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Дисертації з теми "Anticorpi bispecifici"
Rozan, Caroline. "Développement et caractérisation d'anticorps bispécifiques anti-ace xCD16 pour l'immunothérapie des cancers." Thesis, Aix-Marseille, 2012. http://www.theses.fr/2012AIXM5032.
Повний текст джерелаWith fourteen antibodies used in oncology, monoclonal antibodies finally have a place in the therapeutic arsenal against cancer. However one of the modes of action of the most important of these molecules, cell-mediated cytotoxicity antibody-dependent (ADCC), suffers from several limitations due to the need for optimal interaction with the FcγRIIIA. Daniel Baty's team has developed new formats of bispecific antibodies based on the use of single domain llama antibodies (SdAb) that are capable of circumventing most of the these limitations. Phage libraries from immunized llamas were used to select two sdAbs directed against the FcγRIIIA expressed by NK cells and macrophages (with different affinities for FcγRIII), as well as one SdAb directed against the tumor antigen carcinoembryonic (CEA). Using CH1 and Ck domains of human IgG1 as a motif for heterodimerization and sdabs previously selected, we have developed innovative anti-CEA and anti-FcγRIII formats of bispecific antibodies Fab-like named bsFabs. These molecules are easy to produce, very stable and can trigger tumor cell lysis by human NK cells at picomolar concentrations. They do not bind FcγRIIB inhibitory receptor, do not compete with serum IgG and their cytotoxic activity is independent of FcγRIIIA polymorphism. In addition, they slow tumor growth in mouse model. In terms of pharmacokinetics, although bsFabs have a reasonable tumor retention, one of the limitations of these formats is size, which leads to rapid renal elimination. Such findings led us to consider the creation of new antibody formats to both increase tumor retention and secondly the half-life of antibodies in the body
Fayon, Maxime. "Développement et évaluation d'anticorps bispécifiques dans le traitement du Myélome multiple." Thesis, Université de Paris (2019-....), 2019. http://www.theses.fr/2019UNIP7057.
Повний текст джерелаMultiple Myeloma (MM) is a hematological malignancy characterized by the uncontrolled proliferation of clonal tumor plasma cells in the bone marrow. Current treatments, including proteasome inhibitors and immunomodulatory drugs, have improved response and survival rates. However, these treatments are not able to cure patients and sub-groups of patients still show rapid relapse, chemo resistance and low survival rates.Recently, novel immunotherapeutic strategies have been developed to complement these conventional treatments. Bi-and Tri-Specific antibodies have shown to efficiently reduce tumor growth in different hematological diseases. These antibodies on one hand recognize proteins that are expressed on the surface of the tumor cells and on the other hand proteins that are expressed on the surface of cytotoxic cells of the immune system. Clinical trials carried out using BiTEs (Bispecific T-cell Engagers) that recognize CD19 on the surface of tumor cells and CD3 on the surface of T cells, have shown efficient treatment of B acute lymphoblastic leukemia. These promising results have prompted similar strategies targeting antigens expressed on the surface of tumor cells in MM. We have built a new BiTE antibody (Bi38-3), that targets CD38, an antigen highly expressed on tumor plasma cells and also recruits and activate T cells through CD3e. Our results demonstrate that Bi38-3 specifically recognizes malignant plasma cells. We showed that this antibody stimulated cell-lytic activity of T cells isolated from healthy donors against MM cell lines in vitro. In the presence of these antibodies we observed that T cells, isolated from healthy donors, have a lytic effect on MM cell lines in vitro. Interestingly, Bi38-3 does not exhibit cytotoxic effect against B, T and NK cells that express low levels of CD38 compared to MM cell lines. These results have been confirmed using T cells and tumor plasma cells isolated from newly diagnosed and relapsed MM patients. Moreover, Bi38-3 is able to efficiently reduce myeloma tumor growth in a MM pre-clinical mouse xenograft model.Altogether, these results suggest that Bi38-3 represents a promising new immunotherapeutic drug for the treatment of MM that could be used either alone or in combination with immunomodulatory drugs, to improve the prognosis of relapsed or refractory patients
Lamendour, Lucille. "Modulation des fonctions des cellules dendritiques humaines par des fragments d'anticorps." Thesis, Tours, 2018. http://www.theses.fr/2018TOUR3303/document.
