The Experts below are selected from a list of 300 Experts worldwide ranked by ideXlab platform
Horst Kunz - One of the best experts on this subject based on the ideXlab platform.
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a fully Synthetic glycopeptide antitumor Vaccine based on multiple antigen presentation on a hyperbranched polymer
Chemistry: A European Journal, 2014Co-Authors: Markus Glaffig, Bjorn Palitzsch, Sebastian Hartmann, Christoph Schull, Lutz Nuhn, Bastian Gerlitzki, Edgar Schmitt, Holger Frey, Horst KunzAbstract:For antitumor Vaccines both the selected tumor-associated antigen, as well as the mode of its presentation, affect the immune response. According to the principle of multiple antigen presentation, a tumor-associated MUC1 glycopeptide combined with the immunostimulating T-cell epitope P2 from tetanus toxoid was coupled to a multi-functionalized hyperbranched polyglycerol by "click chemistry". This globular polymeric carrier has a flexible dendrimer-like structure, which allows optimal antigen presentation to the immune system. The resulting fully Synthetic Vaccine induced strong immune responses in mice and IgG antibodies recognizing human breast-cancer cells.
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towards a fully Synthetic muc1 based anticancer Vaccine efficient conjugation of glycopeptides with mono di and tetravalent lipopeptides using click chemistry
Chemistry: A European Journal, 2011Co-Authors: Hui Cai, Zhihua Huang, Lei Shi, Yufen Zhao, Horst KunzAbstract:Abstract The membrane-bound tumor-associated glycoprotein MUC1 is aberrantly glycosylated in cancer cells compared with normal cells, and is therefore considered an attractive target for cancer immunotherapy. However, tumor-associated glycopeptides from MUC1 do not elicit a sufficiently robust immune response. Therefore, antitumor Vaccines were developed, which consist of MUC1 glycopeptides as the B epitopes and immune-stimulating toll-like receptor 2 (TLR 2) lipopeptide ligands. These fully Synthetic Vaccine candidates were prepared by solid-phase synthesis of the MUC1 glycopeptides. The Pam(3) Cys lipopeptide, also synthesized on solid-phase, was C-terminally coupled to oligovalent lysine cores, which N-terminally incorporate O-propargyl oligoethylene glycol acyl side chains. The MUC1 glycopeptides and lipopeptide lysine constructs were then conjugated by click chemistry to give oligovalent Synthetic Vaccines. Oligovalent glycopeptide-lipopeptide conjugates are considered more immunogenic than their monovalent analogues.
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Synthetic Glycopeptides for the Construction of Anticancer Vaccines
2008Co-Authors: Horst Kunz, Sven Wittrock, Sebastian Dziadek, Torsten BeckerAbstract:Glycopeptides of the tandem repeat region of the tumor-associated epithelial mucin MUC 1 containing tumor-associated saccharide antigens have been synthesized and conjugated to carrier proteins or T-cell epitope peptides. The T, sialyl T N , 2,6- and 2,3-sialyl T antigen amino acid building blocks were obtained by biomimetic syntheses starting from the monosaccharide T N antigen conjugate. To synthesize the MUC1 glycopeptides solid-phase methods with varied anchors were applied. Conjugation of Synthetic glycopeptides to bovine serum albumin were achieved by selective reactions at squaric esters. Solid-phase fragment condensation proved successful for constructions of MUC1 glycopeptide-T-cell epitope conjugates. Immunization of mice with a Synthetic Vaccine consisting of a MUC1 glycopeptide and a T-cell epitope from ovalbumin induced a specific immune response. The elicited antibody only reacted with the glycopeptide. Neither its peptide nor the glycan in a different peptide were recognized. This precise differentiation by antibodies induced by chemically pure Vaccines is considered promising for the development of antitumor Vaccines.
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Synthetic glycopeptides for the development of cancer Vaccines.
