips.After inhaling different concentrations of acetylcholine, the Penh value of mice in the WIN 62, 577 intervention group and the dexamethasone group was significantly lower than that in the asthmatic group( P<0.05). Compared with the asthmatic group, the number of WBC and EOS in BALF decreased significantly in the WIN 62, 577 intervention group and the dexamethasone group( P<0.01). HE staining showed that the inflammatory changes in the lung tissue of mice in the WIN 62, 577 intervention group were significantly reduced, the bronchial epithelium did not fall off significantly, the mucosal edema was not obvious, the smooth muscle proliferation was reduced, and the inflammatory cell infiltration was reduced, similar to the airway changes in the dexamethasone group. Conclusion:Neurokinin-1 receptor antagonist WIN 62, 577 can reduce airway inflammation and airway hyperresponsiveness in asthmatic mice.

Effect of dexamethasone on expression of sensory neuropeptide substance P in asthmatic mice / 国际儿科学杂志

Objective:To explore the effect of dexamethasone on the expression of sensory neuropeptide substance P(SP)in asthmatic mice.Methods:Thirty-two BALB/c mice 6~7 weeks were randomly divided into 4 groups: control group, asthmatic group, WIN 62, 577(SP receptor antagonist)intervention group and dexamethasone intervention group.The acute asthma models were established in BALB/c mice by sensitizing and challenging with ovalbumin.The WIN 62, 577 intervention group was given WIN 62, 577 300 μg intraperitoneal injection 1h before each challenge, once a day for 7 consecutive days; the dexamethasone group was given intraperitoneal injection of dexamethasone 2 mg/kg 1h before each challenge, once a day for 7 consecutive days.Results:ELISA results showed that the level of SP[(45.78±9.15)ng/L] in BALF in the asthmatic group was significantly higher than that in the control group[(17.02±2.80)ng/L]( P<0.01); the SP level in BALF in the WIN 62, 577 intervention group [(25.26±3.48)ng/L]was significantly lower than that in the asthmatic group[(45.78±9.15)ng/L]( P<0.01); compared with the asthmatic group[(45.78±9.15)ng/L], the SP level in BALF was significantly reduced after dexamethasone intervention[(34.03±4.38)ng/L]( P=0.002). Compared with the control group[(6883.32±1734.89)ng/L], the level of SP in the serum of mice in the asthmatic group[(1 0247.62±2 667.38)ng/L] was significantly higher( P=0.001); compared with the asthmatic group[(10 247.62±2 667.38)ng/L], the level of SP in the serum of the WIN 62, 577 intervention group[(4 285.99±1 926.36)ng/L] was significantly lower( P<0.01); compared with the asthmatic group[(10 247.62±2 667.38)ng/L], the serum SP level was significantly reduced after dexamethasone intervention [(6 787.22±1 907.45)ng/L]( P=0.001). The results of immunohistochemistry showed that SP and NK-1R expression could be seen in the mouse airway epithelium, perivascular and smooth muscle layer; compared with the control group, SP and NK-1R expression in the airway of asthmatic mice was significantly increased; compared with the asthmatic group, SP and NK-1R expression in the airway of WIN 62, 577 intervention group and dexamethasone intervention group was significantly decreased. Conclusion:Dexamethasone inhibited the expression of SP in the airway of asthmatic mice.

The role of mitochondria in the pathogenesis of bronchial asthma / 国际儿科学杂志

Bronchial asthma is a heterogeneous disease characterized by chronic airway inflammation,and its pathogenesis is complex.Epithelial mitochondrial damage is one of the important pathogenesis of asthma and an important bridge between airway inflammation and airway remodeling.Inhibition of mitochondrial damage,and thus inhibition of oxidative stress,may be an effective method to reduce epithelial cell damage and inhibit airway remodeling,which may be a breakthrough in asthma treatment.This review summarizes the role of mitoehondria in the pathogenesis of asthma.

Effect of hydrogen on autophagy during inflammatory responses following lung injury in burned mice / 中华麻醉学杂志

Objective To evaluate the effect of hydrogen on autophagy during inflammatory responses following lung injury in burned mice.Methods Ninety-six clean-grade healthy male ICR mice,aged 6 weeks,weighing 20-25 g,were divided into 4 groups (n=24 each) using a random number table:sham operation group (SH group),H2 group (H2 group),burn group (B group) and burn plus H2 group (B+H2 group).Forty percent of the total body surface was shaved with 80 g/L sodium sulfide and then exposed to a 92 ℃ scald device for 18 s in B and B+H2 groups.Forty percent of the total body surface was shaved with 80 g/L sodium sulfide and then exposed to a scald device of skin temperature for 18 s in SH and H2 groups.Mice inhaled 2％ H2 for 1 h starting from 1 and 6 h after burn in H2 and B+H2 groups.The animals were sacrificed at 24 h after burn and lungs were removed for determination of wet/dry weight ratio (W/D rario),expression of autophagy-related microtubule-associated protein 1 light chain 3 (LC3) (by Western blot),activity of myeloperoxidase (MPO),and contents of interleukin-6 (IL-6) and high mobility group box 1 (HMGBI) (by enzyme-linked immunosorbent assay).The ratio of LC3-Ⅱ to LC3-Ⅰ expression (LC3-Ⅱ/LC3-Ⅰ) was calculated.The bronchoalveolar lavage fluid (BALF) was collected at 24 h after burn to detect the concentrations of IL-6 and HMGB1 and to count neutrophil.Results Compared with group SH,the W/D ratio,levels of LC3-Ⅱ/LC3-Ⅰ,MPO,IL-6 and HMGB1,concentrations of IL-6 and HMGB1 in BALF and neutrophil count were significantly increased at 24 h after scald in B and B+H2 groups (P＜0.05).Compared with group B,the W/D ratio,levels of LC3-Ⅱ/LC3-Ⅰ,MPO,IL-6 and HMGB1,concentrations of IL-6 and HMGBl in BALF and neutrophil count were significantly decreased at 24 h after scald in group B+H2 (P＜0.05).Conclusion Hydrogen can alleviate the lung injury in burned mice,and the mechanism is related to enhancing autophagy.

