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Anticancer Natural Products: Evolution and their Biosynthetic Site-Selective Conjugation to AntibodiesVanner, Stephanie January 2014 (has links)
Natural products are an important resource for cancer therapy, with highly potent
and diverse anticancer activities. Natural product biosynthesis is well comprehended,
however the evolutionary principles governing the alteration of enzymatic assembly lines
to yield molecules with activity toward distinct various cellular targets are not
understood. This gap in knowledge hinders efforts to synthetically combinatorialize
assembly lines to yield “unnatural” natural products with important or hybrid activity
toward up-regulated targets in cancer. Furthermore, natural products did not evolve in the
context of mammalian systems and would benefit from a delivery mechanism to
cancerous cells to improve their ability to generate successful clinical outcomes.
Consequently, natural products were linked to antibodies targeted to cell surface proteins
up-regulated on cancer cells, generating antibody-drug conjugates (ADC). The
conjugation methodology is problematic by yielding ADCs with varying numbers of
drugs loaded per antibody. This lack of batch-to-batch standardization limits our ability to
completely evaluate the safety profiles and efficacy of ADCs and determine proper
dosages for patients. In this research, light was shed on biosynthetic evolutionary changes
through the study of the antimycin-type family of depsipeptides, specifically
demonstrating that modular insertions or deletions lead to natural product structural
diversification. Additionally, a novel biosynthetic enzymatic method was established to
site-selectively conjugate natural products to antibodies in order to facilitate the
development of more sophisticated cancer therapies. / Thesis / Master of Science (MSc)
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Anticorps anti-FP4/héparine et protéases : nouvelles stratégies thérapeutiques dans les thrombopénies induites par l'héparine / Anti-PF4/heparin antibodies and proteasis : new therapeutic strategies for heparin-induced thrombocytopeniaKizlik-Masson, Claire 14 December 2018 (has links)
Les Thrombopénies Induites par l’Héparine (TIH) sont une complication sévère des traitements par l’héparine dues à des IgG qui ciblent le facteur plaquettaire 4 modifié par l’héparine (FP4/H) et induisent une activation cellulaire via FcγRIIA, conduisant à des complications thrombotiques. Nous avons caractérisé 5B9, IgG1 monoclonale chimérique anti-FP4/H mimant parfaitement les anticorps de TIH et qui est donc un excellent outil pour étudier la physiopathologie des TIH. La pathogénicité des anticorps (Ac) de TIH implique leur fixation aux FcγR. Nous avons montré que le clivage de la région charnière des IgG de TIH par IdeS inhibe ces interactions IgG-FcγR et supprime la pathogénicité des Ac. Nous avons aussi construit un Antibody-Drug Conjugate (ADC) antithrombotique, en bioconjuguant le tirofiban (inhibiteur de l’agrégation plaquettaire) et 5B9 déglycosylé grâce à un linker clivable par la thrombine, protéase générée en excès lors d’une TIH. / Heparin Induced Thrombocytopenia (HIT) is a rare but severe complication of heparin treatments. HIT is due to IgG antibodies specific to platelet factor 4 modified by heparin (PF4/H), which activate blood cells, (especially platelets) after binding to FcγRIIA, this process explaining frequent thrombotic complications. We characterized 5B9, a chimeric IgG1 targeting PF4/H and which fully mimics human HIT antibodies. Therefore, 5B9 is a perfect tool for studying the physiopathology of HIT. IgG antibodies to PF4/H are pathogenic by interacting with FcγR. In this regard, we showed that cleavage by IdeS, a bacterial protease, of the hinge of anti-PF4/H IgG, fully suppressed their pathogenicity. Furthermore, we designed an antithrombotic Antibody-Drug Conjugate that combined tirofiban, a GPIIbIIIa inhibitor with deglycosylated 5B9 using a thrombin cleavable linker.
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Developing Methods and Targeted Therapeutics to Address Complications of Ibrutinib Treatment in Chronic Lymphocytic LeukemiaHu, Eileen Yifan 07 October 2020 (has links)
No description available.