Current opinion in molecular therapeutics, 2007Co-Authors: Angela Liakatos, Horst KunzAbstract:Abstract The tumor-associated carbohydrate antigens and glycopeptide antigens derived from, for example, the MUC1 mucin glycoprotein, are attractive targets for the immunotherapy of cancer, owing to their expression by malignant cells. The use of Synthetic glycopeptides as partial or full components of Vaccines targeting these antigens is a favorable approach for the development of cancer immunotherapies because of their ability to be generated as homogenous formulations. Tumor-associated antigens often exhibit poor immunogenicity; therefore, their conjugation to immunostimulants is essential to engage the immune system. Tremendous progress has been made in identifying the structural components of a Synthetic Vaccine required to elicit a highly selective and strong immune response, as well as appropriate carriers for their multivalent presentation. It is anticipated that advances in organic synthesis will ultimately aid the development of a fully Synthetic Vaccine incorporating important glycopeptide antigens for the treatment of cancer.
Geert-jan Boons - One of the best experts on this subject based on the ideXlab platform.
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linear synthesis and immunological properties of a fully Synthetic Vaccine candidate containing a sialylated muc1 glycopeptide
Chemical Communications, 2015Co-Authors: Pamela Thompson, Vani Lakshminarayanan, Nitin T Supekar, Judy M Bradley, Peter A Cohen, Margreet A Wolfert, Sandra J Gendler, Geert-jan BoonsAbstract:A strategy for the linear synthesis of a sialylated glycolipopeptide cancer Vaccine candidate has been developed using a strategically designed sialyl-Tn building block and microwave-assisted solid-phase peptide synthesis. The glycolipopeptide elicited potent humoral and cellular immune responses. T-cells primed by such a Vaccine candidate could be restimulated by tumor-associated MUC1.
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Robust immune responses elicited by a fully Synthetic three-component Vaccine
Nature Chemical Biology, 2007Co-Authors: Sampat Ingale, Margreet A Wolfert, Jidnyasa Gaekwad, Therese Buskas, Geert-jan BoonsAbstract:The overexpression of saccharides such as Globo-H, Lewis^Y and Tn antigen is a common feature of oncogenic transformed cells. Endeavors to exploit this aberrant glycosylation for cancer Vaccine development have been complicated by difficulties in eliciting high titers of IgG antibodies against classical conjugates of tumor-associated carbohydrates to carrier proteins. We have designed, chemically synthesized and immunologically evaluated a number of fully Synthetic Vaccine candidates to establish strategies to overcome the poor immunogenicity of tumor-associated carbohydrates and glycopeptides. We have found that a three-component Vaccine composed of a TLR2 agonist, a promiscuous peptide T-helper epitope and a tumor-associated glycopeptide can elicit in mice exceptionally high titers of IgG antibodies that can recognize cancer cells expressing the tumor-associated carbohydrate. The superior properties of the Vaccine candidate are attributed to the local production of cytokines, upregulation of co-stimulatory proteins, enhanced uptake by macrophages and dendritic cells and avoidance of epitope suppression.
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Synthetic carbohydrate-based Vaccines: synthesis of an L-glycero-D-manno-heptose antigen–T-epitope–lipopeptide conjugate
Chemical Communications, 1997Co-Authors: Frank Reichel, Peter R. Ashton, Geert-jan BoonsAbstract:A facile and highly efficient synthesis of a glycopeptidolipid containing a heptose sugar, a Synthetic T-epitope and a Synthetic immunoadjuvant is presented which represents an important step towards the development of a fully Synthetic Vaccine against Neisseria meningitidis.
Ira Pastan - One of the best experts on this subject based on the ideXlab platform.
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Strategies to Reduce the Immunogenicity of Recombinant Immunotoxins.
American Journal of Pathology, 2018Co-Authors: Ronit Mazor, Emily M. King, Ira PastanAbstract:Recombinant immunotoxins (RITs) are genetically engineered proteins being developed to treat cancer. They are composed of an Fv that targets a cancer antigen and a fragment of a bacterial toxin that kills tumor cells. Because the toxin is a foreign protein, it is immunogenic. The clinical success of RITs in patients with a normal immune system is limited by their immunogenicity. In this review, we discuss our progress in therapeutic protein deimmunization and the balancing act between immunogenicity and therapeutic potency. One approach is to prevent the activation of B cells by mapping and elimination of B-cell epitopes. A second approach is to prevent helper T-cell activation by interfering with major histocompatibility complex II presentation or T-cell recognition. Immunizing mice with RITs that were deimmunized by elimination of the murine B- or T-cell epitopes showed that both approaches are effective. Another approach to control immunogenicity is to modify the host immune system. Nanoparticles containing Synthetic Vaccine particles encapsulating rapamycin can induce immune tolerance and prevent anti-drug antibody formation. This treatment restores RIT anti-tumor activity that is otherwise neutralized because of immunogenicity.
