1.Progress on pharmacokinetic study of antibody-drug conjugates.
Jian-jun GUO ; Ran GAO ; Teng-fei QUAN ; Ling-yu ZHU ; Ben SHI ; Yong-yue ZHAO ; Jing ZHU ; Meng-sha LI ; Hai-zhi BU
Acta Pharmaceutica Sinica 2015;50(10):1203-1209
Antibody-drug conjugate (ADC) is a new class of therapeutics composed of a monoclonal antibody and small cytotoxin moieties conjugated through a chemical linker. ADC molecules bind to the target antigens expressed on the tumor cell surfaces guided by the monoclonal antibody component. The binding ADC molecules can be internalized and subsequently the toxin moieties can be released within the tumor cells via chemical and/or enzymatic reactions to kill the target cells. The conjugation combines the merits of both components, i.e., the high target specificity of the monoclonal antibody and the highly potent cell killing activity of the cytotoxin moieties. However, such complexities make the pharmacokinetic and metabolic studies of ADCs highly challenging. The major challenges should include characterization of absorption, distribution, metabolism and excretion, investigation of underlying mechanisms, assessment of pharmacokinetic- pharmacodynamic relationship, and analytical method development of ADC drugs. This review will discuss common pharmacokinetic issues and considerations, as well as tools and strategies that can be utilized to characterize the pharmacokinetic and metabolic properties of ADCs.
Antibodies, Monoclonal
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pharmacokinetics
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Cytotoxins
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pharmacokinetics
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Humans
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Immunoconjugates
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pharmacokinetics
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Neoplasms
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drug therapy
2.Construction of protein-protein interaction network of parkinson's disease associated proteins
Zhi-Quan XIAO ; Xia TANG ; Ji-Feng GUO ; Dan HE ; Lu SHEN ; Xin-Xiang YAN ; Bei-Sha TANG
Chinese Journal of Neuromedicine 2010;9(5):480-486
Objective To construct the protein-protein interaction network of Parkinson's disease (PD) associated proteins. Methods PD-related proteins and their interaction proteins were collected by bioinformatics method from HGNC, OPHID and UniHI database. A protein-protein interaction network of PD associated proteins was designed by ProteoLens software; each protein was evaluated by its contribution to the network and the relevance scores were calculated, thus the coefficient of association of each protein in the network was noted. Results A protein-protein interaction network containing 463 PD associated proteins and 767 their interaction proteins was obtained with its index aggregation reaching 90.5% (P=0.008). The relevance scores of SNCA, PARK2, DRD2, HTRA2,NDUFV2, DJ1, DRD1, DRD3, TRAP1 and ND3 were much higher than that of the others, which indicated their important roles in the pathogenesis of PD. The relevance scores of APP, UBE2I, CLIC6 and UBB were a little higher among all the preteins, indicating that they also participated in the pathogenesis of PD. Some novel proteins, such as FLNA, FREQ, BIRC7, EPB41, EPB41L1, GIPC1,GNAZ, GRB2, KCNJ9, MAPK1, BAG5 and CYC, may also involved in the pathogenesis of PD.Conclusion A scientific and practical protein-protein interaction network of PD associated proteins is successfully constructed, which further confirms the role of some proteins in the pathogenesis of PD.Some novel proteins that might involve in PD are obtained too.
3.Estrogen deficiency on growth of intracranial aneurysm in rats
Shuang-Quan WANG ; Chuan-Zhi DUAN ; Xiao-Dan JIANG ; Bin JI ; Mou-Xuan DU ; Sha XUE ; Peng ZHANG ; Zhi-Qiang FA ; Jian-Qi WANG
Chinese Journal of Neuromedicine 2009;8(12):1217-1220
Objective To construct an aneurismal model with estrogen deficiency and investigate the mechanism of estrogen deficiency in the formation and development of intracranial aneurysm. Methods Female Wistar rats were randomly divided into experimental, sham-operative and blank control groups (n=10). Rats in the experimental group were ovariectomized and those in the sham-operative group were removed the adipose issue nearby the ovary only; while the rats in the blank control group were done nothing. Two weeks after the ovariectomized or sham operation, elastase dropped around the right external carotid artery and the crotch of the carotid artery and the carotid artery was ligated by two lines at 1.5 mm far from the crotch, and then sheared between the two lines to successfully induce the aneurysm. At 6 weeks of the successful construction of aneurysm model, the estrogen was detected and the aneurysm was harvested for pathological staining. Results The experimental group showed a lower estrogen level (105.00±12.96 pmol/L) than the sham-operative group (178.50±25.96 pmol/L) and the blank control group (180.40±18.70 pmol/L, P<0.05). Aneurismal length dilatation rates in the experimental group and the sham-operative group were (131.31±6.63)% and (109.90±3.44) %, respectively (P<0.05). Aneurismal diameter dilatation rates in the experimental group and sham-operative group were (125.10±5.49) % and (106.82±2.49) %, respectively (P<0.05). Conclusion Estrogen deficiency may promote the formation and development of the intracranial aneurysm. This experiment provides a simple model for investigating the relationship between estrogen deficiency and aneurysm development.