Повний текст джерелаThe immune system protects an organism from the development of pathogens and actively participates in maintaining immune tolerance. Dendritic cells (DC) are specialized cells in the balance and anti-inflammatory immune response. DC play an important role in many pathological contexts, including organ transplantation, oncology and inflammatory diseases. Various factors, both intrinsic and extrinsic, can modulate. Because they are capable to inducing a tolerogenic response, these cells represent interesting targets for the immune response in the context of organ transplantation and in inflammatory pathologies. Some pathogens use mechanisms of escape to the immune system by promoting the induction of immune tolerance. This modulation is achieved by targeting the pathogen recognition receptors (PRRs) present on the surface of DC, inducing the synthesis of an anti-inflammatory cytokine IL-10, one of the main inducers of immune tolerance. Our strategy was to construct a bispecific antibody targeting two different PPRs from an anti-PRR antibody library. Our work shows that this bispecific antibody is able to direct the DC to a pro-tolerogenic profile. This bispecific antibody induces a semi-mature DC phenotype with a secretion profile of pro-tolerogenic cytokines such as IL-10 and few inflammatory cytokines. The immune tolerance profile of these DC remains to be explored. Our work opens interesting perspectives on the association of PRRs in order to obtain the modulation of the cells of the immunity
Del, Bano Joanie. "Développement d'anticorps bispécifiques pour l'immunothérapie des cancers." Thesis, Aix-Marseille, 2018. http://www.theses.fr/2018AIXM0161.
Повний текст джерелаMounting evidence of the key contribution of NK cells in immunity against cancer has boosted the investigations on NK cell-based therapies. Among these strategies, monoclonal antibody-based therapeutics (mAbs) are currently the fastest growing segment of the medicine market. Despite therapeutic innovations, triple negative breast cancers (TNBC) remain insensitive to the current targeted or hormono-therapies. Our objective is to manipulate NK cell functions and tumor targets using an original format of nanobody-based bispecific antibodies (bsFab) to revert the dampened immune response for treating TNBC. Thus, we generate two bsFabs able to crosslink NK and tumor cells. NK antitumor effects driven by mAbs and bsFabs, alone or in combination, were investigated in vitro and in vivo on preclinical TNBC models. Here, we demonstrate the potential of bsFabs to enlarge the number of patients eligible for breast cancer immunotherapy and prompt to consider combination strategies
Kakwata-Nkor, Deluce Nora. "Induction de sous-populations de cellules dendritiques humaines pro-tolérogènes par des fragments d’anticorps bispécifiques." Thesis, Tours, 2019. http://www.theses.fr/2019TOUR3805.
Повний текст джерелаDendritic cells (DCs) have a central role in immunity and induce both specific immunity and immune tolerance thanks to their surface pathogen receptors (PPRs). The immune tolerance induced by tolerant DCs (Tol-DCs) appears as an interesting way to explore in order to improve the long-term transplantation outcome. Four DC subsets, at least, have been identified including conventional DCs (BDCA-1; BDCA-3), plasmacytoid DCs (pDC), Inflammatory DCs(MoDC) and Langerhans cells (LC). For each DC subset, an array of pathogen recognition receptors (PRRs) have been identified on their surface. The PRRs profile differs between DC subsets providing an individual responsiveness to target specific pathogens as well as to trigger and modulate immunological responses. The aim is to target DC subset PRRs by bispecific antibodies (BsAb) in order to induce physiological tolerance. Monocyte derived DC (moDC) and monocyte derived Langerhans DC (moLC) were obtained from CD14+ cells. The plasmacytoïd DC (pDC) were purified from an enriched DC cells fraction obtained by Percoll® gradient of PBMCs. The moDC, pDC and moLC subsets were analyzed by phenotype labelling and FACS. A Bispecific Ab (tandem scFv) were built to target PRR on DC subsets. The tandem is made of 2 scFv of 55KDa. The BsAb were produced using insect S2 (BIC05) or CHO cell (BIC15 or BIC25) and purified by protein L column. Each scFV recognize a PRR on DC. Each BsAb have been evaluated on its DC target and on PBMC at the phenotypic and functional levels by evaluating the maturation markers (CD83, CD86, CD25 and HLA-DR), cytokine secretions (IL-10, IL-12p70 and IFN- ) and the capacity to activate naïve T-cell as well as to induce regulatory T-cell (Treg)
Turini, Marc. "Développement d'anticorps bispécifiques de lama pour le traitement de cancers du sein réfractaires à l'action du trastuzumab." Thesis, Aix-Marseille, 2014. http://www.theses.fr/2014AIXM4021.
