Yinchuan, China
Yinchuan, China

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Zhao H.,Genzyme | Karman J.,Genzyme | Jiang J.-L.,Genzyme | Zhang J.,Genzyme | And 9 more authors.
PLoS ONE | Year: 2013

Crosslinking ligand-engaged cytotoxic T lymphocyte antigen-4 (CTLA-4) to the T cell receptor (TCR) with a bispecific fusion protein (BsB) comprised of a mutant mouse CD80 and lymphocyte activation antigen-3 (LAG-3) has been shown to attenuate TCR signaling and to direct T-cell differentiation toward Foxp3+ regulatory T cells (Tregs) in an allogenic mixed lymphocyte reaction (MLR). Here, we show that antigen-specific Tregs can also be induced in an antigen-specific setting in vitro. Treatment of non-obese diabetic (NOD) female mice between 9-12 weeks of age with a short course of BsB elicited a transient increase of Tregs in the blood and moderately delayed the onset of autoimmune type 1 diabetes (T1D). However, a longer course of treatment (10 weeks) of 4-13 weeks-old female NOD animals with BsB significantly delayed the onset of disease or protected animals from developing diabetes, with only 13% of treated animals developing diabetes by 35 weeks of age compared to 80% of the animals in the control group. Histopathological analysis of the pancreata of the BsB-treated mice that remained non-diabetic revealed the preservation of insulin-producing β-cells despite the presence of different degrees of insulitis. Thus, a bifunctional protein capable of engaging CTLA-4 and MHCII and indirectly co-ligating CTLA-4 to the TCR protected NOD mice from developing T1D. © 2013 Zhao et al.


Li G.,Guangdong Laboratory Animals Monitoring Institute | Wu Y.,Guangdong Laboratory Animals Monitoring Institute | Jia H.,Guangdong Laboratory Animals Monitoring Institute | Tang L.,Guangdong Laboratory Animals Monitoring Institute | And 4 more authors.
Biology Open | Year: 2016

Tumor necrosis factor alpha (TNFα) plays a key role in the pathogenesis of rheumatoid arthritis (RA). Blockade of TNFα by monoclonal antibody has been widely used for the therapy of RA since the 1990s; however, its mechanism of efficacy, and potential safety concerns of the treatment are still not fully understood. This study sought to establish a transgenic arthritic mouse model by overexpressing human TNFα (hTNFα) and to apply this model as a means to evaluate therapeutic consequences of TNFα inhibitors. The transgenic mouse line (TgTC) with FVB background was generated by incorporating 3?-modified hTNFα gene sequences. A progressively erosive polyarthritis developed in the TgTC mice, with many characteristics observed in human rheumatoid arthritis, including polyarticular swelling, impairment of movement, synovial hyperplasia, and cartilage and bone erosion. Gene expression analysis demonstrated that hTNFα is not only expressed in hyperplastic synovial membrane, but also in tissues without lesions, including brain, lung and kidney. Treatment of the TgTC mice with anti-hTNFα monoclonal antibodies (mAb) significantly decreased the level of hTNFα in the diseased joint and effectively prevented development of arthritis in a dose-dependent response fashion. Our results indicated that the TgTC mice represent a genetic model which can be used to comprehensively investigate the pathogenesis and therapeutics of TNFα-related diseases. © 2016. Published by The Company of Biologists Ltd |.


PubMed | Guangdong Laboratory Animals Monitoring Institute and Livzon MabPharm Inc.
Type: Journal Article | Journal: Biology open | Year: 2016

Tumor necrosis factor alpha (TNF) plays a key role in the pathogenesis of rheumatoid arthritis (RA). Blockade of TNF by monoclonal antibody has been widely used for the therapy of RA since the 1990s; however, its mechanism of efficacy, and potential safety concerns of the treatment are still not fully understood. This study sought to establish a transgenic arthritic mouse model by overexpressing human TNF (hTNF) and to apply this model as a means to evaluate therapeutic consequences of TNF inhibitors. The transgenic mouse line (TgTC) with FVB background was generated by incorporating 3-modifiedhTNFgene sequences. A progressively erosive polyarthritis developed in the TgTC mice, with many characteristics observed in human rheumatoid arthritis, including polyarticular swelling, impairment of movement, synovial hyperplasia, and cartilage and bone erosion. Gene expression analysis demonstrated that hTNF is not only expressed in hyperplastic synovial membrane, but also in tissues without lesions, including brain, lung and kidney. Treatment of the TgTC mice with anti-hTNF monoclonal antibodies (mAb) significantly decreased the level of hTNF in the diseased joint and effectively prevented development of arthritis in a dose-dependent response fashion. Our results indicated that the TgTC mice represent a genetic model which can be used to comprehensively investigate the pathogenesis and therapeutics of TNF-related diseases.


Song Y.,Shenyang Pharmaceutical University | Huang Z.,Shenyang Pharmaceutical University | Song Y.,Jiangsu Hansoh Pharmaceutical Co. | Tian Q.,Shenyang Pharmaceutical University | And 5 more authors.
International Journal of Nanomedicine | Year: 2014

The applications of ethylenediaminetetraacetic acid (EDTA) have been expanded from the treatment of heavy metal poisoning to chelation therapies for atherosclerosis, heart disease, and cancers, in which EDTA reduces morbidity and mortality by chelating toxic metal ions. In this study, EDTA was used in a drug delivery system by adopting an NH4EDTA gradient method to load doxorubicin into liposomes with the goal of increasing therapeutic effects and decreasing drug-related cytotoxicity. The particle size of the optimum NH4EDTA gradient liposomes was 79.4±1.87nm, and the entrapment efficiency was 95.54%±0.59%. In vitro studies revealed that liposomes prepared using an NH4EDTA gradient possessed longterm stability and delayed drug release. The in vivo studies also showed the superiority of the new doxorubicin formulation. Compared with an equivalent drug dose (5mg/kg) prepared by (NH4)2SO4gradient, NH4EDTA gradient liposomes showed no significant differences in tumor inhibition ratio, but cardiotoxicity and liposome-related immune organ damage were lower, and no drug-related deaths were observed. These results show that use of the NH4EDTA gradient method to load doxorubicin into liposomes could significantly reduce drug toxicity without influencing antitumor activity. © 2014 Song et al.