4.Effect of endogeneous gangliosides on integrin alpha2beta1-mediated adhesion of neuroblastoma cells to collagen.
Zhi-Ping LIU ; Fei-Qiu WEN ; Yi-Xin CHEN ; Sha-Yan WANG ; Ke-Ying ZHOU ; Quan XIA
Chinese Journal of Contemporary Pediatrics 2007;9(1):42-46
OBJECTIVETo study the effect of endogeneous gangliosides (Gls) on integrin alpha2beta1-mediated adhesion of neuroblastoma cells to collagen (Col).
METHODSNeuroblastoma SK-N-SH cell line was cultured in the modified eagle's medium with the presence of 10 mum D-threo-1-phenyl-2-decanolamino-3-morphinolin-1-propanol (D-PDMP), an inhibitor of glucosylceramide synthase. Flow cytometry was used to detect the expression of integrin alpha2beta1 in the cell line. The effects of Mg2(+) and monoclonal antibodies to integrin alpha2beta1 on the adhesion of the cell line to immobilized Col were observed. The adhesion cell number was measured with the BCA method and presented with absorptance A570.
RESULTSThere was a high expression of integrin alpha2beta1 in the SK-N-SH cell line without D-PDMP treatment. Endogenous Gls in the cells were almost depleted after 6-day exposure to D-PDMP, but the integrin alpha2beta1 expression was not significantly changed. 1 mmoL/L Mg2(+) treatment increased significantly the number of adhesion cells in the SK-N-SH cell line. The adhesion to Col of the SK-N-SH cells exposed to D-PDMP which Gls was depleted was significantly reduced compared with the control SK-N-SH cells treated with 1 mmoL/L Mg2(+) (A570: 0.33 +/- 0.016 vs 0.57 +/- 0.033; P < 0.01). After endogeneous Gls was added into the Gls-depleted SK-N-SH cells, the adhesion of the cells was restored (A570: 0.52 +/- 0.035). The adhesion of SK-N-SH cells was significantly blocked by anti-alpha2 and anti-beta1 monoclonal antibodies, with A570 of 0.31 +/- 0.018 and 0.36 +/- 0.021 respectively.
CONCLUSIONSEndogenous tumor Gls increases neuroblastoma cell adhesion to Col by regulating the function of integrin alpha2beta1, but has no effects on the integrin expression. It is suggested that tumor Gls may play a role in migration, invasion and metastasis of tumor cells.
Antibodies, Monoclonal ; immunology ; Cell Adhesion ; Cell Line, Tumor ; Collagen ; physiology ; Gangliosides ; physiology ; Humans ; Integrin alpha2beta1 ; physiology ; Magnesium ; pharmacology ; Morpholines ; pharmacology ; Neuroblastoma ; pathology
5.Effect of N-acetyl-cysteine and depakine pretreatment on ferrous chloride-induced membrane potential and peroxidate changes in rat cortex neurons.
Yuan-xiang LIN ; Ru-xiang XU ; Xiao-dan JIANG ; De-zhi KANG ; Yi-quan KE ; Mou-xuan DU ; Ying-qian CAI ; Ling-sha QIN
Journal of Southern Medical University 2006;26(4):448-451
OBJECTIVETo investigate the effect of N-acetyl-cysteine (NAC) and depakine (DP) on the changes of membrane potential and peroxidate in rat cortex neurons exposed to ferrous chloride (FeCl(2)).