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Monoklonala antikroppar - en översiktsstudieHeckscher, Hans January 2016 (has links)
No description available.
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Characterization of the antibodies and antibody technologies to improve the pharmaceutical activity / 薬学的活性を改善するための抗体および抗体技術に関する研究Shinmi, Daisuke 23 January 2018 (has links)
京都大学 / 0048 / 新制・論文博士 / 博士(工学) / 乙第13145号 / 論工博第4163号 / 新制||工||1687(附属図書館) / (主査)教授 森 泰生, 教授 浜地 格, 教授 梅田 眞郷 / 学位規則第4条第2項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DFAM
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Preventing Postoperative Immunosuppression by Inhibition of PI3Kγ in Surgery-Induced Myeloid Derived Suppressor CellsTennakoon Mudiyansel, Gimantha Gayashan 27 June 2023 (has links)
Surgery-induced myeloid derived suppressor cells (sxMDSC)s mediate postoperative suppression of Natural Killer (NK) cells, which enables postoperative cancer recurrence and metastases. Currently, no therapeutics against sxMDSCs have been developed. Recent research has identified that the myeloid-restricted PI3K isoform (PI3Kγ) mediates MDSC activity. I targeted PI3Kγ in sxMDSCs as a therapeutic to reduce postoperative NK cell suppression and metastatic burden. Additionally, I investigated the efficacy of a sxMDSC-specific antibody-drug conjugate (ADC) with a PI3Kγ inhibitor payload. Pharmacological inhibition of PI3Kγ in sxMDSCs led to reduced AKT phosphorylation and reduced suppression of NK cytotoxicity in human and murine models. PI3Kγ inhibition also reduced postoperative metastatic burden. Despite the novelty of the sxMDSC-specific ADC, it didn’t provide considerable benefits in reducing NK cell suppression compared to the unconjugated PI3Kγ inhibitor. However, this is a “first iteration” in what could be a powerful approach to targeting sxMDSCs, thereby preventing postoperative metastatic burden.
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Modification and application of glycosidases to create homogeneous glycoconjugatesYamamoto, Keisuke January 2013 (has links)
In the post-genomic era, recognition of the importance of sugars is increasing in biological research. For the precise analysis of their functions, homogeneous materials are required. Chemical synthesis is a powerful tool for preparation of homogeneous oligosaccharides and glycoconjugates. Glycosidases are potent catalysts for this purpose because they realize high stereo- and regio- selectivities under conditions benign to biomolecules without repetitive protection/deprotection procedures. A glycosynthase is an aritificial enzyme which is derived from a glycosidase and is devised for glycosylation reaction. To suppress the mechanistically inherent oligomerization side reaction of this class of biocatalysts, a glycosidase with plastic substrate recognition was engineered to afford the first α-mannosynthase. This novel biocatalyst showed low occurrence of oligomerized products as designed and was applied to prepare a wide range of oligosaccharides. Glycosidases are also valuable tools for glycan engineering of glycoconjugates, which is a pivotal issue in the development of pharmaceutical agents, including immunoglobulin G (IgG)-based drugs. EndoS, an endo-β-N-acetylglucosaminidase from Streptococcus pyogenes, natively cleaves N-glycans on IgG specifically. When the latent glycosylation activity of this enzyme was applied, the N-glycan remodelling of full-length IgG was successfully achieved for the first time and a highly pure glycoform was obtained using the chemically synthesized oxazoline tetrasaccharide as glycosyl donor. This biocatalytic reaction allows development of a novel type of antibody-drug conjugates (ADCs) in which drug molecules are linked to N-glycans site-specifically. For this purpose, glycans with bioorthogonal reaction handles were synthesized and conjugated to IgG. A model reaction using a dye compound as reaction partner worked successfully and the synthetic method for this newly designed ADC was validated. Glycan trimming of glycoproteins expressed from Pichia pastoris was performed using exoglycosidases to derive homogeneous glycoform. Jack Bean α-mannosidase (JBM) trimmed native N-glycans down to the core trisaccharide structure but some of the glycoforms were discovered to be resistant to the JBM activity. Enzymatic analyses using exoglycosidases suggested that the JBM-resistant factor was likely to be β-mannoside. In summary, this work advanced application of modified glycosidases for preparation of oligosaccharides and also demonstrated biocatalytic utility of glycosidases to produce biologically relevant glycoconjugates with homogeneous glycoforms.
