Kadcyla® is an ADC that has been given FDA approval in early 2013 for the treatment of metastatic breast cancer. However, issues with the toxicity of the highly potent payload (e.g. dose-limiting thrombocytopenia) have been reported as well as acquired resistance because of insufficient cellular uptake and insufficient lysosomal cleavage of the linker yielding poor drug release. These issues are not specific to this particular ADC and key limitations with the current technologies are limiting the clinical efficacy of these agents.
The two most fundamental issues concern:
i) linkers, as they must be stable to prevent premature drug release but also able to release the payload once internalised into the tumour cell;
ii) DARs, that are typically limited because of potential aggregation and thus inactivation for high DAR ADCs.
We hypothesize that these issues could be overcome with the development of antibody-drug nanoconjugates (ADNs) whereby the antibody is linked directly to the nanoparticle polymer rather than the drug. Furthermore, using the nanoparticle to encapsulate drug means higher DARs (>100) and reduced systemic toxicity due to its shielding within the particle structure. Thus, the overall aim of this project is to exemplify the power of an antibody-targeted drug-loaded nanoparticle platform technology as an alternative to current ADC approaches. This work use optimized formulation techniques to encapsulate cytotoxic agents such sa S-methyl-maytansinoid into polylactide-based nanoparticles (NP) and subsequently functionalize the NP surface with antibodies by existing or new chemistries to facilitate targeting of tumor antigens with antibodies and other ligands using site specific click chemistry approaches
Expected Results: Anticipated results from this research will include the development of novel antibody targeted nanoconjugates, including a range of physiochemical analyses. Leading on from this, we anticipate that we will generate a range of data demonstrating the usefulness of these conjugates towards tumor cells in vitro and tumors in vivo. This will include analyses of tumor cell death, drug uptake and localization.
Planned secondment(s): HDP, A. Pahl, month 25, 3 months: amanitin formulation into nanoconjugates / CNRS, S. Cianferani, month 34, 3 months: new analytical methods to determine nanoconjugates’ DARs.
Project. ‘Targeted Anti-Cancer Therapies’ (TACT) is a ‘European Training Network’ (ETN) research project that received funding by the European Commission under the ‘Horizon 2020 research and innovation programme’ and the ‘Marie Skłodowska-Curie actions’. Being an international and multidisciplinary training and research doctoral programme, TACT aims to train 11 Early-Stage Researchers (ESRs) on the development of state-of-the-art targeted anti-cancer therapeutics and equip them with transferable, future career-enhancing skills. More specifically, TACT’s research programme will focus on key interconnected priority themes for the conception of new and more effective generations of Protein-Drug Conjugates (PDCs): site-specific bioconjugation methods, more potent payloads, more efficient protein-based targeting systems and new analytical tools for acute characterization.
This will be made possible thanks to a unique cooperation between academic and industrial worlds, resulting in a consortium comprising nine beneficiary institutions: University of Strasbourg and CNRS (France); University College of London, Queen’s University of Belfast and Almac Discovery (U. K.); Technical University of Munich and Heidelberg Pharma (Germany); University of Waggeningen (Netherlands); Spirochem AG (Switzerland). Each of these institutions will host and train at least one ESR, who will benefit from an unequalled scientific training in all domains related to the field of PDCs via their main research projects, secondments at other institutions and network-wide meetings.
Applications. The TACT consortium is looking for highly talented, motivated and qualified graduate students in various fields at the interface of chemistry, biology and analytical chemistry to start October, 1st 2020. The candidates will have to possess a strong interest in interdisciplinary research and be willing to take part in various communication activities towards non-scientific public. They will have to be fluent in English, possess a high degree of self-organisation and be able to work collaboratively. Applicants can visit http://www.tact-etn.eu
to visualize the different research projects proposed in this programme.
Candidates should have or expect to obtain a 2:1 or higher Honours degree or equivalent in a relevant biomedical or life sciences subject.
Candidates applying from countries where the first language is not English should produce evidence of their competence through a qualification such as IELTS or TOEFL score.
For a list of English Language qualifications also accepted by the School and University please see the following link: http://www.qub.ac.uk/International/International-students/Applying/English-language-requirements/#English