1.Biotherapy of cancer by anti-EGFR monoclonal antibody.
Jing WANG ; Zhi-Yun MENG ; Sou-Ting FU ; Gui-Fang DOU
Journal of Experimental Hematology 2007;15(5):1135-1138
Epidermal growth factor receptor (EGFR) is mutated, dysregulated or overexpressed in many epithelial malignancies, and EGFR activation has been found to be important in tumor growth and progression. Anti-EGFR monoclonal antibodies target the extracellular domain of EGFR; and show promising anti-tumor potential at clinical trials without severe side effects. In this article the pharmacokenetics and clinical study of 3 anti-EGFR monoclonal antibodies (cetuximab, panitumumab and nimotuzomab) were reviewed.
Antibodies, Monoclonal
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pharmacokinetics
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therapeutic use
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Antibodies, Monoclonal, Humanized
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Antineoplastic Agents
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therapeutic use
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Cetuximab
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Humans
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Neoplasms
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therapy
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Receptor, Epidermal Growth Factor
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antagonists & inhibitors
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immunology
2.Phase I safety and pharmacokinetic study of bevacizumab in Chinese patients with advanced cancer.
Jian-Yu WU ; Xiao-Nan WU ; Li DING ; Yun-Bo ZHAO ; Bin AI ; Yang LI ; Xin HU ; Gang CHENG
Chinese Medical Journal 2010;123(7):901-906
BACKGROUNDbevacizumab is a humanized recombinant vascular endothelial growth factor (VEGF) monoclonal antibody, which specifically binds to VEGF and inhibits tumor cell growth, proliferation and metastasis. We aimed to investigate the safety and pharmacokinetics of bevacizumab in Chinese patients with advanced cancer.
METHODSThirty-nine Chinese patients with metastatic or relapsed cancers who failed prior therapy were enrolled in this phase I study of bevacizumab. Bevacizumab was infused by a calculated pump at doses from 5 mg/kg to 15 mg/kg in 90 minutes. Patients underwent serial pharmacokinetic evaluations. Patients that received at least one infusion of bevacizumab were included in the safety study.
RESULTSThirty-five patients finished all 5 infusions following protocol. One patient withdrew after 3 infusions due to grade 3 proteinuria. Common adverse events possibly related to the study drug were proteinuria (17/39, 43.6%), hypertension (13/39, 33.3%), gingival bleeding (7/39, 17.9%), epistaxis (6/39, 15.4%), pharyngeal inflammation (6/39, 15.4%), fatigue (6/39, 15.4%) and stomatitis (4/39, 10.3%). Bevacizumab pharmacokinetics was linear within the range of 5 mg/kg q2w--10 mg/kg q2w and 15 mg/kg q3w. CL (clearance), Vd (volume of distribution at elimination) and Vss (volume of distribution at steady state) were similar after single and multiple doses at 5, 10 and 15 mg/kg.
CONCLUSIONSBevacizumab is well tolerated in Chinese patients. No unexpected adverse events were observed. There is no racial difference in the pharmacokinetics.
Adult ; Aged ; Angiogenesis Inhibitors ; adverse effects ; pharmacokinetics ; therapeutic use ; Antibodies, Monoclonal ; adverse effects ; pharmacokinetics ; therapeutic use ; Antibodies, Monoclonal, Humanized ; Asian Continental Ancestry Group ; Bevacizumab ; Female ; Humans ; Male ; Middle Aged ; Neoplasms ; drug therapy
3.Glycosylation engineering of therapeutic IgG antibodies: challenges for the safety, functionality and efficacy.
Yusuke MIMURA ; Toshihiko KATOH ; Radka SALDOVA ; Roisin O'FLAHERTY ; Tomonori IZUMI ; Yuka MIMURA-KIMURA ; Toshiaki UTSUNOMIYA ; Yoichi MIZUKAMI ; Kenji YAMAMOTO ; Tsuneo MATSUMOTO ; Pauline M RUDD
Protein & Cell 2018;9(1):47-62
Glycosylation of the Fc region of IgG has a profound impact on the safety and clinical efficacy of therapeutic antibodies. While the biantennary complex-type oligosaccharide attached to Asn297 of the Fc is essential for antibody effector functions, fucose and outer-arm sugars attached to the core heptasaccharide that generate structural heterogeneity (glycoforms) exhibit unique biological activities. Hence, efficient and quantitative glycan analysis techniques have been increasingly important for the development and quality control of therapeutic antibodies, and glycan profiles of the Fc are recognized as critical quality attributes. In the past decade our understanding of the influence of glycosylation on the structure/function of IgG-Fc has grown rapidly through X-ray crystallographic and nuclear magnetic resonance studies, which provides possibilities for the design of novel antibody therapeutics. Furthermore, the chemoenzymatic glycoengineering approach using endoglycosidase-based glycosynthases may facilitate the development of homogeneous IgG glycoforms with desirable functionality as next-generation therapeutic antibodies. Thus, the Fc glycans are fertile ground for the improvement of the safety, functionality, and efficacy of therapeutic IgG antibodies in the era of precision medicine.