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Polymer-Shell Bonded Phase for Improving Online LC-MS Analysis of Intact Proteins, mAbs, and ADCsTse-Hong Chen (7013258) 13 August 2019 (has links)
<p>LC-MS of protein drugs requires new ideas in bonded phase
design rather than adapting bonded phases from the realm of small-molecule
drugs. The polymer-shell bonded phase is designed to interact with larger
molecules and to shield proteins from the silica substrate. The particles
consist of a core of solid silica and a shell of dense polymer brush. The
polymer layer is thick enough to protect the protein from interactions with
silanols to reduce peak tailing. The polymer contains multiple functional
groups that introduce more selectivity. This design gives unprecedented LC
resolution and MS sensitivity. Our group has developed polymer shell bonded
phases for hydrophobic interaction chromatography (HIC-MS) of antibody-drug
conjugates (ADCs), hydrophilic interaction liquid chromatography (HILIC-MS) of
glycoproteins, and reversed-phase liquid chromatography (RPLC-MS) of monoclonal
antibodies. Since HIC is not in-line compatible with MS due to the high salt
levels, it is laborious to identify the constituents of HIC peaks. An
MS-compatible alternative to HIC is reported here: native reversed phase liquid
chromatography (nRPLC). This employs a mobile phase 50 mM ammonium acetate for
high sensitivity in MS, and elution with a gradient of water/isopropanol. The
nRPLC-MS data show that all ADC species, ranging from drug-to-antibody ratios
of 1 to 8, remained intact and native on the column. As we adapt this concept
to intact proteins, we find that lysozyme and α-chymotrypsinogen A are both
eluted in their native conformations. We also use the polymer-shell concept to
resolve IgG1 free thiol variants by RPLC-MS with 0.5% formic acid. Since there
are always other variants besides the intended ones, the need for high MS
sensitivity is desired to distinguish subtle mass change between disulfide bond
and free thiols. Overall, MS sensitivity increases 10X relative while all of
the thiol variants are well resolved by the polymethylmethacrylate bonded phase.</p>
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Metal mediated mechanisms of drug releaseStenton, Benjamin James January 2018 (has links)
In this thesis will be described research towards the development of bioorthogonal bond-cleavage reactions, and their applications in targeted drug delivery (Figure 1). The first project relates to the development of a palladium mediated bond-cleavage or "decaging" reaction which can cause a propargyl carbamate to decompose and release an amine. This was further developed by the incorporation of a protein modification handle which allowed an amine-bearing drug to be covalently ligated to a protein by a palladium-cleavable linker. This chemistry was demonstrated by the conjugation of the anticancer drug doxorubicin to a tumour targeted anti-HER2 nanobody. The drug could then be delivered to cancer cells upon addition of a palladium complex. The second project relates to the development of a platinum mediated bond-cleavage reaction. This was developed with the aim of using platinum-containing anticancer drugs - such as cisplatin - as a catalyst to cause drug release reactions in tumours. In this reaction an alkyne-containing amide can decompose to release an amine upon addition of platinum complexes, and was applied to the release of prodrugs of the cytotoxins monomethylauristatin E and 5-fluorouracil in cancer cells. A cisplatin-cleavable antibody-drug conjugate was designed and synthesised, and progress towards its biological evaluation will be discussed.
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Conception d'espaceurs pour relever les défis de bioconjugaisonMelkoumov, Alexandre 08 1900 (has links)
No description available.
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