Analysis of 1 415 children's flexible bronchoscopy manifestation and characteristics / 中国小儿急救医学

Objective This retrospective study was based on 1 415 cases that had been done the flex-ible bronchoscopy examination.The data were analysed to investigate the value of flexible bronchoscope in the children's respiratory system diseases diagnosis,treatment and etiological study.Methods A total of 1 415 cases who admitted from June 2012 to December 2013 were included in the study and they were all met the inclusion criteria,had complete clinical data,done bronchoscope examinations,abnormal in the broncho-scope and diagnosed definitely.The endoscopic manifestation,clinical symptoms,X-ray film,laboratory data were analysed.Results In 1 415 cases,55.4% were boy,and 55.5% were younger than 5 years.Two cases (0.14%)were laryngeal cartilage soften,one case(0.07%)was epiglottic cyst,3 cases(0.21 %)were tra-cheomalacia,25 cases(1.8%)were bronchial foreign bodies,20 cases(1.4%)were tracheal bronchus de-formity,8 cases(5.7%)were tracheal stenosis,two cases(0.14%)were bronchial bridge,5 cases(0.35%) were bronchiolitis obliterans,6 cases (0.42%)were bronchiectasis,one case(0.07%)was immotile cilia syndrome,10 cases (0.71%)were bronchial tuberculosis,one case (0.07%)was aspergillosis,one case (0.07%)was pulmonary hemosiderosis,2 cases (0.14%)were pulmonary arteriovenous fistula,9 cases (0.63%)were plastic bronchitis,1 316 cases(93%)were founded tracheal intima inflammation,including the 350 cases(24.7%)of edema,mucosal folds form,279 cases(19.7%)of mucus plug obstruction,176 cases(12.4%)of suppurative obstruction,355 cases(25.1 %)of tracheal mucosal erosion necrosis,156 ca-ses(1 1.1 %)of wall fibrosis,stenosis,occlusion.Mycoplasma pneumoniae was the most common pathogen dectected in alveolar lavage.We also found that mycoplasma pneumonia easily combined the infection of bac-teria.A total of 1 19(22.7%)cases were no pathogens detected.In 1 415 cases,the main adverse reaction in the operations was hypoxemia caused by airway obstruction.Conclusion Flexible bronchoscopy examination is a very safe and reliable operation in diagnosis and treatment of respiratory diseases in pediat-rics,and plays an important role in the diagnosis of congenital developmental airway diseases,detection of pneumonia patho-gens and the treatment of lobe pneumonia.

Clinical feature,lung imaging and bronchoscope characteristics analysis of infant bronchial foreign body / 国际儿科学杂志

Objective To investigate the advantages of pediatric electronic fiber bronchoscope ( FBO) in the infant bronchial foreign body,discuss the clinical features of infant bronchial foreign body,lung imaging characteristics and the kinds of microscopically position,the change of airway mucosa after stimulation by for-eign body under local anesthesia in 30 cases of infant bronchial foreign body. Methods Thirty cases,aged 0 to 3 years,were collected from September to December,2014. All of them were with foreign bodies examined by FBO in pediatric bronchoscopy room in Shengjing Hospital of China Medical University. Results In all infants, 6 cases (20. 0%) without history of inhaled foreign bodies and 24 cases (80. 0%) with a record history of in-haled. In the aspects of signs:normal breath sounds with a history of no choking cough in children were 2 cases (6. 7%) ,wheezing sounds were 3 patients (10. 0%) and weakened side breath sound was 1 case (3. 3%);with a history of choking cough in children,6 cases(20. 0%) with normal breath sounds,12 cases(40. 0%) with wheez-ing,6 cases(20. 0%) with lateral breath sounds less. Lung imaging characteristics was lack of specific perform-ance:only a case of all(n=30)show foreign body directly. Otherwise,other 29 cases had no specificity. Lung em-physema in 13 cases (43. 3%) is the main characteristic,while normal imaging findings in 2 cases (6. 7%). For-eign bodies in 19 cases were in the left lung (63. 4%) and 21 cases(70. 0%) of foreign body stimulated granula-tion inside airway,necrosis sputum bolt in distal obstruction of airway occured in 5 cases (16. 7%). Inhalled time of foreign body in airway was 4. 5 [2. 8,12. 5] day and inhalled time of foreign body in airway correlation coefficient with granulation hyperplasia(r=0. 688,P=0. 000),there was a significant correlation. Main adverse reaction was low oxygen in 6 cases (16. 7%). Conclusion The diagnostic accuracy of FBO under local anesthesia on children is high-er than other methods,and the FBO bronchial foreign bodies under local anesthesia is a safe and effective method.