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1.
Oncoimmunology ; 8(7): 1601480, 2019.
Article in English | MEDLINE | ID: mdl-31143525

ABSTRACT

TLR7 agonists are considered promising drugs for cancer therapy. The currently available compounds are not well tolerated when administered intravenously and therefore are restricted to disease settings amenable for topical application. Here we present the preclinical characterization of SC1, a novel synthetic agonist with exquisite specificity for TLR7. We found that intravenously administered SC1 mediates systemic release of type I interferon, but not of proinflammatory cytokines such as TNFα and IL6, and results in activation of circulating immune cells. Tumors of SC1-treated mice have brisk immune cell infiltrates and are polarized towards a Th1 type signature. Intratumoral CD8+ T cells and CD11b+ conventional dendritic cells (cDCs) are significantly increased, plasmacytoid dendritic cells (pDCs) are strongly activated and macrophages are M1 phenotype polarized, whereas myeloid-derived suppressor cells (MDSCs) are decreased. We further show that treatment of mice with SC1 profoundly inhibits the growth of established syngeneic tumors and results in significantly prolonged survival. Mice, which are tumor-free after SC1 treatment are protected from subsequent tumor rechallenge. The antitumor effect of SC1 depends on antigen-specific CD8+ T cells, which we found to be strongly enriched in the tumors of SC1-treated mice. In conclusion, this study shows that systemically administered SC1 mobilizes innate and adaptive immunity and is highly potent as single agent in mice and thereby provides a rationale for clinical testing of this compound.

3.
Nat Commun ; 8: 14193, 2017 01 31.
Article in English | MEDLINE | ID: mdl-28139658

ABSTRACT

Severe malaria is a life-threatening complication of an infection with the protozoan parasite Plasmodium falciparum, which requires immediate treatment. Safety and efficacy concerns with currently used drugs accentuate the need for new chemotherapeutic options against severe malaria. Here we describe a medicinal chemistry program starting from amicarbalide that led to two compounds with optimized pharmacological and antiparasitic properties. SC81458 and the clinical development candidate, SC83288, are fast-acting compounds that can cure a P. falciparum infection in a humanized NOD/SCID mouse model system. Detailed preclinical pharmacokinetic and toxicological studies reveal no observable drawbacks. Ultra-deep sequencing of resistant parasites identifies the sarco/endoplasmic reticulum Ca2+ transporting PfATP6 as a putative determinant of resistance to SC81458 and SC83288. Features, such as fast parasite killing, good safety margin, a potentially novel mode of action and a distinct chemotype support the clinical development of SC83288, as an intravenous application for the treatment of severe malaria.


Subject(s)
Antimalarials/pharmacology , Calcium-Transporting ATPases/antagonists & inhibitors , Endoplasmic Reticulum/drug effects , Malaria, Falciparum/drug therapy , Plasmodium falciparum/drug effects , Acute Disease , Animals , Antimalarials/chemical synthesis , Antimalarials/pharmacokinetics , Calcium-Transporting ATPases/genetics , Calcium-Transporting ATPases/metabolism , Disease Models, Animal , Drug Resistance , Endoplasmic Reticulum/metabolism , Gene Expression , Humans , Inhibitory Concentration 50 , Ion Transport , Malaria, Falciparum/parasitology , Male , Mice , Mice, Inbred NOD , Mice, SCID , Plasmodium falciparum/genetics , Plasmodium falciparum/growth & development , Plasmodium falciparum/metabolism , Structure-Activity Relationship
4.
Cell Microbiol ; 9(2): 425-37, 2007 Feb.
Article in English | MEDLINE | ID: mdl-16953801

ABSTRACT

Yersinia enterocolitica (Ye) targets mouse dendritic cells (DCs) and inhibits their ability to trigger T cell activation. Here we have investigated whether Ye might interfere with antigen presentation in DCs. Infection of DCs with the Ye wild-type strain reduced OVA uptake by DCs as demonstrated by flow cytometry and confocal laser scan microscopy. In contrast, DCs infected with Yersinia outer protein P (YopP)-deficient mutant strain rapidly internalized OVA. Furthermore, transfection of DCs with YopP, but not with a cysteine protease deficient YopP-C172A mutant, reduced uptake of OVA. This finding suggests that YopP, a virulence factor of Ye, inhibits OVA uptake by DCs. By the use of MAPK inhibitors we provide evidence that YopP mediates reduction of OVA uptake by its ability to block MAPK signalling pathways in host cells. Using transferrin (Tf) as specific marker for clathrin-mediated endocytosis (CME) and lucifer yellow (LY) as specific marker for macropinocytosis (MP) we could show that YopP inhibits CME, whereas other Yops inhibit MP. In keeping with these data, activation and proliferation of OVA-specific T cells was reduced when DCs were treated with MAPK inhibitors. Together, our data demonstrate that (i) MAPK play an important role in antigen uptake by CME in DCs, and (ii) that YopP inhibits this pathway of antigen uptake in DCs, which might contribute to evasion of adaptive immunity.


Subject(s)
Bacterial Proteins/pharmacology , Dendritic Cells/drug effects , Mitogen-Activated Protein Kinases/antagonists & inhibitors , Yersinia enterocolitica/chemistry , Animals , Dendritic Cells/metabolism , Mice , Mice, Inbred BALB C
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