METHODSCultured cortex neurons of newly born SD rats were randomly divided into control group (PBS group), model group (FeCl(2) group), NAC pretreatment group (NAC group), DP pretreatment group (DP group) and NAC+DP pretreatment group (NAC+DP group). In the latter three groups, NAC (0.08 mg/ml) and DP (0.1 mg/ml) were added in the cell culture 2 and 3 h before FeCl(2) (1 mmol/L) exposure, respectively. After exposure to FeCl(2), the membrane potential of the neurons was detected with fluorescent dye DiBAC4(3) (bis-(1,3-dibutylbarbituric acid) trimethine oxonol), and the peroxidate level with 2,7-dichlorofluorescin diacetate (H(2)DCF) by laser confocal scanning microscope (LCSM) and nuclear factor-KappaB (NF-KappaB) level with immunocytochemistry.
RESULTSCompared with FeCl(2) group, the expression of NF-KappaB and peroxidate level in the neurons were decreased significantly in NAC and NAC+DP groups (P<0.01), but not in DP group (P>0.05). FeCl(2) depolarized the membrane potential and increased the expression of NF-KappaB in the neurons. Compared with FeCl(2) group, significant changes in the membrane potential were observed in DP and NAC+DP groups (P<0.01) but not in NAC or PBS group (P>0.05).
CONCLUSIONBoth NAC and DP can protect the neurons from FeCl(2)-induced damage but through different pathways, and their combined use can significantly alleviate neuronal damages due to FeCl(2) exposure. Antioxidants such as NAC in combination with antiepileptic drugs may produce favorable effect in prevention and treatment of posttraumatic epilepsy.
Acetylcysteine ; pharmacology ; Animals ; Animals, Newborn ; Cells, Cultured ; Cerebral Cortex ; cytology ; metabolism ; physiopathology ; Female ; Ferrous Compounds ; pharmacology ; Male ; Membrane Potentials ; drug effects ; Neurons ; cytology ; metabolism ; physiology ; Neuroprotective Agents ; pharmacology ; Peroxides ; metabolism ; Rats ; Rats, Sprague-Dawley ; Valproic Acid ; pharmacology
6.Mutation analysis of ATP13A2 gene in Chinese patients with familial autosomal recessive early-onset parkinsonism.
Dan HE ; Ji-feng GUO ; Lei WANG ; Zhi-quan XIAO ; Li-luo NIE ; Xue-wei ZHANG ; Bei-sha TANG
Chinese Journal of Medical Genetics 2009;26(5):567-570
OBJECTIVETo investigate the mutation characteristics of ATP13A2 gene in Chinese patients with familial autosomal recessive early-onset parkinsonism (AREP).
METHODSMutations of ATP13A2 gene were screened by polymerase chain reaction combined with DNA direct sequencing in patients with familial AREP.
RESULTSNo pathogenic mutations in ATP13A2 gene were detected in this group. Six reported polymorphisms were identified. They were IVS6+70A>G, IVS12+66A>G, m.1849C>T, IVS20-56 G>A, m2671C>T and m2824G>A.
CONCLUSIONATP13A2 gene mutations may be rare in Chinese patients with familial autosomal recessive early-onset parkinsonism.
Adult ; Age of Onset ; Asian Continental Ancestry Group ; genetics ; Base Sequence ; China ; epidemiology ; DNA Mutational Analysis ; Female ; Humans ; Male ; Middle Aged ; Molecular Sequence Data ; Mutation ; Parkinsonian Disorders ; epidemiology ; genetics ; Pedigree ; Polymorphism, Genetic ; Proton-Translocating ATPases ; genetics
7.Disease gene screening of known loci in a Chinese family with autosomal dominant retinitis pigmentosa.
Wei LIU ; Fang LU ; Li-feng QIA ; Zhi-quan SHA ; Xia-oqi LIU ; Shi MA ; Xin TANG ; Jin-xia CHANG ; Zheng-lin YANG ; Bin YE
Chinese Journal of Medical Genetics 2009;26(1):70-73
OBJECTIVETo map the disease-causing gene in a Chinese family with autosomal dominant retinitis pigmentosa.