Повний текст джерелаTrastuzumab is established as standard of care for the treatment of HER2high breast cancers. However, in addition to Fc-related limitations inherent to IgG antibodies, trastuzumab is inefficient to treat low- (triple-negative) or moderate-HER2-overexpressing (hormone-receptor-positive) breast cancers. Based on the unique structural and functional properties of llama single domain antibodies (sdAbs), we report the design of two Fab-like bispecific antibodies targeted to HER2 (HER2bsFab) and mesothelin (MesobsFab), an antigen overexpressed in several human tumors, including triple-negative breast cancers. The two bsFabs display a unique, specific and high affinity for FcγRIII. As a consequence, they do not bind the FcγRIIB inhibitor receptor and bypass competition with endogenous IgGs. HER2bsFab mediated ADCC at picomolar concentration against HER2high as well as HER2moderate cell lines. In vivo HER2bsFab potently inhibited HER2high tumor growth and more importantly, exhibited a net superiority over trastuzumab at inhibiting HER2moderate tumor growth. Moreover, FcγRIIIA-engagement by HER2bsFab was independent of FcγRIIIA-158 polymorphism and induced a stronger NK cells activation in response to target cell recognition. Such findings led us to investigating the efficacy of bsFabs in a context of low-HER2-overexpression displays by triple-negative breast cancers. In vitro characterization showed that both HER2bsFab and MesobsFab trigger efficient lysis of two different triple-negative breast cancer cell lines. Altogether, these findings would enable the treatment of a broader population of patients than that eligible with current HER2-targeted therapies
Тези доповідей конференцій з теми "Anticorpi bispecifici"
De Figueiredo, Wenberger Lanza Daniel, Maria Sílvia Prestes Pedrosa, Matheus Vinícius De Souza Carneiro, and Paula Taquita Serra. "A EFICÁCIA DO TRATAMENTO PARA CORONAVÍRUS COM ANTICORPOS MONOCLONAIS - REVISÃO DE LITERATURA." In I Congresso Brasileiro de Imunologia On-line. Revista Multidisciplinar em Saúde, 2021. http://dx.doi.org/10.51161/rems/994.
Повний текст джерелаPedrosa, Maria Sílvia Prestes, Paula Taquita Serra, Wenberger Lanza Daniel De Figueiredo, and Matheus Vinícius De Souza Carneiro. "EFEITOS ADVERSOS NO TRATAMENTO POR IMUNIZAÇÃO MEDIADA POR ANTICORPOS - REVISÃO DE LITERATURA." In I Congresso Brasileiro de Imunologia On-line. Revista Multidisciplinar em Saúde, 2021. http://dx.doi.org/10.51161/rems/1003.
Повний текст джерелаCarneiro, Matheus Vinícius De Souza, Paula Taquita Serra, Wenberger Lanza Daniel Figueiredo, and Maria Sílvia Prestes Pedrosa. "A EFICÁCIA DA IMUNIZAÇÃO PASSIVA COM ANTICORPOS POLICLONAIS CONTRA COVID-19 - REVISÃO DE LITERATURA." In I Congresso Brasileiro de Imunologia On-line. Revista Multidisciplinar em Saúde, 2021. http://dx.doi.org/10.51161/rems/992.
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