PubMed | Jiangsu Hansoh Pharmaceutical Co., Livzon Mabpharm Inc. and Shenyang Pharmaceutical University
Type: | Journal: International journal of nanomedicine | Year: 2014

The applications of ethylenediaminetetraacetic acid (EDTA) have been expanded from the treatment of heavy metal poisoning to chelation therapies for atherosclerosis, heart disease, and cancers, in which EDTA reduces morbidity and mortality by chelating toxic metal ions. In this study, EDTA was used in a drug delivery system by adopting an NH4EDTA gradient method to load doxorubicin into liposomes with the goal of increasing therapeutic effects and decreasing drug-related cytotoxicity. The particle size of the optimum NH4EDTA gradient liposomes was 79.41.87 nm, and the entrapment efficiency was 95.54%0.59%. In vitro studies revealed that liposomes prepared using an NH4EDTA gradient possessed long-term stability and delayed drug release. The in vivo studies also showed the superiority of the new doxorubicin formulation. Compared with an equivalent drug dose (5 mg/kg) prepared by (NH4)2SO4 gradient, NH4EDTA gradient liposomes showed no significant differences in tumor inhibition ratio, but cardiotoxicity and liposome-related immune organ damage were lower, and no drug-related deaths were observed. These results show that use of the NH4EDTA gradient method to load doxorubicin into liposomes could significantly reduce drug toxicity without influencing antitumor activity.


Ding J.-K.,Livzon Mabpharm Inc. | Peng Y.-C.,Livzon Mabpharm Inc. | Deng Q.-C.,Livzon Mabpharm Inc. | He L.-X.,Livzon Mabpharm Inc. | And 3 more authors.
Chinese Journal of Biologicals | Year: 2014

Objective: To compare the performances of four alkaline-resistant protein A affinity chromatographic media and two small molecular affinity chromatographic media, and provide a reference for selection of purification procedure for monoclonal antibodies (mAbs). Methods: The dynamic binding capacities (DBCs) of four protein A affinity chromatographic media MabSelectSuRe, POROS MabCaptureA, Absolute High Cap and TOYOPEARL AF-rProtein A-650F as well as two small molecular affinity chromatographic media Mabsorbent A2P HF and Fabsorbent F1P HF were determined by plotting breakthrough curves of two purified monoclonal antibodies (mAb1 and mAb2) with retention times of 4, 6 and 8 min, respectively. The performance of these six affinity media, including recovery rate and removal of foreign matters, were further investigated with clarified cell culture supernatant containing mAb2. Results At 5% breakthrough point, the DBCs of these media were 35~73 g/L The recovery rate of mAb2 by Mabsorbent A2P HF was 89%, while those by other five media were not less than 96%. The residual host cell protein (HCP) contents in mAb2 purified by the six media were less than 2 000 ppm, while the residual protein A contents were less than 20 ppm. Conclusion: Taking into consideration of flow rate, DBC, recovery rate and removal of foreign matters, alkaline-resistant protein A or small molecular affinity chromatographic media suitable for downstream purification process of therapeutic antibodies may be selected from the six affinity chromatographic media.


The present invention provides a method for determining glycosylation and terminal modifications of immunoglobulin during immunoglobulin purification process, which can simultaneously and rapidly determine glycosylation, N-terminal pyroglutamination and C-terminal de-lysination of immunoglobulin. The method comprises: 1) separating immunoglobulin by using cation-exchange resin, and collecting different components in according to retention time; 2) denaturing the components of immunoglobulin obtained in step 1) with a denaturant, followed by reducing them with a reducing agent, to separate the light chain and heavy chain; 3) separating the light chain and heavy chain of immunoglobulin of step 2) by using reverse phase ultrahigh pressure liquid chromatography; 4) measuring the molecular weights of the light chain and heavy chain obtained in step 3) with mass spectrum; 5) analyzing the chromatographic data obtained in step 3) and the mass spectrometric data obtained in step 4) to determine glycosylation and terminal modifications of said immunoglobulin.


Patent
Livzon Mabpharm Inc. | Date: 2014-01-08

The present invention provides a humanized anti-TNF monoclonal antibody and the use thereof. The humanized anti-TNF monoclonal antibody significantly reduces the immunogenicity of murine-antibody while retaining the ability of antibody to recognize antigen, compared with conservative mouse chimeric antibody. Therefore, safety of the antibody in clinical applications has been improved.


The present invention provides a method for determining glycosylation and terminal modifications of immunoglobulin during immunoglobulin purification process, which can simultaneously and rapidly determine glycosylation, N-terminal pyroglutamination and C-terminal de-lysination of immunoglobulin. The method comprises: 1) separating immunoglobulin by using cation-exchange resin, and collecting different components in according to retention time; 2) denaturing the components of immunoglobulin obtained in step 1) with a denaturant, followed by reducing them with a reducing agent, to separate the light chain and heavy chain; 3) separating the light chain and heavy chain of immunoglobulin of step 2) by using reverse phase ultrahigh pressure liquid chromatography; 4) measuring the molecular weights of the light chain and heavy chain obtained in step 3) with mass spectrum; 5) analyzing the chromatographic data obtained in step 3) and the mass spectrometric data obtained in step 4) to determine glycosylation and terminal modifications of said immunoglobulin.

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