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Showing 1 to 9 of 9 (0.103 seconds)Spelling suggestions: "subject:"neutralizing antibody"" "subject:"meutralizing antibody""
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HIV-1/SIV Neutralizing Antibody Gene Delivery: A Novel Vaccination ApproachZhang, Jian Chao 26 June 2009 (has links)
No description available.
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The Role of Ykl-40, a Secreted Heparin-Binding Glycoprotein, in Tumor Angiogenesis, Metastasis, and Progression: a Potential Therapeutic TargetFaibish, Michael 01 January 2010 (has links) (PDF)
A new concept quickly gaining ground in the field of cancer research is that the inflammatory process plays a key role in cancer development and metastasis; however, the molecular mechanisms of such an involvement in cancer progression remain largely unspecified. YKL-40, also known as human cartilage glycoprotein 39, is a secreted heparin-binding protein with ties to both cancers and inflammatory disease. In these diseases, YKL-40 has been suggested to play a role in regulating tissue and extracellular matrix remodeling. It has been found that in certain cancers, including breast, colorectal and brain, that high YKL-40 serum levels correlate with poor outcome, and consequently it may serve as a biomarker. Our recent study has shown that tumor-derived YKL-40 acts as an angiogenic factor due to its ability to up-regulate vessel formation and metastasis during tumor development. However, blockade of the function of YKL-40, which implicates therapeutic value, has not been explored yet.
The goal of this project was to better understand the importance of tumor-derived YKL-40 in angiogenesis through both functional and structural studies. By establishing a monoclonal YKL-40 antibody for blocking YKL-40, the function of tumor-derived YKL-40 in inducing endothelial cell angiogenesis and tumor cell survival was uncovered, confirming YKL-40's importance in tumor signaling as well as offering evidence in the benefit of its neutralization. Additionally, a postulated heparin-binding domain on YKL-40 was mutated in hopes of revealing the relevance of this binding ability on YKL-40's function and whether this could serve as a target in inhibiting YKL-40 signaling.
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Model Membranes Study the Lipid-Reactivity of HIV-1 Antibodies and Vaccine AntigenHardy, Gregory January 2014 (has links)
<p>One promising HIV-1 vaccine target is the membrane-proximal external region (MPER) of viral gp41. MPER is poorly immunogenic, however, the two rare neutralizing antibodies (NAbs), 2F5 and 4E10, bind to MPER with great neutralizing ability. Although their neutralizing mechanism represents a promising framework for the design of new HIV-1 liposomal vaccine candidates, this mechanism remains poorly understood. It is known that 2F5 and 4E10 are required to first associate with HIV-1 lipids before binding to the target MPER antigen, however, little is known about how lipid membranes contribute to NAb-antigen binding. To this end we have developed model membrane systems to study NAb and antigen lipid interactions. </p><p>We first created a surface plasmon resonance (SPR) spectroscopy based assay that monitors antibody binding to thiol monolayers, which mimic the surface chemical properties of lipid membranes. Next, we focused on mimicking the lipid phase organization (i.e., domain formation) of native membranes by using supported lipid bilayers (SLBs). We used simple SLB compositions to model the liquid-disordered (Ld) and gel phases. To model the HIV-1 envelope, we used a complex SLB composition that contains an Ld and liquid-ordered (Lo) phase. To reliably create model HIV-1 SLBs, we developed an SLB formation technique that uses amphipathic, α-helical peptides as a catalyst to generate complex SLBs that have a high cholesterol content and contain multiple lipid types. For all SLB surfaces we used atomic force microscopy (AFM) to visualize membrane domains, antigen presentation, and antibody-membrane interactions.</p><p>Results from experiments using thiol surfaces showed that NAb binding to hydrophobic thiol surfaces was significantly greater than that of control monoclonal antibodies. This supports the hypothesis that these NAbs embed into the hydrophobic membrane core. Our results demonstrate that 2F5/4E10 do not interact with the highly ordered gel and Lo domains in the SLB but exclusively bind to the Ld phase. This suggests that 2F5/4E10 require low membrane order and weak lateral lipid-lipid interactions to insert into the hydrophobic membrane interior. Thus, vaccine liposomes that primarily contain an Ld phase are more likely to elicit the production of lipid reactive, 2F5- and 4E10-like antibodies, compared to liposomes that contain an Lo or gel phase. In the context of liposomal antigen presentation, our results show that the presence of the MPER656 antigen can severely limit the Ld area available for antibody interactions. Subsequently, this reduces the amount of MPER656 that is accessible for 2F5/4E10 binding, since MPER656 preferentially localizes to the Ld area. If Ld forming lipid components are used in vaccine liposomes, it is important to ensure that the presence of antigen does not inhibit large-scale Ld formation.</p> / Dissertation