METHODSTwenty-seven micro-satellite markers were randomly selected from the region around the known loci of causative genes, and haplotypes were determined by ABI3100 genetic analyzer. Two-point linkage analysis was performed using MLINK.
RESULTSThe Lod score of each marker vs adRP was below 1.
CONCLUSIONThe phenotype of this family may not be caused by mutation of the known disease-causing genes.
Asian Continental Ancestry Group ; genetics ; China ; Female ; Genes, Dominant ; Genetic Linkage ; Genetic Testing ; Humans ; Male ; Microsatellite Repeats ; genetics ; Mutation ; Pedigree ; Phenotype ; Retinitis Pigmentosa ; diagnosis ; genetics ; pathology
8.Feasibility of local LINGO-1 polyclonal antibody treatment for spinal cord injury in adult rats
Jun L(U) ; Ru-Xiang XU ; Zhi-Qiang FA ; Xiao-Dan JIANG ; Xin LU ; Yi-Quan KE ; Ying-Qian CAI ; Mou-Xuan DU ; Yu-Xi ZOU ; Ling-Sha QIN
Chinese Journal of Neuromedicine 2009;8(5):476-478,483
Objective To analyze the feasibility of local LINGO-1 polyclonal antibody administration for treatment of spinal cord injury in adult rats. Methods Twenty-four adult female SD rats were randomized into sham-operated group, rabbit IgG group and LINGO-1 antibody group. In the latter two groups, partial transaction of the T9 segment of the spinal cord was performed to completely sever the dorsal eorticospinal tract, followed immediately by administration of rabbit IgG and anti-LINGO polyclonal antibody via a mini-osmotic pump, respectively. At 3 and 28 days after the operation, the T8~10 segments of the spinal cord were harvested to prepare cryosections, and immunofluorescence staining was used to analyze the penetration of LINGO-1 polyclonal antibody into the spinal cord tissue and its specific binding to LINGO-1 molecules. Results In LINGO-1 antibody group, the presence of rabbit antibodies was detected at the injured sites of the spinal cord at 3 and 28 days after the operation. The mean immunofluorescence density was significantly lower in L1NGO-1 antibody group than in rabbit IgG group at 3 days after the operation (P<0.05). In rabbit IgG group, the mean immunofluorescence density for LINGO-1 in the crysections pre-treated with LINGO-1 polyclonal antibody was significantly lower than that in sections pre-treated with rabbit IgG(P<0.05). Conclusion Locally administered LINGO-1 polyclonal antibody can penetrate into the injured sites in the spinal cord in a wide time window and recognizes LINGO-1 molecule specifically, suggesting the feasibility of passive immunotherapy for spinal cord injury.
9.Analysis of prognosis factors of craniocerebral traffic injuries
Ru-Xiang XU ; Peng ZHANG ; Xiao-Dan JIANG ; Cheng-Yi LUO ; Yi-Quan KE ; Shi-Zhong ZHANG ; Chuan-Zhi DUAN ; Xiang-Yu WANG ; Qing-Hua WANG ; Sha XUE
Chinese Journal of Neuromedicine 2009;8(11):1127-1130
Objective To explore the clinical factors affecting the prognosis of craniocerebral traffic injuries to provide scientific evidence for ameliorating the prognosis. Methods We retrospectively analyzed the clinical data of 652 patients treated in our hospital for serious injuries in car accidents (Glascow Coma score [GCS] 3~8) between February, 1998 and February, 2008. According to the Glasgow Outcome Scale (GOS) three months after injury, patients were divided into good prognosis and poor prognosis groups. Their gender, age, type of brain injury, admission time, pupil status, blood oxygen saturation, systolic blood pressure, level of blood sugar, Injury Severity Score (ISS) and GCS were compared. Results As compared with the good prognosis group, the poor prognosis group showed a significant low level of blood oxygen saturation and systolic blood pressure, low GCS and pupils status score (P<0.05);it showed a long admission time, a significant high level of blood sugar and high ISS (P<0.05). Bad prognosis appeared in intracranial hematoma, contusion and laceration of the brain. And the level of blood sugar and oxygen, GCS and ISS were the independent factors affected the prognosis. Conclusion The level of oxygen saturation and blood sugar, ISS and GCS can help to evaluate the prognosis of patients with severe brain injury, effectively.