Immune-stimulating antibody conjugates elicit robust myeloid activation and durable anti-tumor immunity II
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PROVIDER: PRJNA663155 | ENA |
REPOSITORIES: ENA
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Project description:Immune-stimulating antibody conjugates elicit robust myeloid activation and durable anti-tumor immunity
| PRJNA663153 | ENA
Project description:Immune-stimulating antibody conjugates elicit robust myeloid activation and durable anti-tumor immunity I
| PRJNA662959 | ENA
Project description:Innate pattern recognition receptors, including toll-like receptors (TLRs), can alter the tumor microenvironment and prime adaptive anti-tumor immunity. However, TLR agonists have not been well-tolerated due to toxicities associated with widespread immune activation following systemic administration. To design a therapeutic that is suitable for systemic delivery and capable of eliciting a tumor-targeted response, we developed a novel class of immune-stimulating antibody conjugates (ISACs) comprising a TLR7/8 agonist conjugated to tumor-targeting antibodies. Systemically administered anti-HER2 ISACs were well-tolerated in vivo and elicited robust activation of intratumoral myeloid cells, resulting in tumor clearance and subsequent immunological memory. In vitro potency and in vivo efficacy required tandem activity driven by intact Fc functionality and TLR agonism to enable phagocytosis and T cell-mediated anti-tumor immunity. ISAC-mediated immunological memory was not limited to HER2, as ISAC-treated mice were protected from rechallenge with a HER2-negative tumor. These results provide strong rationale for the clinical development of ISACs and show that synergy between FcgR and TLR7/8 signaling contributes to the mechanism of ISAC-mediated anti-tumor immunity.
2020-12-03 | GSE157869 | GEO
Project description:Innate pattern recognition receptors, including toll-like receptors (TLRs), can alter the tumor microenvironment and prime adaptive anti-tumor immunity. However, TLR agonists have not been well-tolerated due to toxicities associated with widespreadimmune activation following systemic administration. To design a therapeutic that is suitable for systemic delivery and capable of eliciting a tumor-targeted response, we developed a novel class of immune-stimulating antibody conjugates (ISACs) comprising a TLR7/8 agonist conjugated to tumor-targeting antibodies. Systemically administered anti-HER2 ISACs were well-tolerated in vivo and elicited robust activation of intratumoral myeloid cells, resulting in tumor clearance and subsequent immunological memory. In vitro potency and in vivo efficacy required tandem activity driven by intact Fc functionality and TLR agonism to enable phagocytosis and T cell-mediated anti-tumor immunity. ISAC-mediated immunological memory was not limited to HER2, as ISAC-treated mice were protected from rechallenge with a HER2-negative tumor. These results provide strong rationale for the clinical development of ISACs and show that synergy between FcgR and TLR7/8 signaling contributes to the mechanism of ISAC-mediated anti-tumor immunity.
2020-12-03 | GSE157848 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2020-12-03 | GSE157870 | GEO
Project description:Objectives Pyrrolobenzodiazepine (PBD) dimers, tethered through inert propyldioxy or pentyldioxy linkers, possess potent bactericidal activity against a range of Gram-positive bacteria by virtue of their capacity to cross-link duplex DNA in sequence-selective fashion. Here we attempt to improve the antibacterial activity and cytotoxicity profile of PBD-containing conjugates by extension of dimer linkers and replacement of one PBD unit with phenyl-substituted or benzo-fused heterocycles that facilitate non-covalent interactions with duplex DNA. Methods DNase I footprinting was used to identify high-affinity DNA binding sites. A staphylococcal gene microarray was used to assess epidemic methicillin-resistant Staphylococcus aureus 16 phenotypes induced by PBD conjugates. Molecular dynamics simulations were employed to investigate the accommodation of compounds within the DNA helix. Results Increasing the length of the linker in PBD dimers led to a progressive reduction in antibacterial activity, but not in their cytotoxic capacity. Complex patterns of DNA binding were noted for extended PBD dimers. Modelling of DNA strand cross-linking by PBD dimers indicated distortion of the helix. A majority (26 of 43) of PBD-biaryl conjugates possessed potent antibacterial activity with little or no helical distortion and a more favourable cytotoxicity profile. Bactericidal activity of PBD-biaryl conjugates was determined by inability to excise covalently bound drug molecules from bacterial duplex DNA. Conclusions PBD-biaryl conjugates have a superior antibacterial profile compared with PBD dimers such as ELB-21. We have identified six PBD-biaryl conjugates as potential drug development candidates. [Data is also available from http://bugs.sgul.ac.uk/E-BUGS-118]
2012-04-17 | E-BUGS-118 | biostudies-arrayexpress
Project description:Piperlongumine (PL) conjugates induce targeted protein degradation
| PRJNA851461 | ENA
Project description:Undifferentiated and differentiated Keratinocytes (AG1478 treated) were stained with antibody-RNA conjugates (targeting EGFR and ITGA6) to measure protein-based differentiation changes in conjunction with single-cell transcriptomics.
2019-02-13 | GSE115936 | GEO
Project description:Using this approach the dasatinib-oligonucleotide conjugates was applied to planar arrays of >9,000 human proteins spotted in two technical replicates. All proteins in the commercially available ProtoArray® Human Protein MicroArray (Thermo Fisher Scientific) have been purified and arrayed under native conditions to allow such studies. We adopted this format for investigation of the binding profiles of the drug-oligonucleotide conjugates. Fluorophore-labeled drugs have previously been used to measure binding in protein arrays. The oligonucleotide-conjugated constructed allowed for locally amplified detection via RCA. Circularizing oligonucleotides (padlock probes) were designed with 5’ and 3’ ends complementary to adjacent segments of the oligonucleotides conjugated to the drug molecules. Once converted to oligonucleotide circles by ligation, the probes were replicated through localized RCA, primed by the drug-conjugated oligonucleotides, and visualized using fluorescence-labeled hybridization probes to the repeated sequence of the RCA products. RCA offers a signal enhancement of several hundredfold over singly fluorophore labeled compounds, permitting visualization of even single bound drug probes
2022-09-12 | E-MTAB-12192 | biostudies-arrayexpress
Project description:The ubiquitous efflux transporter ATP-binding cassette sub-family C member 5 (ABCC5) is present at high levels in the blood-brain barrier, neurons and glia, but its in vivo substrates and function are not known. Untargeted metabolomic screens revealed that Abcc5-/- mice accumulate endogenous glutamate conjugates and analogs in several tissues, but brain in particular. The abundant neurotransmitter N-acetylaspartylglutamate (NAAG), for example, was over 2-fold higher in Abcc5-/- brain. In line with ABCC5-mediated transport, the metabolites that accumulated in Abcc5-/- tissues were depleted in cultured cells that overexpressed human ABCC5. Using membrane vesicles, we show that ABCC5 not only transports the metabolites detected in our screen, but also a wide range of peptides containing a C-terminal glutamate. Glutamate conjugates are of physiological relevance because they can affect the function of glutamate, the principal excitatory neurotransmitter in the brain. We found that ABCC5 also transports exogenous glutamate analogs, like the classic excitotoxic neurotoxins kainic acid, domoic acid and N-methyl-D-aspartate (NMDA) and the therapeutic glutamate analog ZJ43. Taken together, we have identified ABCC5 as a general glutamate conjugate and analog transporter that affects the disposition of endogenous metabolites, toxins and drugs.
2015-10-01 | GSE68628 | GEO