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Differential Responses of MET Activations to MET kinase Inhibitor and Neutralizing AntibodyKou, Jianqun, Musich, Phillip R., Staal, Ben, Kang, Liang, Qin, Yuan, Yao, Zhi Q., Zhang, Boheng, Wu, Weizhong, Tam, Angela, Huang, Alan, Hao, Huai Xiang, Vande Woude, George F., Xie, Qian 12 September 2018 (has links)
Background: Aberrant MET tyrosine kinase signaling is known to cause cancer initiation and progression. While MET inhibitors are in clinical trials against several cancer types, the clinical efficacies are controversial and the molecular mechanisms toward sensitivity remain elusive. Methods: With the goal to investigate the molecular basis of MET amplification (MET amp ) and hepatocyte growth factor (HGF) autocrine-driven tumors in response to MET tyrosine kinase inhibitors (TKI) and neutralizing antibodies, we compared cancer cells harboring MET amp (MKN45 and MHCCH97H) or HGF-autocrine (JHH5 and U87) for their sensitivity and downstream biological responses to a MET-TKI (INC280) and an anti-MET monoclonal antibody (MetMab) in vitro, and for tumor inhibition in vivo. Results: We find that cancer cells driven by MET amp are more sensitive to INC280 than are those driven by HGF-autocrine activation. In MET amp cells, INC280 induced a DNA damage response with activation of repair through the p53BP1/ATM signaling pathway. Although MetMab failed to inhibit MET amp cell proliferation and tumor growth, both INC280 and MetMab reduced HGF-autocrine tumor growth. In addition, we also show that HGF stimulation promoted human HUVEC cell tube formation via the Src pathway, which was inhibited by either INC280 or MetMab. These observations suggest that in HGF-autocrine tumors, the endothelial cells are the secondary targets MET inhibitors. Conclusions: Our results demonstrate that MET amp and HGF-autocrine activation favor different molecular mechanisms. While combining MET TKIs and ATM inhibitors may enhance the efficacy for treating tumors harboring MET amp , a combined inhibition of MET and angiogenesis pathways may improve the therapeutic efficacy against HGF-autocrine tumors.
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Mechanism of Maternal Antibody Inhibition and Vaccination Strategies in the presence of Maternal AntibodiesKim, Dhohyung 19 June 2012 (has links)
No description available.
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Development of novel bioassay for the measurement of bioactive insulin-like growth factors in blood samples and treatment strategy targeting the bioactive insulin-like growth factors for non-islet cell tumor hypoglycemia / 血中活性型インスリン様増殖因子を測定する新たなバイオアッセイの開発および非膵島細胞腫瘍性低血糖に対する活性型インスリン様増殖因子を分子標的とした治療戦略Setoyama, Takeshi 25 January 2016 (has links)
京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19399号 / 医博第4050号 / 新制||医||1012(附属図書館) / 32424 / 京都大学大学院医学研究科医学専攻 / (主査)教授 長船 健二, 教授 川口 義弥, 教授 小川 誠司 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM
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Refocusing antibody responses by chemical modification of vaccine antigensSchiffner, Torben January 2014 (has links)
The envelope glycoprotein (Env) of Human Immunodeficiency Virus 1 (HIV-1) has developed several immune-evasion mechanisms to avoid the induction of neutralising antibodies, including immunodominant non-neutralising epitopes, conformational flexibility of conserved epitopes, and spontaneous subunit dissociation, thus impeding vaccine development. Here, chemical modification of Env-based vaccine antigens is explored to overcome these obstacles. Firstly, covalent fixation of Env by chemical cross-linking was used to stabilise the conformationally flexible structure and prevent subunit dissociation. Cross-linked Env constructs showed reduced binding of many non-neutralising antibodies whilst largely maintaining antibody recognition by broadly neutralising antibodies. Compared to unmodified material, immunisation with some of these cross-linked proteins led to the induction of significantly increased antibody titres targeting the conserved CD4 binding site of Env despite similar overall antibody titres. These refocused antibody responses resulted in increased serum neutralising titres compared to animals receiving unmodified protein. Secondly, an epitope masking strategy was developed to reduce or eliminate the immunogenicity of neutralisation-irrelevant surfaces. This was achieved using site-selective addition of theoretically immunosilent glycoconjugates to lysine residues. Masking of model protein hen egg lysozyme (HEL) led to site-selective loss of antibody binding to the modification sites in vitro, which translated into refocusing of antibody responses from masked to unmasked epitopes in vivo. Mutant HIV-1 and influenza virus surface glycoproteins were designed that had lysine residues removed from close proximity to the respective broadly neutralising epitopes, but added throughout the remaining surface. Masking of these mutant proteins with second-generation glycoconjugates led to predictable perturbations of antibody binding in vitro. However, administration of these modified glycoproteins revealed unexpectedly that the masking glycans were highly immunogenic in vivo. Thus, this strategy may well prove useful if truly non-immunogenic glycoconjugates can be identified. Taken together, these chemical modifications of vaccine antigens may allow focused targeting of specific antigenic regions for increased B cell recognition, and may thus be a valuable tool for vaccine antigen design.
