Antibody-drug conjugates (ADCs) are increasingly being designed and used as highly targeted cancer therapies - a modern "magic bullet" approach. They consist of an antibody conjugated to a cytotoxic drug via a chemical linker, thereby enabling delivery of the toxic payload to cancer cells expressing a surface antigen of interest. This approach relies on low level or no expression on healthy cells, high expression on the cancer cells and internalisation of the antigen-ADC complex to allow efficient delivery of the small molecule and a reduction in side effects.
LifeArc has a growing portfolio of ADC programs and has built an assay platform for the screening and characterisation of novel ADCs. One of our most advanced programs is on ALK-ADC. Anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase expressed on neuroblastoma cancer cells, is associated with poor prognosis in young patients. Current therapies target the intracellular signalling cascades, but these kinase inhibitors develop resistance. Instead, a novel approach is being investigated whereby cytotoxic agents are conjugated to ALK-specific antibodies as a mechanism of directly targeting the ALK-expressing neuroblastoma cells.
Antibody target characterisation and validation of internalisation is crucial early in the process, with cell based assays an essential part. This presentation will provide an overview of the cell-based assays set up at LifeArc for this purpose. The suite of assays includes flow cytometry on the Intellicyt iQue screener, imaging on the IncuCyte and high content platforms, and assessment of cell cytotoxicity using secondary antibodies conjugated to potent toxins. The challenges of screening, from the initial stages with hybridoma supernatants through to candidate antibodies, towards effectively identifying antibodies with the desired properties of an ADC will be highlighted.
Rachel Forfar gained a 1st Class Honours degree in Biochemistry from the University of Warwick, having completed an Industrial Placement at Pfizer Pharmaceuticals evaluating the pharmacology of GPCRs in their HTS department. Rachel completed her Ph.D. exploring the expression of GPCRs in yeast at the University of Warwick and went on to a three-year postdoctoral MRC Career Development Fellowship in Edinburgh before joining LifeArc. Rachel is a member of the Asset Delivery team who collaborate with academic researchers to translate research into lead stage therapeutic assets by developing and validating innovative cell-based assays. She has experience in a wide range of in-vitro pharmacology, cell biology and molecular biology techniques applied to both small molecule and biologics drug discovery.