Development of stimuli-sensitive nanoparticles and in vivo evaluation of immunestimulatory TNFSF ligand fusion proteins with FAP-restricted activity

Keywords: checkpoint targeting, bispecific antibody, nanoparticles, surface modification, drug-delivery

1st Hosting institution: Location: InoCure, Prag, Czech Republic; Duration: 18 months

2nd Hosting institution: Location: UKW, Würzburg, Germany; Duration: 18 months


Intended start date: November 2019

Job Description: PhD-student position (3 years): The aim of the project of ESR8 is the in vivo evaluation of the anti-tumoral activities and systemic side effects of already available single chain variable fragment (scFv) antibody based TNFSF ligand fusion proteins activating the murine forms of the co-stimulatory TNFRSF receptors. So far the in vivo evaluation of these mouse-“compatible” fusion proteins is limited by suboptimal bioavailability and pharmacokinetics. To overcome these limitations these fusion proteins we will develop stimuli sensitive particles for optimal targeting and release. The ESR will generate polymers with linkers specifically cleaved by selected proteases (i.e. MMPs, ADAMs). Upon cleavage, the particles will release the embedded bi-specific antibodies and trigger the release at the site of the tumour. The ESR will construct peptide-based bi-functional cross-linkers with UV-reactive groups. The sequence of peptide will be based on specificity of target enzyme. The cross linker will be used to crosslink the core and shell part of particle. Evaluation of in vitro cleavage will be evaluated using purified target enzyme and FTIR and/or UV-VIS analysis of release. Further, the surface properties will be optimized to enable long-term release and targeting. The particles will be optimized for long-term circulation and targeting to the tumour site by passive EPR mechanism and active binding of antibodies/peptides to the surface of particles. The in vivo activities of the nanoparticle-murine fusion protein formulations will be addressed in syngeneic mouse tumour models.

The PhD candidate will be working as part of an international consortium on their search for an immunotherapeutic approach to cancer treatment and will start their 3 year research project in InoCure s.r.o. (Prague, Czech Republic). The work in Prague will be performed for 18 months and will be focused on development of drug-delivery systems with cleavable linkers. Thereafter will the ESR join team of Prof. Wajant at Univerzity of Wurzburg for additional 18 months for testing of therapeutic efficacy on in vitro and in vivo models. This research project will end with a PhD thesis defense at the University of Wurzburg.

This project is part of a collaborative training network of 10 closely related projects in which PhD students will benefit from networking opportunities. This includes a multidisciplinary training programme with network-wide training events that will be provided to the candidates. Herewith, the PhD project will provide the candidate a unique opportunity to obtain knowledge/expertise on important facets of both academia and industry.

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