Animals
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Antibodies, Monoclonal
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adverse effects
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pharmacokinetics
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therapeutic use
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Glycosylation
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Humans
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Immunoglobulin G
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chemistry
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metabolism
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Protein Engineering
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methods
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Receptors, Fc
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chemistry
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metabolism
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Treatment Outcome
4.A novel therapeutic anti-HBV antibody with increased binding to human FcRn improves in vivo PK in mice and monkeys.
Ciming KANG ; Lin XIA ; Yuanzhi CHEN ; Tianying ZHANG ; Yiwen WANG ; Bing ZHOU ; Min YOU ; Quan YUAN ; Chi-Meng TZENG ; Zhiqiang AN ; Wenxin LUO ; Ningshao XIA
Protein & Cell 2018;9(1):130-134
5.The Long-term Clinical Results of a Platelet Glycoprotein IIb/IIIa Receptor Blocker (Abciximab: ReoPro (R) ) Coated Stent in Patients with Coronary Artery Disease.
Weon KIM ; Myung Ho JEONG ; Young Joon HONG ; Seng Hyun LEE ; Woo Seok PARK ; Ju Han KIM ; In Soo KIM ; Myung Ja CHOI ; Young Keun AHN ; Jeong Gwan CHO ; Jong Chun PARK ; Dong Lyun CHO ; Hoon KIM ; Jung Chaee KANG
The Korean Journal of Internal Medicine 2004;19(4):220-229
BACKGROUND: Previously, the inhibition of coronary restenosis with Abciximab (ReoPro (R) ) -coated stent in a porcine model was reported. ReoPro (R) inhibits platelet aggregation, the proliferation of vascular smooth muscle cells and the inflammatory reaction. METHODS: A prospective randomized trial was performed to compare two types of stent for revascularization in the native coronary artery. The primary effective end points were major adverse coronary events (MACE) : cardiac death, acute myocardial infarction, target vessel revascularization (TVR) and restenosis at the 6-month clinical and angiographic follow-ups. RESULTS: One hundred and fifty-five patients were enrolled between August 2001 and June 2003. The mean ages (56.0 +/- 10.0 vs. 56.9 +/- 10.8 years), baseline diameter of stenosis and minimal luminal diameter were no different between the two groups. There was one myocardial infarction and revascularization during the hospital stay in control stent group. During the clinical follow-up there were two myocardial infarctions in control group. Follow-up coronary angiograms were performed in 62.3% (48/77) and 65.4% (51/78) of the coated and control groups, respectively. The diameter of stenosis and late loss were significantly less in the ReoPro (R) -coated stent group compared with the controls (16.4 +/- 5.8% vs. 34.3 +/- 6.1%, p=0.009; and 0.33 +/- 0.28 mm vs. 0.88 +/- 0.41 mm; p=0.002). The restenosis and TVR rates of the ReoPro (R) -coated stent were relatively lower compared with the control stent [14.6% (7/48) vs. 29.4% (15/51), p=0.062; and 9.2% (7/76) vs. 14.7% (11/75) ; p=0.327]. CONCLUSION: A ReoPro (R) -coated stent is safe, and may be effective in the prevention of coronary restenosis.
Antibodies, Monoclonal/pharmacokinetics/*therapeutic use
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Coated Materials, Biocompatible/pharmacokinetics/*therapeutic use
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Coronary Arteriosclerosis/*surgery
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Coronary Restenosis/epidemiology/prevention & control
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Female
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Humans
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Immunoglobulins, Fab/*therapeutic use
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Korea/epidemiology
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Male
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Middle Aged
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Platelet Aggregation Inhibitors/pharmacokinetics/*therapeutic use
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Platelet Glycoprotein GPIIb-IIIa Complex/antagonists & inhibitors
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Prospective Studies
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Research Support, Non-U.S. Gov't
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*Stents
6.Research progress of polyamidoamine dendrimer in targeting drug delivery system.