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abstract 72 induction of immune tolerance to recombinant immunotoxin lmb 100 using Synthetic Vaccine particles encapsulating rapamycin
Cancer Research, 2017Co-Authors: Ronit Mazor, Emily M. King, Takashi Kishimoto, Ira PastanAbstract:Recombinant Immunotoxins (RITs) are genetically engineered proteins designed for cancer therapy. LMB-100 is a second generation RIT that is composed of a humanized Fab targeting mesothelin and a de-immunized fragment of Pseudomonas Exotoxin A. Due to the bacterial origin of the toxin, LMB-100 is immunogenic, although less immunogenic than first generation immunotoxins. Almost all patients treated with LMB-100 made anti-drug antibodies (ADAs) after two or more cycles of treatment that neutralized the RIT and greatly lowered efficacy. Kishimoto et al. demonstrated that Synthetic Vaccine Particles containing Rapamycin (SVP-R) inhibited the formation of ADAs, when administered with a foreign protein such as KLH or Pegsiticase. The SVP-R are taken up by macrophages and dendritic cells and increase the number of regulatory T cells in treated mice. Here we evaluated the efficacy of combination therapy of LMB-100 and SVP-R to eradicate mesothelin expressing tumors while preventing ADA formation. To evaluate if SVP-R can prevent ADAs against LMB-100, we immunized immune-competent mice with a combination of SVP-R and RIT and measured ADAs titers by ELISA and by a functional neutralization assay. We found that the treatment reduced ADA titers by more than 99%. To determine if the mice were tolerized to LMB-100, we treated the mice with two doses of SVP-R and six doses of LMB-100 to induce tolerance; and followed by nine challenges of LMB-100 given over 6 weeks. We found that the ADAs were reduced by 98%, indicating development of immunological tolerance to LMB-100. To show that the tolerance is transferable, we tolerized the mice with six doses of SVP-R and LMB-100 and adoptively transferred their splenocytes to naive recipient mice. The recipient mice were challenged with six doses of LMB-100 and ADA titers were measured. We found that splenocytes from tolerized mice induced a 66% decrease in ADA formation in the recipient mice indicating that the tolerance was mediated by cells of the immune system. To demonstrate that immune suppression is useful in treating tumors, we implanted mouse breast cancer cells expressing human mesothelin into Balb/c mice with a normal immune system and treated them with LMB-100. LMB-100 produced tumor regressions when given before ADAs developed, but was inactive in mice with pre-existing ADAs. However, when mice with preexisting ADAs were treated with LMB-100 and SVP-R, anti-tumor activity was restored and ADAs suppressed (P≤0.0001). SVP-R are being evaluated in humans to prevent ADA to Pegsiticase, an enzyme for refractory gout treatment. Our data indicates that combining SVP-R with LMB-100 should be useful in treating cancer by allowing more treatment cycles and better efficacy. This approach can be used to increase the efficacy of other immunogenic agents such as CAR-T cells, antibody drug conjugates and viral gene therapy vectors Citation Format: Ronit Mazor, Emily King, Takashi Kei Kishimoto, Ira Pastan. Induction of immune tolerance to recombinant immunotoxin LMB-100 using Synthetic Vaccine particles encapsulating rapamycin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 72. doi:10.1158/1538-7445.AM2017-72
Severine Charles - One of the best experts on this subject based on the ideXlab platform.