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Structural studies on a hepatitis C virus-related immunological complex and on Ebola virus polymerase cofactor VP35Fadda, Valeria January 2015 (has links)
Hepatitis C virus (HCV) is one of the leading causes of hepatocellular carcinoma worldwide. HCV-neutralizing antibody AP33 recognizes a linear, highly conserved epitope on the viral entry protein E2, disrupting the interaction with the cellular receptor CD81 that leads to viral entry. AP33-related anti-idiotypes (Ab₂s) have the potential to carry the internal image of the antigen E2, eliciting the production of AP33-like antibodies in humans. This study reports the mid-resolution structure of the Fab fragment of anti-idiotype A164.3 and the high-resolution structure of the Fab fragment of AP33 in complex with the Fv fragment of anti-idiotype B2.1A. Analysis of the structures and comparison with the previously published structure of AP33 in complex with a peptide corresponding to the E2 epitope, suggests that while A164.3 does not mimic the antigen E2, B2.1A is characterized by high surface complementarity with AP33 and functional antigen mimicry. Thus, B2.1A can be classified as an Ab₂-β, a subgroup of anti-idiotypes carrying the internal image of the antigen. Preliminary binding studies show that AP33 binds B2.1A with nanomolar affinity, supporting the role of B2.1A as an idiotypic vaccine candidate. Zaire ebola virus causes severe, often lethal hemorrhagic fever in humans. Ebola virus polymerase cofactor VP35 is a multifunctional protein involved in, among other functions, dsRNA binding and inhibition of the host's interferon pathways. VP35 contains an N-terminal oligomerization domain and a C-terminal dsRNA-binding domain (RBD). Preliminary results on the oligomerization domain of VP35 suggest that this region contains a coiled-coil motif, as previously reported. In order to validate a recently-discovered dsRNA end-capping pocket as a drug target, the structure of VP35 RBD I278A mutant was solved at high resolution, showing that even a small perturbation in the binding pocket can cause dramatic binding impairment due to loss of contacts with dsRNA.
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Female-Specific Role of Ciliary Neurotrophic Factor in the Medial Amygdala in Promoting Stress ResponsesJia, Cuihong, Gill, Wesley D., Lovins, Chiharu, Brown, Russell W., Hagg, Theo 01 March 2022 (has links)
Ciliary neurotrophic factor (CNTF) is produced by astrocytes which have been implicated in regulating stress responses. We found that CNTF in the medial amygdala (MeA) promotes despair or passive coping, i.e., immobility in an acute forced swim stress, in female mice, while having no effect in males. Neutralizing CNTF antibody injected into the MeA of wildtype females reduced activation of downstream STAT3 (Y705) 24 and 48 h later. In concert, the antibody reduced immobility in the swim test in females and only after MeA injection, but not when injected in the central or basolateral amygdala. Antibody injected into the male MeA did not affect immobility. These data reveal a unique role of CNTF in female MeA in promoting despair or passive coping behavior. Moreover, 4 weeks of chronic unpredictable stress (CUS) increased immobility in the swim test and reduced sucrose preference in wildtype CNTF+/+, but not CNTF-/- littermate, females. Following CUS, 10 min of restraint stress increased plasma corticosterone levels only in CNTF+/+ females. In males, the CUS effects were present in both genotypes. Further, CUS increased CNTF expression in the MeA of female, but not male, mice. CUS did not alter CNTF in the female hippocampus, hypothalamus and bed nucleus of stria terminalis. This suggests that MeA CNTF has a female-specific role in promoting CUS-induced despair or passive coping, behavioral anhedonia and neuroendocrine responses. Compared to CNTF+/+ mice, CNTF-/- mice did not show differences in CUS-induced anxiety-like behavior and sensorimotor gating function as measured by elevated T-Maze, open field and pre-pulse inhibition of the acoustic startle response. Together, this study reveals a novel CNTF-mediated female-specific mechanism in stress responses and points to opportunities for developing treatments for stress-related disorders in women.
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