Rong-min DING ; Hua HE ; Juan LI
Acta Pharmaceutica Sinica 2011;46(5):493-501
Targeting drug delivery system (TDDS) is one of the most concerned research fields in cancer treatment because it can bind selectively and react with the target diseased sites at the cellular or sub-cellular level, making distribution and release of drugs in a controlled manner, thus enhance therapeutic effects and reduce toxic and side-effects on normal cells. Polyamidoamine dendrimer (PAMAMD) is a kind of newly developed polymer in nanometer degree. Hyper-branched, monodispersity, three-dimensional structure and host-guest entrapment ability make it used as drug carrier, gene delivery system and imaging agent. Various targeting ligands, which have high affinity to specific organs, tissues or cells in human body, can be linked to surface functional groups of PAMAMD. And drugs and theoretical gene are carried by encapsulation or chemical conjugation. Finally, PAMAMD targeting drug delivery system can carry drugs and theoretical gene to diseased sites and then release them for targeted therapy. The PAMAMD-based conjugates have small size, ligh permeability and retention effect (EPR), low toxicity and so on. The research progress of PAMAMD modified by different ligands in targeting drug delivery system is reviewed, and research direction of the PAMAMD targeting delivery system in the future is also suggested.
Amino Acids
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administration & dosage
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chemistry
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Animals
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Antibodies, Monoclonal
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administration & dosage
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chemistry
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Antineoplastic Agents
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administration & dosage
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therapeutic use
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Biotin
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administration & dosage
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chemistry
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Dendrimers
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administration & dosage
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chemistry
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Drug Carriers
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administration & dosage
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chemistry
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Drug Delivery Systems
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Folic Acid
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administration & dosage
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chemistry
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Gene Transfer Techniques
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Humans
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Ligands
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Neoplasms
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drug therapy
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Polyamines
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administration & dosage
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chemistry
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pharmacokinetics
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Polyethylene Glycols
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administration & dosage
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chemistry
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Transferrin
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administration & dosage
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chemistry
7.Application of anti-CD103 immunotoxin for saving islet allograft in context of transplantation.
Chinese Medical Journal 2010;123(24):3644-3651
BACKGROUNDPrevious studies using knockout mice document a key role for the integrin CD103 in promoting organ allograft rejection and graft-versus-host disease. However, a determination of whether blockade of the CD103 pathway represents a viable therapeutic strategy for intervention in these processes has proven problematic due to the lack of reagents that efficiently deplete CD103(+) cells from wild type hosts. To circumvent this problem, in the present study, we invented an anti-CD103 immunotoxin (M290-SAP). We investigated whether M290-SAP has capacity to eliminate CD103-expressing cells in vivo and protect transplanted islets from destroying by host immune cells.
METHODSFlow cytometry was used to analyze the efficacy of M290-SAP in depleting CD103-expressing cells in vivo. Then using allogenic islet transplantation models as well as NOD mice with recent onset type 1 diabetes, the therapeutic efficacy of CD103-expressing cell depletion was addressed.
RESULTSM290-SAP dramatically reduces the frequency and absolute numbers of CD103-expressing leukocytes in peripheral lymphatic tissues of treated mice. Balb/c islets transplanted into streptozotocin-induced diabetic C57BL/6 mice under single M290-SAP treatment showed an indefinite survival time compared with untreated mice, M290-treated mice and IgG-SAP treated mice (mean survival time, > 100 days vs. < 20 days). C57BL/6 islets transplanted into hyperglycemic NOD mice under single M290-SAP treatment showed a pronounced delay in allograft rejection compared with untreated mice (mean survival time 12 - 13 days vs. < 7 days). Immunological analysis of mice with long-term islet allograft survival revealed an obvious atrophy thymus and severe downregulation of alloimmunity of CD8 subpopulation response to allogenic stimulation.
CONCLUSIONRegardless of the underlying mechanisms, these data document that depletion of CD103-expressing cells represents a viable strategy for therapeutic intervention in islet allograft rejection.
Animals ; Antibodies, Monoclonal ; pharmacokinetics ; therapeutic use ; toxicity ; Antigens, CD ; analysis ; Female ; Graft Rejection ; prevention & control ; Graft Survival ; drug effects ; Integrin alpha Chains ; analysis ; antagonists & inhibitors ; Islets of Langerhans Transplantation ; immunology ; mortality ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mice, Inbred NOD ; Thymocytes ; classification ; drug effects ; Transplantation, Homologous