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MRC DiMeN Doctoral Training Partnership: Developing Novel Bispecific Antibody-Drug Conjugates to Treat Leukaemia


Project Description

Acute myeloid leukaemia (AML) is the second most common leukaemia, accounting for 32% of all leukaemia in diagnosed in adults. AML is an aggressive malignancy of the bone marrow, as is characterized by uncontrolled proliferation of undifferentiated myeloid lineage cells and dismal survival rates, particularly among older patients. AML presents a significant clinical burden to the NHS because the intensive chemotherapy regimens necessary to bring the disease under control often result in hospitalisation due to side effects. There is therefore distinct clinical need of new therapies that will more specifically target the tumour with minimal toxicity.
Disease relapse is also a problem that is common in AML because the bulk of malignant undifferentiated myeloid lineage cells that define this disease arise from, and are sustained by, a rare population of progenitor cells called leukemic stem cells (LSC). LSCs have the capacity for self-renewal, long-term clonal propagation and for differentiation, but it is their capacity for quiescence that provides them with resistance to front line therapies. Specific removal of LSCs would therefore be a distinct advantage in the therapy of AML, and could potentially be achieved using novel bi-specific antibody drug conjugates (ADCs) that are able to recognise and kill these cells by binding defined surface antigens and through internalisation of a toxic cargo.

Objectives.
Our principle goal is to remove the leukemic stem cells (LSC) that give rise to the malignant myeloid lineage cells that define AML. With our industrial partner, BiVictriX, we plan to focus on identification, development and testing of novel ADCs that target LSCs in AML.

Experimental approach.
Our experimental approach will utilize state-of-the-art techniques in covering areas of immunology, cell biology, molecular biology, biotechnology alongside advanced data analysis approaches. Primarily we will use mass cytometry (CyTOF), a novel technology that utilises ‘heavy metal tagged probes’ allowing measurement of >40 phenotypic attributes per cell, to provide foundation data that will help to accelerate identification of novel combinations of antigens to inform the Bivictrix development pipeline of ADC targets. Comparisons of cell populations derived from AML and other patients will allow identification of surface antigen phenotypes, such as but not restricted to expressed CD34, CD38, CD133 and CD90, that differentiate LSCs from non-malignant counterpart cells. Alongside this, a collaboration with the Liverpool Centre for Cell Imaging (CCI) will allow visualisation and testing of ADC binding to its targets, ADC internalisation and cargo-mediated killing.

Benefits of being in the DiMeN DTP:
This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.
We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.

Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards
Further information on the programme can be found on our website:
http://www.dimen.org.uk/

Funding Notes

iCASE Award: Industrial partnership project
Fully funded by the MRC for 3.5yrs, including a minimum of 3 months working within the industry partner. Enhanced stipend, tuition fees and budget for consumables, travel and subsistence.
Studentships commence: 1st October 2020.

To qualify, you must be a UK or EU citizen who has been resident in the UK/EU for 3 years prior to commencement. Applicants must have obtained, or be about to obtain, at least a 2.1 honours degree (or equivalent) in a relevant subject. All applications are scored blindly based on merit. Please read additional guidance here: View Website
Good luck.

References

Multiplexed profiling of RNA and protein expression signatures in individual cells using flow or mass cytometry. Duckworth AD, Gherardini PF, Sykorova M, Yasin F, Nolan GP, Slupsky JR, Kalakonda N. Nat Protoc. 2019 Mar;14(3):901-920.

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