Developing Novel Bispecific Antibody-Drug Conjugates to Treat Leukaemia

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 antibody-drug conjugates (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.
We also intend to functionally characterize the efficacy of these novel ADCs through a combination of (i) advanced microspcopy to study uptake and processing of the ADC in cell line models; (ii) a range of cytototoxicity assays testing the specificity and selectivity of the ADCs in cell line models expressing appropriate antigens; (iii) finally to determine the effectiveness in patient material in vitro.