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Antigen-selective modulation of AAV immunogenicity with tolerogenic rapamycin nanoparticles enables successful vector re-administration
Nature Communications, 2018Co-Authors: Florence Boisgérault, Amine Meliani, Romain Hardet, Solenne Marmier, Fanny Collaud, Giuseppe Ronzitti, Christian Leborgne, Helena Costa Verdera, Marcelo Simon Sola, Severine CharlesAbstract:Gene therapy mediated by recombinant adeno-associated virus (AAV) vectors is a promising treatment for systemic monogenic diseases. However, vector immunogenicity represents a major limitation to gene transfer with AAV vectors, particularly for vector re-administration. Here, we demonstrate that Synthetic Vaccine particles encapsulating rapamycin (SVP[Rapa]), co-administered with AAV vectors, prevents the induction of anti-capsid humoral and cell-mediated responses. This allows successful vector re-administration in mice and nonhuman primates. SVP[Rapa] dosed with AAV vectors reduces B and T cell activation in an antigen-selective manner, inhibits CD8+ T cell infiltration in the liver, and efficiently blocks memory T cell responses. SVP[Rapa] immunomodulatory effects can be transferred from treated to naive mice by adoptive transfer of splenocytes, and is inhibited by depletion of CD25+ T cells, suggesting a role for regulatory T cells. Co-administration of SVP[Rapa] with AAV vector represents a powerful strategy to modulate vector immunogenicity and enable effective vector re-administration.
Paolo Costantino - One of the best experts on this subject based on the ideXlab platform.
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Preparation, characterization and immunogenicity of HIV-1 related high-mannose oligosaccharides-CRM_197 glycoconjugates
Glycoconjugate Journal, 2010Co-Authors: Anna Kabanova, Roberto Adamo, Daniela Proietti, Francesco Berti, Marta Tontini, Rino Rappuoli, Paolo CostantinoAbstract:The dense glycan shield on the surface of human immunodeficiency virus type 1 (HIV-1) gp120 masks conserved protein epitopes and facilitates virus entry via interaction to glycan binding proteins on susceptible host cells. The broadly neutralizing monoclonal antibody 2G12 binds a cluster of high-mannose oligosaccharides on the gp120 subunit of HIV-1 Env protein. This oligomannose epitope is currently being considered for the design of a Synthetic Vaccine. The cluster nature of the 2G12 epitope suggests that a multivalent antigen presentation is important to develop a carbohydrate-based Vaccine candidate. In this work we describe the development of neoglycoconjugates displaying clustered HIV-1 related oligomannose carbohydrates. We exploited flexible polyamidoamine (PAMAM) scaffold to generate four- and eight-valent sugar clusters of HIV-1-related oligomannose antigens Man_4, Man_6 and Man_9. The multivalent presentation of oligomannoses increased the avidity of Man_4 and Man_9 to 2G12. The Synthetic glycodendrons were then covalently coupled to the protein carrier CRM_197, formulated with the adjuvant MF59, and used to immunize two animal species. Oligomannose-specific IgG antibodies were generated; however, the antisera failed to recognize recombinant HIV-1 gp120 proteins. We conclude that further structural vaccinology work is needed to identify an antigen presentation that closely matches in vivo the structure of the epitope mapped by 2G12.
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Preparation, characterization and immunogenicity of HIV-1 related high-mannose oligosaccharides-CRM197 glycoconjugates
Glycoconjugate journal, 2010Co-Authors: Anna Kabanova, Roberto Adamo, Daniela Proietti, Francesco Berti, Marta Tontini, Rino Rappuoli, Paolo CostantinoAbstract:The dense glycan shield on the surface of human immunodeficiency virus type 1 (HIV-1) gp120 masks conserved protein epitopes and facilitates virus entry via interaction to glycan binding proteins on susceptible host cells. The broadly neutralizing monoclonal antibody 2G12 binds a cluster of high-mannose oligosaccharides on the gp120 subunit of HIV-1 Env protein. This oligomannose epitope is currently being considered for the design of a Synthetic Vaccine. The cluster nature of the 2G12 epitope suggests that a multivalent antigen presentation is important to develop a carbohydrate-based Vaccine candidate. In this work we describe the development of neoglycoconjugates displaying clustered HIV-1 related oligomannose carbohydrates. We exploited flexible polyamidoamine (PAMAM) scaffold to generate four- and eight-valent sugar clusters of HIV-1-related oligomannose antigens Man4, Man6 and Man9. The multivalent presentation of oligomannoses increased the avidity of Man4 and Man9 to 2G12. The Synthetic glycodendrons were then covalently coupled to the protein carrier CRM197, formulated with the adjuvant MF59, and used to immunize two animal species. Oligomannose-specific IgG antibodies were generated; however, the antisera failed to recognize recombinant HIV-1 gp120 proteins. We conclude that further structural vaccinology work is needed to identify an antigen presentation that closely matches in vivo the structure of the epitope mapped by 2G12.
